Rare and histologically indistinguishable from osteosarcoma of bone.
Most common presentation is an enlarging mass in the thigh or buttock.
Secondary extraosseous osteosarcoma usually arises in the field of prior external beam radiation or brachytherapy.
Radiographic pattern of mineralization is central amorphous or cloudlike.
On cross sectional imaging, the soft-tissue mass is separate from the underlying bone and periosteum.
Aside from multiple myeloma, osteosarcoma is the most common primary malignancy of bone, but extraosseous osteosarcoma is rare and accounts for only 1% of soft-tissue sarcomas and only 4% of all osteosarcomas.1-3 Benign mesenchymal tumors, such as lipomas, are common, and they are estimated to outnumber their malignant counterparts by more than a factor of 100. However, the true ratio is unknown, as many clinically benign lipomas are not biopsied.4 Conventional lipoma is the most common lipoma and is biologically indolent. Conventional lipoma generally does not transform biologically into a more aggressive type of neoplasm—unlike atypical lipomatous tumors, which may demonstrate this type of evolution with multiple local recurrences.
This article is the first report of a case of radiation-associated extraosseous osteosarcoma that developed within a benign conventional lipoma. The patient provided written informed consent for print and electronic publication of this case report.
Case Report
In March 2013, a 72-year-old woman presented to a general surgeon with a right thigh mass of several weeks’ duration. The patient, who had a remote history of thyroid carcinoma, underwent thyroidectomy in 1991, excision of melanoma of the chest in 1998, and resection and adjuvant external beam radiotherapy (30 fractions) for Merkel cell carcinoma of the right proximal lateral leg (malignancy images unavailable) at an outside institution in 2003. Regional lymph node dissection at the time was negative. The patient remained disease-free the next 10 years. On presentation, magnetic resonance imaging (MRI) showed a 2.2-cm mass encircled by a tumor of lipomatous tissue within the vastus intermedius muscle, adjacent to but separate from the right distal femur (Figures 1A-1C).
Clinical examination findings suggested the sarcoma had arisen at the margins of the radiation field, but more than 10 years had passed since initial treatment, and records were unavailable for confirmation. Results of a computed tomography (CT)-guided biopsy performed at an outside institution revealed a high-grade malignancy, either an extraosseous osteosarcoma or a dedifferentiated liposarcoma. After the biopsy, the patient developed a severe medial compartment hematoma that required angiography and embolization. She was then referred to the division of orthopedic surgical oncology at our institution.
Physical examination revealed marked ecchymosis of the left groin at the access site for embolization as well as massive ecchymosis and swelling along the right distal thigh, medial knee, and medial lower leg. The neurovascular structures were intact with full motor function and sensation distally, as well as normal distal pulses. No inguinal adenopathy was identified. The proximal portion of the prior radiation tattoo was at the inferior extent of the lesion on MRI.
The patient was treated with doxorubicin and ifosfamide (2 cycles) while waiting for the hematoma to shrink. Contrast-enhanced MRI showed a 2.2-cm enhancing mass with isointense T1 signal and heterogeneously hyperintense STIR (short tau inversion recovery) signal surrounded by a circumscribed nonenhancing lipomatous tumor within the vastus intermedius muscle, adjacent to the distal femoral cortex. There was no invasion of the bone, and a fat plane between the enhancing mass and the femoral cortex was identified (Figures 2A-2E).
Fluorine 18 (18F) fluorodeoxyglucose (FDG) positron emission tomography (PET)/CT (FDG-PET/CT) showed marked hypermetabolic activity within the soft-tissue mass (maximum standardized uptake value, 7.0), surrounded by metabolically nonactive fat. No hypermetabolic lung, bone, or soft-tissue metastases were seen. CT and plain radiographs showed the nonfat portion of the tumor had soft-tissue density and contained a central and peripheral curvilinear pattern of mineralization (Figures 3A-3C, 4A-4B).
The primary differential diagnosis included myositis ossificans, chondrosseous lipoma, parosteal lipoma (ossifying variant), liposarcoma with metaplastic bone, and dedifferentiated liposarcoma with osteosarcoma or chondrosarcoma component (see Discussion section).
After 3 cycles of neoadjuvant chemotherapy with doxorubicin and ifosfamide, MRI showed a marked reduction in hematoma size, to 2.4 cm × 0.7 cm × 3.2 cm (estimated volume, ~3 mL), from 10 cm × 3.4 cm × 7.3 cm (estimated volume, ~130 mL), so the decision was made to proceed with surgery, excising the hematoma and sarcoma separately. First, wide resection of the hematoma yielded a 7-cm × 4-cm resection specimen with negative margins on frozen section. Subsequently, definitive radical resection of the tumor with wide margins yielded a 13-cm × 9-cm × 4-cm specimen. The resection specimen contained an intramuscular, mobile, encapsulated 2.0-cm × 1.5-cm × 1.0-cm mass with 2 components. The first was a tan-white solid mass containing thin deposits of calcified matrix, and the second, which surrounded the first, was composed of well-circumscribed soft yellow lobulated adipose tissue (Figure 5).
Microscopic evaluation revealed that the tan-white mass consisted of a hypercellular proliferation of malignant spindle and polyhedral cells that exhibited marked pleomorphism and hyperchromasia and produced extracellular coarse lace-like neoplastic bone characteristic of a high-grade extraskeletal osteosarcoma (Figures 6A-6D).
The sarcoma was sharply demarcated from the surrounding fatty component, which consisted of lobules of mature white adipocytes with no cytologic atypia, characteristic of a lipoma. An estimated 60% of the neoplasm was the lipoma, and the other 40% was the osteosarcoma. Immunohistochemistry revealed the tumor cells from both components to be negative for desmin, myogenin, CDK4, and MDM2. P16 showed cytoplasmic staining of the malignant cells, and these results helped exclude the possibility of dedifferentiated liposarcoma. All resection margins were negative, including the deep margin of the femoral periosteum. In addition, the resected hematoma did not contain malignant cells.
After surgery, the patient’s dermatologist performed a shave biopsy of a lentiginous lesion anterior to the knee. Subsequently, the patient began having increasing knee pain and developed, on the lower extremity, small areas of erythema that were attributed to mild cellulitis. Four months after surgery, emergent contrast-enhanced MRI showed enhancement of thickened synovium of the knee joint (Figure 7).
The patient underwent arthroscopic lavage and synovial biopsy for septic arthritis after knee aspiration yielded 51,000 white blood cells with a negative bacterial culture. The biopsy yielded acute and chronic inflammatory cells compatible with infection. No malignant cells were identified, and the bacterial culture was negative.
Since the lavage, the patient remained in good condition. There was no evidence of local recurrence on contrast-enhanced MRI (Figure 8), or metastases the first year, and she remained clinically free of disease the first 22 months of follow-up.
Discussion
Extraosseous osteosarcoma, typically a high-grade malignant neoplasm of the soft tissues that produces osteoid or cartilaginous matrix, is histologically indistinguishable from osteosarcoma of bone.
It usually occurs in the sixth decade of life, and there is a slight male predominance.1,3,5,6 The most common presentation is an enlarging mass that may be painful. This mass often originates within the deep soft tissues of the lower extremities, especially the thigh and buttock, and less frequently in the upper extremity, retroperitoneum, and torso.6 Secondary extraosseous osteosarcoma accounts for 4% to 13% of extraosseous osteosarcoma and usually arises in the field of prior external beam radiation or brachytherapy.1-3
Conventional lipoma, the most common subtype of lipoma, is a benign mesenchymal tumor. Other subtypes are hibernoma, fibrolipoma, angiolipoma, myelolipoma, spindle-cell lipoma, pleomorphic lipoma, and atypical lipomatous tumor.7 Atypical lipomatous tumor and well-differentiated liposarcoma are distinguished from each other by location: The World Health Organization recommends the term atypical lipomatous tumor for tumors that arise in the extremities and trunk lesions and well-differentiated liposarcoma for neoplasms that develop in the retroperitoneum, peritoneum, mediastinum, spermatic cord, and thoracic cavity.8 On PET, hypermetabolic activity is nonspecific and can be seen in malignant tumors and some benign reactive processes, such as evolving heterotopic ossification. However, simple lipomas, including those with mature ossification or dystrophic calcification, do not manifest increased FDG avidity.9
We are not aware of any published cases of extraosseous osteosarcoma arising within a conventional lipoma. A limited number of cases of coexisting conventional lipoma and spindle-cell lipoma or liposarcoma have been reported.10-13 Retroperitoneal liposarcoma with areas of dedifferentiation into osteosarcoma has also been described.14 Development of malignant fibrous histiocytoma and liposarcoma have also been reported within intraosseous lipomas.15 One theory is based on premalignancy as a biological concept as opposed to a morphologic one. In other words, lesions that may be considered morphologically benign may already have the biological phenotype for malignancy that is not yet reflected morphologically.16 However, it has been suggested that such findings may instead result from initial sampling error or histologic misdiagnosis.17,18There is a spectrum of findings on imaging studies of extraosseous osteosarcoma. Plain radiographs show a soft-tissue density with variable degrees of central calcification that reflects mineralization of deposited neoplastic bone. The pattern of calcification is characteristically amorphous or cloudlike, as opposed to the ring-and-arc observed in cartilage matrix. On CT, the soft-tissue mass of extraosseous osteosarcoma is separate from the underlying bone and periosteum—a defining characteristic that distinguishes it from conventional intramedullary and juxtacortical osteosarcoma.6 The central pattern of amorphous calcification helps to differentiate extraosseous osteosarcoma from heterotopic ossification, which characteristically demonstrates zonation, with trabecular architecture and mature cortical bone peripherally.1 Enhancement of extraskeletal osteosarcoma tends to be heterogeneous and depends on the quantity of necrosis. Extraskeletal osteosarcoma tends to be isointense on T1-weighted MRI and mildly hyperintense on T2-weighted MRI.1,6 Areas of very low signal intensity on both T1- and T2-weighted MRI may reflect mineralization.19 If intratumoral hemorrhage has occurred, there may be signal intensity of blood products of various ages.1,3 Tumors with abundant hemorrhage can be mistaken for hematoma. FDG-PET radiotracer accumulation tends to be intense peripherally with variable central activity depending on quantity of necrosis and hemorrhage.1The radiologic differential diagnosis includes myositis ossificans, chondrosseous lipoma, parosteal lipoma (ossifying variant), liposarcoma with metaplastic bone, dedifferentiated liposarcoma with osteosarcoma or chondrosarcoma component, and malignant mesenchymoma. Other common soft-tissue sarcomas, such as fibrosarcoma, leiomyosarcoma, and pleomorphic undifferentiated sarcoma, are excluded by the presence of fat within the tumor. The radiographic pattern of osteoid matrix produced by the tumor in our patient may be seen in heterotopic ossification, but the absence of mature ossification with zonation was evidence against heterotopic ossification, and microscopically it was neoplastic rather than reactive osteoid. In addition, it is possible that, because of the small size of the soft-tissue component, it was difficult to appreciate the less mature osteoid matrix peripherally. The lack of characteristic rings and arcs helps exclude benign and malignant cartilage containing neoplasms. Malignant mesenchymoma is a diagnosis of exclusion, and such tumors are usually better classified as sarcomas that have undergone heterologous differentiation.
The histologic diagnosis of extraosseous osteosarcoma requires identification of malignant mesenchymal cells that secrete neoplastic osteoid that may or may not mineralize. It is important to exclude the possibility that the malignant bone-forming tumor is part of a different type of sarcoma, the most common being dedifferentiated liposarcoma. Immunohistochemistry can be helpful in this situation, as dedifferentiated liposarcomas demonstrate nuclear expression of MDM2, CDK4, and p16, a constellation of findings rare in conventional and extraosseous osteosarcoma.20-23 Osteosarcoma has not previously been reported as arising in a lipoma; in our patient’s case, we excluded the possibility that the fatty component represented an underlying atypical lipomatous tumor/well-differentiated or dedifferentiated liposarcoma on the basis of morphology and lack of expression of MDM2, CDK4, and p16.
Although histologically identical to osteosarcoma of bone, extraosseous osteosarcoma is treated differently because of its relatively decreased chemosensitivity and radiosensitivity. Treatment tends to be focused on limb-sparing wide local excision, and local recurrence complicates about 50% of cases.1 Neoadjuvant or adjuvant treatment with radiation or chemotherapy is often provided.6 Platinum and doxorubicin chemotherapeutic agents, which are first-line treatments for osteosarcoma of bone, tend to be less effective in extraosseous osteosarcoma, and ifosfamide is more often used instead.5
Primary extraosseous osteosarcoma classically has a poor prognosis, with 2- to 3-year mortality of 50%, and prognosis tends to be worse for secondary radiation-induced sarcomas than for primary sarcomas.2,6 However, with there being improved treatment protocols involving surgery and chemoradiation, more recent 5-year survival rates without metastatic disease are between 60% and 80%, though there is no definite consensus regarding the optimal systemic therapy regimen.1,24 In a 2014 review of 53 patients who presented with localized disease, Choi and colleagues25 identified a 3-year cumulative 39% incidence of death caused by disease, and in 2016 Sio and colleagues26 reported that 55% of patients, most of whom had stage 3 disease, were alive at median follow-up of 45 months. Similar to osteosarcoma of bone, metastases may develop up to 10 years after primary treatment and are most commonly to the lung (80%-88%). Because extraosseous osteosarcoma is rare, no definite prognostic factors have been determined, but metastases at presentation and large tumor size (>5 cm) likely portend a worse prognosis.2,3,27 Fibroblastic and chondroblastic subtypes may have a slightly better prognosis.6,28
Conclusion
Extraosseous osteosarcoma is a rare malignancy that should be considered in the appropriate clinical and imaging scenario. This article is the first report of a case of a radiation-associated extraosseous osteosarcoma that developed within a lipoma with preoperative and postoperative multimodality imaging.
Am J Orthop. 2017;46(3):E200-E206. Copyright Frontline Medical Communications Inc. 2017. All rights reserved.
References
1. Mc Auley G, Jagannathan J, O’Regan K, et al. Extraskeletal osteosarcoma: spectrum of imaging findings. AJR Am J Roentgenol. 2012;198(1):W31-W37.
2. Vikram S, Salih S, Krishnan A, et al. Radiation-induced extra-osseous osteosarcoma—a case report and review of literature. Indian J Surg Oncol. 2013;4(4):374-377.
3. Rosenberg AE. Extraskeletal osteosarcoma. In: Fletcher CDM, Bridge JA, Hogendoorn PCW, Mertens F, eds. WHO Classification of Tumours of Soft Tissue and Bone. 4th ed. Lyon, France: IARC; 2013:161-162.
4. Ramnani BG, Kumar A, Chandak S, Ranjan A, Patel MK. Clinicopathological profile of benign soft tissue tumours: a study in a tertiary care hospital in Western India. J Clin Diagn Res. 2014;8(10):FC01-FC04.
5. Ahmad SA, Patel SR, Ballo MT, et al. Extraosseous osteosarcoma: response to treatment and long-term outcome. J Clin Oncol. 2002;20(2):521-527.
6. Mavrogenis AF, Papadogeorgou E, Papagelopoulos PJ. Extraskeletal osteosarcoma: a case report. Acta Orthop Traumatol Turc. 2012;46(3):215-219.
7. Morell N, Quinn RH. Lipoma. orthoinfo.aaos.org/topic.cfm?topic=a00631. Published 2012. Accessed December 28, 2014.
8. Kransdorf MJ, Bancroft LW, Peterson JJ, Murphey MD, Foster WC, Temple HT. Imaging of fatty tumors: distinction of lipoma and well-differentiated liposarcoma. Radiology. 2002;224(1):99-104.
9. Suzuki R, Watanabe H, Yanagawa T, et al. PET evaluation of fatty tumors in the extremity: possibility of using the standardized uptake value (SUV) to differentiate benign tumors from liposarcoma. Ann Nucl Med. 2005;19(8):661-670.
10. Laliotis A, De Bree E, Vasilaki S, Papadakis M, Melissas J. Co-existence of intramuscular spindle cell lipoma with an intramuscular ordinary lipoma: report of a case. Pol J Pathol. 2013;64(3):224-227.
11. Wright C. Liposarcoma arising in a simple lipoma. J Pathol Bacteriol. 1948;60:483-487.
12. Sampson CC, Saunders EH, Green WE, Laurey JR. Liposarcoma developing in a lipoma. Arch Pathol. 1960;69:506-510.
13. Sternberg SS. Liposarcoma arising within a subcutaneous lipoma. Cancer. 1952;5(5):975-978.
14. Ho L, Wassef H, Chang D, Boswell W, Henderson R, Seto J. Liposarcoma of the retroperitoneum with dedifferentiation to osteosarcoma: a case report. Clin Nucl Med. 2011;36(5):400-402.
15. Milgram JW. Malignant transformation in bone lipomas. Skeletal Radiol. 1990;19(5):347-352.
16. Mentzel T. Biological continuum of benign, atypical, and malignant mesenchymal neoplasms—does it exist? J Pathol. 2000;190(5):523-525.
17. Murphey MD, Carroll JF, Flemming DJ, Pope TL, Gannon FH, Kransdorf MJ. From the archives of the AFIP: benign musculoskeletal lipomatous lesions. Radiographics. 2004;24(5):1433-1466.
18. Zornig C, Schröder S. Does malignant transformation of benign soft-tissue tumours occur? A clinicomorphological study of ten initially misdiagnosed soft-tissue sarcomas. J Cancer Res Clin Oncol. 1992;118(2):166-169.
19. Dönmez FY, Tüzün U, Başaran C, Tunaci M, Bilgiç B, Acunaş G. MRI findings in parosteal osteosarcoma: correlation with histopathology. Diagn Interv Radiol. 2008;14(3):142-152.
20. Mariño-Enriquez A, Hornick JL, Dal Cin P, Cibas ES, Qian X. Dedifferentiated liposarcoma and pleomorphic liposarcoma: a comparative study of cytomorphology and MDM2/CDK4 expression on fine-needle aspiration. Cancer Cytopathol. 2014;122(2):128-137.
21. Yoshida A, Ushiku T, Motoi T, et al. MDM2 and CDK4 immunohistochemical coexpression in high-grade osteosarcoma: correlation with a dedifferentiated subtype. Am J Surg Pathol. 2012;36(3):423-431.
22. Thway K, Flora R, Shah C, Olmos D, Fisher C. Diagnostic utility of p16, CDK4, and MDM2 as an immunohistochemical panel in distinguishing well-differentiated and dedifferentiated liposarcomas from other adipocytic tumors. Am J Surg Pathol. 2012;36(3):462-469.
23. Lokka S, Scheel AH, Dango S, et al. Challenging dedifferentiated liposarcoma identified by MDM2-amplification, a report of two cases. BMC Clin Pathol. 2014;14:36.
24. American Cancer Society. Cancer Facts & Figures 2015. Atlanta, GA: American Cancer Society; 2015.
25. Choi LE, Healey JH, Kuk D, Brennan MF. Analysis of outcomes in extraskeletal osteosarcoma: a review of fifty-three cases. J Bone Joint Surg Am. 2014;96(1):e2.
26. Sio TT, Vu CC, Sohawon S, et al. Extraskeletal osteosarcoma: an international Rare Cancer Network study. Am J Clin Oncol. 2016;39(1):32-36.
27. Bane BL, Evans HL, Ro JY, et al. Extraskeletal osteosarcoma. A clinicopathologic review of 26 cases. Cancer. 1990;65(12):2762-2770.
28. Lee JS, Fetsch JF, Wasdhal DA, Lee BP, Pritchard DJ, Nascimento AG. A review of 40 patients with extraskeletal osteosarcoma. Cancer. 1995;76(11):2253-2259.
Rare and histologically indistinguishable from osteosarcoma of bone.
Most common presentation is an enlarging mass in the thigh or buttock.
Secondary extraosseous osteosarcoma usually arises in the field of prior external beam radiation or brachytherapy.
Radiographic pattern of mineralization is central amorphous or cloudlike.
On cross sectional imaging, the soft-tissue mass is separate from the underlying bone and periosteum.
Aside from multiple myeloma, osteosarcoma is the most common primary malignancy of bone, but extraosseous osteosarcoma is rare and accounts for only 1% of soft-tissue sarcomas and only 4% of all osteosarcomas.1-3 Benign mesenchymal tumors, such as lipomas, are common, and they are estimated to outnumber their malignant counterparts by more than a factor of 100. However, the true ratio is unknown, as many clinically benign lipomas are not biopsied.4 Conventional lipoma is the most common lipoma and is biologically indolent. Conventional lipoma generally does not transform biologically into a more aggressive type of neoplasm—unlike atypical lipomatous tumors, which may demonstrate this type of evolution with multiple local recurrences.
This article is the first report of a case of radiation-associated extraosseous osteosarcoma that developed within a benign conventional lipoma. The patient provided written informed consent for print and electronic publication of this case report.
Case Report
In March 2013, a 72-year-old woman presented to a general surgeon with a right thigh mass of several weeks’ duration. The patient, who had a remote history of thyroid carcinoma, underwent thyroidectomy in 1991, excision of melanoma of the chest in 1998, and resection and adjuvant external beam radiotherapy (30 fractions) for Merkel cell carcinoma of the right proximal lateral leg (malignancy images unavailable) at an outside institution in 2003. Regional lymph node dissection at the time was negative. The patient remained disease-free the next 10 years. On presentation, magnetic resonance imaging (MRI) showed a 2.2-cm mass encircled by a tumor of lipomatous tissue within the vastus intermedius muscle, adjacent to but separate from the right distal femur (Figures 1A-1C).
Clinical examination findings suggested the sarcoma had arisen at the margins of the radiation field, but more than 10 years had passed since initial treatment, and records were unavailable for confirmation. Results of a computed tomography (CT)-guided biopsy performed at an outside institution revealed a high-grade malignancy, either an extraosseous osteosarcoma or a dedifferentiated liposarcoma. After the biopsy, the patient developed a severe medial compartment hematoma that required angiography and embolization. She was then referred to the division of orthopedic surgical oncology at our institution.
Physical examination revealed marked ecchymosis of the left groin at the access site for embolization as well as massive ecchymosis and swelling along the right distal thigh, medial knee, and medial lower leg. The neurovascular structures were intact with full motor function and sensation distally, as well as normal distal pulses. No inguinal adenopathy was identified. The proximal portion of the prior radiation tattoo was at the inferior extent of the lesion on MRI.
The patient was treated with doxorubicin and ifosfamide (2 cycles) while waiting for the hematoma to shrink. Contrast-enhanced MRI showed a 2.2-cm enhancing mass with isointense T1 signal and heterogeneously hyperintense STIR (short tau inversion recovery) signal surrounded by a circumscribed nonenhancing lipomatous tumor within the vastus intermedius muscle, adjacent to the distal femoral cortex. There was no invasion of the bone, and a fat plane between the enhancing mass and the femoral cortex was identified (Figures 2A-2E).
Fluorine 18 (18F) fluorodeoxyglucose (FDG) positron emission tomography (PET)/CT (FDG-PET/CT) showed marked hypermetabolic activity within the soft-tissue mass (maximum standardized uptake value, 7.0), surrounded by metabolically nonactive fat. No hypermetabolic lung, bone, or soft-tissue metastases were seen. CT and plain radiographs showed the nonfat portion of the tumor had soft-tissue density and contained a central and peripheral curvilinear pattern of mineralization (Figures 3A-3C, 4A-4B).
The primary differential diagnosis included myositis ossificans, chondrosseous lipoma, parosteal lipoma (ossifying variant), liposarcoma with metaplastic bone, and dedifferentiated liposarcoma with osteosarcoma or chondrosarcoma component (see Discussion section).
After 3 cycles of neoadjuvant chemotherapy with doxorubicin and ifosfamide, MRI showed a marked reduction in hematoma size, to 2.4 cm × 0.7 cm × 3.2 cm (estimated volume, ~3 mL), from 10 cm × 3.4 cm × 7.3 cm (estimated volume, ~130 mL), so the decision was made to proceed with surgery, excising the hematoma and sarcoma separately. First, wide resection of the hematoma yielded a 7-cm × 4-cm resection specimen with negative margins on frozen section. Subsequently, definitive radical resection of the tumor with wide margins yielded a 13-cm × 9-cm × 4-cm specimen. The resection specimen contained an intramuscular, mobile, encapsulated 2.0-cm × 1.5-cm × 1.0-cm mass with 2 components. The first was a tan-white solid mass containing thin deposits of calcified matrix, and the second, which surrounded the first, was composed of well-circumscribed soft yellow lobulated adipose tissue (Figure 5).
Microscopic evaluation revealed that the tan-white mass consisted of a hypercellular proliferation of malignant spindle and polyhedral cells that exhibited marked pleomorphism and hyperchromasia and produced extracellular coarse lace-like neoplastic bone characteristic of a high-grade extraskeletal osteosarcoma (Figures 6A-6D).
The sarcoma was sharply demarcated from the surrounding fatty component, which consisted of lobules of mature white adipocytes with no cytologic atypia, characteristic of a lipoma. An estimated 60% of the neoplasm was the lipoma, and the other 40% was the osteosarcoma. Immunohistochemistry revealed the tumor cells from both components to be negative for desmin, myogenin, CDK4, and MDM2. P16 showed cytoplasmic staining of the malignant cells, and these results helped exclude the possibility of dedifferentiated liposarcoma. All resection margins were negative, including the deep margin of the femoral periosteum. In addition, the resected hematoma did not contain malignant cells.
After surgery, the patient’s dermatologist performed a shave biopsy of a lentiginous lesion anterior to the knee. Subsequently, the patient began having increasing knee pain and developed, on the lower extremity, small areas of erythema that were attributed to mild cellulitis. Four months after surgery, emergent contrast-enhanced MRI showed enhancement of thickened synovium of the knee joint (Figure 7).
The patient underwent arthroscopic lavage and synovial biopsy for septic arthritis after knee aspiration yielded 51,000 white blood cells with a negative bacterial culture. The biopsy yielded acute and chronic inflammatory cells compatible with infection. No malignant cells were identified, and the bacterial culture was negative.
Since the lavage, the patient remained in good condition. There was no evidence of local recurrence on contrast-enhanced MRI (Figure 8), or metastases the first year, and she remained clinically free of disease the first 22 months of follow-up.
Discussion
Extraosseous osteosarcoma, typically a high-grade malignant neoplasm of the soft tissues that produces osteoid or cartilaginous matrix, is histologically indistinguishable from osteosarcoma of bone.
It usually occurs in the sixth decade of life, and there is a slight male predominance.1,3,5,6 The most common presentation is an enlarging mass that may be painful. This mass often originates within the deep soft tissues of the lower extremities, especially the thigh and buttock, and less frequently in the upper extremity, retroperitoneum, and torso.6 Secondary extraosseous osteosarcoma accounts for 4% to 13% of extraosseous osteosarcoma and usually arises in the field of prior external beam radiation or brachytherapy.1-3
Conventional lipoma, the most common subtype of lipoma, is a benign mesenchymal tumor. Other subtypes are hibernoma, fibrolipoma, angiolipoma, myelolipoma, spindle-cell lipoma, pleomorphic lipoma, and atypical lipomatous tumor.7 Atypical lipomatous tumor and well-differentiated liposarcoma are distinguished from each other by location: The World Health Organization recommends the term atypical lipomatous tumor for tumors that arise in the extremities and trunk lesions and well-differentiated liposarcoma for neoplasms that develop in the retroperitoneum, peritoneum, mediastinum, spermatic cord, and thoracic cavity.8 On PET, hypermetabolic activity is nonspecific and can be seen in malignant tumors and some benign reactive processes, such as evolving heterotopic ossification. However, simple lipomas, including those with mature ossification or dystrophic calcification, do not manifest increased FDG avidity.9
We are not aware of any published cases of extraosseous osteosarcoma arising within a conventional lipoma. A limited number of cases of coexisting conventional lipoma and spindle-cell lipoma or liposarcoma have been reported.10-13 Retroperitoneal liposarcoma with areas of dedifferentiation into osteosarcoma has also been described.14 Development of malignant fibrous histiocytoma and liposarcoma have also been reported within intraosseous lipomas.15 One theory is based on premalignancy as a biological concept as opposed to a morphologic one. In other words, lesions that may be considered morphologically benign may already have the biological phenotype for malignancy that is not yet reflected morphologically.16 However, it has been suggested that such findings may instead result from initial sampling error or histologic misdiagnosis.17,18There is a spectrum of findings on imaging studies of extraosseous osteosarcoma. Plain radiographs show a soft-tissue density with variable degrees of central calcification that reflects mineralization of deposited neoplastic bone. The pattern of calcification is characteristically amorphous or cloudlike, as opposed to the ring-and-arc observed in cartilage matrix. On CT, the soft-tissue mass of extraosseous osteosarcoma is separate from the underlying bone and periosteum—a defining characteristic that distinguishes it from conventional intramedullary and juxtacortical osteosarcoma.6 The central pattern of amorphous calcification helps to differentiate extraosseous osteosarcoma from heterotopic ossification, which characteristically demonstrates zonation, with trabecular architecture and mature cortical bone peripherally.1 Enhancement of extraskeletal osteosarcoma tends to be heterogeneous and depends on the quantity of necrosis. Extraskeletal osteosarcoma tends to be isointense on T1-weighted MRI and mildly hyperintense on T2-weighted MRI.1,6 Areas of very low signal intensity on both T1- and T2-weighted MRI may reflect mineralization.19 If intratumoral hemorrhage has occurred, there may be signal intensity of blood products of various ages.1,3 Tumors with abundant hemorrhage can be mistaken for hematoma. FDG-PET radiotracer accumulation tends to be intense peripherally with variable central activity depending on quantity of necrosis and hemorrhage.1The radiologic differential diagnosis includes myositis ossificans, chondrosseous lipoma, parosteal lipoma (ossifying variant), liposarcoma with metaplastic bone, dedifferentiated liposarcoma with osteosarcoma or chondrosarcoma component, and malignant mesenchymoma. Other common soft-tissue sarcomas, such as fibrosarcoma, leiomyosarcoma, and pleomorphic undifferentiated sarcoma, are excluded by the presence of fat within the tumor. The radiographic pattern of osteoid matrix produced by the tumor in our patient may be seen in heterotopic ossification, but the absence of mature ossification with zonation was evidence against heterotopic ossification, and microscopically it was neoplastic rather than reactive osteoid. In addition, it is possible that, because of the small size of the soft-tissue component, it was difficult to appreciate the less mature osteoid matrix peripherally. The lack of characteristic rings and arcs helps exclude benign and malignant cartilage containing neoplasms. Malignant mesenchymoma is a diagnosis of exclusion, and such tumors are usually better classified as sarcomas that have undergone heterologous differentiation.
The histologic diagnosis of extraosseous osteosarcoma requires identification of malignant mesenchymal cells that secrete neoplastic osteoid that may or may not mineralize. It is important to exclude the possibility that the malignant bone-forming tumor is part of a different type of sarcoma, the most common being dedifferentiated liposarcoma. Immunohistochemistry can be helpful in this situation, as dedifferentiated liposarcomas demonstrate nuclear expression of MDM2, CDK4, and p16, a constellation of findings rare in conventional and extraosseous osteosarcoma.20-23 Osteosarcoma has not previously been reported as arising in a lipoma; in our patient’s case, we excluded the possibility that the fatty component represented an underlying atypical lipomatous tumor/well-differentiated or dedifferentiated liposarcoma on the basis of morphology and lack of expression of MDM2, CDK4, and p16.
Although histologically identical to osteosarcoma of bone, extraosseous osteosarcoma is treated differently because of its relatively decreased chemosensitivity and radiosensitivity. Treatment tends to be focused on limb-sparing wide local excision, and local recurrence complicates about 50% of cases.1 Neoadjuvant or adjuvant treatment with radiation or chemotherapy is often provided.6 Platinum and doxorubicin chemotherapeutic agents, which are first-line treatments for osteosarcoma of bone, tend to be less effective in extraosseous osteosarcoma, and ifosfamide is more often used instead.5
Primary extraosseous osteosarcoma classically has a poor prognosis, with 2- to 3-year mortality of 50%, and prognosis tends to be worse for secondary radiation-induced sarcomas than for primary sarcomas.2,6 However, with there being improved treatment protocols involving surgery and chemoradiation, more recent 5-year survival rates without metastatic disease are between 60% and 80%, though there is no definite consensus regarding the optimal systemic therapy regimen.1,24 In a 2014 review of 53 patients who presented with localized disease, Choi and colleagues25 identified a 3-year cumulative 39% incidence of death caused by disease, and in 2016 Sio and colleagues26 reported that 55% of patients, most of whom had stage 3 disease, were alive at median follow-up of 45 months. Similar to osteosarcoma of bone, metastases may develop up to 10 years after primary treatment and are most commonly to the lung (80%-88%). Because extraosseous osteosarcoma is rare, no definite prognostic factors have been determined, but metastases at presentation and large tumor size (>5 cm) likely portend a worse prognosis.2,3,27 Fibroblastic and chondroblastic subtypes may have a slightly better prognosis.6,28
Conclusion
Extraosseous osteosarcoma is a rare malignancy that should be considered in the appropriate clinical and imaging scenario. This article is the first report of a case of a radiation-associated extraosseous osteosarcoma that developed within a lipoma with preoperative and postoperative multimodality imaging.
Am J Orthop. 2017;46(3):E200-E206. Copyright Frontline Medical Communications Inc. 2017. All rights reserved.
Take-Home Points
Rare and histologically indistinguishable from osteosarcoma of bone.
Most common presentation is an enlarging mass in the thigh or buttock.
Secondary extraosseous osteosarcoma usually arises in the field of prior external beam radiation or brachytherapy.
Radiographic pattern of mineralization is central amorphous or cloudlike.
On cross sectional imaging, the soft-tissue mass is separate from the underlying bone and periosteum.
Aside from multiple myeloma, osteosarcoma is the most common primary malignancy of bone, but extraosseous osteosarcoma is rare and accounts for only 1% of soft-tissue sarcomas and only 4% of all osteosarcomas.1-3 Benign mesenchymal tumors, such as lipomas, are common, and they are estimated to outnumber their malignant counterparts by more than a factor of 100. However, the true ratio is unknown, as many clinically benign lipomas are not biopsied.4 Conventional lipoma is the most common lipoma and is biologically indolent. Conventional lipoma generally does not transform biologically into a more aggressive type of neoplasm—unlike atypical lipomatous tumors, which may demonstrate this type of evolution with multiple local recurrences.
This article is the first report of a case of radiation-associated extraosseous osteosarcoma that developed within a benign conventional lipoma. The patient provided written informed consent for print and electronic publication of this case report.
Case Report
In March 2013, a 72-year-old woman presented to a general surgeon with a right thigh mass of several weeks’ duration. The patient, who had a remote history of thyroid carcinoma, underwent thyroidectomy in 1991, excision of melanoma of the chest in 1998, and resection and adjuvant external beam radiotherapy (30 fractions) for Merkel cell carcinoma of the right proximal lateral leg (malignancy images unavailable) at an outside institution in 2003. Regional lymph node dissection at the time was negative. The patient remained disease-free the next 10 years. On presentation, magnetic resonance imaging (MRI) showed a 2.2-cm mass encircled by a tumor of lipomatous tissue within the vastus intermedius muscle, adjacent to but separate from the right distal femur (Figures 1A-1C).
Clinical examination findings suggested the sarcoma had arisen at the margins of the radiation field, but more than 10 years had passed since initial treatment, and records were unavailable for confirmation. Results of a computed tomography (CT)-guided biopsy performed at an outside institution revealed a high-grade malignancy, either an extraosseous osteosarcoma or a dedifferentiated liposarcoma. After the biopsy, the patient developed a severe medial compartment hematoma that required angiography and embolization. She was then referred to the division of orthopedic surgical oncology at our institution.
Physical examination revealed marked ecchymosis of the left groin at the access site for embolization as well as massive ecchymosis and swelling along the right distal thigh, medial knee, and medial lower leg. The neurovascular structures were intact with full motor function and sensation distally, as well as normal distal pulses. No inguinal adenopathy was identified. The proximal portion of the prior radiation tattoo was at the inferior extent of the lesion on MRI.
The patient was treated with doxorubicin and ifosfamide (2 cycles) while waiting for the hematoma to shrink. Contrast-enhanced MRI showed a 2.2-cm enhancing mass with isointense T1 signal and heterogeneously hyperintense STIR (short tau inversion recovery) signal surrounded by a circumscribed nonenhancing lipomatous tumor within the vastus intermedius muscle, adjacent to the distal femoral cortex. There was no invasion of the bone, and a fat plane between the enhancing mass and the femoral cortex was identified (Figures 2A-2E).
Fluorine 18 (18F) fluorodeoxyglucose (FDG) positron emission tomography (PET)/CT (FDG-PET/CT) showed marked hypermetabolic activity within the soft-tissue mass (maximum standardized uptake value, 7.0), surrounded by metabolically nonactive fat. No hypermetabolic lung, bone, or soft-tissue metastases were seen. CT and plain radiographs showed the nonfat portion of the tumor had soft-tissue density and contained a central and peripheral curvilinear pattern of mineralization (Figures 3A-3C, 4A-4B).
The primary differential diagnosis included myositis ossificans, chondrosseous lipoma, parosteal lipoma (ossifying variant), liposarcoma with metaplastic bone, and dedifferentiated liposarcoma with osteosarcoma or chondrosarcoma component (see Discussion section).
After 3 cycles of neoadjuvant chemotherapy with doxorubicin and ifosfamide, MRI showed a marked reduction in hematoma size, to 2.4 cm × 0.7 cm × 3.2 cm (estimated volume, ~3 mL), from 10 cm × 3.4 cm × 7.3 cm (estimated volume, ~130 mL), so the decision was made to proceed with surgery, excising the hematoma and sarcoma separately. First, wide resection of the hematoma yielded a 7-cm × 4-cm resection specimen with negative margins on frozen section. Subsequently, definitive radical resection of the tumor with wide margins yielded a 13-cm × 9-cm × 4-cm specimen. The resection specimen contained an intramuscular, mobile, encapsulated 2.0-cm × 1.5-cm × 1.0-cm mass with 2 components. The first was a tan-white solid mass containing thin deposits of calcified matrix, and the second, which surrounded the first, was composed of well-circumscribed soft yellow lobulated adipose tissue (Figure 5).
Microscopic evaluation revealed that the tan-white mass consisted of a hypercellular proliferation of malignant spindle and polyhedral cells that exhibited marked pleomorphism and hyperchromasia and produced extracellular coarse lace-like neoplastic bone characteristic of a high-grade extraskeletal osteosarcoma (Figures 6A-6D).
The sarcoma was sharply demarcated from the surrounding fatty component, which consisted of lobules of mature white adipocytes with no cytologic atypia, characteristic of a lipoma. An estimated 60% of the neoplasm was the lipoma, and the other 40% was the osteosarcoma. Immunohistochemistry revealed the tumor cells from both components to be negative for desmin, myogenin, CDK4, and MDM2. P16 showed cytoplasmic staining of the malignant cells, and these results helped exclude the possibility of dedifferentiated liposarcoma. All resection margins were negative, including the deep margin of the femoral periosteum. In addition, the resected hematoma did not contain malignant cells.
After surgery, the patient’s dermatologist performed a shave biopsy of a lentiginous lesion anterior to the knee. Subsequently, the patient began having increasing knee pain and developed, on the lower extremity, small areas of erythema that were attributed to mild cellulitis. Four months after surgery, emergent contrast-enhanced MRI showed enhancement of thickened synovium of the knee joint (Figure 7).
The patient underwent arthroscopic lavage and synovial biopsy for septic arthritis after knee aspiration yielded 51,000 white blood cells with a negative bacterial culture. The biopsy yielded acute and chronic inflammatory cells compatible with infection. No malignant cells were identified, and the bacterial culture was negative.
Since the lavage, the patient remained in good condition. There was no evidence of local recurrence on contrast-enhanced MRI (Figure 8), or metastases the first year, and she remained clinically free of disease the first 22 months of follow-up.
Discussion
Extraosseous osteosarcoma, typically a high-grade malignant neoplasm of the soft tissues that produces osteoid or cartilaginous matrix, is histologically indistinguishable from osteosarcoma of bone.
It usually occurs in the sixth decade of life, and there is a slight male predominance.1,3,5,6 The most common presentation is an enlarging mass that may be painful. This mass often originates within the deep soft tissues of the lower extremities, especially the thigh and buttock, and less frequently in the upper extremity, retroperitoneum, and torso.6 Secondary extraosseous osteosarcoma accounts for 4% to 13% of extraosseous osteosarcoma and usually arises in the field of prior external beam radiation or brachytherapy.1-3
Conventional lipoma, the most common subtype of lipoma, is a benign mesenchymal tumor. Other subtypes are hibernoma, fibrolipoma, angiolipoma, myelolipoma, spindle-cell lipoma, pleomorphic lipoma, and atypical lipomatous tumor.7 Atypical lipomatous tumor and well-differentiated liposarcoma are distinguished from each other by location: The World Health Organization recommends the term atypical lipomatous tumor for tumors that arise in the extremities and trunk lesions and well-differentiated liposarcoma for neoplasms that develop in the retroperitoneum, peritoneum, mediastinum, spermatic cord, and thoracic cavity.8 On PET, hypermetabolic activity is nonspecific and can be seen in malignant tumors and some benign reactive processes, such as evolving heterotopic ossification. However, simple lipomas, including those with mature ossification or dystrophic calcification, do not manifest increased FDG avidity.9
We are not aware of any published cases of extraosseous osteosarcoma arising within a conventional lipoma. A limited number of cases of coexisting conventional lipoma and spindle-cell lipoma or liposarcoma have been reported.10-13 Retroperitoneal liposarcoma with areas of dedifferentiation into osteosarcoma has also been described.14 Development of malignant fibrous histiocytoma and liposarcoma have also been reported within intraosseous lipomas.15 One theory is based on premalignancy as a biological concept as opposed to a morphologic one. In other words, lesions that may be considered morphologically benign may already have the biological phenotype for malignancy that is not yet reflected morphologically.16 However, it has been suggested that such findings may instead result from initial sampling error or histologic misdiagnosis.17,18There is a spectrum of findings on imaging studies of extraosseous osteosarcoma. Plain radiographs show a soft-tissue density with variable degrees of central calcification that reflects mineralization of deposited neoplastic bone. The pattern of calcification is characteristically amorphous or cloudlike, as opposed to the ring-and-arc observed in cartilage matrix. On CT, the soft-tissue mass of extraosseous osteosarcoma is separate from the underlying bone and periosteum—a defining characteristic that distinguishes it from conventional intramedullary and juxtacortical osteosarcoma.6 The central pattern of amorphous calcification helps to differentiate extraosseous osteosarcoma from heterotopic ossification, which characteristically demonstrates zonation, with trabecular architecture and mature cortical bone peripherally.1 Enhancement of extraskeletal osteosarcoma tends to be heterogeneous and depends on the quantity of necrosis. Extraskeletal osteosarcoma tends to be isointense on T1-weighted MRI and mildly hyperintense on T2-weighted MRI.1,6 Areas of very low signal intensity on both T1- and T2-weighted MRI may reflect mineralization.19 If intratumoral hemorrhage has occurred, there may be signal intensity of blood products of various ages.1,3 Tumors with abundant hemorrhage can be mistaken for hematoma. FDG-PET radiotracer accumulation tends to be intense peripherally with variable central activity depending on quantity of necrosis and hemorrhage.1The radiologic differential diagnosis includes myositis ossificans, chondrosseous lipoma, parosteal lipoma (ossifying variant), liposarcoma with metaplastic bone, dedifferentiated liposarcoma with osteosarcoma or chondrosarcoma component, and malignant mesenchymoma. Other common soft-tissue sarcomas, such as fibrosarcoma, leiomyosarcoma, and pleomorphic undifferentiated sarcoma, are excluded by the presence of fat within the tumor. The radiographic pattern of osteoid matrix produced by the tumor in our patient may be seen in heterotopic ossification, but the absence of mature ossification with zonation was evidence against heterotopic ossification, and microscopically it was neoplastic rather than reactive osteoid. In addition, it is possible that, because of the small size of the soft-tissue component, it was difficult to appreciate the less mature osteoid matrix peripherally. The lack of characteristic rings and arcs helps exclude benign and malignant cartilage containing neoplasms. Malignant mesenchymoma is a diagnosis of exclusion, and such tumors are usually better classified as sarcomas that have undergone heterologous differentiation.
The histologic diagnosis of extraosseous osteosarcoma requires identification of malignant mesenchymal cells that secrete neoplastic osteoid that may or may not mineralize. It is important to exclude the possibility that the malignant bone-forming tumor is part of a different type of sarcoma, the most common being dedifferentiated liposarcoma. Immunohistochemistry can be helpful in this situation, as dedifferentiated liposarcomas demonstrate nuclear expression of MDM2, CDK4, and p16, a constellation of findings rare in conventional and extraosseous osteosarcoma.20-23 Osteosarcoma has not previously been reported as arising in a lipoma; in our patient’s case, we excluded the possibility that the fatty component represented an underlying atypical lipomatous tumor/well-differentiated or dedifferentiated liposarcoma on the basis of morphology and lack of expression of MDM2, CDK4, and p16.
Although histologically identical to osteosarcoma of bone, extraosseous osteosarcoma is treated differently because of its relatively decreased chemosensitivity and radiosensitivity. Treatment tends to be focused on limb-sparing wide local excision, and local recurrence complicates about 50% of cases.1 Neoadjuvant or adjuvant treatment with radiation or chemotherapy is often provided.6 Platinum and doxorubicin chemotherapeutic agents, which are first-line treatments for osteosarcoma of bone, tend to be less effective in extraosseous osteosarcoma, and ifosfamide is more often used instead.5
Primary extraosseous osteosarcoma classically has a poor prognosis, with 2- to 3-year mortality of 50%, and prognosis tends to be worse for secondary radiation-induced sarcomas than for primary sarcomas.2,6 However, with there being improved treatment protocols involving surgery and chemoradiation, more recent 5-year survival rates without metastatic disease are between 60% and 80%, though there is no definite consensus regarding the optimal systemic therapy regimen.1,24 In a 2014 review of 53 patients who presented with localized disease, Choi and colleagues25 identified a 3-year cumulative 39% incidence of death caused by disease, and in 2016 Sio and colleagues26 reported that 55% of patients, most of whom had stage 3 disease, were alive at median follow-up of 45 months. Similar to osteosarcoma of bone, metastases may develop up to 10 years after primary treatment and are most commonly to the lung (80%-88%). Because extraosseous osteosarcoma is rare, no definite prognostic factors have been determined, but metastases at presentation and large tumor size (>5 cm) likely portend a worse prognosis.2,3,27 Fibroblastic and chondroblastic subtypes may have a slightly better prognosis.6,28
Conclusion
Extraosseous osteosarcoma is a rare malignancy that should be considered in the appropriate clinical and imaging scenario. This article is the first report of a case of a radiation-associated extraosseous osteosarcoma that developed within a lipoma with preoperative and postoperative multimodality imaging.
Am J Orthop. 2017;46(3):E200-E206. Copyright Frontline Medical Communications Inc. 2017. All rights reserved.
References
1. Mc Auley G, Jagannathan J, O’Regan K, et al. Extraskeletal osteosarcoma: spectrum of imaging findings. AJR Am J Roentgenol. 2012;198(1):W31-W37.
2. Vikram S, Salih S, Krishnan A, et al. Radiation-induced extra-osseous osteosarcoma—a case report and review of literature. Indian J Surg Oncol. 2013;4(4):374-377.
3. Rosenberg AE. Extraskeletal osteosarcoma. In: Fletcher CDM, Bridge JA, Hogendoorn PCW, Mertens F, eds. WHO Classification of Tumours of Soft Tissue and Bone. 4th ed. Lyon, France: IARC; 2013:161-162.
4. Ramnani BG, Kumar A, Chandak S, Ranjan A, Patel MK. Clinicopathological profile of benign soft tissue tumours: a study in a tertiary care hospital in Western India. J Clin Diagn Res. 2014;8(10):FC01-FC04.
5. Ahmad SA, Patel SR, Ballo MT, et al. Extraosseous osteosarcoma: response to treatment and long-term outcome. J Clin Oncol. 2002;20(2):521-527.
6. Mavrogenis AF, Papadogeorgou E, Papagelopoulos PJ. Extraskeletal osteosarcoma: a case report. Acta Orthop Traumatol Turc. 2012;46(3):215-219.
7. Morell N, Quinn RH. Lipoma. orthoinfo.aaos.org/topic.cfm?topic=a00631. Published 2012. Accessed December 28, 2014.
8. Kransdorf MJ, Bancroft LW, Peterson JJ, Murphey MD, Foster WC, Temple HT. Imaging of fatty tumors: distinction of lipoma and well-differentiated liposarcoma. Radiology. 2002;224(1):99-104.
9. Suzuki R, Watanabe H, Yanagawa T, et al. PET evaluation of fatty tumors in the extremity: possibility of using the standardized uptake value (SUV) to differentiate benign tumors from liposarcoma. Ann Nucl Med. 2005;19(8):661-670.
10. Laliotis A, De Bree E, Vasilaki S, Papadakis M, Melissas J. Co-existence of intramuscular spindle cell lipoma with an intramuscular ordinary lipoma: report of a case. Pol J Pathol. 2013;64(3):224-227.
11. Wright C. Liposarcoma arising in a simple lipoma. J Pathol Bacteriol. 1948;60:483-487.
12. Sampson CC, Saunders EH, Green WE, Laurey JR. Liposarcoma developing in a lipoma. Arch Pathol. 1960;69:506-510.
13. Sternberg SS. Liposarcoma arising within a subcutaneous lipoma. Cancer. 1952;5(5):975-978.
14. Ho L, Wassef H, Chang D, Boswell W, Henderson R, Seto J. Liposarcoma of the retroperitoneum with dedifferentiation to osteosarcoma: a case report. Clin Nucl Med. 2011;36(5):400-402.
15. Milgram JW. Malignant transformation in bone lipomas. Skeletal Radiol. 1990;19(5):347-352.
16. Mentzel T. Biological continuum of benign, atypical, and malignant mesenchymal neoplasms—does it exist? J Pathol. 2000;190(5):523-525.
17. Murphey MD, Carroll JF, Flemming DJ, Pope TL, Gannon FH, Kransdorf MJ. From the archives of the AFIP: benign musculoskeletal lipomatous lesions. Radiographics. 2004;24(5):1433-1466.
18. Zornig C, Schröder S. Does malignant transformation of benign soft-tissue tumours occur? A clinicomorphological study of ten initially misdiagnosed soft-tissue sarcomas. J Cancer Res Clin Oncol. 1992;118(2):166-169.
19. Dönmez FY, Tüzün U, Başaran C, Tunaci M, Bilgiç B, Acunaş G. MRI findings in parosteal osteosarcoma: correlation with histopathology. Diagn Interv Radiol. 2008;14(3):142-152.
20. Mariño-Enriquez A, Hornick JL, Dal Cin P, Cibas ES, Qian X. Dedifferentiated liposarcoma and pleomorphic liposarcoma: a comparative study of cytomorphology and MDM2/CDK4 expression on fine-needle aspiration. Cancer Cytopathol. 2014;122(2):128-137.
21. Yoshida A, Ushiku T, Motoi T, et al. MDM2 and CDK4 immunohistochemical coexpression in high-grade osteosarcoma: correlation with a dedifferentiated subtype. Am J Surg Pathol. 2012;36(3):423-431.
22. Thway K, Flora R, Shah C, Olmos D, Fisher C. Diagnostic utility of p16, CDK4, and MDM2 as an immunohistochemical panel in distinguishing well-differentiated and dedifferentiated liposarcomas from other adipocytic tumors. Am J Surg Pathol. 2012;36(3):462-469.
23. Lokka S, Scheel AH, Dango S, et al. Challenging dedifferentiated liposarcoma identified by MDM2-amplification, a report of two cases. BMC Clin Pathol. 2014;14:36.
24. American Cancer Society. Cancer Facts & Figures 2015. Atlanta, GA: American Cancer Society; 2015.
25. Choi LE, Healey JH, Kuk D, Brennan MF. Analysis of outcomes in extraskeletal osteosarcoma: a review of fifty-three cases. J Bone Joint Surg Am. 2014;96(1):e2.
26. Sio TT, Vu CC, Sohawon S, et al. Extraskeletal osteosarcoma: an international Rare Cancer Network study. Am J Clin Oncol. 2016;39(1):32-36.
27. Bane BL, Evans HL, Ro JY, et al. Extraskeletal osteosarcoma. A clinicopathologic review of 26 cases. Cancer. 1990;65(12):2762-2770.
28. Lee JS, Fetsch JF, Wasdhal DA, Lee BP, Pritchard DJ, Nascimento AG. A review of 40 patients with extraskeletal osteosarcoma. Cancer. 1995;76(11):2253-2259.
References
1. Mc Auley G, Jagannathan J, O’Regan K, et al. Extraskeletal osteosarcoma: spectrum of imaging findings. AJR Am J Roentgenol. 2012;198(1):W31-W37.
2. Vikram S, Salih S, Krishnan A, et al. Radiation-induced extra-osseous osteosarcoma—a case report and review of literature. Indian J Surg Oncol. 2013;4(4):374-377.
3. Rosenberg AE. Extraskeletal osteosarcoma. In: Fletcher CDM, Bridge JA, Hogendoorn PCW, Mertens F, eds. WHO Classification of Tumours of Soft Tissue and Bone. 4th ed. Lyon, France: IARC; 2013:161-162.
4. Ramnani BG, Kumar A, Chandak S, Ranjan A, Patel MK. Clinicopathological profile of benign soft tissue tumours: a study in a tertiary care hospital in Western India. J Clin Diagn Res. 2014;8(10):FC01-FC04.
5. Ahmad SA, Patel SR, Ballo MT, et al. Extraosseous osteosarcoma: response to treatment and long-term outcome. J Clin Oncol. 2002;20(2):521-527.
6. Mavrogenis AF, Papadogeorgou E, Papagelopoulos PJ. Extraskeletal osteosarcoma: a case report. Acta Orthop Traumatol Turc. 2012;46(3):215-219.
7. Morell N, Quinn RH. Lipoma. orthoinfo.aaos.org/topic.cfm?topic=a00631. Published 2012. Accessed December 28, 2014.
8. Kransdorf MJ, Bancroft LW, Peterson JJ, Murphey MD, Foster WC, Temple HT. Imaging of fatty tumors: distinction of lipoma and well-differentiated liposarcoma. Radiology. 2002;224(1):99-104.
9. Suzuki R, Watanabe H, Yanagawa T, et al. PET evaluation of fatty tumors in the extremity: possibility of using the standardized uptake value (SUV) to differentiate benign tumors from liposarcoma. Ann Nucl Med. 2005;19(8):661-670.
10. Laliotis A, De Bree E, Vasilaki S, Papadakis M, Melissas J. Co-existence of intramuscular spindle cell lipoma with an intramuscular ordinary lipoma: report of a case. Pol J Pathol. 2013;64(3):224-227.
11. Wright C. Liposarcoma arising in a simple lipoma. J Pathol Bacteriol. 1948;60:483-487.
12. Sampson CC, Saunders EH, Green WE, Laurey JR. Liposarcoma developing in a lipoma. Arch Pathol. 1960;69:506-510.
13. Sternberg SS. Liposarcoma arising within a subcutaneous lipoma. Cancer. 1952;5(5):975-978.
14. Ho L, Wassef H, Chang D, Boswell W, Henderson R, Seto J. Liposarcoma of the retroperitoneum with dedifferentiation to osteosarcoma: a case report. Clin Nucl Med. 2011;36(5):400-402.
15. Milgram JW. Malignant transformation in bone lipomas. Skeletal Radiol. 1990;19(5):347-352.
16. Mentzel T. Biological continuum of benign, atypical, and malignant mesenchymal neoplasms—does it exist? J Pathol. 2000;190(5):523-525.
17. Murphey MD, Carroll JF, Flemming DJ, Pope TL, Gannon FH, Kransdorf MJ. From the archives of the AFIP: benign musculoskeletal lipomatous lesions. Radiographics. 2004;24(5):1433-1466.
18. Zornig C, Schröder S. Does malignant transformation of benign soft-tissue tumours occur? A clinicomorphological study of ten initially misdiagnosed soft-tissue sarcomas. J Cancer Res Clin Oncol. 1992;118(2):166-169.
19. Dönmez FY, Tüzün U, Başaran C, Tunaci M, Bilgiç B, Acunaş G. MRI findings in parosteal osteosarcoma: correlation with histopathology. Diagn Interv Radiol. 2008;14(3):142-152.
20. Mariño-Enriquez A, Hornick JL, Dal Cin P, Cibas ES, Qian X. Dedifferentiated liposarcoma and pleomorphic liposarcoma: a comparative study of cytomorphology and MDM2/CDK4 expression on fine-needle aspiration. Cancer Cytopathol. 2014;122(2):128-137.
21. Yoshida A, Ushiku T, Motoi T, et al. MDM2 and CDK4 immunohistochemical coexpression in high-grade osteosarcoma: correlation with a dedifferentiated subtype. Am J Surg Pathol. 2012;36(3):423-431.
22. Thway K, Flora R, Shah C, Olmos D, Fisher C. Diagnostic utility of p16, CDK4, and MDM2 as an immunohistochemical panel in distinguishing well-differentiated and dedifferentiated liposarcomas from other adipocytic tumors. Am J Surg Pathol. 2012;36(3):462-469.
23. Lokka S, Scheel AH, Dango S, et al. Challenging dedifferentiated liposarcoma identified by MDM2-amplification, a report of two cases. BMC Clin Pathol. 2014;14:36.
24. American Cancer Society. Cancer Facts & Figures 2015. Atlanta, GA: American Cancer Society; 2015.
25. Choi LE, Healey JH, Kuk D, Brennan MF. Analysis of outcomes in extraskeletal osteosarcoma: a review of fifty-three cases. J Bone Joint Surg Am. 2014;96(1):e2.
26. Sio TT, Vu CC, Sohawon S, et al. Extraskeletal osteosarcoma: an international Rare Cancer Network study. Am J Clin Oncol. 2016;39(1):32-36.
27. Bane BL, Evans HL, Ro JY, et al. Extraskeletal osteosarcoma. A clinicopathologic review of 26 cases. Cancer. 1990;65(12):2762-2770.
28. Lee JS, Fetsch JF, Wasdhal DA, Lee BP, Pritchard DJ, Nascimento AG. A review of 40 patients with extraskeletal osteosarcoma. Cancer. 1995;76(11):2253-2259.
Leukocytoclastic vasculitis (LCV) is a disease characterized by inflammation of small vessels with characteristic clinical findings of petechiae and palpable purpura.1 Numerous etiologies have been described, but the disease commonly remains idiopathic.2,3 Leukocytoclastic vasculitis often spontaneously resolves within weeks and requires only symptomatic treatment. Chronic or severe disease can require systemic medical treatment with agents such as colchicine, dapsone, and corticosteroids. These agents are effective but carry risks of serious side effects.4,5 These side effects and/or medical contraindications prevent some patients from taking systemic medications for LCV. We present a case of LCV that resolved after treatment with topical dapsone, highlighting a potential new treatment ofLCV with a markedly better side-effect profile.
Case Report
A 60-year-old woman with recent upper respiratory tract and sinus infections presented to our dermatology clinic with painful palpable purpura on the bilateral shins, thighs, and dorsal aspects of the feet of several months’ duration (Figure, A). Her primary care provider initiated treatment with amoxicillin and doxycycline for the infections. When the rash developed approximately 1.5 weeks following initiation of her symptoms, the patient was referred to the dermatology and rheumatology departments at our institution. The treating dermatologist (M.B.T.) obtained a 4-mm punch biopsy from the right lower leg and LCV was shown on histology. The patient completed a 14-day course of doxycycline and amoxicillin without resolution of the eruption. After an extensive investigation, the treating rheumatologist concluded that the LCV was idiopathic or secondary to an infection or drug exposure. The rheumatologist started the patient on oral prednisone for the chronic symptomatic LCV, but she was intolerant of this medication and discontinued it after 1 week. Our dermatology clinic started her on triamcinolone cream 0.1% twice daily, but she continued to experience new and worsening lesions. At her follow-up appointment 1 month later, triamcinolone cream was discontinued and dapsone gel 5% twice daily was started. She experienced resolution of her previously recalcitrant LCV within 3 weeks (Figure, B).
Petechiae and purpura from leukocytoclastic vasculitis affecting the bilateral shins before (A) and after 3 weeks of treatment with topical dapsone (B).
Comment
Established therapies for LCV carry serious side-effect profiles, which can preclude their use.5 Therefore, a topical therapeutic alternative for LCV would be ideal. Systemic prednisone is the first-line therapy for chronic and/or symptomatic LCV, but its side effects include suppression of the hypothalamic-pituitary-adrenal axis, immunosuppression, osteonecrosis, and glucose intolerance.5 Colchicine therapy carries risks for blood dyscrasia, immunosuppression, and gastrointestinal tract upset. Systemic dapsone also is an effective therapy for chronic and/or symptomatic LCV.5,6 However, systemic dapsone requires glucose-6-phosphate dehydrogenase deficiency screening and routine monitoring of blood counts, and it also carries the risk for serious adverse effects including neuropathy, blood dyscrasia, and hypersensitivity syndrome.5,6 Topical dapsone may provide similar efficacy with far fewer adverse effects and has proven to be a safe treatment of acne, even when used in patients with glucose-6-phosphate dehydrogenase deficiency. It displays low systemic absorption and does not accumulate over time once a steady state is reached.7 It also has been shown to be beneficial in other vasculopathies such as erythema elevatum diutinum and in other neutrophilic inflammatory disorders such as pyoderma gangrenosum.8,9 A case of methemoglobinemia due to topical dapsone has been reported.10 Although this effect is rare, clinicians should be aware of such adverse effects when using medications for off-label purposes.
Leukocytoclastic vasculitis can spontaneously resolve; however, our patient’s disease was chronic for several months, and she continued to develop new lesions without signs of resolution. After initiating topical dapsone, she experienced resolution within 3 weeks.
Conclusion
Topical dapsone is a novel approach for treating LCV. Given this drug’s favorable side-effect profile compared to the currently available therapeutic alternatives, we believe it is a reasonable option in select patients. Further investigation is needed to prove its efficacy, but it could be an ideal alternative for patients with contraindications to traditional therapies and/or for those unable to tolerate systemic therapy.
References
Koutkia P, Mylonakis E, Rounds S, et al. Leucocytoclastic vasculitis: an update for the clinician. Scand J Rheumatol. 2001;30:315-322.
Af Ekenstam E, Callen JP. Cutaneous leukocytoclastic vasculitis. clinical and laboratory features of 82 patients seen in private practice. Arch Dermatol. 1984;120:484-489.
Gyselbrecht L, de Keyser F, Ongenae K, et al. Etiological factors and underlying conditions in patientswith leucocytoclastic vasculitis. Clin Exp Rheumatol. 1996;14:665-668.
Sais G, Vidaller A, Jucglà A, et al. Colchicine in the treatment of cutaneous leukocytoclastic vasculitis. results of a prospective, randomized controlled trial. Arch Dermatol. 1995;131:1399-1402.
Sunderkotter C, Bonsmann G, Sindrilaru A, et al. Management of leukocytoclastic vasculitis: clinical review. J Dermatol Treat. 2005;16:193-206.
Zhu YI, Stiller MJ. Dapsone and sulfones in dermatology: overview and update. J Am Acad Dermatol. 2001;45:420-434.
Stotland M, Shalita AR, Kissling RF. Dapsone 5% gel: a review of its efficacy and safety in the treatment of acne vulgaris. Am J Clin Dermatol. 2009;10:221-227.
Frieling GW, Williams NL, Lim SJ, et al. Novel use of topical dapsone 5% gel for erythema elevatum diutinum: safer and effective. J Drugs Dermatol. 2013;12:481-484.
Handler MZ, Hamilton H, Aires D. Treatment of peristomal pyoderma gangrenosum with topical crushed dapsone. J Drugs Dermatol. 2011;10:1059-1061.
Swartzentruber GS, Yanta JH, Pizon AF. Methemoglobi-nemia as a complication of topical dapsone. N Engl J Med. 2015;372:491-492.
From the Department of Dermatology, Texas Tech University Health Sciences Center, Lubbock.
The authors report no conflict of interest.
Correspondence: Michelle B. Tarbox, MD, Texas Tech University Health Sciences Center, Department of Dermatology, 3601 4th St, Stop 9400, Lubbock, TX 79430-9400 (Michelle.tarbox@ttuhsc.edu).
From the Department of Dermatology, Texas Tech University Health Sciences Center, Lubbock.
The authors report no conflict of interest.
Correspondence: Michelle B. Tarbox, MD, Texas Tech University Health Sciences Center, Department of Dermatology, 3601 4th St, Stop 9400, Lubbock, TX 79430-9400 (Michelle.tarbox@ttuhsc.edu).
Author and Disclosure Information
From the Department of Dermatology, Texas Tech University Health Sciences Center, Lubbock.
The authors report no conflict of interest.
Correspondence: Michelle B. Tarbox, MD, Texas Tech University Health Sciences Center, Department of Dermatology, 3601 4th St, Stop 9400, Lubbock, TX 79430-9400 (Michelle.tarbox@ttuhsc.edu).
Leukocytoclastic vasculitis (LCV) is a disease characterized by inflammation of small vessels with characteristic clinical findings of petechiae and palpable purpura.1 Numerous etiologies have been described, but the disease commonly remains idiopathic.2,3 Leukocytoclastic vasculitis often spontaneously resolves within weeks and requires only symptomatic treatment. Chronic or severe disease can require systemic medical treatment with agents such as colchicine, dapsone, and corticosteroids. These agents are effective but carry risks of serious side effects.4,5 These side effects and/or medical contraindications prevent some patients from taking systemic medications for LCV. We present a case of LCV that resolved after treatment with topical dapsone, highlighting a potential new treatment ofLCV with a markedly better side-effect profile.
Case Report
A 60-year-old woman with recent upper respiratory tract and sinus infections presented to our dermatology clinic with painful palpable purpura on the bilateral shins, thighs, and dorsal aspects of the feet of several months’ duration (Figure, A). Her primary care provider initiated treatment with amoxicillin and doxycycline for the infections. When the rash developed approximately 1.5 weeks following initiation of her symptoms, the patient was referred to the dermatology and rheumatology departments at our institution. The treating dermatologist (M.B.T.) obtained a 4-mm punch biopsy from the right lower leg and LCV was shown on histology. The patient completed a 14-day course of doxycycline and amoxicillin without resolution of the eruption. After an extensive investigation, the treating rheumatologist concluded that the LCV was idiopathic or secondary to an infection or drug exposure. The rheumatologist started the patient on oral prednisone for the chronic symptomatic LCV, but she was intolerant of this medication and discontinued it after 1 week. Our dermatology clinic started her on triamcinolone cream 0.1% twice daily, but she continued to experience new and worsening lesions. At her follow-up appointment 1 month later, triamcinolone cream was discontinued and dapsone gel 5% twice daily was started. She experienced resolution of her previously recalcitrant LCV within 3 weeks (Figure, B).
Petechiae and purpura from leukocytoclastic vasculitis affecting the bilateral shins before (A) and after 3 weeks of treatment with topical dapsone (B).
Comment
Established therapies for LCV carry serious side-effect profiles, which can preclude their use.5 Therefore, a topical therapeutic alternative for LCV would be ideal. Systemic prednisone is the first-line therapy for chronic and/or symptomatic LCV, but its side effects include suppression of the hypothalamic-pituitary-adrenal axis, immunosuppression, osteonecrosis, and glucose intolerance.5 Colchicine therapy carries risks for blood dyscrasia, immunosuppression, and gastrointestinal tract upset. Systemic dapsone also is an effective therapy for chronic and/or symptomatic LCV.5,6 However, systemic dapsone requires glucose-6-phosphate dehydrogenase deficiency screening and routine monitoring of blood counts, and it also carries the risk for serious adverse effects including neuropathy, blood dyscrasia, and hypersensitivity syndrome.5,6 Topical dapsone may provide similar efficacy with far fewer adverse effects and has proven to be a safe treatment of acne, even when used in patients with glucose-6-phosphate dehydrogenase deficiency. It displays low systemic absorption and does not accumulate over time once a steady state is reached.7 It also has been shown to be beneficial in other vasculopathies such as erythema elevatum diutinum and in other neutrophilic inflammatory disorders such as pyoderma gangrenosum.8,9 A case of methemoglobinemia due to topical dapsone has been reported.10 Although this effect is rare, clinicians should be aware of such adverse effects when using medications for off-label purposes.
Leukocytoclastic vasculitis can spontaneously resolve; however, our patient’s disease was chronic for several months, and she continued to develop new lesions without signs of resolution. After initiating topical dapsone, she experienced resolution within 3 weeks.
Conclusion
Topical dapsone is a novel approach for treating LCV. Given this drug’s favorable side-effect profile compared to the currently available therapeutic alternatives, we believe it is a reasonable option in select patients. Further investigation is needed to prove its efficacy, but it could be an ideal alternative for patients with contraindications to traditional therapies and/or for those unable to tolerate systemic therapy.
Leukocytoclastic vasculitis (LCV) is a disease characterized by inflammation of small vessels with characteristic clinical findings of petechiae and palpable purpura.1 Numerous etiologies have been described, but the disease commonly remains idiopathic.2,3 Leukocytoclastic vasculitis often spontaneously resolves within weeks and requires only symptomatic treatment. Chronic or severe disease can require systemic medical treatment with agents such as colchicine, dapsone, and corticosteroids. These agents are effective but carry risks of serious side effects.4,5 These side effects and/or medical contraindications prevent some patients from taking systemic medications for LCV. We present a case of LCV that resolved after treatment with topical dapsone, highlighting a potential new treatment ofLCV with a markedly better side-effect profile.
Case Report
A 60-year-old woman with recent upper respiratory tract and sinus infections presented to our dermatology clinic with painful palpable purpura on the bilateral shins, thighs, and dorsal aspects of the feet of several months’ duration (Figure, A). Her primary care provider initiated treatment with amoxicillin and doxycycline for the infections. When the rash developed approximately 1.5 weeks following initiation of her symptoms, the patient was referred to the dermatology and rheumatology departments at our institution. The treating dermatologist (M.B.T.) obtained a 4-mm punch biopsy from the right lower leg and LCV was shown on histology. The patient completed a 14-day course of doxycycline and amoxicillin without resolution of the eruption. After an extensive investigation, the treating rheumatologist concluded that the LCV was idiopathic or secondary to an infection or drug exposure. The rheumatologist started the patient on oral prednisone for the chronic symptomatic LCV, but she was intolerant of this medication and discontinued it after 1 week. Our dermatology clinic started her on triamcinolone cream 0.1% twice daily, but she continued to experience new and worsening lesions. At her follow-up appointment 1 month later, triamcinolone cream was discontinued and dapsone gel 5% twice daily was started. She experienced resolution of her previously recalcitrant LCV within 3 weeks (Figure, B).
Petechiae and purpura from leukocytoclastic vasculitis affecting the bilateral shins before (A) and after 3 weeks of treatment with topical dapsone (B).
Comment
Established therapies for LCV carry serious side-effect profiles, which can preclude their use.5 Therefore, a topical therapeutic alternative for LCV would be ideal. Systemic prednisone is the first-line therapy for chronic and/or symptomatic LCV, but its side effects include suppression of the hypothalamic-pituitary-adrenal axis, immunosuppression, osteonecrosis, and glucose intolerance.5 Colchicine therapy carries risks for blood dyscrasia, immunosuppression, and gastrointestinal tract upset. Systemic dapsone also is an effective therapy for chronic and/or symptomatic LCV.5,6 However, systemic dapsone requires glucose-6-phosphate dehydrogenase deficiency screening and routine monitoring of blood counts, and it also carries the risk for serious adverse effects including neuropathy, blood dyscrasia, and hypersensitivity syndrome.5,6 Topical dapsone may provide similar efficacy with far fewer adverse effects and has proven to be a safe treatment of acne, even when used in patients with glucose-6-phosphate dehydrogenase deficiency. It displays low systemic absorption and does not accumulate over time once a steady state is reached.7 It also has been shown to be beneficial in other vasculopathies such as erythema elevatum diutinum and in other neutrophilic inflammatory disorders such as pyoderma gangrenosum.8,9 A case of methemoglobinemia due to topical dapsone has been reported.10 Although this effect is rare, clinicians should be aware of such adverse effects when using medications for off-label purposes.
Leukocytoclastic vasculitis can spontaneously resolve; however, our patient’s disease was chronic for several months, and she continued to develop new lesions without signs of resolution. After initiating topical dapsone, she experienced resolution within 3 weeks.
Conclusion
Topical dapsone is a novel approach for treating LCV. Given this drug’s favorable side-effect profile compared to the currently available therapeutic alternatives, we believe it is a reasonable option in select patients. Further investigation is needed to prove its efficacy, but it could be an ideal alternative for patients with contraindications to traditional therapies and/or for those unable to tolerate systemic therapy.
References
Koutkia P, Mylonakis E, Rounds S, et al. Leucocytoclastic vasculitis: an update for the clinician. Scand J Rheumatol. 2001;30:315-322.
Af Ekenstam E, Callen JP. Cutaneous leukocytoclastic vasculitis. clinical and laboratory features of 82 patients seen in private practice. Arch Dermatol. 1984;120:484-489.
Gyselbrecht L, de Keyser F, Ongenae K, et al. Etiological factors and underlying conditions in patientswith leucocytoclastic vasculitis. Clin Exp Rheumatol. 1996;14:665-668.
Sais G, Vidaller A, Jucglà A, et al. Colchicine in the treatment of cutaneous leukocytoclastic vasculitis. results of a prospective, randomized controlled trial. Arch Dermatol. 1995;131:1399-1402.
Sunderkotter C, Bonsmann G, Sindrilaru A, et al. Management of leukocytoclastic vasculitis: clinical review. J Dermatol Treat. 2005;16:193-206.
Zhu YI, Stiller MJ. Dapsone and sulfones in dermatology: overview and update. J Am Acad Dermatol. 2001;45:420-434.
Stotland M, Shalita AR, Kissling RF. Dapsone 5% gel: a review of its efficacy and safety in the treatment of acne vulgaris. Am J Clin Dermatol. 2009;10:221-227.
Frieling GW, Williams NL, Lim SJ, et al. Novel use of topical dapsone 5% gel for erythema elevatum diutinum: safer and effective. J Drugs Dermatol. 2013;12:481-484.
Handler MZ, Hamilton H, Aires D. Treatment of peristomal pyoderma gangrenosum with topical crushed dapsone. J Drugs Dermatol. 2011;10:1059-1061.
Swartzentruber GS, Yanta JH, Pizon AF. Methemoglobi-nemia as a complication of topical dapsone. N Engl J Med. 2015;372:491-492.
References
Koutkia P, Mylonakis E, Rounds S, et al. Leucocytoclastic vasculitis: an update for the clinician. Scand J Rheumatol. 2001;30:315-322.
Af Ekenstam E, Callen JP. Cutaneous leukocytoclastic vasculitis. clinical and laboratory features of 82 patients seen in private practice. Arch Dermatol. 1984;120:484-489.
Gyselbrecht L, de Keyser F, Ongenae K, et al. Etiological factors and underlying conditions in patientswith leucocytoclastic vasculitis. Clin Exp Rheumatol. 1996;14:665-668.
Sais G, Vidaller A, Jucglà A, et al. Colchicine in the treatment of cutaneous leukocytoclastic vasculitis. results of a prospective, randomized controlled trial. Arch Dermatol. 1995;131:1399-1402.
Sunderkotter C, Bonsmann G, Sindrilaru A, et al. Management of leukocytoclastic vasculitis: clinical review. J Dermatol Treat. 2005;16:193-206.
Zhu YI, Stiller MJ. Dapsone and sulfones in dermatology: overview and update. J Am Acad Dermatol. 2001;45:420-434.
Stotland M, Shalita AR, Kissling RF. Dapsone 5% gel: a review of its efficacy and safety in the treatment of acne vulgaris. Am J Clin Dermatol. 2009;10:221-227.
Frieling GW, Williams NL, Lim SJ, et al. Novel use of topical dapsone 5% gel for erythema elevatum diutinum: safer and effective. J Drugs Dermatol. 2013;12:481-484.
Handler MZ, Hamilton H, Aires D. Treatment of peristomal pyoderma gangrenosum with topical crushed dapsone. J Drugs Dermatol. 2011;10:1059-1061.
Swartzentruber GS, Yanta JH, Pizon AF. Methemoglobi-nemia as a complication of topical dapsone. N Engl J Med. 2015;372:491-492.
Leukocytoclastic vasculitis is characterized by inflammation of small vessels with characteristic clinical findings of petechiae and palpable purpura.
Leukocytoclastic vasculitis often spontaneously resolves within weeks and requires only symptomatic treatment, but chronic or severe disease can require systemic medical treatment with agents such as colchicine, dapsone, and corticosteroids.
Muckle-Wells syndrome (MWS) was first described in 1962 and is part of a broad category of hereditary periodic fever syndromes that include the autoinflammatory syndromes and the cryopyrin-associated periodic syndromes (CAPSs). Unlike autoimmune diseases, autoinflammatory syndromes are not associated with antigen-specific T-cell responses or high titers of autoantibodies but are related to disorders of the innate immune system. Basal cell nevus syndrome (BCNS), or Gorlin syndrome, is a rare genodermatosis inherited in an autosomal-dominant fashion that is characterized by a broad range of anomalies. Most notable is the early and strong predisposition to develop several to hundreds of basal cell carcinomas (BCCs). Classic clinical features of MWS and a thorough history and physical examination can assist in the diagnosis of this rare entity.
Case Report
A 35-year-old woman with a history of BCNS, which had been diagnosed at 24 years of age based on the presence of more than 2 BCCs and a family history of BCNS in her mother, presented with intermittent pruritic urticaria on the chest and back, episodic fevers, associated joint pain and swelling that worsened several hours after exercise, headache, conjunctivitis, blurred vision, and severe debilitating fatigue that had been present since childhood. The symptoms had progressively worsened with age and symptom-free intervals became shorter. She was diagnosed by her rheumatologist with biopsy-proven MWS and a positive NLRP3 (NLR family pyrin domain containing 3) gene mutation at 29 years of age. She was treated unsuccessfully with prednisone and antihistamines and entered a trial with anakinra. She showed improvement for 2 weeks but developed severe swelling and erythema at the injection sites at week 3, along with large leathery patches on the legs and difficulty ambulating.
The patient subsequently underwent excision of her BCCs and reported each site became erythematous, edematous, warm, and painful 6 hours after excision, which lasted for hours to days (Figures 1–3). After the first excision on the right forearm, she was seen in the emergency department, started on intravenous antibiotics and prednisone, and kept overnight in the hospital. She was discharged the following day and the edema in the right forearm subsided over several days. Bacterial culture and laboratory evaluation for infection were negative after the first excision on the right forearm. Because of the symptoms she experienced following this excision, she was referred to the plastic surgery department for excision followed by postoperative monitoring in the hospital. The patient continued to undergo excisions for BCCs and developed more severe symptoms including erythema, edema, warmth, and tenderness at the surrounding sites. Once again, the excision sites were cultured and laboratory work to rule out infection was ordered with a negative result. After several excisions and subsequent clinical findings, the patients’ symptoms were deemed consistent with MWS and not a result of infectious etiology. A diagnosis of MWS and BCNS with exacerbation of MWS with surgical procedures was made.
Figure 1. Erythema, edema, warmth, and tenderness surrounding the excision site on the right forearm 6 hours after basal cell carcinoma excision.
Figure 2. Erythema, edema, warmth, and tenderness surrounding the excision site on the right arm spreading distally to include the right wrist 24 hours after basal cell carcinoma excision.
Figure 3. Erythema, edema, warmth, and tenderness on the right wrist distal from the excision site 3 days after basal cell carcinoma excision.
The patient has continued therapy with rilonacept for MWS, which is managed by her rheumatologist. She has tolerated rilonacept without adverse effects and has experienced a reduction in symptoms that has enhanced her quality of life and allows for further treatment of her BCNS. Her dermatologist (J.W.L.) has been treating her BCCs with vismodegib, but treatment has been sporadic due to muscle cramping after 7 days of therapy. She reported subjective improvement to her dermatologist and has tried alternating 7 days on and 7 days off vismodegib. The muscle cramping still has limited her treatment with this regimen, and she is currently on a trial of 3 days on, 4 days off per week.
Comment
Classification and Clinical Presentation The hereditary periodic fever syndromes include the autoinflammatory syndromes and the CAPSs. The autoinflammatory syndromes include familial Mediterranean fever, hyperimmunoglobulinemia D with periodic fever syndrome, and tumor necrosis factor receptor–associated periodic syndrome. The CAPSs are similar but distinct and include familial cold autoinflammatory syndrome, neonatal-onset multisystem inflammatory disease (also known as chronic infantile neurologic cutaneous and articular syndrome, or cutaneous articular syndrome) and MWS.1,2
Cryopyrin-associated periodic syndromes are rare inherited diseases that result from mutations in the NLRP3 gene. There is a gain-of-function mutation on the NLRP3 gene located on the long arm of chromosome 1 at position 44, which codes for cryopyrin. An NLRP3 gene mutation causes cryopyrin to become hyperactive, leading to the formation of an inflammasome, which is a group of cryopyrin molecules. Inflammasomes, along with other proteins, activate caspase 1 to produce excess IL-1β, leading to persistent inflammatory symptoms.3 IL-1β is one of the key mediators of the body’s response to microbial invasion, inflammation, immunologic reactions, and tissue injury. It affects a large range of cells and organs. Although IL-1β production is critical for the control of pathogenic infections, excessive cytokine production is harmful to the host and can even be fatal.3,4
Cryopyrin-associated periodic syndromes encompass a disease continuum. The 3 distinct entities share many overlapping features as well as unique and distinguishing characteristics. Familial cold autoinflammatory syndrome is the mildest phenotype and is inherited in an autosomal-dominant fashion. It is characterized by a chronic urticarial eruption that starts early in infancy or childhood. The distribution of the cutaneous eruption is widespread and favors the arms and legs over the face and trunk. A low-grade fever often is seen along with musculoskeletal concerns of arthralgia and pain. Other commonly reported symptoms include conjunctivitis, myalgia, fatigue, and headache. Neurologic symptoms can include headaches. Symptoms usually begin 1 to 2 hours after cold exposure and last less than 24 hours.5-8
Neonatal-onset multisystem inflammatory disease is the most severe phenotype and occurs sporadically. Continuous symptoms and flares are characteristic and the length of the flare can vary from minutes to days. The cutaneous eruption favors the face, trunk, arms, and legs, and varies in intensity, beginning in infancy or childhood. Fever may be intermittent, mild, or absent. Rheumatologic manifestations include arthralgia and swelling, with approximately one-third of patients experiencing severe disabling arthropathy that causes gross joint deformity. Ocular findings include conjunctivitis, uveitis, papilledema, and even blindness. Neurologic sequelae include headaches, sensorineural hearing loss, and aseptic meningitis. Amyloidosis has been seen as a late complication.5,8
Muckle-Wells syndrome is a rare hereditary inflammatory disorder. It has no ethnic predisposition and is mostly inherited in an autosomal-dominant fashion. Classically, the condition is characterized by recurrent urticaria beginning at birth with intermittent episodic fever and malaise. The eruption has a predilection for the face, trunk, arms, and legs, which is similar to neonatal-onset multisystem inflammatory disease. Associated myalgia and arthralgia are common as well as ocular findings of conjunctivitis and episcleritis. Neurologic manifestations include headache and progressive sensorineural hearing loss in 60% to 70% of patients.6 Abdominal pain may be seen along with rare serositis in MWS but is rare in the other CAPSs. Amyloidosis caused by chronic inflammation is the most serious complication of MWS and is seen in approximately one-third of patients, manifesting as proteinuria followed by renal impairment. Symptoms of MWS may occur daily but vary individually, are broad in intensity and duration, and can last 1 to 2 days before resolving spontaneously. The symptoms can result from metabolic stressors including cold, stress, and exercise, as well as microbial pathogens. Leukocytosis and increased acute-phase reactants are observed during episodes of inflammation.4,6,8
Histopathology Mild phenotypic variability exists between individuals, and many of the symptoms overlap in CAPSs. Although CAPSs display several distinguishing clinical characteristics, interestingly they share the same histopathological features regardless of the syndrome. The typical histopathological finding is a dermal neutrophilic infiltrate that tends to be perivascular and also may be perieccrine. Vasodilation and dermal edema also may be seen. These histopathological findings contrast with the typical lymphocytic and eosinophilic infiltrate seen in classic urticaria. Similar histopathologic findings have been seen in other neutrophilic urticarial dermatoses such as Schnitzler syndrome.4,6
Differential The differential diagnoses for CAPSs include Schnitzler syndrome, cold urticaria, systemic-onset juvenile idiopathic arthritis/adult-onset Still disease, and deficiency in IL-1ra. It is important to consider these differential diagnoses for management and treatment options.
Management The discovery of the NLRP3 gene mutation as well as an understanding of IL-1 biology has led to targeted therapy for these syndromes. Cryopyrin-associated periodic syndromes are mediated by IL-1β with an in vivo rate 5 times higher than in healthy patients.4 The blockade of IL-1β results in complete resolution of symptoms.
In the last several years, anakinra, rilonacept, and canakinumab have shown efficacy in targeting IL-1β as receptor antagonists. Anakinra is a short-acting recombinant IL-1ra with a half-life of 4 to 6 hours. This short half-life requires daily injections and the most common adverse events included injection-site reaction and upper respiratory tract infection.2,4 Rilonacept is a dimeric fusion protein that contains binding regions for the type 1 receptor and the IL-1 receptor accessory protein and is fused to the fragment, crystallizable (Fc) portion of human IgG1. Rilonacept is long acting with a circulating half-life of 8.6 days and offers patients ease of dosing with weekly subcutaneous injections. Rilonacept generally is well tolerated, with the most frequent adverse effects being injection-site reaction, upper respiratory tract infection, headache, arthralgia, and diarrhea.2,7
The newest of the treatments for patients with CAPS is canakinumab. It is a fully human IL-1β monoclonal antibody that is specific for IL-1β and not other members of the IL-1 family. It has a mean half-life of 26 days and is dosed subcutaneously once every 8 weeks. The most common adverse effects include nasopharyngitis, rhinitis, nausea, diarrhea, and vertigo.4 In one study, most patients did not report injection-site reactions.7 Studies also are underway on VX-765, a caspace-1 targeted therapy that acts upstream in the IL-1β pathway. Treatment with anakinra, rilonacept, and canakinumab generally offers rapid and sustained remission in the majority of MWS patients and helps prevent the development of systemic amyloidosis and lessens the potential for end organ damage.2,7
MWS and BCNS Our patient had an unusual presentation of MWS complicated by BCNS, another rare autosomal-dominant inherited genodermatosis. In an extensive review of PubMed articles indexed for MEDLINE using the search terms Muckle-Wells syndrome and basal cell nevus syndrome, no association was identified between MWS and BCNS. Basal cell nevus syndrome is linked to PTCH1 (patched 1) gene mutation with an incidence of 1:150,000 in the United States and Europe and is characterized by a broad range of anomalies including skeletal abnormalities, ectopic calcification, odontogenic keratocysts, facial dysmorphism with macrocephaly, palmoplantar pits, and numerous tumors. Most notable is the early and strong predisposition to develop several to hundreds of BCCs.9
Conclusion
Muckle-Wells syndrome may go undiagnosed for many years or may be misdiagnosed as refractory urticaria, as in our patient. It is important to include periodic fever syndromes in the differential diagnosis of refractory urticaria with episodic fever to diagnose these cases of MWS earlier.
References
Kagami S, Saeki H, Kuwano Y, et al. A probable case of Muckle-Wells syndrome. J Dermatol.2006;2:118-121.
Kanazawa N, Furukawa F. Autoinflammatory syndromes with a dermatological perspective. J Dermatol.2007;34:601-618.
Martinon F, Tschopp J. Inflammatory caspases: linking an intracellular innate immune system to autoinflammatory diseases. Cell. 2004;117:561-574.
Mueller SM, Itin P, Haeusermann P. Muckle-Wells syndrome effectively treated with canakinumab: is the recommended dosing schedule mandatory? Dermatology. 2011;223:113-118.
Neven B, Prieur A, Quartier dit Maire P. Cryopyrinopathies: update on pathogenesis and treatment. Nat Clin Pract Rheumatol. 2008;4:481-489.
Newell L, August S, Foria V, et al. Lifelong urticaria and multiple unexplained systemic symptoms. Clin Exp Dermatol.2011;36:431-433.
Yu JR, Kieron KS. Cryopyrin-associated periodic syndrome: an update on diagnosis and treatment response. Curr Allergy Asthma Rep.2011;11:12-20.
Bolognia JL, Jorizzo JL, Rapini RP, et al, eds.Dermatology. 2nd ed. Barcelona, Spain: Mosby Elsevier; 2008. 9. Göppner D, Leverkus M. Basal cell carcinoma: from the molecular understanding of the pathogenesis to targeted therapy of progressive disease. J Skin Cancer. 2011;2011:650258.
Dr. Wagener is from Aesthetic Surgery Associates, Allentown, Pennsylvania. Dr. Laskas is from Dermatology Limited, Media, Pennsylvania. Drs. Purcell and Ermolovich are from Advanced Dermatology Associates, Allentown.
The authors report no conflict of interest.
Correspondence: Marie Wagener, DO, Aesthetic Surgery Associates, Integrated Health Campus, 250 Centronia Rd, Ste 301, Allentown, PA 18104 (m.lewars@gmail.com).
Dr. Wagener is from Aesthetic Surgery Associates, Allentown, Pennsylvania. Dr. Laskas is from Dermatology Limited, Media, Pennsylvania. Drs. Purcell and Ermolovich are from Advanced Dermatology Associates, Allentown.
The authors report no conflict of interest.
Correspondence: Marie Wagener, DO, Aesthetic Surgery Associates, Integrated Health Campus, 250 Centronia Rd, Ste 301, Allentown, PA 18104 (m.lewars@gmail.com).
Author and Disclosure Information
Dr. Wagener is from Aesthetic Surgery Associates, Allentown, Pennsylvania. Dr. Laskas is from Dermatology Limited, Media, Pennsylvania. Drs. Purcell and Ermolovich are from Advanced Dermatology Associates, Allentown.
The authors report no conflict of interest.
Correspondence: Marie Wagener, DO, Aesthetic Surgery Associates, Integrated Health Campus, 250 Centronia Rd, Ste 301, Allentown, PA 18104 (m.lewars@gmail.com).
Muckle-Wells syndrome (MWS) was first described in 1962 and is part of a broad category of hereditary periodic fever syndromes that include the autoinflammatory syndromes and the cryopyrin-associated periodic syndromes (CAPSs). Unlike autoimmune diseases, autoinflammatory syndromes are not associated with antigen-specific T-cell responses or high titers of autoantibodies but are related to disorders of the innate immune system. Basal cell nevus syndrome (BCNS), or Gorlin syndrome, is a rare genodermatosis inherited in an autosomal-dominant fashion that is characterized by a broad range of anomalies. Most notable is the early and strong predisposition to develop several to hundreds of basal cell carcinomas (BCCs). Classic clinical features of MWS and a thorough history and physical examination can assist in the diagnosis of this rare entity.
Case Report
A 35-year-old woman with a history of BCNS, which had been diagnosed at 24 years of age based on the presence of more than 2 BCCs and a family history of BCNS in her mother, presented with intermittent pruritic urticaria on the chest and back, episodic fevers, associated joint pain and swelling that worsened several hours after exercise, headache, conjunctivitis, blurred vision, and severe debilitating fatigue that had been present since childhood. The symptoms had progressively worsened with age and symptom-free intervals became shorter. She was diagnosed by her rheumatologist with biopsy-proven MWS and a positive NLRP3 (NLR family pyrin domain containing 3) gene mutation at 29 years of age. She was treated unsuccessfully with prednisone and antihistamines and entered a trial with anakinra. She showed improvement for 2 weeks but developed severe swelling and erythema at the injection sites at week 3, along with large leathery patches on the legs and difficulty ambulating.
The patient subsequently underwent excision of her BCCs and reported each site became erythematous, edematous, warm, and painful 6 hours after excision, which lasted for hours to days (Figures 1–3). After the first excision on the right forearm, she was seen in the emergency department, started on intravenous antibiotics and prednisone, and kept overnight in the hospital. She was discharged the following day and the edema in the right forearm subsided over several days. Bacterial culture and laboratory evaluation for infection were negative after the first excision on the right forearm. Because of the symptoms she experienced following this excision, she was referred to the plastic surgery department for excision followed by postoperative monitoring in the hospital. The patient continued to undergo excisions for BCCs and developed more severe symptoms including erythema, edema, warmth, and tenderness at the surrounding sites. Once again, the excision sites were cultured and laboratory work to rule out infection was ordered with a negative result. After several excisions and subsequent clinical findings, the patients’ symptoms were deemed consistent with MWS and not a result of infectious etiology. A diagnosis of MWS and BCNS with exacerbation of MWS with surgical procedures was made.
Figure 1. Erythema, edema, warmth, and tenderness surrounding the excision site on the right forearm 6 hours after basal cell carcinoma excision.
Figure 2. Erythema, edema, warmth, and tenderness surrounding the excision site on the right arm spreading distally to include the right wrist 24 hours after basal cell carcinoma excision.
Figure 3. Erythema, edema, warmth, and tenderness on the right wrist distal from the excision site 3 days after basal cell carcinoma excision.
The patient has continued therapy with rilonacept for MWS, which is managed by her rheumatologist. She has tolerated rilonacept without adverse effects and has experienced a reduction in symptoms that has enhanced her quality of life and allows for further treatment of her BCNS. Her dermatologist (J.W.L.) has been treating her BCCs with vismodegib, but treatment has been sporadic due to muscle cramping after 7 days of therapy. She reported subjective improvement to her dermatologist and has tried alternating 7 days on and 7 days off vismodegib. The muscle cramping still has limited her treatment with this regimen, and she is currently on a trial of 3 days on, 4 days off per week.
Comment
Classification and Clinical Presentation The hereditary periodic fever syndromes include the autoinflammatory syndromes and the CAPSs. The autoinflammatory syndromes include familial Mediterranean fever, hyperimmunoglobulinemia D with periodic fever syndrome, and tumor necrosis factor receptor–associated periodic syndrome. The CAPSs are similar but distinct and include familial cold autoinflammatory syndrome, neonatal-onset multisystem inflammatory disease (also known as chronic infantile neurologic cutaneous and articular syndrome, or cutaneous articular syndrome) and MWS.1,2
Cryopyrin-associated periodic syndromes are rare inherited diseases that result from mutations in the NLRP3 gene. There is a gain-of-function mutation on the NLRP3 gene located on the long arm of chromosome 1 at position 44, which codes for cryopyrin. An NLRP3 gene mutation causes cryopyrin to become hyperactive, leading to the formation of an inflammasome, which is a group of cryopyrin molecules. Inflammasomes, along with other proteins, activate caspase 1 to produce excess IL-1β, leading to persistent inflammatory symptoms.3 IL-1β is one of the key mediators of the body’s response to microbial invasion, inflammation, immunologic reactions, and tissue injury. It affects a large range of cells and organs. Although IL-1β production is critical for the control of pathogenic infections, excessive cytokine production is harmful to the host and can even be fatal.3,4
Cryopyrin-associated periodic syndromes encompass a disease continuum. The 3 distinct entities share many overlapping features as well as unique and distinguishing characteristics. Familial cold autoinflammatory syndrome is the mildest phenotype and is inherited in an autosomal-dominant fashion. It is characterized by a chronic urticarial eruption that starts early in infancy or childhood. The distribution of the cutaneous eruption is widespread and favors the arms and legs over the face and trunk. A low-grade fever often is seen along with musculoskeletal concerns of arthralgia and pain. Other commonly reported symptoms include conjunctivitis, myalgia, fatigue, and headache. Neurologic symptoms can include headaches. Symptoms usually begin 1 to 2 hours after cold exposure and last less than 24 hours.5-8
Neonatal-onset multisystem inflammatory disease is the most severe phenotype and occurs sporadically. Continuous symptoms and flares are characteristic and the length of the flare can vary from minutes to days. The cutaneous eruption favors the face, trunk, arms, and legs, and varies in intensity, beginning in infancy or childhood. Fever may be intermittent, mild, or absent. Rheumatologic manifestations include arthralgia and swelling, with approximately one-third of patients experiencing severe disabling arthropathy that causes gross joint deformity. Ocular findings include conjunctivitis, uveitis, papilledema, and even blindness. Neurologic sequelae include headaches, sensorineural hearing loss, and aseptic meningitis. Amyloidosis has been seen as a late complication.5,8
Muckle-Wells syndrome is a rare hereditary inflammatory disorder. It has no ethnic predisposition and is mostly inherited in an autosomal-dominant fashion. Classically, the condition is characterized by recurrent urticaria beginning at birth with intermittent episodic fever and malaise. The eruption has a predilection for the face, trunk, arms, and legs, which is similar to neonatal-onset multisystem inflammatory disease. Associated myalgia and arthralgia are common as well as ocular findings of conjunctivitis and episcleritis. Neurologic manifestations include headache and progressive sensorineural hearing loss in 60% to 70% of patients.6 Abdominal pain may be seen along with rare serositis in MWS but is rare in the other CAPSs. Amyloidosis caused by chronic inflammation is the most serious complication of MWS and is seen in approximately one-third of patients, manifesting as proteinuria followed by renal impairment. Symptoms of MWS may occur daily but vary individually, are broad in intensity and duration, and can last 1 to 2 days before resolving spontaneously. The symptoms can result from metabolic stressors including cold, stress, and exercise, as well as microbial pathogens. Leukocytosis and increased acute-phase reactants are observed during episodes of inflammation.4,6,8
Histopathology Mild phenotypic variability exists between individuals, and many of the symptoms overlap in CAPSs. Although CAPSs display several distinguishing clinical characteristics, interestingly they share the same histopathological features regardless of the syndrome. The typical histopathological finding is a dermal neutrophilic infiltrate that tends to be perivascular and also may be perieccrine. Vasodilation and dermal edema also may be seen. These histopathological findings contrast with the typical lymphocytic and eosinophilic infiltrate seen in classic urticaria. Similar histopathologic findings have been seen in other neutrophilic urticarial dermatoses such as Schnitzler syndrome.4,6
Differential The differential diagnoses for CAPSs include Schnitzler syndrome, cold urticaria, systemic-onset juvenile idiopathic arthritis/adult-onset Still disease, and deficiency in IL-1ra. It is important to consider these differential diagnoses for management and treatment options.
Management The discovery of the NLRP3 gene mutation as well as an understanding of IL-1 biology has led to targeted therapy for these syndromes. Cryopyrin-associated periodic syndromes are mediated by IL-1β with an in vivo rate 5 times higher than in healthy patients.4 The blockade of IL-1β results in complete resolution of symptoms.
In the last several years, anakinra, rilonacept, and canakinumab have shown efficacy in targeting IL-1β as receptor antagonists. Anakinra is a short-acting recombinant IL-1ra with a half-life of 4 to 6 hours. This short half-life requires daily injections and the most common adverse events included injection-site reaction and upper respiratory tract infection.2,4 Rilonacept is a dimeric fusion protein that contains binding regions for the type 1 receptor and the IL-1 receptor accessory protein and is fused to the fragment, crystallizable (Fc) portion of human IgG1. Rilonacept is long acting with a circulating half-life of 8.6 days and offers patients ease of dosing with weekly subcutaneous injections. Rilonacept generally is well tolerated, with the most frequent adverse effects being injection-site reaction, upper respiratory tract infection, headache, arthralgia, and diarrhea.2,7
The newest of the treatments for patients with CAPS is canakinumab. It is a fully human IL-1β monoclonal antibody that is specific for IL-1β and not other members of the IL-1 family. It has a mean half-life of 26 days and is dosed subcutaneously once every 8 weeks. The most common adverse effects include nasopharyngitis, rhinitis, nausea, diarrhea, and vertigo.4 In one study, most patients did not report injection-site reactions.7 Studies also are underway on VX-765, a caspace-1 targeted therapy that acts upstream in the IL-1β pathway. Treatment with anakinra, rilonacept, and canakinumab generally offers rapid and sustained remission in the majority of MWS patients and helps prevent the development of systemic amyloidosis and lessens the potential for end organ damage.2,7
MWS and BCNS Our patient had an unusual presentation of MWS complicated by BCNS, another rare autosomal-dominant inherited genodermatosis. In an extensive review of PubMed articles indexed for MEDLINE using the search terms Muckle-Wells syndrome and basal cell nevus syndrome, no association was identified between MWS and BCNS. Basal cell nevus syndrome is linked to PTCH1 (patched 1) gene mutation with an incidence of 1:150,000 in the United States and Europe and is characterized by a broad range of anomalies including skeletal abnormalities, ectopic calcification, odontogenic keratocysts, facial dysmorphism with macrocephaly, palmoplantar pits, and numerous tumors. Most notable is the early and strong predisposition to develop several to hundreds of BCCs.9
Conclusion
Muckle-Wells syndrome may go undiagnosed for many years or may be misdiagnosed as refractory urticaria, as in our patient. It is important to include periodic fever syndromes in the differential diagnosis of refractory urticaria with episodic fever to diagnose these cases of MWS earlier.
Muckle-Wells syndrome (MWS) was first described in 1962 and is part of a broad category of hereditary periodic fever syndromes that include the autoinflammatory syndromes and the cryopyrin-associated periodic syndromes (CAPSs). Unlike autoimmune diseases, autoinflammatory syndromes are not associated with antigen-specific T-cell responses or high titers of autoantibodies but are related to disorders of the innate immune system. Basal cell nevus syndrome (BCNS), or Gorlin syndrome, is a rare genodermatosis inherited in an autosomal-dominant fashion that is characterized by a broad range of anomalies. Most notable is the early and strong predisposition to develop several to hundreds of basal cell carcinomas (BCCs). Classic clinical features of MWS and a thorough history and physical examination can assist in the diagnosis of this rare entity.
Case Report
A 35-year-old woman with a history of BCNS, which had been diagnosed at 24 years of age based on the presence of more than 2 BCCs and a family history of BCNS in her mother, presented with intermittent pruritic urticaria on the chest and back, episodic fevers, associated joint pain and swelling that worsened several hours after exercise, headache, conjunctivitis, blurred vision, and severe debilitating fatigue that had been present since childhood. The symptoms had progressively worsened with age and symptom-free intervals became shorter. She was diagnosed by her rheumatologist with biopsy-proven MWS and a positive NLRP3 (NLR family pyrin domain containing 3) gene mutation at 29 years of age. She was treated unsuccessfully with prednisone and antihistamines and entered a trial with anakinra. She showed improvement for 2 weeks but developed severe swelling and erythema at the injection sites at week 3, along with large leathery patches on the legs and difficulty ambulating.
The patient subsequently underwent excision of her BCCs and reported each site became erythematous, edematous, warm, and painful 6 hours after excision, which lasted for hours to days (Figures 1–3). After the first excision on the right forearm, she was seen in the emergency department, started on intravenous antibiotics and prednisone, and kept overnight in the hospital. She was discharged the following day and the edema in the right forearm subsided over several days. Bacterial culture and laboratory evaluation for infection were negative after the first excision on the right forearm. Because of the symptoms she experienced following this excision, she was referred to the plastic surgery department for excision followed by postoperative monitoring in the hospital. The patient continued to undergo excisions for BCCs and developed more severe symptoms including erythema, edema, warmth, and tenderness at the surrounding sites. Once again, the excision sites were cultured and laboratory work to rule out infection was ordered with a negative result. After several excisions and subsequent clinical findings, the patients’ symptoms were deemed consistent with MWS and not a result of infectious etiology. A diagnosis of MWS and BCNS with exacerbation of MWS with surgical procedures was made.
Figure 1. Erythema, edema, warmth, and tenderness surrounding the excision site on the right forearm 6 hours after basal cell carcinoma excision.
Figure 2. Erythema, edema, warmth, and tenderness surrounding the excision site on the right arm spreading distally to include the right wrist 24 hours after basal cell carcinoma excision.
Figure 3. Erythema, edema, warmth, and tenderness on the right wrist distal from the excision site 3 days after basal cell carcinoma excision.
The patient has continued therapy with rilonacept for MWS, which is managed by her rheumatologist. She has tolerated rilonacept without adverse effects and has experienced a reduction in symptoms that has enhanced her quality of life and allows for further treatment of her BCNS. Her dermatologist (J.W.L.) has been treating her BCCs with vismodegib, but treatment has been sporadic due to muscle cramping after 7 days of therapy. She reported subjective improvement to her dermatologist and has tried alternating 7 days on and 7 days off vismodegib. The muscle cramping still has limited her treatment with this regimen, and she is currently on a trial of 3 days on, 4 days off per week.
Comment
Classification and Clinical Presentation The hereditary periodic fever syndromes include the autoinflammatory syndromes and the CAPSs. The autoinflammatory syndromes include familial Mediterranean fever, hyperimmunoglobulinemia D with periodic fever syndrome, and tumor necrosis factor receptor–associated periodic syndrome. The CAPSs are similar but distinct and include familial cold autoinflammatory syndrome, neonatal-onset multisystem inflammatory disease (also known as chronic infantile neurologic cutaneous and articular syndrome, or cutaneous articular syndrome) and MWS.1,2
Cryopyrin-associated periodic syndromes are rare inherited diseases that result from mutations in the NLRP3 gene. There is a gain-of-function mutation on the NLRP3 gene located on the long arm of chromosome 1 at position 44, which codes for cryopyrin. An NLRP3 gene mutation causes cryopyrin to become hyperactive, leading to the formation of an inflammasome, which is a group of cryopyrin molecules. Inflammasomes, along with other proteins, activate caspase 1 to produce excess IL-1β, leading to persistent inflammatory symptoms.3 IL-1β is one of the key mediators of the body’s response to microbial invasion, inflammation, immunologic reactions, and tissue injury. It affects a large range of cells and organs. Although IL-1β production is critical for the control of pathogenic infections, excessive cytokine production is harmful to the host and can even be fatal.3,4
Cryopyrin-associated periodic syndromes encompass a disease continuum. The 3 distinct entities share many overlapping features as well as unique and distinguishing characteristics. Familial cold autoinflammatory syndrome is the mildest phenotype and is inherited in an autosomal-dominant fashion. It is characterized by a chronic urticarial eruption that starts early in infancy or childhood. The distribution of the cutaneous eruption is widespread and favors the arms and legs over the face and trunk. A low-grade fever often is seen along with musculoskeletal concerns of arthralgia and pain. Other commonly reported symptoms include conjunctivitis, myalgia, fatigue, and headache. Neurologic symptoms can include headaches. Symptoms usually begin 1 to 2 hours after cold exposure and last less than 24 hours.5-8
Neonatal-onset multisystem inflammatory disease is the most severe phenotype and occurs sporadically. Continuous symptoms and flares are characteristic and the length of the flare can vary from minutes to days. The cutaneous eruption favors the face, trunk, arms, and legs, and varies in intensity, beginning in infancy or childhood. Fever may be intermittent, mild, or absent. Rheumatologic manifestations include arthralgia and swelling, with approximately one-third of patients experiencing severe disabling arthropathy that causes gross joint deformity. Ocular findings include conjunctivitis, uveitis, papilledema, and even blindness. Neurologic sequelae include headaches, sensorineural hearing loss, and aseptic meningitis. Amyloidosis has been seen as a late complication.5,8
Muckle-Wells syndrome is a rare hereditary inflammatory disorder. It has no ethnic predisposition and is mostly inherited in an autosomal-dominant fashion. Classically, the condition is characterized by recurrent urticaria beginning at birth with intermittent episodic fever and malaise. The eruption has a predilection for the face, trunk, arms, and legs, which is similar to neonatal-onset multisystem inflammatory disease. Associated myalgia and arthralgia are common as well as ocular findings of conjunctivitis and episcleritis. Neurologic manifestations include headache and progressive sensorineural hearing loss in 60% to 70% of patients.6 Abdominal pain may be seen along with rare serositis in MWS but is rare in the other CAPSs. Amyloidosis caused by chronic inflammation is the most serious complication of MWS and is seen in approximately one-third of patients, manifesting as proteinuria followed by renal impairment. Symptoms of MWS may occur daily but vary individually, are broad in intensity and duration, and can last 1 to 2 days before resolving spontaneously. The symptoms can result from metabolic stressors including cold, stress, and exercise, as well as microbial pathogens. Leukocytosis and increased acute-phase reactants are observed during episodes of inflammation.4,6,8
Histopathology Mild phenotypic variability exists between individuals, and many of the symptoms overlap in CAPSs. Although CAPSs display several distinguishing clinical characteristics, interestingly they share the same histopathological features regardless of the syndrome. The typical histopathological finding is a dermal neutrophilic infiltrate that tends to be perivascular and also may be perieccrine. Vasodilation and dermal edema also may be seen. These histopathological findings contrast with the typical lymphocytic and eosinophilic infiltrate seen in classic urticaria. Similar histopathologic findings have been seen in other neutrophilic urticarial dermatoses such as Schnitzler syndrome.4,6
Differential The differential diagnoses for CAPSs include Schnitzler syndrome, cold urticaria, systemic-onset juvenile idiopathic arthritis/adult-onset Still disease, and deficiency in IL-1ra. It is important to consider these differential diagnoses for management and treatment options.
Management The discovery of the NLRP3 gene mutation as well as an understanding of IL-1 biology has led to targeted therapy for these syndromes. Cryopyrin-associated periodic syndromes are mediated by IL-1β with an in vivo rate 5 times higher than in healthy patients.4 The blockade of IL-1β results in complete resolution of symptoms.
In the last several years, anakinra, rilonacept, and canakinumab have shown efficacy in targeting IL-1β as receptor antagonists. Anakinra is a short-acting recombinant IL-1ra with a half-life of 4 to 6 hours. This short half-life requires daily injections and the most common adverse events included injection-site reaction and upper respiratory tract infection.2,4 Rilonacept is a dimeric fusion protein that contains binding regions for the type 1 receptor and the IL-1 receptor accessory protein and is fused to the fragment, crystallizable (Fc) portion of human IgG1. Rilonacept is long acting with a circulating half-life of 8.6 days and offers patients ease of dosing with weekly subcutaneous injections. Rilonacept generally is well tolerated, with the most frequent adverse effects being injection-site reaction, upper respiratory tract infection, headache, arthralgia, and diarrhea.2,7
The newest of the treatments for patients with CAPS is canakinumab. It is a fully human IL-1β monoclonal antibody that is specific for IL-1β and not other members of the IL-1 family. It has a mean half-life of 26 days and is dosed subcutaneously once every 8 weeks. The most common adverse effects include nasopharyngitis, rhinitis, nausea, diarrhea, and vertigo.4 In one study, most patients did not report injection-site reactions.7 Studies also are underway on VX-765, a caspace-1 targeted therapy that acts upstream in the IL-1β pathway. Treatment with anakinra, rilonacept, and canakinumab generally offers rapid and sustained remission in the majority of MWS patients and helps prevent the development of systemic amyloidosis and lessens the potential for end organ damage.2,7
MWS and BCNS Our patient had an unusual presentation of MWS complicated by BCNS, another rare autosomal-dominant inherited genodermatosis. In an extensive review of PubMed articles indexed for MEDLINE using the search terms Muckle-Wells syndrome and basal cell nevus syndrome, no association was identified between MWS and BCNS. Basal cell nevus syndrome is linked to PTCH1 (patched 1) gene mutation with an incidence of 1:150,000 in the United States and Europe and is characterized by a broad range of anomalies including skeletal abnormalities, ectopic calcification, odontogenic keratocysts, facial dysmorphism with macrocephaly, palmoplantar pits, and numerous tumors. Most notable is the early and strong predisposition to develop several to hundreds of BCCs.9
Conclusion
Muckle-Wells syndrome may go undiagnosed for many years or may be misdiagnosed as refractory urticaria, as in our patient. It is important to include periodic fever syndromes in the differential diagnosis of refractory urticaria with episodic fever to diagnose these cases of MWS earlier.
References
Kagami S, Saeki H, Kuwano Y, et al. A probable case of Muckle-Wells syndrome. J Dermatol.2006;2:118-121.
Kanazawa N, Furukawa F. Autoinflammatory syndromes with a dermatological perspective. J Dermatol.2007;34:601-618.
Martinon F, Tschopp J. Inflammatory caspases: linking an intracellular innate immune system to autoinflammatory diseases. Cell. 2004;117:561-574.
Mueller SM, Itin P, Haeusermann P. Muckle-Wells syndrome effectively treated with canakinumab: is the recommended dosing schedule mandatory? Dermatology. 2011;223:113-118.
Neven B, Prieur A, Quartier dit Maire P. Cryopyrinopathies: update on pathogenesis and treatment. Nat Clin Pract Rheumatol. 2008;4:481-489.
Newell L, August S, Foria V, et al. Lifelong urticaria and multiple unexplained systemic symptoms. Clin Exp Dermatol.2011;36:431-433.
Yu JR, Kieron KS. Cryopyrin-associated periodic syndrome: an update on diagnosis and treatment response. Curr Allergy Asthma Rep.2011;11:12-20.
Bolognia JL, Jorizzo JL, Rapini RP, et al, eds.Dermatology. 2nd ed. Barcelona, Spain: Mosby Elsevier; 2008. 9. Göppner D, Leverkus M. Basal cell carcinoma: from the molecular understanding of the pathogenesis to targeted therapy of progressive disease. J Skin Cancer. 2011;2011:650258.
References
Kagami S, Saeki H, Kuwano Y, et al. A probable case of Muckle-Wells syndrome. J Dermatol.2006;2:118-121.
Kanazawa N, Furukawa F. Autoinflammatory syndromes with a dermatological perspective. J Dermatol.2007;34:601-618.
Martinon F, Tschopp J. Inflammatory caspases: linking an intracellular innate immune system to autoinflammatory diseases. Cell. 2004;117:561-574.
Mueller SM, Itin P, Haeusermann P. Muckle-Wells syndrome effectively treated with canakinumab: is the recommended dosing schedule mandatory? Dermatology. 2011;223:113-118.
Neven B, Prieur A, Quartier dit Maire P. Cryopyrinopathies: update on pathogenesis and treatment. Nat Clin Pract Rheumatol. 2008;4:481-489.
Newell L, August S, Foria V, et al. Lifelong urticaria and multiple unexplained systemic symptoms. Clin Exp Dermatol.2011;36:431-433.
Yu JR, Kieron KS. Cryopyrin-associated periodic syndrome: an update on diagnosis and treatment response. Curr Allergy Asthma Rep.2011;11:12-20.
Bolognia JL, Jorizzo JL, Rapini RP, et al, eds.Dermatology. 2nd ed. Barcelona, Spain: Mosby Elsevier; 2008. 9. Göppner D, Leverkus M. Basal cell carcinoma: from the molecular understanding of the pathogenesis to targeted therapy of progressive disease. J Skin Cancer. 2011;2011:650258.
An urticarial rash occurring in childhood with symptoms of fever, joint pain, and swelling along with visual symptoms should prompt consideration of a cryopyrin-associated periodic syndrome.
Histopathology shows a dermal neutrophilic infiltrate that tends to be perivascular and also may be perieccrine. This atypical urticaria contrasts with the typical lymphocytic and eosinophilic infiltrate seen in classic urticaria.
A 29-year-old man presented to the ED with a 3-day history of constant left-sided low back pain that radiated to his left buttock and groin. The patient stated the pain worsened with movement, making it difficult for him to walk. He reported lifting heavy boxes at work, but denied any trauma. The patient also denied recent fevers, chills, chest pain, dyspnea, abdominal pain, urinary or fecal incontinence, weakness, numbness, or saddle anesthesia. Regarding his medical history, he had an appendectomy as a child, but reported no other surgeries or medical issues. His social history was significant for narcotic and inhalant use and daily tobacco use. The patient also reported taking heroin intravenously (IV) 6 months prior.
Vital signs at presentation were: heart rate (HR), 92 beats/min; respiratory rate, 15 breaths/min; blood pressure, 118/80 mm Hg; and temperature, 98.2°F. Oxygen saturation was 98% on room air.
The patient was a well-developed young man in no apparent distress. Dermatological examination showed bilateral track marks in the antecubital fossa. The musculoskeletal (MSK) examination demonstrated left gluteal tenderness to palpation and decreased active and passive range of motion of the left hip, especially with internal rotation and flexion. He had no midline tenderness, and the lower extremities had normal pulses and no motor or sensory deficits.
The patient’s pain improved with IV fluids, diazepam, and ketorolac, and he was able to ambulate with assistance. He was clinically diagnosed with sciatica, and discharged home with prescriptions for diazepam and ibuprofen. He was also instructed to follow-up with an orthopedist within 7 days from discharge.
The patient returned to the ED the following day with similar complaints of unabating left-sided pain and difficulty ambulating. His vital signs were notable for an elevated HR of 106 beats/min. Physical examination findings were unchanged from his presentation the previous day, and an X-ray of the lumbar spine showed no abnormalities.
After receiving IV analgesics, the patient’s pain improved and his tachycardia resolved. He was discharged home with instructions to continue taking diazepam, and was also given prescriptions for prednisone and oxycodone/acetaminophen. He was instructed to follow-up with an orthopedist within 24 hours.
Over the next 9 days, the patient was seen twice by an orthopedist, who ordered imaging of the lumbar spine, including a repeat X-ray and contrast-enhanced magnetic resonance imaging (MRI), both of which were unremarkable. The patient completed the prescribed course of diclofenac, oxycodone/acetaminophen, and prednisone, but experienced only minimal pain relief.The orthopedist prescribed the diclofenac to supplement the medication regimen that he was already on.
At the second follow-up visit, the orthopedist ordered an MRI of the patient’s left hip, which demonstrated inflammation of the left sacroiliac joint (SIJ) with effusion, and a 1-cm by 1-cm collection adjacent to the left psoas muscle; these findings were concerning for septic arthritis (Figure). Based on the MRI study, a computed tomography (CT)-guided arthrocentesis of the left SIJ was performed by an interventional radiologist.
Figure Following the arthrocentesis, the orthopedist referred the patient to the ED. At this presentation,the emergency physician (EP) ordered blood cultures, blood work, urinalysis, and a urinary toxicology screen, and started the patient on IV ceftriaxone and vancomycin. The laboratory studies were significant for the following elevated inflammatory markers: erythrocyte sedimentation rate (ESR), 19 mm/h; C-reactive protein (CRP), 2.45 mg/L; white blood cell count (WBC), 13.6 K/uL with normal differential; and lactate level, 2.6 mg/dL. The toxicology screen was positive for opioids. The basic metabolic panel, chest X-ray, and urinalysis were all unremarkable. An electrocardiogram showed sinus tachycardia.
The patient was admitted to the hospital, and infectious disease services was contacted. While awaiting transport to the inpatient floor, the patient admitted to IV drug use 4 weeks prior to his initial presentation—not the 6 months he initially reported at the first ED visit.
The blood cultures grew Candida parapsilosis, and culture from the SIJ arthrocentesis grew Pseudomonas aeruginosa. The infectious disease physician switched the patient’s antibiotic therapy to IV cefepime and fluconazole. The patient also was seen by an orthopedist, who determined that no surgical intervention was required.
Follow-up laboratory studies showed inflammatory markers peaking at the following levels: ESR, 36 mm/h; CRP, 4.84 mg/L; and WBC, 32.1 K/uL with 90% neutrophils. These markers normalized throughout his hospital stay. The patient was also tested for hepatitis and human immunodeficiency virus, both of which were negative. A transesophageal echocardiogram showed no obvious masses or vegetations.
The patient had an uncomplicated hospital course, and was discharged home on hospital day 6 with a 4-week prescription of oral fluconazole and levofloxacin, and instructed to follow-up with both infectious disease and the orthopedist. To address his history of IV drug use, he also was given follow-up with pain management.
One month later, the patient returned a fourth time to the ED for evaluation of bilateral lower extremity pain and swelling. He stated that he had been mostly bed-bound at home since his discharge from the hospital due to continued pain with weight-bearing.
The patient’s vital signs were normal. The EP ordered a duplex ultrasound study, which showed extensive bilateral lower extremity deep vein thrombosis. He was started on subcutaneous therapeutic enoxaparin and admitted to the inpatient hospital. During admission,a left lower lobe pulmonary artery embolism was found on chest CT angiography, though he had no cardiac or respiratory symptoms. He was discharged home with a 3-month prescription for oral rivaroxaban.
At a 4-month follow-up visit, the patient reported minimal residual disability after completing the course of treatment. During the follow-up, the patient denied using IV heroin; he was referred to a pain management specialist, who placed the patient on methadone.
Discussion
Infectious sacroiliitis (ISI) is a rare form of infectious arthritis affecting the SIJ, with an incidence of 1 to 2 reported cases per year.1 The literature on ISI currently consists only of case reports and case series. This infection is often diagnosed after the disease has progressed, with a mean time to diagnosis of 43.3 days.2
Infectious arthritis of any joint has a prevalence of 2 to 10 per 100,000 people. In 50% of cases, the knee is the joint most commonly affected, followed by the hip, shoulder, and elbow.3 Regardless of location, infectious arthritis is associated with significant morbidity and mortality due to sepsis and irreversible loss of joint function.4
Risk factors for ISI include IV drug use, pregnancy, trauma, endocarditis, and immunosuppression.1 The decision to initiate the workup for ISI can be difficult to make because the condition may present without signs of an infectious etiology, such as toxic appearance, inflammatory changes surrounding the joint, or even fever—only 41% of affected patients in one case series were febrile.2 The workup is often time-consuming, invasive, and expensive.
Although delayed diagnosis and treatment of septic arthritis is associated with significant adverse effects, there is unfortunately no consensus to guide the workup for ISI. As opposed to Kocher’s criteria for the differentiation of septic hip arthritis from transient synovitis in pediatric patients or well-known red-flags for further evaluation of low back pain, physicians are left without much guidance when considering laboratory workup or imaging decisions to evaluate for ISI.
Sacroiliac Joint
As previously noted, the SIJ is not commonly affected by infection. It is a diarthrodial, L-shaped joint comprised of the posterior ilium and sacrum, and is a near-rigid structure with very limited movement that provides stability to the axial skeleton.5 The SIJ is often overlooked as a secondary cause of low back pain in younger patients with rheumatologic conditions (eg, ankylosing spondylitis, Reiter syndrome), pregnancy-associated ligamentous laxity, and osteoarthritis in elderly patients. In one study, 88.2% of sacroiliitis cases were inflammatory, 8.8% infectious, and 2.9% degenerative.6
Signs and Symptoms
As our case illustrates, ISI often presents with nonspecific symptoms and physical findings.7 Patients typically present with fever, painful manipulation of the SIJ, and unilateral lumbo-gluteal pain.2 The components of the history and physical examination suspicious for an infectious etiology include the subacute presentation; unresolved pain despite treatment; tenderness to palpation; decreased range of motion; and recent IV drug use, which increases the risk of infectious disease due to unsterile practices and direct inoculation of pathogens into the bloodstream8 and a further predilection into the axial skeleton. 9 It is important to obtain an accurate social history; however, patients may not be forthright about disclosing sensitive information such as sexual history and illicit drug use.
Physical Assessment
The SIJ is best appreciated in the seated patient by palpating one fingerbreadth medial to the posterior superior iliac spine as he or she slowly bends forward.10 Tenderness elicited while in this position is suggestive of SIJ inflammation. The area of tenderness may be lower than anticipated and lateral to the gluteal cleft, as synovial fluid is typically relegated to the lower half of the joint.
Several adjunctive physical examination maneuvers, such as the Gaenslen test and Flexion Abduction External Rotation test (FABER test or Patrick’s test) can isolate SIJ pathology or dysfunction. The Gaenslen test is performed by asking the patient to lie supine and flex the affected hip and knee, with the lumbar spine flat against the examination table. Hyperextending the contralateral thigh downward will reproduce pain in the affected SIJ.
The FABER test is a simple but less specific examination technique to assess joint pain in the hip, lumbar, and sacroiliac joints.11 In this assessment, the clinician flexes the patient’s affected knee to 90°, externally rotates the hip, and applies downward pressure on the knee. Pain reproduced in the affected SI region is sensitive for joint inflammation.
Laboratory and Imaging Studies
Laboratory studies typically show inconsistent and nonspecific findings, such as the elevated ESR and CRP levels seen in our patient.2,12 Imaging studies to assess the SIJ for signs of infection are therefore essential for confirming infection.
Magnetic resonance imaging is the preferred imaging modality to assess for ISI, since it has the highest sensitivity in visualizing joint effusion and bone marrow edema compared to other modalities. Computed tomography, however, can be helpful in visualizing associated abscesses and guiding arthrocentesis.12 Plain X-ray may not demonstrate early changes in bone.13 The confirmatory study for ISI is synovial fluid analysis and culture.7
Treatment
Infectious sacroiliitis secondary to P aeruginosa, a gram-negative bacillus, is difficult to treat because of the glycocalyx and slime production that protects the pathogen from antibiotics, the development of multiple-antimicrobial resistance, and poor drug penetration into bones and abscesses.14 Antibiotic treatment should cover Staphylococcus aureus and may be broadened to cover gram-negative bacilli. The recommended duration of treatment is at least a 2-week course of IV antibiotics, followed by a 6-week course of oral antibiotics.2 Therapy also includes pain control and surgical intervention for abscesses, osteomyelitis, and refractory cases.7
Complications
Complications and long-term sequelae are common in ISI, often due to late diagnosis of the condition.Our case illustrates the delayed diagnosis of Pseudomonas ISI with candidemia in a young man with a history of IV drug use presenting with atraumatic low back pain. His clinical course was complicated by a thromboembolic event, likely secondary to immobility and a hypercoagulable state from infection and inflammation.15 Infectious sacroiliitis secondary to P aeruginosa is most commonly seen in patients with immunosuppression, hospitalization, and IV drug use.2
Summary
Infectious sacroiliitis remains a diagnostic challenge for physicians due to its rare incidence and nonspecific clinical manifestations. Our case illustrates the importance of maintaining a high level of clinical suspicion for infectious arthritis in young patients presenting with common MSK complaints in the presence of infectious risk factors. Emergency physicians should consider red flags, abnormal vital signs, and patient recidivism when deciding on the most appropriate workup.
References
1. Mancarella L, De Santis M, Magarelli N, Ierardi AM, Bonomo L, Ferraccioli G. Septic sacroiliitis: an uncommon septic arthritis. Clin Exp Rheumatol. 2009;27(6):1004-1008. 2. Hermet M, Minichiello E, Flipo RM, et al. Infectious sacroiliitis: a retrospective, multicentre study of 39 adults. BMC Infect Dis. 2012;12:305.doi:10.1186/1471-2334-12-305. 3. Abelson A. Septic Arthritis. Cleveland Clinic. http://www.clevelandclinicmeded.com/medicalpubs/diseasemanagement/rheumatology/septic-arthritis. Published August 2010. Accessed October 28, 2016. 4. Goldenberg DL. Septic arthritis. Lancet. 1998;351(9097):197-202. doi:10.1016/S0140-6736(97)09522-6. 5. Vleeming A, Schuenke MD, Masi AT, Carreiro JE, Danneels L, Willard FH. The sacroiliac joint: an overview of its anatomy, function and potential clinical implications. J Anat. 2012;221(6):537-567. doi:10.1111/j.1469-7580.2012.01564.x. 6. Owlia MB, Danesh-Ardakani M. Frequency of sacroiliitis among patients with low back pain. Electron Physician. 2016;8(3):2094-2100. doi:10.19082/2094. 7. Zimmermann B 3rd, Mikolich DJ, Lally EV. Septic sacroiliitis. Semin Arthritis Rheum. 1996;26(3):592-604. 8. Brtalik D, Pariyadath M. A case report of infectious sacroiliitis in an adult presenting to the emergency department with inability to walk. J Emerg Med. 2017:52(3)e65-e68. doi:10.1016/j.jemermed.2016.10.022. 9. Ferraro K, Cohen MA. Acute septic sacroiliitis in an injection drug user. Am J Emerg Med. 2004;22(1):60-61. 10. Safran M, Botser IB. Hip anatomy and biomechanics. In: Miller MD, Thompson SR, eds. DeLee & Drez’s Orthopaedic Sports Medicine. Vol 2. 4th ed. Philadelphia, PA: Elsevier Saunders; 2015:917-932.e1. 11. LeBlond RF, Brown DD, Suneja M, Szot JF. The spine, pelvic, and extremities. In: LeBlond RF, Brown DD, Suneja M, Szot JF. eds. DeGowin’s Diagnostic Examination. 10th ed. New York, NY: McGraw-Hill; 2015:508-576. 12. Scott KR, Rising KL, Conlon LW. Infectious sacroiliitis. J Emerg Med. 2014;47(3):83-84. doi:10.1016/j.jemermed.2014.05.001. 13. Cinar M, Sanal HT, Yilmaz S, et al. Radiological followup of the evolution of inflammatory process in sacroiliac joint with magnetic resonance imaging: a case with pyogenic sacroiliitis. Case Rep Rheumatol. 2012;2012:509136. doi:10.1155/2012/509136. 14. Calza L, Manfredi R, Marinacci G, Fortunato L, Chiodo F. Community-acquired Pseudomonas aeruginosa sacro-iliitis in a previously healthy patient. J Med Microbiol. 2002;51(7):620-622. 15. Levi M, Keller TT, van Gorp E, ten Cate H. Infection and inflammation and the coagulation system. Cardiovasc Res. 2003;60(1):26-39.
A 29-year-old man presented for evaluation of unabating left-sided low back pain that radiated to his left buttock and groin.
A 29-year-old man presented for evaluation of unabating left-sided low back pain that radiated to his left buttock and groin.
Case
A 29-year-old man presented to the ED with a 3-day history of constant left-sided low back pain that radiated to his left buttock and groin. The patient stated the pain worsened with movement, making it difficult for him to walk. He reported lifting heavy boxes at work, but denied any trauma. The patient also denied recent fevers, chills, chest pain, dyspnea, abdominal pain, urinary or fecal incontinence, weakness, numbness, or saddle anesthesia. Regarding his medical history, he had an appendectomy as a child, but reported no other surgeries or medical issues. His social history was significant for narcotic and inhalant use and daily tobacco use. The patient also reported taking heroin intravenously (IV) 6 months prior.
Vital signs at presentation were: heart rate (HR), 92 beats/min; respiratory rate, 15 breaths/min; blood pressure, 118/80 mm Hg; and temperature, 98.2°F. Oxygen saturation was 98% on room air.
The patient was a well-developed young man in no apparent distress. Dermatological examination showed bilateral track marks in the antecubital fossa. The musculoskeletal (MSK) examination demonstrated left gluteal tenderness to palpation and decreased active and passive range of motion of the left hip, especially with internal rotation and flexion. He had no midline tenderness, and the lower extremities had normal pulses and no motor or sensory deficits.
The patient’s pain improved with IV fluids, diazepam, and ketorolac, and he was able to ambulate with assistance. He was clinically diagnosed with sciatica, and discharged home with prescriptions for diazepam and ibuprofen. He was also instructed to follow-up with an orthopedist within 7 days from discharge.
The patient returned to the ED the following day with similar complaints of unabating left-sided pain and difficulty ambulating. His vital signs were notable for an elevated HR of 106 beats/min. Physical examination findings were unchanged from his presentation the previous day, and an X-ray of the lumbar spine showed no abnormalities.
After receiving IV analgesics, the patient’s pain improved and his tachycardia resolved. He was discharged home with instructions to continue taking diazepam, and was also given prescriptions for prednisone and oxycodone/acetaminophen. He was instructed to follow-up with an orthopedist within 24 hours.
Over the next 9 days, the patient was seen twice by an orthopedist, who ordered imaging of the lumbar spine, including a repeat X-ray and contrast-enhanced magnetic resonance imaging (MRI), both of which were unremarkable. The patient completed the prescribed course of diclofenac, oxycodone/acetaminophen, and prednisone, but experienced only minimal pain relief.The orthopedist prescribed the diclofenac to supplement the medication regimen that he was already on.
At the second follow-up visit, the orthopedist ordered an MRI of the patient’s left hip, which demonstrated inflammation of the left sacroiliac joint (SIJ) with effusion, and a 1-cm by 1-cm collection adjacent to the left psoas muscle; these findings were concerning for septic arthritis (Figure). Based on the MRI study, a computed tomography (CT)-guided arthrocentesis of the left SIJ was performed by an interventional radiologist.
Figure Following the arthrocentesis, the orthopedist referred the patient to the ED. At this presentation,the emergency physician (EP) ordered blood cultures, blood work, urinalysis, and a urinary toxicology screen, and started the patient on IV ceftriaxone and vancomycin. The laboratory studies were significant for the following elevated inflammatory markers: erythrocyte sedimentation rate (ESR), 19 mm/h; C-reactive protein (CRP), 2.45 mg/L; white blood cell count (WBC), 13.6 K/uL with normal differential; and lactate level, 2.6 mg/dL. The toxicology screen was positive for opioids. The basic metabolic panel, chest X-ray, and urinalysis were all unremarkable. An electrocardiogram showed sinus tachycardia.
The patient was admitted to the hospital, and infectious disease services was contacted. While awaiting transport to the inpatient floor, the patient admitted to IV drug use 4 weeks prior to his initial presentation—not the 6 months he initially reported at the first ED visit.
The blood cultures grew Candida parapsilosis, and culture from the SIJ arthrocentesis grew Pseudomonas aeruginosa. The infectious disease physician switched the patient’s antibiotic therapy to IV cefepime and fluconazole. The patient also was seen by an orthopedist, who determined that no surgical intervention was required.
Follow-up laboratory studies showed inflammatory markers peaking at the following levels: ESR, 36 mm/h; CRP, 4.84 mg/L; and WBC, 32.1 K/uL with 90% neutrophils. These markers normalized throughout his hospital stay. The patient was also tested for hepatitis and human immunodeficiency virus, both of which were negative. A transesophageal echocardiogram showed no obvious masses or vegetations.
The patient had an uncomplicated hospital course, and was discharged home on hospital day 6 with a 4-week prescription of oral fluconazole and levofloxacin, and instructed to follow-up with both infectious disease and the orthopedist. To address his history of IV drug use, he also was given follow-up with pain management.
One month later, the patient returned a fourth time to the ED for evaluation of bilateral lower extremity pain and swelling. He stated that he had been mostly bed-bound at home since his discharge from the hospital due to continued pain with weight-bearing.
The patient’s vital signs were normal. The EP ordered a duplex ultrasound study, which showed extensive bilateral lower extremity deep vein thrombosis. He was started on subcutaneous therapeutic enoxaparin and admitted to the inpatient hospital. During admission,a left lower lobe pulmonary artery embolism was found on chest CT angiography, though he had no cardiac or respiratory symptoms. He was discharged home with a 3-month prescription for oral rivaroxaban.
At a 4-month follow-up visit, the patient reported minimal residual disability after completing the course of treatment. During the follow-up, the patient denied using IV heroin; he was referred to a pain management specialist, who placed the patient on methadone.
Discussion
Infectious sacroiliitis (ISI) is a rare form of infectious arthritis affecting the SIJ, with an incidence of 1 to 2 reported cases per year.1 The literature on ISI currently consists only of case reports and case series. This infection is often diagnosed after the disease has progressed, with a mean time to diagnosis of 43.3 days.2
Infectious arthritis of any joint has a prevalence of 2 to 10 per 100,000 people. In 50% of cases, the knee is the joint most commonly affected, followed by the hip, shoulder, and elbow.3 Regardless of location, infectious arthritis is associated with significant morbidity and mortality due to sepsis and irreversible loss of joint function.4
Risk factors for ISI include IV drug use, pregnancy, trauma, endocarditis, and immunosuppression.1 The decision to initiate the workup for ISI can be difficult to make because the condition may present without signs of an infectious etiology, such as toxic appearance, inflammatory changes surrounding the joint, or even fever—only 41% of affected patients in one case series were febrile.2 The workup is often time-consuming, invasive, and expensive.
Although delayed diagnosis and treatment of septic arthritis is associated with significant adverse effects, there is unfortunately no consensus to guide the workup for ISI. As opposed to Kocher’s criteria for the differentiation of septic hip arthritis from transient synovitis in pediatric patients or well-known red-flags for further evaluation of low back pain, physicians are left without much guidance when considering laboratory workup or imaging decisions to evaluate for ISI.
Sacroiliac Joint
As previously noted, the SIJ is not commonly affected by infection. It is a diarthrodial, L-shaped joint comprised of the posterior ilium and sacrum, and is a near-rigid structure with very limited movement that provides stability to the axial skeleton.5 The SIJ is often overlooked as a secondary cause of low back pain in younger patients with rheumatologic conditions (eg, ankylosing spondylitis, Reiter syndrome), pregnancy-associated ligamentous laxity, and osteoarthritis in elderly patients. In one study, 88.2% of sacroiliitis cases were inflammatory, 8.8% infectious, and 2.9% degenerative.6
Signs and Symptoms
As our case illustrates, ISI often presents with nonspecific symptoms and physical findings.7 Patients typically present with fever, painful manipulation of the SIJ, and unilateral lumbo-gluteal pain.2 The components of the history and physical examination suspicious for an infectious etiology include the subacute presentation; unresolved pain despite treatment; tenderness to palpation; decreased range of motion; and recent IV drug use, which increases the risk of infectious disease due to unsterile practices and direct inoculation of pathogens into the bloodstream8 and a further predilection into the axial skeleton. 9 It is important to obtain an accurate social history; however, patients may not be forthright about disclosing sensitive information such as sexual history and illicit drug use.
Physical Assessment
The SIJ is best appreciated in the seated patient by palpating one fingerbreadth medial to the posterior superior iliac spine as he or she slowly bends forward.10 Tenderness elicited while in this position is suggestive of SIJ inflammation. The area of tenderness may be lower than anticipated and lateral to the gluteal cleft, as synovial fluid is typically relegated to the lower half of the joint.
Several adjunctive physical examination maneuvers, such as the Gaenslen test and Flexion Abduction External Rotation test (FABER test or Patrick’s test) can isolate SIJ pathology or dysfunction. The Gaenslen test is performed by asking the patient to lie supine and flex the affected hip and knee, with the lumbar spine flat against the examination table. Hyperextending the contralateral thigh downward will reproduce pain in the affected SIJ.
The FABER test is a simple but less specific examination technique to assess joint pain in the hip, lumbar, and sacroiliac joints.11 In this assessment, the clinician flexes the patient’s affected knee to 90°, externally rotates the hip, and applies downward pressure on the knee. Pain reproduced in the affected SI region is sensitive for joint inflammation.
Laboratory and Imaging Studies
Laboratory studies typically show inconsistent and nonspecific findings, such as the elevated ESR and CRP levels seen in our patient.2,12 Imaging studies to assess the SIJ for signs of infection are therefore essential for confirming infection.
Magnetic resonance imaging is the preferred imaging modality to assess for ISI, since it has the highest sensitivity in visualizing joint effusion and bone marrow edema compared to other modalities. Computed tomography, however, can be helpful in visualizing associated abscesses and guiding arthrocentesis.12 Plain X-ray may not demonstrate early changes in bone.13 The confirmatory study for ISI is synovial fluid analysis and culture.7
Treatment
Infectious sacroiliitis secondary to P aeruginosa, a gram-negative bacillus, is difficult to treat because of the glycocalyx and slime production that protects the pathogen from antibiotics, the development of multiple-antimicrobial resistance, and poor drug penetration into bones and abscesses.14 Antibiotic treatment should cover Staphylococcus aureus and may be broadened to cover gram-negative bacilli. The recommended duration of treatment is at least a 2-week course of IV antibiotics, followed by a 6-week course of oral antibiotics.2 Therapy also includes pain control and surgical intervention for abscesses, osteomyelitis, and refractory cases.7
Complications
Complications and long-term sequelae are common in ISI, often due to late diagnosis of the condition.Our case illustrates the delayed diagnosis of Pseudomonas ISI with candidemia in a young man with a history of IV drug use presenting with atraumatic low back pain. His clinical course was complicated by a thromboembolic event, likely secondary to immobility and a hypercoagulable state from infection and inflammation.15 Infectious sacroiliitis secondary to P aeruginosa is most commonly seen in patients with immunosuppression, hospitalization, and IV drug use.2
Summary
Infectious sacroiliitis remains a diagnostic challenge for physicians due to its rare incidence and nonspecific clinical manifestations. Our case illustrates the importance of maintaining a high level of clinical suspicion for infectious arthritis in young patients presenting with common MSK complaints in the presence of infectious risk factors. Emergency physicians should consider red flags, abnormal vital signs, and patient recidivism when deciding on the most appropriate workup.
Case
A 29-year-old man presented to the ED with a 3-day history of constant left-sided low back pain that radiated to his left buttock and groin. The patient stated the pain worsened with movement, making it difficult for him to walk. He reported lifting heavy boxes at work, but denied any trauma. The patient also denied recent fevers, chills, chest pain, dyspnea, abdominal pain, urinary or fecal incontinence, weakness, numbness, or saddle anesthesia. Regarding his medical history, he had an appendectomy as a child, but reported no other surgeries or medical issues. His social history was significant for narcotic and inhalant use and daily tobacco use. The patient also reported taking heroin intravenously (IV) 6 months prior.
Vital signs at presentation were: heart rate (HR), 92 beats/min; respiratory rate, 15 breaths/min; blood pressure, 118/80 mm Hg; and temperature, 98.2°F. Oxygen saturation was 98% on room air.
The patient was a well-developed young man in no apparent distress. Dermatological examination showed bilateral track marks in the antecubital fossa. The musculoskeletal (MSK) examination demonstrated left gluteal tenderness to palpation and decreased active and passive range of motion of the left hip, especially with internal rotation and flexion. He had no midline tenderness, and the lower extremities had normal pulses and no motor or sensory deficits.
The patient’s pain improved with IV fluids, diazepam, and ketorolac, and he was able to ambulate with assistance. He was clinically diagnosed with sciatica, and discharged home with prescriptions for diazepam and ibuprofen. He was also instructed to follow-up with an orthopedist within 7 days from discharge.
The patient returned to the ED the following day with similar complaints of unabating left-sided pain and difficulty ambulating. His vital signs were notable for an elevated HR of 106 beats/min. Physical examination findings were unchanged from his presentation the previous day, and an X-ray of the lumbar spine showed no abnormalities.
After receiving IV analgesics, the patient’s pain improved and his tachycardia resolved. He was discharged home with instructions to continue taking diazepam, and was also given prescriptions for prednisone and oxycodone/acetaminophen. He was instructed to follow-up with an orthopedist within 24 hours.
Over the next 9 days, the patient was seen twice by an orthopedist, who ordered imaging of the lumbar spine, including a repeat X-ray and contrast-enhanced magnetic resonance imaging (MRI), both of which were unremarkable. The patient completed the prescribed course of diclofenac, oxycodone/acetaminophen, and prednisone, but experienced only minimal pain relief.The orthopedist prescribed the diclofenac to supplement the medication regimen that he was already on.
At the second follow-up visit, the orthopedist ordered an MRI of the patient’s left hip, which demonstrated inflammation of the left sacroiliac joint (SIJ) with effusion, and a 1-cm by 1-cm collection adjacent to the left psoas muscle; these findings were concerning for septic arthritis (Figure). Based on the MRI study, a computed tomography (CT)-guided arthrocentesis of the left SIJ was performed by an interventional radiologist.
Figure Following the arthrocentesis, the orthopedist referred the patient to the ED. At this presentation,the emergency physician (EP) ordered blood cultures, blood work, urinalysis, and a urinary toxicology screen, and started the patient on IV ceftriaxone and vancomycin. The laboratory studies were significant for the following elevated inflammatory markers: erythrocyte sedimentation rate (ESR), 19 mm/h; C-reactive protein (CRP), 2.45 mg/L; white blood cell count (WBC), 13.6 K/uL with normal differential; and lactate level, 2.6 mg/dL. The toxicology screen was positive for opioids. The basic metabolic panel, chest X-ray, and urinalysis were all unremarkable. An electrocardiogram showed sinus tachycardia.
The patient was admitted to the hospital, and infectious disease services was contacted. While awaiting transport to the inpatient floor, the patient admitted to IV drug use 4 weeks prior to his initial presentation—not the 6 months he initially reported at the first ED visit.
The blood cultures grew Candida parapsilosis, and culture from the SIJ arthrocentesis grew Pseudomonas aeruginosa. The infectious disease physician switched the patient’s antibiotic therapy to IV cefepime and fluconazole. The patient also was seen by an orthopedist, who determined that no surgical intervention was required.
Follow-up laboratory studies showed inflammatory markers peaking at the following levels: ESR, 36 mm/h; CRP, 4.84 mg/L; and WBC, 32.1 K/uL with 90% neutrophils. These markers normalized throughout his hospital stay. The patient was also tested for hepatitis and human immunodeficiency virus, both of which were negative. A transesophageal echocardiogram showed no obvious masses or vegetations.
The patient had an uncomplicated hospital course, and was discharged home on hospital day 6 with a 4-week prescription of oral fluconazole and levofloxacin, and instructed to follow-up with both infectious disease and the orthopedist. To address his history of IV drug use, he also was given follow-up with pain management.
One month later, the patient returned a fourth time to the ED for evaluation of bilateral lower extremity pain and swelling. He stated that he had been mostly bed-bound at home since his discharge from the hospital due to continued pain with weight-bearing.
The patient’s vital signs were normal. The EP ordered a duplex ultrasound study, which showed extensive bilateral lower extremity deep vein thrombosis. He was started on subcutaneous therapeutic enoxaparin and admitted to the inpatient hospital. During admission,a left lower lobe pulmonary artery embolism was found on chest CT angiography, though he had no cardiac or respiratory symptoms. He was discharged home with a 3-month prescription for oral rivaroxaban.
At a 4-month follow-up visit, the patient reported minimal residual disability after completing the course of treatment. During the follow-up, the patient denied using IV heroin; he was referred to a pain management specialist, who placed the patient on methadone.
Discussion
Infectious sacroiliitis (ISI) is a rare form of infectious arthritis affecting the SIJ, with an incidence of 1 to 2 reported cases per year.1 The literature on ISI currently consists only of case reports and case series. This infection is often diagnosed after the disease has progressed, with a mean time to diagnosis of 43.3 days.2
Infectious arthritis of any joint has a prevalence of 2 to 10 per 100,000 people. In 50% of cases, the knee is the joint most commonly affected, followed by the hip, shoulder, and elbow.3 Regardless of location, infectious arthritis is associated with significant morbidity and mortality due to sepsis and irreversible loss of joint function.4
Risk factors for ISI include IV drug use, pregnancy, trauma, endocarditis, and immunosuppression.1 The decision to initiate the workup for ISI can be difficult to make because the condition may present without signs of an infectious etiology, such as toxic appearance, inflammatory changes surrounding the joint, or even fever—only 41% of affected patients in one case series were febrile.2 The workup is often time-consuming, invasive, and expensive.
Although delayed diagnosis and treatment of septic arthritis is associated with significant adverse effects, there is unfortunately no consensus to guide the workup for ISI. As opposed to Kocher’s criteria for the differentiation of septic hip arthritis from transient synovitis in pediatric patients or well-known red-flags for further evaluation of low back pain, physicians are left without much guidance when considering laboratory workup or imaging decisions to evaluate for ISI.
Sacroiliac Joint
As previously noted, the SIJ is not commonly affected by infection. It is a diarthrodial, L-shaped joint comprised of the posterior ilium and sacrum, and is a near-rigid structure with very limited movement that provides stability to the axial skeleton.5 The SIJ is often overlooked as a secondary cause of low back pain in younger patients with rheumatologic conditions (eg, ankylosing spondylitis, Reiter syndrome), pregnancy-associated ligamentous laxity, and osteoarthritis in elderly patients. In one study, 88.2% of sacroiliitis cases were inflammatory, 8.8% infectious, and 2.9% degenerative.6
Signs and Symptoms
As our case illustrates, ISI often presents with nonspecific symptoms and physical findings.7 Patients typically present with fever, painful manipulation of the SIJ, and unilateral lumbo-gluteal pain.2 The components of the history and physical examination suspicious for an infectious etiology include the subacute presentation; unresolved pain despite treatment; tenderness to palpation; decreased range of motion; and recent IV drug use, which increases the risk of infectious disease due to unsterile practices and direct inoculation of pathogens into the bloodstream8 and a further predilection into the axial skeleton. 9 It is important to obtain an accurate social history; however, patients may not be forthright about disclosing sensitive information such as sexual history and illicit drug use.
Physical Assessment
The SIJ is best appreciated in the seated patient by palpating one fingerbreadth medial to the posterior superior iliac spine as he or she slowly bends forward.10 Tenderness elicited while in this position is suggestive of SIJ inflammation. The area of tenderness may be lower than anticipated and lateral to the gluteal cleft, as synovial fluid is typically relegated to the lower half of the joint.
Several adjunctive physical examination maneuvers, such as the Gaenslen test and Flexion Abduction External Rotation test (FABER test or Patrick’s test) can isolate SIJ pathology or dysfunction. The Gaenslen test is performed by asking the patient to lie supine and flex the affected hip and knee, with the lumbar spine flat against the examination table. Hyperextending the contralateral thigh downward will reproduce pain in the affected SIJ.
The FABER test is a simple but less specific examination technique to assess joint pain in the hip, lumbar, and sacroiliac joints.11 In this assessment, the clinician flexes the patient’s affected knee to 90°, externally rotates the hip, and applies downward pressure on the knee. Pain reproduced in the affected SI region is sensitive for joint inflammation.
Laboratory and Imaging Studies
Laboratory studies typically show inconsistent and nonspecific findings, such as the elevated ESR and CRP levels seen in our patient.2,12 Imaging studies to assess the SIJ for signs of infection are therefore essential for confirming infection.
Magnetic resonance imaging is the preferred imaging modality to assess for ISI, since it has the highest sensitivity in visualizing joint effusion and bone marrow edema compared to other modalities. Computed tomography, however, can be helpful in visualizing associated abscesses and guiding arthrocentesis.12 Plain X-ray may not demonstrate early changes in bone.13 The confirmatory study for ISI is synovial fluid analysis and culture.7
Treatment
Infectious sacroiliitis secondary to P aeruginosa, a gram-negative bacillus, is difficult to treat because of the glycocalyx and slime production that protects the pathogen from antibiotics, the development of multiple-antimicrobial resistance, and poor drug penetration into bones and abscesses.14 Antibiotic treatment should cover Staphylococcus aureus and may be broadened to cover gram-negative bacilli. The recommended duration of treatment is at least a 2-week course of IV antibiotics, followed by a 6-week course of oral antibiotics.2 Therapy also includes pain control and surgical intervention for abscesses, osteomyelitis, and refractory cases.7
Complications
Complications and long-term sequelae are common in ISI, often due to late diagnosis of the condition.Our case illustrates the delayed diagnosis of Pseudomonas ISI with candidemia in a young man with a history of IV drug use presenting with atraumatic low back pain. His clinical course was complicated by a thromboembolic event, likely secondary to immobility and a hypercoagulable state from infection and inflammation.15 Infectious sacroiliitis secondary to P aeruginosa is most commonly seen in patients with immunosuppression, hospitalization, and IV drug use.2
Summary
Infectious sacroiliitis remains a diagnostic challenge for physicians due to its rare incidence and nonspecific clinical manifestations. Our case illustrates the importance of maintaining a high level of clinical suspicion for infectious arthritis in young patients presenting with common MSK complaints in the presence of infectious risk factors. Emergency physicians should consider red flags, abnormal vital signs, and patient recidivism when deciding on the most appropriate workup.
References
1. Mancarella L, De Santis M, Magarelli N, Ierardi AM, Bonomo L, Ferraccioli G. Septic sacroiliitis: an uncommon septic arthritis. Clin Exp Rheumatol. 2009;27(6):1004-1008. 2. Hermet M, Minichiello E, Flipo RM, et al. Infectious sacroiliitis: a retrospective, multicentre study of 39 adults. BMC Infect Dis. 2012;12:305.doi:10.1186/1471-2334-12-305. 3. Abelson A. Septic Arthritis. Cleveland Clinic. http://www.clevelandclinicmeded.com/medicalpubs/diseasemanagement/rheumatology/septic-arthritis. Published August 2010. Accessed October 28, 2016. 4. Goldenberg DL. Septic arthritis. Lancet. 1998;351(9097):197-202. doi:10.1016/S0140-6736(97)09522-6. 5. Vleeming A, Schuenke MD, Masi AT, Carreiro JE, Danneels L, Willard FH. The sacroiliac joint: an overview of its anatomy, function and potential clinical implications. J Anat. 2012;221(6):537-567. doi:10.1111/j.1469-7580.2012.01564.x. 6. Owlia MB, Danesh-Ardakani M. Frequency of sacroiliitis among patients with low back pain. Electron Physician. 2016;8(3):2094-2100. doi:10.19082/2094. 7. Zimmermann B 3rd, Mikolich DJ, Lally EV. Septic sacroiliitis. Semin Arthritis Rheum. 1996;26(3):592-604. 8. Brtalik D, Pariyadath M. A case report of infectious sacroiliitis in an adult presenting to the emergency department with inability to walk. J Emerg Med. 2017:52(3)e65-e68. doi:10.1016/j.jemermed.2016.10.022. 9. Ferraro K, Cohen MA. Acute septic sacroiliitis in an injection drug user. Am J Emerg Med. 2004;22(1):60-61. 10. Safran M, Botser IB. Hip anatomy and biomechanics. In: Miller MD, Thompson SR, eds. DeLee & Drez’s Orthopaedic Sports Medicine. Vol 2. 4th ed. Philadelphia, PA: Elsevier Saunders; 2015:917-932.e1. 11. LeBlond RF, Brown DD, Suneja M, Szot JF. The spine, pelvic, and extremities. In: LeBlond RF, Brown DD, Suneja M, Szot JF. eds. DeGowin’s Diagnostic Examination. 10th ed. New York, NY: McGraw-Hill; 2015:508-576. 12. Scott KR, Rising KL, Conlon LW. Infectious sacroiliitis. J Emerg Med. 2014;47(3):83-84. doi:10.1016/j.jemermed.2014.05.001. 13. Cinar M, Sanal HT, Yilmaz S, et al. Radiological followup of the evolution of inflammatory process in sacroiliac joint with magnetic resonance imaging: a case with pyogenic sacroiliitis. Case Rep Rheumatol. 2012;2012:509136. doi:10.1155/2012/509136. 14. Calza L, Manfredi R, Marinacci G, Fortunato L, Chiodo F. Community-acquired Pseudomonas aeruginosa sacro-iliitis in a previously healthy patient. J Med Microbiol. 2002;51(7):620-622. 15. Levi M, Keller TT, van Gorp E, ten Cate H. Infection and inflammation and the coagulation system. Cardiovasc Res. 2003;60(1):26-39.
References
1. Mancarella L, De Santis M, Magarelli N, Ierardi AM, Bonomo L, Ferraccioli G. Septic sacroiliitis: an uncommon septic arthritis. Clin Exp Rheumatol. 2009;27(6):1004-1008. 2. Hermet M, Minichiello E, Flipo RM, et al. Infectious sacroiliitis: a retrospective, multicentre study of 39 adults. BMC Infect Dis. 2012;12:305.doi:10.1186/1471-2334-12-305. 3. Abelson A. Septic Arthritis. Cleveland Clinic. http://www.clevelandclinicmeded.com/medicalpubs/diseasemanagement/rheumatology/septic-arthritis. Published August 2010. Accessed October 28, 2016. 4. Goldenberg DL. Septic arthritis. Lancet. 1998;351(9097):197-202. doi:10.1016/S0140-6736(97)09522-6. 5. Vleeming A, Schuenke MD, Masi AT, Carreiro JE, Danneels L, Willard FH. The sacroiliac joint: an overview of its anatomy, function and potential clinical implications. J Anat. 2012;221(6):537-567. doi:10.1111/j.1469-7580.2012.01564.x. 6. Owlia MB, Danesh-Ardakani M. Frequency of sacroiliitis among patients with low back pain. Electron Physician. 2016;8(3):2094-2100. doi:10.19082/2094. 7. Zimmermann B 3rd, Mikolich DJ, Lally EV. Septic sacroiliitis. Semin Arthritis Rheum. 1996;26(3):592-604. 8. Brtalik D, Pariyadath M. A case report of infectious sacroiliitis in an adult presenting to the emergency department with inability to walk. J Emerg Med. 2017:52(3)e65-e68. doi:10.1016/j.jemermed.2016.10.022. 9. Ferraro K, Cohen MA. Acute septic sacroiliitis in an injection drug user. Am J Emerg Med. 2004;22(1):60-61. 10. Safran M, Botser IB. Hip anatomy and biomechanics. In: Miller MD, Thompson SR, eds. DeLee & Drez’s Orthopaedic Sports Medicine. Vol 2. 4th ed. Philadelphia, PA: Elsevier Saunders; 2015:917-932.e1. 11. LeBlond RF, Brown DD, Suneja M, Szot JF. The spine, pelvic, and extremities. In: LeBlond RF, Brown DD, Suneja M, Szot JF. eds. DeGowin’s Diagnostic Examination. 10th ed. New York, NY: McGraw-Hill; 2015:508-576. 12. Scott KR, Rising KL, Conlon LW. Infectious sacroiliitis. J Emerg Med. 2014;47(3):83-84. doi:10.1016/j.jemermed.2014.05.001. 13. Cinar M, Sanal HT, Yilmaz S, et al. Radiological followup of the evolution of inflammatory process in sacroiliac joint with magnetic resonance imaging: a case with pyogenic sacroiliitis. Case Rep Rheumatol. 2012;2012:509136. doi:10.1155/2012/509136. 14. Calza L, Manfredi R, Marinacci G, Fortunato L, Chiodo F. Community-acquired Pseudomonas aeruginosa sacro-iliitis in a previously healthy patient. J Med Microbiol. 2002;51(7):620-622. 15. Levi M, Keller TT, van Gorp E, ten Cate H. Infection and inflammation and the coagulation system. Cardiovasc Res. 2003;60(1):26-39.
A 20-year-old woman with no significant medical history presented to the ED with a several-month history of worsening abdominal pain. She reported that although she previously had been evaluated at multiple EDs, no cause of her abdominal pain had been identified. The patient further noted that the pain had significantly increased the day of this presentation.
Figure 1
Physical examination revealed guarding and rebound tenderness in the midabdomen. Computed tomography (CT) studies of the abdomen and pelvis were performed; representative scout and axial images of the upper abdomen are shown above (Figures 1 and 2).
Figure 2
What is the suspected diagnosis?
Answer
The scout image of the abdomen revealed a distended stomach (white arrows, Figure 3), which displaced multiple loops of small bowel into the lower abdomen. The axial image through the upper abdomen showed air and solid material within the distended stomach (white arrows, Figure 4). Multiple foci of extraluminal (free) air were seen anteriorly (white asterisks, Figure 4). A coronal reformat of the CT better demonstrated the distended stomach filled with debris (white arrows, Figure 5), extraluminal air (white asterisk, Figure 5), and pneumatosis (air within the walls of multiple small bowel loops; red arrows, Figure 5).
These findings indicated a bowel obstruction and perforation due to the presence of a gastric bezoar. Upon further questioning, the patient admitted to a stress-related habit of eating her own hair (trichophagia) over the past 3 to 4 months.
Figure 3
Bezoars
Gastric bezoars are aggregates of nondigestible material that collect within the gastrointestinal system, usually fruit/vegetable matter (phytobezoars) or hair (trichobezoars). Phytobezoars are most common in patients with a history of reduced gastric motility and/or prior gastric surgery. Trichobezoars, similar to the one seen in this case, typically occur in young women and/or patients with psychiatric illness.1
Gastric bezoars are typically located in the gastric body but may extend into the small bowel and cause bowel obstruction. Trichobezoars that extend into the small bowel are referred to as “Rapunzel syndrome” (based on the fairy tale of the princess with long hair).
Figure 4
Clinical Presentation
Patients with gastric bezoars often present to the ED with nonspecific complaints of abdominal pain, including early satiety, weight loss, signs of anemia, abdominal pain, bloating, and symptoms of small bowel obstruction (SBO).2 Obtaining a thorough history is important to identify trichophagia, as only a small percentage of patients have evidence of alopecia on examination.
Figure 5
Workup
The workup for patients with gastric bezoars typically involves multiple imaging modalities. While abdominal radiography may demonstrate distention of the stomach, these findings are often nonspecific, and the characteristic feature of a mass with a diffusely mottled appearance is visualized in less than 20% of cases.
Computed tomography is the test of choice for detecting a bezoar, with a reported sensitivity of 97%.3 This modality is also useful for assessing the size of a bezoar and evaluating for complications such as SBO, perforation (free-air), or pneumatosis—all of which were revealed on this patient’s CT studies.
Treatment
The treatment for patients with large or obstructing gastric bezoars is surgical resection; both open and laparoscopic techniques have been described in the literature.2,4 The patient in this case was admitted to the hospital, where she underwent surgical removal of the bezoar. She was discharged home on hospital day 6 with outpatient psychiatric follow-up.
References
1. Guniganti P, Bradenham CH, Raptis C, Menias CO, Mellnick VM. Radiographics. 2015;35(7):1909-1921. doi:10.1148/rg.2015150062. 2. Fallon SC, Slater BJ, Larimer EL, Brandt ML, Lopez ME. The surgical management of Rapunzel syndrome: a case series and literature review. J Pediatr Surg. 2013;48(4):830-834. doi:10.1016/j.jpedsurg.2012.07.046. 3. Ripollés T, García-Aguayo J, Martínez MJ, Gil P. Gastrointestinal Bezoars: Sonographic and CT Characteristics. AJR Am J Roentgenol. 2001;177(1):65-69. doi:10.2214/ajr.177.1.1770065. 4. Flaherty DC, Aguilar F, Pradhan B, Grewal H. Rapunzel syndrome due to ingested hair extensions: Surgical and psychiatric considerations. Int J Surg Case Rep. 2015;17:155-157. doi:10.1016/j.ijscr.2015.11.009.
An otherwise healthy 20-year-old woman presented for evaluation of severe chronic abdominal pain.
An otherwise healthy 20-year-old woman presented for evaluation of severe chronic abdominal pain.
A 20-year-old woman with no significant medical history presented to the ED with a several-month history of worsening abdominal pain. She reported that although she previously had been evaluated at multiple EDs, no cause of her abdominal pain had been identified. The patient further noted that the pain had significantly increased the day of this presentation.
Figure 1
Physical examination revealed guarding and rebound tenderness in the midabdomen. Computed tomography (CT) studies of the abdomen and pelvis were performed; representative scout and axial images of the upper abdomen are shown above (Figures 1 and 2).
Figure 2
What is the suspected diagnosis?
Answer
The scout image of the abdomen revealed a distended stomach (white arrows, Figure 3), which displaced multiple loops of small bowel into the lower abdomen. The axial image through the upper abdomen showed air and solid material within the distended stomach (white arrows, Figure 4). Multiple foci of extraluminal (free) air were seen anteriorly (white asterisks, Figure 4). A coronal reformat of the CT better demonstrated the distended stomach filled with debris (white arrows, Figure 5), extraluminal air (white asterisk, Figure 5), and pneumatosis (air within the walls of multiple small bowel loops; red arrows, Figure 5).
These findings indicated a bowel obstruction and perforation due to the presence of a gastric bezoar. Upon further questioning, the patient admitted to a stress-related habit of eating her own hair (trichophagia) over the past 3 to 4 months.
Figure 3
Bezoars
Gastric bezoars are aggregates of nondigestible material that collect within the gastrointestinal system, usually fruit/vegetable matter (phytobezoars) or hair (trichobezoars). Phytobezoars are most common in patients with a history of reduced gastric motility and/or prior gastric surgery. Trichobezoars, similar to the one seen in this case, typically occur in young women and/or patients with psychiatric illness.1
Gastric bezoars are typically located in the gastric body but may extend into the small bowel and cause bowel obstruction. Trichobezoars that extend into the small bowel are referred to as “Rapunzel syndrome” (based on the fairy tale of the princess with long hair).
Figure 4
Clinical Presentation
Patients with gastric bezoars often present to the ED with nonspecific complaints of abdominal pain, including early satiety, weight loss, signs of anemia, abdominal pain, bloating, and symptoms of small bowel obstruction (SBO).2 Obtaining a thorough history is important to identify trichophagia, as only a small percentage of patients have evidence of alopecia on examination.
Figure 5
Workup
The workup for patients with gastric bezoars typically involves multiple imaging modalities. While abdominal radiography may demonstrate distention of the stomach, these findings are often nonspecific, and the characteristic feature of a mass with a diffusely mottled appearance is visualized in less than 20% of cases.
Computed tomography is the test of choice for detecting a bezoar, with a reported sensitivity of 97%.3 This modality is also useful for assessing the size of a bezoar and evaluating for complications such as SBO, perforation (free-air), or pneumatosis—all of which were revealed on this patient’s CT studies.
Treatment
The treatment for patients with large or obstructing gastric bezoars is surgical resection; both open and laparoscopic techniques have been described in the literature.2,4 The patient in this case was admitted to the hospital, where she underwent surgical removal of the bezoar. She was discharged home on hospital day 6 with outpatient psychiatric follow-up.
A 20-year-old woman with no significant medical history presented to the ED with a several-month history of worsening abdominal pain. She reported that although she previously had been evaluated at multiple EDs, no cause of her abdominal pain had been identified. The patient further noted that the pain had significantly increased the day of this presentation.
Figure 1
Physical examination revealed guarding and rebound tenderness in the midabdomen. Computed tomography (CT) studies of the abdomen and pelvis were performed; representative scout and axial images of the upper abdomen are shown above (Figures 1 and 2).
Figure 2
What is the suspected diagnosis?
Answer
The scout image of the abdomen revealed a distended stomach (white arrows, Figure 3), which displaced multiple loops of small bowel into the lower abdomen. The axial image through the upper abdomen showed air and solid material within the distended stomach (white arrows, Figure 4). Multiple foci of extraluminal (free) air were seen anteriorly (white asterisks, Figure 4). A coronal reformat of the CT better demonstrated the distended stomach filled with debris (white arrows, Figure 5), extraluminal air (white asterisk, Figure 5), and pneumatosis (air within the walls of multiple small bowel loops; red arrows, Figure 5).
These findings indicated a bowel obstruction and perforation due to the presence of a gastric bezoar. Upon further questioning, the patient admitted to a stress-related habit of eating her own hair (trichophagia) over the past 3 to 4 months.
Figure 3
Bezoars
Gastric bezoars are aggregates of nondigestible material that collect within the gastrointestinal system, usually fruit/vegetable matter (phytobezoars) or hair (trichobezoars). Phytobezoars are most common in patients with a history of reduced gastric motility and/or prior gastric surgery. Trichobezoars, similar to the one seen in this case, typically occur in young women and/or patients with psychiatric illness.1
Gastric bezoars are typically located in the gastric body but may extend into the small bowel and cause bowel obstruction. Trichobezoars that extend into the small bowel are referred to as “Rapunzel syndrome” (based on the fairy tale of the princess with long hair).
Figure 4
Clinical Presentation
Patients with gastric bezoars often present to the ED with nonspecific complaints of abdominal pain, including early satiety, weight loss, signs of anemia, abdominal pain, bloating, and symptoms of small bowel obstruction (SBO).2 Obtaining a thorough history is important to identify trichophagia, as only a small percentage of patients have evidence of alopecia on examination.
Figure 5
Workup
The workup for patients with gastric bezoars typically involves multiple imaging modalities. While abdominal radiography may demonstrate distention of the stomach, these findings are often nonspecific, and the characteristic feature of a mass with a diffusely mottled appearance is visualized in less than 20% of cases.
Computed tomography is the test of choice for detecting a bezoar, with a reported sensitivity of 97%.3 This modality is also useful for assessing the size of a bezoar and evaluating for complications such as SBO, perforation (free-air), or pneumatosis—all of which were revealed on this patient’s CT studies.
Treatment
The treatment for patients with large or obstructing gastric bezoars is surgical resection; both open and laparoscopic techniques have been described in the literature.2,4 The patient in this case was admitted to the hospital, where she underwent surgical removal of the bezoar. She was discharged home on hospital day 6 with outpatient psychiatric follow-up.
References
1. Guniganti P, Bradenham CH, Raptis C, Menias CO, Mellnick VM. Radiographics. 2015;35(7):1909-1921. doi:10.1148/rg.2015150062. 2. Fallon SC, Slater BJ, Larimer EL, Brandt ML, Lopez ME. The surgical management of Rapunzel syndrome: a case series and literature review. J Pediatr Surg. 2013;48(4):830-834. doi:10.1016/j.jpedsurg.2012.07.046. 3. Ripollés T, García-Aguayo J, Martínez MJ, Gil P. Gastrointestinal Bezoars: Sonographic and CT Characteristics. AJR Am J Roentgenol. 2001;177(1):65-69. doi:10.2214/ajr.177.1.1770065. 4. Flaherty DC, Aguilar F, Pradhan B, Grewal H. Rapunzel syndrome due to ingested hair extensions: Surgical and psychiatric considerations. Int J Surg Case Rep. 2015;17:155-157. doi:10.1016/j.ijscr.2015.11.009.
References
1. Guniganti P, Bradenham CH, Raptis C, Menias CO, Mellnick VM. Radiographics. 2015;35(7):1909-1921. doi:10.1148/rg.2015150062. 2. Fallon SC, Slater BJ, Larimer EL, Brandt ML, Lopez ME. The surgical management of Rapunzel syndrome: a case series and literature review. J Pediatr Surg. 2013;48(4):830-834. doi:10.1016/j.jpedsurg.2012.07.046. 3. Ripollés T, García-Aguayo J, Martínez MJ, Gil P. Gastrointestinal Bezoars: Sonographic and CT Characteristics. AJR Am J Roentgenol. 2001;177(1):65-69. doi:10.2214/ajr.177.1.1770065. 4. Flaherty DC, Aguilar F, Pradhan B, Grewal H. Rapunzel syndrome due to ingested hair extensions: Surgical and psychiatric considerations. Int J Surg Case Rep. 2015;17:155-157. doi:10.1016/j.ijscr.2015.11.009.
A 57-year-old African American woman was being treated at our clinicfor neurogenic urinary incontinence (UI). The UI, which occurred day and night, began 2 years earlier following a laminectomy of vertebrae C3 to C6 with spinal fusion of C3 to C7 for cervical spinal stenosis. The UI persisted despite physical therapy and trials of oxybutynin and imipramine.Since the surgery, the patient had also been experiencing chronic (debilitating) neuropathic pain in both legs, and the sensation of incomplete bladder emptying. She denied bowel incontinence or saddle anesthesia. Her prescription medications included hydrocodone-acetaminophen 7.5/325 mg every 6 hours as needed for pain and lisinopril 20 mg/d for essential hypertension. The patient’s body mass index (BMI) was 23.3.
A urine culture initially grew Klebsiella pneumoniae,whichwe successfully treated with ciprofloxacin.A urinalysis was unremarkable, and blood urea nitrogen and creatinine levels were within normal limits.
We started the patient on oral duloxetine30 mg/d for her neuropathic pain. The patient hadn’t undergone a urologic evaluation before starting duloxetine, so no urodynamic studies or measurements had been conducted. At that point, we sent the patient to a urologist for an evaluation.
At a follow-up visit with one of our clinic providers <3 months later, the patient reported that the duloxetine was providing her with some pain relief and that she was “waking up dry” in the mornings and having fewer UI symptoms throughout the day, as well as at night. The patient denied any adverse effects such as nausea, gastrointestinal upset, weight changes, xerostomia, fatigue, insomnia, headaches, or dizziness. Duloxetine was titrated up to 60 mg/d for better control of her neuropathic pain. At the next follow-up visit at our clinic 3 months later, her UI was 80% to 90% improved and she was able to stop her opioid pain medications.
DISCUSSION
UI is a significant problem in the United States and around the world. For women, the prevalence of UI ranges from 15% to 69%; among men, the prevalence is 5% to 24%.1-3 The economic burden of UI includes both medical and nonmedical (eg, pads, diapers, laundry, and dry cleaning) care. The total national cost was estimated at $66 billion in 2007: $49 billion for direct medical costs, $2 billion for direct nonmedical costs, and $15 billion for indirect costs.4 And those costs are expected to increase 25% by 2020, mainly because of the aging population.
Risk factors for UIother than gender include advancing age, obesity, non-Hispanic white race, depression, hypertension, type 2 diabetes mellitus, neurologic disease, and functional limitations/general poor health.5-7 Comorbid depression and BMI >30, as well as the presence and duration of diabetes, increase the odds for developing UI.7,8
Duloxetine has been shown to be effective for the treatment of stress and mixed urinary incontinence. This case suggests it may be useful for neurogenic urinary incontinence, as well.
Risk factors for women include hysterectomy,7 increasing parity, and delivery of at least one infant >9.5 pounds; the risk is the same for both vaginal and cesarean-section delivery.6 Specific risk factors for men include prostate cancer, prostate surgery, and prostate radiation.5
Significant, chronic comorbidities of UI include depression and chronic pain. While quality of life is negatively affected by UI alone, the coexistence of depression and UI produces an additive negative effect on quality of life.9
Types and treatment of UI
There are 5 types of UI: urge, stress, overflow, functional, and mixed.10
Urge incontinence is the leakage of urine following a sensation of sudden urgency to void.
Stress incontinence is urine leakage associated with increased intra-abdominal pressure such as with coughing or sneezing and is typically associated with weakened pelvic floor musculature.
Overflow incontinence is more common in men, and is typically caused by prostatic disease. The urethral outlet is obstructed leading to increased pressure within the bladder and subsequent leakage of urine.
Functional incontinence is caused by physical or cognitive impairment leading to a decreased ability to get to a bathroom quickly enough to void.
Mixed incontinence is when symptoms of stress and urgency incontinence are present.
There are 3 broad categoriesof treatment methods for urinary incontinence: behavioral, pharmacologic, and surgical. Behavioral interventions are subdivided into caregiver-dependent (prompted voiding, habit retraining, and timed voiding) and patient-directed (bladder training, pelvic floor muscle training, strategies for bladder control, education, and self-monitoring) techniques. Pharmacologic treatment typically consists of antimuscarinics (eg, oxybutynin, tolterodine, solifenacin) and tricyclic antidepressants (eg, imipramine).11 Injections of onabotulinumtoxinA into the detrusor muscle have also been shown to reduce the symptoms of urinary incontinence.12 Surgical options for treatment of UI include retro-pubic suspension, slings, and, in some instances, artificial urethral sphincters.13
A novel treatment for neurogenic UI?
Despite the many treatments available for UI, none comprehensively addresses UI and its common comorbidities.
The role of duloxetine.Normal micturition is regulated by the somatic nervous system and an autonomic reflex arc; the neurotransmitters serotonin and norepinephrine play an important role in the neural regulation of micturition and urinary continence. Duloxetine, alone or as an adjunctive treatment,is a potential novel therapy that treats 2 common comorbidities of UI—chronic pain and depression.
As a selective serotonin norepinephrine reuptake inhibitor (SNRI), duloxetine acts at the molecular level to block the reuptake of serotonin and norepinephrine from synaptic clefts. Specifically, the medication blocks the 5-hydroxytryptamine (5-HT) reuptake transporters, as well as the norepinephrine transporters, of pre-synaptic neurons.14 Thus, the concentrations of 5-HT and norepinephrineincrease in the synaptic cleft.
Functionally, the accumulation of norepinephrine inhibits micturition by relaxing the detrusor muscle and constricting the urethral smooth muscle. In addition, a higher concentration of 5-HT at the neuromuscular junction leads to constriction of the external urethral sphincter.
Duloxetine has been shown to be effective in the treatment of other types of UI, such as stress UI15 and mixed UI.16 Additionally, it was found to be effective when compared with placebo in women with overactive bladder syndrome17 and in women with multiple sclerosis and depression.18 However, we are not aware of any cases using duloxetine for the treatment of neurogenic UI.
THE TAKEAWAY
Duloxetine is a potential novel drug choice for the treatment of neurogenic UI. Its effects on serotonin and norepinephrine at the synaptic cleft and neuromuscular junction could provide relief for those who have not found relief from other therapies. Further research—particularly a prospective, randomized controlled trial—is needed to determine if duloxetine is, in fact, more than just a theoretical candidate to treat UI and, if so, the most effective dosing.
Offering duloxetine for the treatment of neurogenic urinary incontinence would potentially address coexisting conditions, such as pain or depression.
Offering duloxetine for the treatment of neurogenic UI would potentially address coexisting conditions—such as pain or depression—thus improving patient compliance and reducing health care spending. Before beginning therapy, urodynamic studies to identify the type of UI should be completed, or, at a minimum, post-void residual volume should be measured.
ACKNOWLEDGEMENTS The authors would like to thank Julie Hughbanks, MLS, Library Manager, Parkview Health Resource Library, for her assistance with the library searches used for this case report.
References
1. Markland AD, Richter HE, Fwu CW, et al. Prevalence and trends of urinary incontinence in adults in the United States, 2001 to 2008. J Urol. 2011;186:589-593.
2. Buckley BS, Lapitan MC; Epidemiology Committee of the Fourth International Consultation on Incontinence, Paris, 2008. Prevalence of urinary incontinence in men, women, and children—current evidence: findings of the Fourth International Consultation on Incontinence. Urology. 2010;76:265-270.
3. Gorina Y, Schappert S, Bercovitz A, et al. Prevalence of incontinence among older Americans. Vital Health Stat 3. 2014;1-33.
4. Coyne KS, Wein A, Nicholson S, et al. Economic burden of urgency urinary incontinence in the United States: a systematic review. J Manag Care Pharm. 2014;20:130-140.
5. Shamliyan TA, Wyman JF, Ping R, et al. Male urinary incontinence: prevalence, risk factors, and preventive interventions. Rev Urol. 2009;11:145-165.
6. Matthews CA, Whitehead WE, Townsend MK, et al. Risk factors for urinary, fecal, or dual incontinence in the Nurses’ Health Study. Obstet Gynecol. 2013;122:539-545.
7. Danforth KN, Townsend MK, Lifford K, et al. Risk factors for urinary incontinence among middle-aged women. Am J Obstet Gynecol. 2006;194:339-345.
8. Lifford KL, Curhan GC, Hu FB, et al. Type 2 diabetes mellitus and risk of developing urinary incontinence. J Am Geriatr Soc. 2005;53:1851-1857.
9. Avery JC, Stocks NP, Duggan P, et al. Identifying the quality of life effects of urinary incontinence with depression in an Australian population. BMC Urol. 2013;13:11.
12. Cox L, Cameron A. OnabotulinumtoxinA for the treatment of overactive bladder. Res Rep Urol. 2014;6:79-89.
13. Dmochowski RR, Blaivas JM, Gormley EA, et al. Update of AUA guideline on the surgical management of female stress urinary incontinence. J Urol. 2010;183:1906-1914.
15. Li J, Yang L, Pu C, et al. The role of duloxetine in stress urinary incontinence: a systematic review and meta-analysis. Int Urol Nephrol. 2013;45:679-686.
16. Bent AE, Gousse AE, Hendrix SL, et al. Duloxetine compared with placebo for the treatment of women with mixed urinary incontinence. Neurourol Urodyn. 2008;27:212-221.
17. Steers WD, Herschorn S, Kreder KJ, et al; Duloxetine OAB Study Group. Duloxetine compared with placebo for treating women with symptoms of overactive bladder. BJU Int. 2007;100:337-345.
18. Di Rezze S, Frasca V, Inghilleri M, et al. Duloxetine for the treatment of overactive bladder syndrome in multiple sclerosis: a pilot study. Clin Neuropharmacol. 2012;35:231-234.
Ark City Clinic, Arkansas City, Kans. (Dr. Keesling); University of Saint Francis, Fort Wayne, Ind. (Dr. Wilson); Fort Wayne Medical Education Program, Ind. (Dr. Wilkins) wilkins@fwmep.edu
The authors reported no potential conflict of interest relevant to this article.
Adapted from a poster presentation, Indiana Academy of Family Physicians 2015 Research Day, May 7, 2015, Indianapolis, Ind
Ark City Clinic, Arkansas City, Kans. (Dr. Keesling); University of Saint Francis, Fort Wayne, Ind. (Dr. Wilson); Fort Wayne Medical Education Program, Ind. (Dr. Wilkins) wilkins@fwmep.edu
The authors reported no potential conflict of interest relevant to this article.
Adapted from a poster presentation, Indiana Academy of Family Physicians 2015 Research Day, May 7, 2015, Indianapolis, Ind
Author and Disclosure Information
Ark City Clinic, Arkansas City, Kans. (Dr. Keesling); University of Saint Francis, Fort Wayne, Ind. (Dr. Wilson); Fort Wayne Medical Education Program, Ind. (Dr. Wilkins) wilkins@fwmep.edu
The authors reported no potential conflict of interest relevant to this article.
Adapted from a poster presentation, Indiana Academy of Family Physicians 2015 Research Day, May 7, 2015, Indianapolis, Ind
A 57-year-old African American woman was being treated at our clinicfor neurogenic urinary incontinence (UI). The UI, which occurred day and night, began 2 years earlier following a laminectomy of vertebrae C3 to C6 with spinal fusion of C3 to C7 for cervical spinal stenosis. The UI persisted despite physical therapy and trials of oxybutynin and imipramine.Since the surgery, the patient had also been experiencing chronic (debilitating) neuropathic pain in both legs, and the sensation of incomplete bladder emptying. She denied bowel incontinence or saddle anesthesia. Her prescription medications included hydrocodone-acetaminophen 7.5/325 mg every 6 hours as needed for pain and lisinopril 20 mg/d for essential hypertension. The patient’s body mass index (BMI) was 23.3.
A urine culture initially grew Klebsiella pneumoniae,whichwe successfully treated with ciprofloxacin.A urinalysis was unremarkable, and blood urea nitrogen and creatinine levels were within normal limits.
We started the patient on oral duloxetine30 mg/d for her neuropathic pain. The patient hadn’t undergone a urologic evaluation before starting duloxetine, so no urodynamic studies or measurements had been conducted. At that point, we sent the patient to a urologist for an evaluation.
At a follow-up visit with one of our clinic providers <3 months later, the patient reported that the duloxetine was providing her with some pain relief and that she was “waking up dry” in the mornings and having fewer UI symptoms throughout the day, as well as at night. The patient denied any adverse effects such as nausea, gastrointestinal upset, weight changes, xerostomia, fatigue, insomnia, headaches, or dizziness. Duloxetine was titrated up to 60 mg/d for better control of her neuropathic pain. At the next follow-up visit at our clinic 3 months later, her UI was 80% to 90% improved and she was able to stop her opioid pain medications.
DISCUSSION
UI is a significant problem in the United States and around the world. For women, the prevalence of UI ranges from 15% to 69%; among men, the prevalence is 5% to 24%.1-3 The economic burden of UI includes both medical and nonmedical (eg, pads, diapers, laundry, and dry cleaning) care. The total national cost was estimated at $66 billion in 2007: $49 billion for direct medical costs, $2 billion for direct nonmedical costs, and $15 billion for indirect costs.4 And those costs are expected to increase 25% by 2020, mainly because of the aging population.
Risk factors for UIother than gender include advancing age, obesity, non-Hispanic white race, depression, hypertension, type 2 diabetes mellitus, neurologic disease, and functional limitations/general poor health.5-7 Comorbid depression and BMI >30, as well as the presence and duration of diabetes, increase the odds for developing UI.7,8
Duloxetine has been shown to be effective for the treatment of stress and mixed urinary incontinence. This case suggests it may be useful for neurogenic urinary incontinence, as well.
Risk factors for women include hysterectomy,7 increasing parity, and delivery of at least one infant >9.5 pounds; the risk is the same for both vaginal and cesarean-section delivery.6 Specific risk factors for men include prostate cancer, prostate surgery, and prostate radiation.5
Significant, chronic comorbidities of UI include depression and chronic pain. While quality of life is negatively affected by UI alone, the coexistence of depression and UI produces an additive negative effect on quality of life.9
Types and treatment of UI
There are 5 types of UI: urge, stress, overflow, functional, and mixed.10
Urge incontinence is the leakage of urine following a sensation of sudden urgency to void.
Stress incontinence is urine leakage associated with increased intra-abdominal pressure such as with coughing or sneezing and is typically associated with weakened pelvic floor musculature.
Overflow incontinence is more common in men, and is typically caused by prostatic disease. The urethral outlet is obstructed leading to increased pressure within the bladder and subsequent leakage of urine.
Functional incontinence is caused by physical or cognitive impairment leading to a decreased ability to get to a bathroom quickly enough to void.
Mixed incontinence is when symptoms of stress and urgency incontinence are present.
There are 3 broad categoriesof treatment methods for urinary incontinence: behavioral, pharmacologic, and surgical. Behavioral interventions are subdivided into caregiver-dependent (prompted voiding, habit retraining, and timed voiding) and patient-directed (bladder training, pelvic floor muscle training, strategies for bladder control, education, and self-monitoring) techniques. Pharmacologic treatment typically consists of antimuscarinics (eg, oxybutynin, tolterodine, solifenacin) and tricyclic antidepressants (eg, imipramine).11 Injections of onabotulinumtoxinA into the detrusor muscle have also been shown to reduce the symptoms of urinary incontinence.12 Surgical options for treatment of UI include retro-pubic suspension, slings, and, in some instances, artificial urethral sphincters.13
A novel treatment for neurogenic UI?
Despite the many treatments available for UI, none comprehensively addresses UI and its common comorbidities.
The role of duloxetine.Normal micturition is regulated by the somatic nervous system and an autonomic reflex arc; the neurotransmitters serotonin and norepinephrine play an important role in the neural regulation of micturition and urinary continence. Duloxetine, alone or as an adjunctive treatment,is a potential novel therapy that treats 2 common comorbidities of UI—chronic pain and depression.
As a selective serotonin norepinephrine reuptake inhibitor (SNRI), duloxetine acts at the molecular level to block the reuptake of serotonin and norepinephrine from synaptic clefts. Specifically, the medication blocks the 5-hydroxytryptamine (5-HT) reuptake transporters, as well as the norepinephrine transporters, of pre-synaptic neurons.14 Thus, the concentrations of 5-HT and norepinephrineincrease in the synaptic cleft.
Functionally, the accumulation of norepinephrine inhibits micturition by relaxing the detrusor muscle and constricting the urethral smooth muscle. In addition, a higher concentration of 5-HT at the neuromuscular junction leads to constriction of the external urethral sphincter.
Duloxetine has been shown to be effective in the treatment of other types of UI, such as stress UI15 and mixed UI.16 Additionally, it was found to be effective when compared with placebo in women with overactive bladder syndrome17 and in women with multiple sclerosis and depression.18 However, we are not aware of any cases using duloxetine for the treatment of neurogenic UI.
THE TAKEAWAY
Duloxetine is a potential novel drug choice for the treatment of neurogenic UI. Its effects on serotonin and norepinephrine at the synaptic cleft and neuromuscular junction could provide relief for those who have not found relief from other therapies. Further research—particularly a prospective, randomized controlled trial—is needed to determine if duloxetine is, in fact, more than just a theoretical candidate to treat UI and, if so, the most effective dosing.
Offering duloxetine for the treatment of neurogenic urinary incontinence would potentially address coexisting conditions, such as pain or depression.
Offering duloxetine for the treatment of neurogenic UI would potentially address coexisting conditions—such as pain or depression—thus improving patient compliance and reducing health care spending. Before beginning therapy, urodynamic studies to identify the type of UI should be completed, or, at a minimum, post-void residual volume should be measured.
ACKNOWLEDGEMENTS The authors would like to thank Julie Hughbanks, MLS, Library Manager, Parkview Health Resource Library, for her assistance with the library searches used for this case report.
THE CASE
A 57-year-old African American woman was being treated at our clinicfor neurogenic urinary incontinence (UI). The UI, which occurred day and night, began 2 years earlier following a laminectomy of vertebrae C3 to C6 with spinal fusion of C3 to C7 for cervical spinal stenosis. The UI persisted despite physical therapy and trials of oxybutynin and imipramine.Since the surgery, the patient had also been experiencing chronic (debilitating) neuropathic pain in both legs, and the sensation of incomplete bladder emptying. She denied bowel incontinence or saddle anesthesia. Her prescription medications included hydrocodone-acetaminophen 7.5/325 mg every 6 hours as needed for pain and lisinopril 20 mg/d for essential hypertension. The patient’s body mass index (BMI) was 23.3.
A urine culture initially grew Klebsiella pneumoniae,whichwe successfully treated with ciprofloxacin.A urinalysis was unremarkable, and blood urea nitrogen and creatinine levels were within normal limits.
We started the patient on oral duloxetine30 mg/d for her neuropathic pain. The patient hadn’t undergone a urologic evaluation before starting duloxetine, so no urodynamic studies or measurements had been conducted. At that point, we sent the patient to a urologist for an evaluation.
At a follow-up visit with one of our clinic providers <3 months later, the patient reported that the duloxetine was providing her with some pain relief and that she was “waking up dry” in the mornings and having fewer UI symptoms throughout the day, as well as at night. The patient denied any adverse effects such as nausea, gastrointestinal upset, weight changes, xerostomia, fatigue, insomnia, headaches, or dizziness. Duloxetine was titrated up to 60 mg/d for better control of her neuropathic pain. At the next follow-up visit at our clinic 3 months later, her UI was 80% to 90% improved and she was able to stop her opioid pain medications.
DISCUSSION
UI is a significant problem in the United States and around the world. For women, the prevalence of UI ranges from 15% to 69%; among men, the prevalence is 5% to 24%.1-3 The economic burden of UI includes both medical and nonmedical (eg, pads, diapers, laundry, and dry cleaning) care. The total national cost was estimated at $66 billion in 2007: $49 billion for direct medical costs, $2 billion for direct nonmedical costs, and $15 billion for indirect costs.4 And those costs are expected to increase 25% by 2020, mainly because of the aging population.
Risk factors for UIother than gender include advancing age, obesity, non-Hispanic white race, depression, hypertension, type 2 diabetes mellitus, neurologic disease, and functional limitations/general poor health.5-7 Comorbid depression and BMI >30, as well as the presence and duration of diabetes, increase the odds for developing UI.7,8
Duloxetine has been shown to be effective for the treatment of stress and mixed urinary incontinence. This case suggests it may be useful for neurogenic urinary incontinence, as well.
Risk factors for women include hysterectomy,7 increasing parity, and delivery of at least one infant >9.5 pounds; the risk is the same for both vaginal and cesarean-section delivery.6 Specific risk factors for men include prostate cancer, prostate surgery, and prostate radiation.5
Significant, chronic comorbidities of UI include depression and chronic pain. While quality of life is negatively affected by UI alone, the coexistence of depression and UI produces an additive negative effect on quality of life.9
Types and treatment of UI
There are 5 types of UI: urge, stress, overflow, functional, and mixed.10
Urge incontinence is the leakage of urine following a sensation of sudden urgency to void.
Stress incontinence is urine leakage associated with increased intra-abdominal pressure such as with coughing or sneezing and is typically associated with weakened pelvic floor musculature.
Overflow incontinence is more common in men, and is typically caused by prostatic disease. The urethral outlet is obstructed leading to increased pressure within the bladder and subsequent leakage of urine.
Functional incontinence is caused by physical or cognitive impairment leading to a decreased ability to get to a bathroom quickly enough to void.
Mixed incontinence is when symptoms of stress and urgency incontinence are present.
There are 3 broad categoriesof treatment methods for urinary incontinence: behavioral, pharmacologic, and surgical. Behavioral interventions are subdivided into caregiver-dependent (prompted voiding, habit retraining, and timed voiding) and patient-directed (bladder training, pelvic floor muscle training, strategies for bladder control, education, and self-monitoring) techniques. Pharmacologic treatment typically consists of antimuscarinics (eg, oxybutynin, tolterodine, solifenacin) and tricyclic antidepressants (eg, imipramine).11 Injections of onabotulinumtoxinA into the detrusor muscle have also been shown to reduce the symptoms of urinary incontinence.12 Surgical options for treatment of UI include retro-pubic suspension, slings, and, in some instances, artificial urethral sphincters.13
A novel treatment for neurogenic UI?
Despite the many treatments available for UI, none comprehensively addresses UI and its common comorbidities.
The role of duloxetine.Normal micturition is regulated by the somatic nervous system and an autonomic reflex arc; the neurotransmitters serotonin and norepinephrine play an important role in the neural regulation of micturition and urinary continence. Duloxetine, alone or as an adjunctive treatment,is a potential novel therapy that treats 2 common comorbidities of UI—chronic pain and depression.
As a selective serotonin norepinephrine reuptake inhibitor (SNRI), duloxetine acts at the molecular level to block the reuptake of serotonin and norepinephrine from synaptic clefts. Specifically, the medication blocks the 5-hydroxytryptamine (5-HT) reuptake transporters, as well as the norepinephrine transporters, of pre-synaptic neurons.14 Thus, the concentrations of 5-HT and norepinephrineincrease in the synaptic cleft.
Functionally, the accumulation of norepinephrine inhibits micturition by relaxing the detrusor muscle and constricting the urethral smooth muscle. In addition, a higher concentration of 5-HT at the neuromuscular junction leads to constriction of the external urethral sphincter.
Duloxetine has been shown to be effective in the treatment of other types of UI, such as stress UI15 and mixed UI.16 Additionally, it was found to be effective when compared with placebo in women with overactive bladder syndrome17 and in women with multiple sclerosis and depression.18 However, we are not aware of any cases using duloxetine for the treatment of neurogenic UI.
THE TAKEAWAY
Duloxetine is a potential novel drug choice for the treatment of neurogenic UI. Its effects on serotonin and norepinephrine at the synaptic cleft and neuromuscular junction could provide relief for those who have not found relief from other therapies. Further research—particularly a prospective, randomized controlled trial—is needed to determine if duloxetine is, in fact, more than just a theoretical candidate to treat UI and, if so, the most effective dosing.
Offering duloxetine for the treatment of neurogenic urinary incontinence would potentially address coexisting conditions, such as pain or depression.
Offering duloxetine for the treatment of neurogenic UI would potentially address coexisting conditions—such as pain or depression—thus improving patient compliance and reducing health care spending. Before beginning therapy, urodynamic studies to identify the type of UI should be completed, or, at a minimum, post-void residual volume should be measured.
ACKNOWLEDGEMENTS The authors would like to thank Julie Hughbanks, MLS, Library Manager, Parkview Health Resource Library, for her assistance with the library searches used for this case report.
References
1. Markland AD, Richter HE, Fwu CW, et al. Prevalence and trends of urinary incontinence in adults in the United States, 2001 to 2008. J Urol. 2011;186:589-593.
2. Buckley BS, Lapitan MC; Epidemiology Committee of the Fourth International Consultation on Incontinence, Paris, 2008. Prevalence of urinary incontinence in men, women, and children—current evidence: findings of the Fourth International Consultation on Incontinence. Urology. 2010;76:265-270.
3. Gorina Y, Schappert S, Bercovitz A, et al. Prevalence of incontinence among older Americans. Vital Health Stat 3. 2014;1-33.
4. Coyne KS, Wein A, Nicholson S, et al. Economic burden of urgency urinary incontinence in the United States: a systematic review. J Manag Care Pharm. 2014;20:130-140.
5. Shamliyan TA, Wyman JF, Ping R, et al. Male urinary incontinence: prevalence, risk factors, and preventive interventions. Rev Urol. 2009;11:145-165.
6. Matthews CA, Whitehead WE, Townsend MK, et al. Risk factors for urinary, fecal, or dual incontinence in the Nurses’ Health Study. Obstet Gynecol. 2013;122:539-545.
7. Danforth KN, Townsend MK, Lifford K, et al. Risk factors for urinary incontinence among middle-aged women. Am J Obstet Gynecol. 2006;194:339-345.
8. Lifford KL, Curhan GC, Hu FB, et al. Type 2 diabetes mellitus and risk of developing urinary incontinence. J Am Geriatr Soc. 2005;53:1851-1857.
9. Avery JC, Stocks NP, Duggan P, et al. Identifying the quality of life effects of urinary incontinence with depression in an Australian population. BMC Urol. 2013;13:11.
12. Cox L, Cameron A. OnabotulinumtoxinA for the treatment of overactive bladder. Res Rep Urol. 2014;6:79-89.
13. Dmochowski RR, Blaivas JM, Gormley EA, et al. Update of AUA guideline on the surgical management of female stress urinary incontinence. J Urol. 2010;183:1906-1914.
15. Li J, Yang L, Pu C, et al. The role of duloxetine in stress urinary incontinence: a systematic review and meta-analysis. Int Urol Nephrol. 2013;45:679-686.
16. Bent AE, Gousse AE, Hendrix SL, et al. Duloxetine compared with placebo for the treatment of women with mixed urinary incontinence. Neurourol Urodyn. 2008;27:212-221.
17. Steers WD, Herschorn S, Kreder KJ, et al; Duloxetine OAB Study Group. Duloxetine compared with placebo for treating women with symptoms of overactive bladder. BJU Int. 2007;100:337-345.
18. Di Rezze S, Frasca V, Inghilleri M, et al. Duloxetine for the treatment of overactive bladder syndrome in multiple sclerosis: a pilot study. Clin Neuropharmacol. 2012;35:231-234.
References
1. Markland AD, Richter HE, Fwu CW, et al. Prevalence and trends of urinary incontinence in adults in the United States, 2001 to 2008. J Urol. 2011;186:589-593.
2. Buckley BS, Lapitan MC; Epidemiology Committee of the Fourth International Consultation on Incontinence, Paris, 2008. Prevalence of urinary incontinence in men, women, and children—current evidence: findings of the Fourth International Consultation on Incontinence. Urology. 2010;76:265-270.
3. Gorina Y, Schappert S, Bercovitz A, et al. Prevalence of incontinence among older Americans. Vital Health Stat 3. 2014;1-33.
4. Coyne KS, Wein A, Nicholson S, et al. Economic burden of urgency urinary incontinence in the United States: a systematic review. J Manag Care Pharm. 2014;20:130-140.
5. Shamliyan TA, Wyman JF, Ping R, et al. Male urinary incontinence: prevalence, risk factors, and preventive interventions. Rev Urol. 2009;11:145-165.
6. Matthews CA, Whitehead WE, Townsend MK, et al. Risk factors for urinary, fecal, or dual incontinence in the Nurses’ Health Study. Obstet Gynecol. 2013;122:539-545.
7. Danforth KN, Townsend MK, Lifford K, et al. Risk factors for urinary incontinence among middle-aged women. Am J Obstet Gynecol. 2006;194:339-345.
8. Lifford KL, Curhan GC, Hu FB, et al. Type 2 diabetes mellitus and risk of developing urinary incontinence. J Am Geriatr Soc. 2005;53:1851-1857.
9. Avery JC, Stocks NP, Duggan P, et al. Identifying the quality of life effects of urinary incontinence with depression in an Australian population. BMC Urol. 2013;13:11.
12. Cox L, Cameron A. OnabotulinumtoxinA for the treatment of overactive bladder. Res Rep Urol. 2014;6:79-89.
13. Dmochowski RR, Blaivas JM, Gormley EA, et al. Update of AUA guideline on the surgical management of female stress urinary incontinence. J Urol. 2010;183:1906-1914.
15. Li J, Yang L, Pu C, et al. The role of duloxetine in stress urinary incontinence: a systematic review and meta-analysis. Int Urol Nephrol. 2013;45:679-686.
16. Bent AE, Gousse AE, Hendrix SL, et al. Duloxetine compared with placebo for the treatment of women with mixed urinary incontinence. Neurourol Urodyn. 2008;27:212-221.
17. Steers WD, Herschorn S, Kreder KJ, et al; Duloxetine OAB Study Group. Duloxetine compared with placebo for treating women with symptoms of overactive bladder. BJU Int. 2007;100:337-345.
18. Di Rezze S, Frasca V, Inghilleri M, et al. Duloxetine for the treatment of overactive bladder syndrome in multiple sclerosis: a pilot study. Clin Neuropharmacol. 2012;35:231-234.
Systemic mastocytosis is a heterogeneous disorder of stem cell origin defined by abnormal hyperplasia and accumulation of mast cells (MCs) in one or more tissues.1,2 The most commonly affected tissues are the bone marrow, gastrointestinal tract, and skin. Based on a number of major and minor criteria defined by the World Health Organization (WHO), the mastocytoses are subdivided into 7 variants that range from isolated cutaneous involvement to widespread systemic disease.1-4 The most frequently diagnosed subtype is indolent systemic mastocytosis (ISM), a chronic disorder characterized by diffuse cutaneous macules and papules as well as bone marrow involvement in the form of multifocal dense infiltrates of MCs that frequently are phenotypically positive for c-KIT and tryptase. Serum tryptase levels are nearly invariably elevated in patients with this condition.1,2
Symptoms of ISM are determined by the intermittent release of histamine and leukotrienes from hyperproliferating MCs as well as IL-6 and eosinophil chemotactic factors. As the burden of MC secretory products increases, patients experience worsening pruritus, flushing, palpitations, vomiting, and anaphylaxis in severe instances.1,2,5 The mainstay of treatment of this condition involves symptom control through the inhibition of MC mediators.1 The majority of patients respond well to antihistamines, antileukotriene agents, and oral corticosteroids during severe episodes of MC degranulation.1,2,5
Unfortunately, some patients are unable to achieve adequate symptom control through the use of mediator-targeting treatments alone. In these cases, physicians often are faced with the following treatment dilemma: Either attempt to use therapies such as interferon alfa, which is cytoreductive to MCs, or 2-chlorodeoxyadenosine to reduce the overall MC burden, or turn to newer nonimmunosuppressive second-line options. We present the case of a patient with chronic ISM with progressive cutaneous lesions and poorly controlled pruritus that was previously managed with topical corticosteroids and antihistamines who responded favorably to treatment with narrowband UVB (NB-UVB) phototherapy.
Case Report
A 57-year-old woman presented with a 10-year history of widespread red-brown macules and papules on the trunk and upper and lower extremities. The lesions were intermittently pruritic, a symptom that was exacerbated on sun and heat exposure. A skin biopsy performed by an outside dermatologist 9 years prior confirmed the presence of mastocytosis. The patient was originally treated with triamcinolone cream and oral antihistamines, which controlled her symptoms successfully for nearly a decade.
At the current presentation, the patient reported increasingly severe pruritus and lesional spread to the neck and face of 15 months’ duration. She denied any symptoms of flushing, diarrhea, syncopal episodes, or lightheadedness. Physical examination revealed a well-appearing middle-aged woman with multiple 3- to 8-mm, red-brown, blanchable macules and papules with areas coalescing into plaques that primarily involved the legs (Figure 1A); arms; back; and to a lesser extent the abdomen, neck, and face. There was no palpable lymphadenopathy.
Figure 1. Indolent systemic mastocytosis with red-brown macular and papular lesions on the thighs before (A) and after 20 cycles (B) and 40 cycles (C) of narrowband UVB phototherapy.
Laboratory results revealed a complete blood cell count and basic metabolic profile within reference range; however, the serum tryptase level was elevated at 65 ng/mL (reference range, <11.4 ng/mL). A positron emission tomography–computed tomography scan was negative, as well as a c-KIT mutation analysis. A review of the skin biopsy from 9 years prior demonstrated slight acanthosis with dermal proliferation of mononuclear cells (Figure 2A), some of which had abundant cytoplasm and oval-shaped nuclei. There were few eosinophils and marked dermal telangiectasias. Giemsa stain revealed increased numbers of MCs in the upper dermis (Figure 2B). A bone marrow biopsy performed 9 years later showed multifocal lesions composed of MCs with associated lymphoid aggregates without notable myelodyspoiesis (or myeloproliferative neoplasm). These features were all consistent with WHO criteria for ISM. Based on the most current clinical, laboratory, and histopathologic findings, the patient was diagnosed with category IB ISM.
Figure 2. Indolent systemic mastocytosis skin biopsy demonstrating acanthosis and dermal mononuclear cell proliferation (A)(H&E, original magnification ×20) as well as increased mast cell density in the upper dermis (B)(Giemsa, original magnification ×20).
The patient’s symptoms had remained stable for 9 years with a regimen of triamcinolone cream 0.1% twice daily, doxepin cream 5% daily as needed, and oral fexofenadine 180 mg once daily. The patient continues to use topical steroids and oral antihistamines. Due to inadequate symptom control, breakthrough pruritus, and the development of new skin lesions on the head and neck, she was started on NB-UVB treatment 2 months after presentation. The patient’s symptoms and the extent of cutaneous maculopapular lesions improved after 20 light treatments (Figure 1B), with even more dramatic results after 40 cycles of therapy (Figure 1C). Overall, the lower legs have proved most recalcitrant to this treatment modality. She is currently continuing to receive NB-UVB treatment twice weekly.
Comment
Systemic mastocytosis is a heterogeneous disorder characterized by the proliferation and accumulation of atypical MCs in tissues, principally in the bone marrow and skin, though involvement of the gastrointestinal tract, liver, spleen, and lymphatic system also have been reported.1,2,6 The WHO classification of mastocytosis divides this condition into 7 subtypes.4 Indolent systemic mastocytosis is the most common variant.2,6 The etiology of ISM is not fully understood, but there is evidence suggesting that an activating mutation of KIT proto-oncogene receptor tyrosine kinase, KIT (usually D816V), present in the MCs of nearly 80% of patients with ISM may be involved.1,3-5,7 Patients occasionally present with predominantly cutaneous findings but typically seek medical attention due to the recurrent systemic symptoms of the disease (eg, pruritus, flushing, syncope, palpitations, headache, dyspepsia, vomiting, diarrhea), which are related to the release of MC mediators.1,2
The management of ISM is complex and based primarily on symptom reduction without alteration of disease course.1,2,5,7 Patients should avoid symptom triggers such as heat, humidity, emotional and physical stress, alcohol, and certain medications (ie, aspirin, opioids, radiocontrast agents).7 Patients are initially treated with histamine H1- and H2-receptor antagonists to alleviate MC mediator release symptoms.1,2,8 Although H1 blockers are most effective in mitigating cutaneous symptoms and limiting pruritus, H2 blockers are used to control gastric hypersecretion and dyspepsia.2 Proton pump inhibitors are useful in patients with peptic ulcer disease who are unresponsive to H2-receptor antagonist therapy.2,7 Cromolyn sodium and ketotifen fumarate are MC stabilizers that help prevent degranulation, which is helpful in relieving most major ISM symptoms. Leukotriene antagonists, such as zafirlukast, montelukast sodium, or zileuton, also may be employed to target the proinflammatory and pruritogenic leukotrienes, also products of the MC protein.2,7 Imatinib mesylate and masitinib mesylate, both tyrosine kinase inhibitors, have been shown to improve symptoms and reduce MC mediator levels in ISM; however, most patients harbor the resistant KIT D816V mutation, which limits the utility of this medication.Patients with sensitive KIT mutations or those who have the wild-type KIT D816 mutation may be more appropriate candidates for imatinib or masitinib therapy, which can ameliorate symptoms of flushing, pruritus, and depression.7-10 Treatment with omalizumab, a humanized murine anti-IgE monoclonal antibody, can be effective in treating recurrent, treatment-refractory anaphylaxis in ISM patients.5,7
Symptoms unresponsive to these therapies can be effectively treated with a short course of oral corticosteroids,6,7 while MC cytoreductive therapies such as interferon alfa or 2-chlorodeoxyadenosine (cladribine/2-CdA) are reserved for refractory cases.2,7 Alternative therapies such as NB-UVB2 or psoralen plus UVA phototherapy11 also have demonstrated success in treating ISM symptoms. In the past, NB-UVB has shown efficacy in controlling pruriginous conditions ranging from chronic urticaria12,13 to atopic dermatitis14 to psoriasis.15 This evidence has spurred studies to evaluate if NB-UVB has a role in the management of uncontrolled cases of cutaneous and ISM.2,13,16,17 To date, the evidence has been promising. The majority of patients treated with this regimen report subjective reduction in pruritus in addition to clinical cutaneous disease burden.2,11 Also, laboratory analysis demonstrates decreased levels of tryptase in patients utilizing NB-UVB phototherapy.2 Thus far, the use of NB-UVB phototherapy in the treatment of pruriginous disorders such as ISM has not been associated with any severe side effects such as increased rates of anaphylaxis, though some research has suggested that this therapy may lower the threshold for patients to develop symptomatic dermographism.12 Overall, patients treated with NB-UVB phototherapy report improved quality of life related to more effective symptom control.16
Although ISM is currently considered an incurable chronic condition,6 this case illustrates that symptomatic management is possible, even in cases of long-standing, severe disease. Patients should still be encouraged to avoid triggering factors and be vigilant in preventing potential anaphylaxis. However, NB-UVB phototherapy provides a supplemental or alternative treatment choice when other therapies have failed. We hope that the success of NB-UVB demonstrated in this case provides further evidence that this light-based therapy is a valuable treatment option in mastocytosis patients with unremitting or poorly controlled symptoms.
Brazzelli V, Grasso V, Manna G, et al. Indolent systemic mastocytosis treated with narrow-band UVB phototherapy: study of five cases [published online May 13, 2011]. J Eur Acad Dermatol Venereol. 2012;26:465-469.
Pardanani A, Lim KH, Lasho TL, et al. WHO subvariants of indolent mastocytosis: clinical details and prognostic evaluation in 159 consecutive adults. Blood. 2010;115:150-151.
Vardiman JW, Thiele J, Arber DA, et al. The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes [published online April 8, 2009]. Blood. 2009;114:937-951.
Wolff K, Komar M, Petzelbauer P. Clinical and histopathological aspects of cutaneous mastocytosis. Leuk Res. 2001;25:519-528.
Marone G, Spadaro G, Granata F, et al. Treatment of mastocytosis: pharmacologic basis and current concepts. Leuk Res. 2001;25:583-594.
Pardanani A. How I treat patients with indolent and smoldering mastocytosis (rare conditions but difficult to manage)[published online February 20, 2013]. Blood. 2013;121:3085-3094.
Hartmann K, Henz BM. Mastocytosis: recent advances in defining the disease. Br J Dermatol. 2001;144:682-695.
Vega-Ruiz A, Cortes JE, Sever M, et al. Phase II study of imatinib mesylate as therapy for patients with systemic mastocytosis. Leuk Res. 2009;33:1481-1484.
Lortholary O, Chandesris MO, Bulai Livideanu C, et al. Masitinib for treatment of severely symptomatic indolent systemic mastocytosis: a randomised, placebo-controlled, phase 3 study. Lancet. 2017;389:612-620.
Godt O, Proksch E, Streit V, et al. Short-and long-term effectiveness of oral and bath PUVA therapy in urticaria pigmentosa and systemic mastocytosis. Dermatology. 1997;1:35-39.
Berroeta L, Clark C, Ibbotson SH, et al. Narrow-band (TL-01) ultraviolet B phototherapy for chronic urticaria. Clin Exp Dermatol. 2004;29:91-99.
Engin B, Ozdemir M, Balevi A, et al. Treatment of chronic urticaria with narrowband ultraviolet B phototherapy: a randomized controlled trial. Acta Derm Venereol. 2008;3:247-251.
Meduri NB, Vandergriff T, Rasmussen H, et al. Phototherapy in the management of atopic dermatitis: a systemic review. Photodermatol Photoimmunol Photomed. 2007;23:106-112.
Nguyen T, Gattu S, Pugashetti R, et al. Practice of phototherapy in the treatment of moderate-to severe psoriasis. Curr Probl Dermatol. 2009;38:59-78.
Brazzelli V, Grassi S, Merante S, et al. Narrow-band UVB phototherapy and psoralen-ultraviolet A photochemotherapy in the treatment of cutaneous mastocytosis: a study in 20 patients. Photodermatol Photoimmunol Photomed. 2016;32:238-246.
Prignano F, Troiano M, Lotti T. Cutaneous mastocytosis: successful treatment with narrowband ultraviolet B phototherapy. Clin Exp Dermatol. 2010;35:914-915.
Drs. Husain, Waterman, and DeSimone are from Georgetown University Hospital/Washington Hospital Center, Washington, DC. Dr. Ellison is from the James H. Quillen College of Medicine, East Tennessee State University, Mountain Home.
The authors report no conflict of interest.
Correspondence: Zain Husain, MD, 8803 Old Courthouse Rd, Vienna, VA 22182 (zhusain5@gmail.com).
Drs. Husain, Waterman, and DeSimone are from Georgetown University Hospital/Washington Hospital Center, Washington, DC. Dr. Ellison is from the James H. Quillen College of Medicine, East Tennessee State University, Mountain Home.
The authors report no conflict of interest.
Correspondence: Zain Husain, MD, 8803 Old Courthouse Rd, Vienna, VA 22182 (zhusain5@gmail.com).
Author and Disclosure Information
Drs. Husain, Waterman, and DeSimone are from Georgetown University Hospital/Washington Hospital Center, Washington, DC. Dr. Ellison is from the James H. Quillen College of Medicine, East Tennessee State University, Mountain Home.
The authors report no conflict of interest.
Correspondence: Zain Husain, MD, 8803 Old Courthouse Rd, Vienna, VA 22182 (zhusain5@gmail.com).
Systemic mastocytosis is a heterogeneous disorder of stem cell origin defined by abnormal hyperplasia and accumulation of mast cells (MCs) in one or more tissues.1,2 The most commonly affected tissues are the bone marrow, gastrointestinal tract, and skin. Based on a number of major and minor criteria defined by the World Health Organization (WHO), the mastocytoses are subdivided into 7 variants that range from isolated cutaneous involvement to widespread systemic disease.1-4 The most frequently diagnosed subtype is indolent systemic mastocytosis (ISM), a chronic disorder characterized by diffuse cutaneous macules and papules as well as bone marrow involvement in the form of multifocal dense infiltrates of MCs that frequently are phenotypically positive for c-KIT and tryptase. Serum tryptase levels are nearly invariably elevated in patients with this condition.1,2
Symptoms of ISM are determined by the intermittent release of histamine and leukotrienes from hyperproliferating MCs as well as IL-6 and eosinophil chemotactic factors. As the burden of MC secretory products increases, patients experience worsening pruritus, flushing, palpitations, vomiting, and anaphylaxis in severe instances.1,2,5 The mainstay of treatment of this condition involves symptom control through the inhibition of MC mediators.1 The majority of patients respond well to antihistamines, antileukotriene agents, and oral corticosteroids during severe episodes of MC degranulation.1,2,5
Unfortunately, some patients are unable to achieve adequate symptom control through the use of mediator-targeting treatments alone. In these cases, physicians often are faced with the following treatment dilemma: Either attempt to use therapies such as interferon alfa, which is cytoreductive to MCs, or 2-chlorodeoxyadenosine to reduce the overall MC burden, or turn to newer nonimmunosuppressive second-line options. We present the case of a patient with chronic ISM with progressive cutaneous lesions and poorly controlled pruritus that was previously managed with topical corticosteroids and antihistamines who responded favorably to treatment with narrowband UVB (NB-UVB) phototherapy.
Case Report
A 57-year-old woman presented with a 10-year history of widespread red-brown macules and papules on the trunk and upper and lower extremities. The lesions were intermittently pruritic, a symptom that was exacerbated on sun and heat exposure. A skin biopsy performed by an outside dermatologist 9 years prior confirmed the presence of mastocytosis. The patient was originally treated with triamcinolone cream and oral antihistamines, which controlled her symptoms successfully for nearly a decade.
At the current presentation, the patient reported increasingly severe pruritus and lesional spread to the neck and face of 15 months’ duration. She denied any symptoms of flushing, diarrhea, syncopal episodes, or lightheadedness. Physical examination revealed a well-appearing middle-aged woman with multiple 3- to 8-mm, red-brown, blanchable macules and papules with areas coalescing into plaques that primarily involved the legs (Figure 1A); arms; back; and to a lesser extent the abdomen, neck, and face. There was no palpable lymphadenopathy.
Figure 1. Indolent systemic mastocytosis with red-brown macular and papular lesions on the thighs before (A) and after 20 cycles (B) and 40 cycles (C) of narrowband UVB phototherapy.
Laboratory results revealed a complete blood cell count and basic metabolic profile within reference range; however, the serum tryptase level was elevated at 65 ng/mL (reference range, <11.4 ng/mL). A positron emission tomography–computed tomography scan was negative, as well as a c-KIT mutation analysis. A review of the skin biopsy from 9 years prior demonstrated slight acanthosis with dermal proliferation of mononuclear cells (Figure 2A), some of which had abundant cytoplasm and oval-shaped nuclei. There were few eosinophils and marked dermal telangiectasias. Giemsa stain revealed increased numbers of MCs in the upper dermis (Figure 2B). A bone marrow biopsy performed 9 years later showed multifocal lesions composed of MCs with associated lymphoid aggregates without notable myelodyspoiesis (or myeloproliferative neoplasm). These features were all consistent with WHO criteria for ISM. Based on the most current clinical, laboratory, and histopathologic findings, the patient was diagnosed with category IB ISM.
Figure 2. Indolent systemic mastocytosis skin biopsy demonstrating acanthosis and dermal mononuclear cell proliferation (A)(H&E, original magnification ×20) as well as increased mast cell density in the upper dermis (B)(Giemsa, original magnification ×20).
The patient’s symptoms had remained stable for 9 years with a regimen of triamcinolone cream 0.1% twice daily, doxepin cream 5% daily as needed, and oral fexofenadine 180 mg once daily. The patient continues to use topical steroids and oral antihistamines. Due to inadequate symptom control, breakthrough pruritus, and the development of new skin lesions on the head and neck, she was started on NB-UVB treatment 2 months after presentation. The patient’s symptoms and the extent of cutaneous maculopapular lesions improved after 20 light treatments (Figure 1B), with even more dramatic results after 40 cycles of therapy (Figure 1C). Overall, the lower legs have proved most recalcitrant to this treatment modality. She is currently continuing to receive NB-UVB treatment twice weekly.
Comment
Systemic mastocytosis is a heterogeneous disorder characterized by the proliferation and accumulation of atypical MCs in tissues, principally in the bone marrow and skin, though involvement of the gastrointestinal tract, liver, spleen, and lymphatic system also have been reported.1,2,6 The WHO classification of mastocytosis divides this condition into 7 subtypes.4 Indolent systemic mastocytosis is the most common variant.2,6 The etiology of ISM is not fully understood, but there is evidence suggesting that an activating mutation of KIT proto-oncogene receptor tyrosine kinase, KIT (usually D816V), present in the MCs of nearly 80% of patients with ISM may be involved.1,3-5,7 Patients occasionally present with predominantly cutaneous findings but typically seek medical attention due to the recurrent systemic symptoms of the disease (eg, pruritus, flushing, syncope, palpitations, headache, dyspepsia, vomiting, diarrhea), which are related to the release of MC mediators.1,2
The management of ISM is complex and based primarily on symptom reduction without alteration of disease course.1,2,5,7 Patients should avoid symptom triggers such as heat, humidity, emotional and physical stress, alcohol, and certain medications (ie, aspirin, opioids, radiocontrast agents).7 Patients are initially treated with histamine H1- and H2-receptor antagonists to alleviate MC mediator release symptoms.1,2,8 Although H1 blockers are most effective in mitigating cutaneous symptoms and limiting pruritus, H2 blockers are used to control gastric hypersecretion and dyspepsia.2 Proton pump inhibitors are useful in patients with peptic ulcer disease who are unresponsive to H2-receptor antagonist therapy.2,7 Cromolyn sodium and ketotifen fumarate are MC stabilizers that help prevent degranulation, which is helpful in relieving most major ISM symptoms. Leukotriene antagonists, such as zafirlukast, montelukast sodium, or zileuton, also may be employed to target the proinflammatory and pruritogenic leukotrienes, also products of the MC protein.2,7 Imatinib mesylate and masitinib mesylate, both tyrosine kinase inhibitors, have been shown to improve symptoms and reduce MC mediator levels in ISM; however, most patients harbor the resistant KIT D816V mutation, which limits the utility of this medication.Patients with sensitive KIT mutations or those who have the wild-type KIT D816 mutation may be more appropriate candidates for imatinib or masitinib therapy, which can ameliorate symptoms of flushing, pruritus, and depression.7-10 Treatment with omalizumab, a humanized murine anti-IgE monoclonal antibody, can be effective in treating recurrent, treatment-refractory anaphylaxis in ISM patients.5,7
Symptoms unresponsive to these therapies can be effectively treated with a short course of oral corticosteroids,6,7 while MC cytoreductive therapies such as interferon alfa or 2-chlorodeoxyadenosine (cladribine/2-CdA) are reserved for refractory cases.2,7 Alternative therapies such as NB-UVB2 or psoralen plus UVA phototherapy11 also have demonstrated success in treating ISM symptoms. In the past, NB-UVB has shown efficacy in controlling pruriginous conditions ranging from chronic urticaria12,13 to atopic dermatitis14 to psoriasis.15 This evidence has spurred studies to evaluate if NB-UVB has a role in the management of uncontrolled cases of cutaneous and ISM.2,13,16,17 To date, the evidence has been promising. The majority of patients treated with this regimen report subjective reduction in pruritus in addition to clinical cutaneous disease burden.2,11 Also, laboratory analysis demonstrates decreased levels of tryptase in patients utilizing NB-UVB phototherapy.2 Thus far, the use of NB-UVB phototherapy in the treatment of pruriginous disorders such as ISM has not been associated with any severe side effects such as increased rates of anaphylaxis, though some research has suggested that this therapy may lower the threshold for patients to develop symptomatic dermographism.12 Overall, patients treated with NB-UVB phototherapy report improved quality of life related to more effective symptom control.16
Although ISM is currently considered an incurable chronic condition,6 this case illustrates that symptomatic management is possible, even in cases of long-standing, severe disease. Patients should still be encouraged to avoid triggering factors and be vigilant in preventing potential anaphylaxis. However, NB-UVB phototherapy provides a supplemental or alternative treatment choice when other therapies have failed. We hope that the success of NB-UVB demonstrated in this case provides further evidence that this light-based therapy is a valuable treatment option in mastocytosis patients with unremitting or poorly controlled symptoms.
Systemic mastocytosis is a heterogeneous disorder of stem cell origin defined by abnormal hyperplasia and accumulation of mast cells (MCs) in one or more tissues.1,2 The most commonly affected tissues are the bone marrow, gastrointestinal tract, and skin. Based on a number of major and minor criteria defined by the World Health Organization (WHO), the mastocytoses are subdivided into 7 variants that range from isolated cutaneous involvement to widespread systemic disease.1-4 The most frequently diagnosed subtype is indolent systemic mastocytosis (ISM), a chronic disorder characterized by diffuse cutaneous macules and papules as well as bone marrow involvement in the form of multifocal dense infiltrates of MCs that frequently are phenotypically positive for c-KIT and tryptase. Serum tryptase levels are nearly invariably elevated in patients with this condition.1,2
Symptoms of ISM are determined by the intermittent release of histamine and leukotrienes from hyperproliferating MCs as well as IL-6 and eosinophil chemotactic factors. As the burden of MC secretory products increases, patients experience worsening pruritus, flushing, palpitations, vomiting, and anaphylaxis in severe instances.1,2,5 The mainstay of treatment of this condition involves symptom control through the inhibition of MC mediators.1 The majority of patients respond well to antihistamines, antileukotriene agents, and oral corticosteroids during severe episodes of MC degranulation.1,2,5
Unfortunately, some patients are unable to achieve adequate symptom control through the use of mediator-targeting treatments alone. In these cases, physicians often are faced with the following treatment dilemma: Either attempt to use therapies such as interferon alfa, which is cytoreductive to MCs, or 2-chlorodeoxyadenosine to reduce the overall MC burden, or turn to newer nonimmunosuppressive second-line options. We present the case of a patient with chronic ISM with progressive cutaneous lesions and poorly controlled pruritus that was previously managed with topical corticosteroids and antihistamines who responded favorably to treatment with narrowband UVB (NB-UVB) phototherapy.
Case Report
A 57-year-old woman presented with a 10-year history of widespread red-brown macules and papules on the trunk and upper and lower extremities. The lesions were intermittently pruritic, a symptom that was exacerbated on sun and heat exposure. A skin biopsy performed by an outside dermatologist 9 years prior confirmed the presence of mastocytosis. The patient was originally treated with triamcinolone cream and oral antihistamines, which controlled her symptoms successfully for nearly a decade.
At the current presentation, the patient reported increasingly severe pruritus and lesional spread to the neck and face of 15 months’ duration. She denied any symptoms of flushing, diarrhea, syncopal episodes, or lightheadedness. Physical examination revealed a well-appearing middle-aged woman with multiple 3- to 8-mm, red-brown, blanchable macules and papules with areas coalescing into plaques that primarily involved the legs (Figure 1A); arms; back; and to a lesser extent the abdomen, neck, and face. There was no palpable lymphadenopathy.
Figure 1. Indolent systemic mastocytosis with red-brown macular and papular lesions on the thighs before (A) and after 20 cycles (B) and 40 cycles (C) of narrowband UVB phototherapy.
Laboratory results revealed a complete blood cell count and basic metabolic profile within reference range; however, the serum tryptase level was elevated at 65 ng/mL (reference range, <11.4 ng/mL). A positron emission tomography–computed tomography scan was negative, as well as a c-KIT mutation analysis. A review of the skin biopsy from 9 years prior demonstrated slight acanthosis with dermal proliferation of mononuclear cells (Figure 2A), some of which had abundant cytoplasm and oval-shaped nuclei. There were few eosinophils and marked dermal telangiectasias. Giemsa stain revealed increased numbers of MCs in the upper dermis (Figure 2B). A bone marrow biopsy performed 9 years later showed multifocal lesions composed of MCs with associated lymphoid aggregates without notable myelodyspoiesis (or myeloproliferative neoplasm). These features were all consistent with WHO criteria for ISM. Based on the most current clinical, laboratory, and histopathologic findings, the patient was diagnosed with category IB ISM.
Figure 2. Indolent systemic mastocytosis skin biopsy demonstrating acanthosis and dermal mononuclear cell proliferation (A)(H&E, original magnification ×20) as well as increased mast cell density in the upper dermis (B)(Giemsa, original magnification ×20).
The patient’s symptoms had remained stable for 9 years with a regimen of triamcinolone cream 0.1% twice daily, doxepin cream 5% daily as needed, and oral fexofenadine 180 mg once daily. The patient continues to use topical steroids and oral antihistamines. Due to inadequate symptom control, breakthrough pruritus, and the development of new skin lesions on the head and neck, she was started on NB-UVB treatment 2 months after presentation. The patient’s symptoms and the extent of cutaneous maculopapular lesions improved after 20 light treatments (Figure 1B), with even more dramatic results after 40 cycles of therapy (Figure 1C). Overall, the lower legs have proved most recalcitrant to this treatment modality. She is currently continuing to receive NB-UVB treatment twice weekly.
Comment
Systemic mastocytosis is a heterogeneous disorder characterized by the proliferation and accumulation of atypical MCs in tissues, principally in the bone marrow and skin, though involvement of the gastrointestinal tract, liver, spleen, and lymphatic system also have been reported.1,2,6 The WHO classification of mastocytosis divides this condition into 7 subtypes.4 Indolent systemic mastocytosis is the most common variant.2,6 The etiology of ISM is not fully understood, but there is evidence suggesting that an activating mutation of KIT proto-oncogene receptor tyrosine kinase, KIT (usually D816V), present in the MCs of nearly 80% of patients with ISM may be involved.1,3-5,7 Patients occasionally present with predominantly cutaneous findings but typically seek medical attention due to the recurrent systemic symptoms of the disease (eg, pruritus, flushing, syncope, palpitations, headache, dyspepsia, vomiting, diarrhea), which are related to the release of MC mediators.1,2
The management of ISM is complex and based primarily on symptom reduction without alteration of disease course.1,2,5,7 Patients should avoid symptom triggers such as heat, humidity, emotional and physical stress, alcohol, and certain medications (ie, aspirin, opioids, radiocontrast agents).7 Patients are initially treated with histamine H1- and H2-receptor antagonists to alleviate MC mediator release symptoms.1,2,8 Although H1 blockers are most effective in mitigating cutaneous symptoms and limiting pruritus, H2 blockers are used to control gastric hypersecretion and dyspepsia.2 Proton pump inhibitors are useful in patients with peptic ulcer disease who are unresponsive to H2-receptor antagonist therapy.2,7 Cromolyn sodium and ketotifen fumarate are MC stabilizers that help prevent degranulation, which is helpful in relieving most major ISM symptoms. Leukotriene antagonists, such as zafirlukast, montelukast sodium, or zileuton, also may be employed to target the proinflammatory and pruritogenic leukotrienes, also products of the MC protein.2,7 Imatinib mesylate and masitinib mesylate, both tyrosine kinase inhibitors, have been shown to improve symptoms and reduce MC mediator levels in ISM; however, most patients harbor the resistant KIT D816V mutation, which limits the utility of this medication.Patients with sensitive KIT mutations or those who have the wild-type KIT D816 mutation may be more appropriate candidates for imatinib or masitinib therapy, which can ameliorate symptoms of flushing, pruritus, and depression.7-10 Treatment with omalizumab, a humanized murine anti-IgE monoclonal antibody, can be effective in treating recurrent, treatment-refractory anaphylaxis in ISM patients.5,7
Symptoms unresponsive to these therapies can be effectively treated with a short course of oral corticosteroids,6,7 while MC cytoreductive therapies such as interferon alfa or 2-chlorodeoxyadenosine (cladribine/2-CdA) are reserved for refractory cases.2,7 Alternative therapies such as NB-UVB2 or psoralen plus UVA phototherapy11 also have demonstrated success in treating ISM symptoms. In the past, NB-UVB has shown efficacy in controlling pruriginous conditions ranging from chronic urticaria12,13 to atopic dermatitis14 to psoriasis.15 This evidence has spurred studies to evaluate if NB-UVB has a role in the management of uncontrolled cases of cutaneous and ISM.2,13,16,17 To date, the evidence has been promising. The majority of patients treated with this regimen report subjective reduction in pruritus in addition to clinical cutaneous disease burden.2,11 Also, laboratory analysis demonstrates decreased levels of tryptase in patients utilizing NB-UVB phototherapy.2 Thus far, the use of NB-UVB phototherapy in the treatment of pruriginous disorders such as ISM has not been associated with any severe side effects such as increased rates of anaphylaxis, though some research has suggested that this therapy may lower the threshold for patients to develop symptomatic dermographism.12 Overall, patients treated with NB-UVB phototherapy report improved quality of life related to more effective symptom control.16
Although ISM is currently considered an incurable chronic condition,6 this case illustrates that symptomatic management is possible, even in cases of long-standing, severe disease. Patients should still be encouraged to avoid triggering factors and be vigilant in preventing potential anaphylaxis. However, NB-UVB phototherapy provides a supplemental or alternative treatment choice when other therapies have failed. We hope that the success of NB-UVB demonstrated in this case provides further evidence that this light-based therapy is a valuable treatment option in mastocytosis patients with unremitting or poorly controlled symptoms.
Brazzelli V, Grasso V, Manna G, et al. Indolent systemic mastocytosis treated with narrow-band UVB phototherapy: study of five cases [published online May 13, 2011]. J Eur Acad Dermatol Venereol. 2012;26:465-469.
Pardanani A, Lim KH, Lasho TL, et al. WHO subvariants of indolent mastocytosis: clinical details and prognostic evaluation in 159 consecutive adults. Blood. 2010;115:150-151.
Vardiman JW, Thiele J, Arber DA, et al. The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes [published online April 8, 2009]. Blood. 2009;114:937-951.
Wolff K, Komar M, Petzelbauer P. Clinical and histopathological aspects of cutaneous mastocytosis. Leuk Res. 2001;25:519-528.
Marone G, Spadaro G, Granata F, et al. Treatment of mastocytosis: pharmacologic basis and current concepts. Leuk Res. 2001;25:583-594.
Pardanani A. How I treat patients with indolent and smoldering mastocytosis (rare conditions but difficult to manage)[published online February 20, 2013]. Blood. 2013;121:3085-3094.
Hartmann K, Henz BM. Mastocytosis: recent advances in defining the disease. Br J Dermatol. 2001;144:682-695.
Vega-Ruiz A, Cortes JE, Sever M, et al. Phase II study of imatinib mesylate as therapy for patients with systemic mastocytosis. Leuk Res. 2009;33:1481-1484.
Lortholary O, Chandesris MO, Bulai Livideanu C, et al. Masitinib for treatment of severely symptomatic indolent systemic mastocytosis: a randomised, placebo-controlled, phase 3 study. Lancet. 2017;389:612-620.
Godt O, Proksch E, Streit V, et al. Short-and long-term effectiveness of oral and bath PUVA therapy in urticaria pigmentosa and systemic mastocytosis. Dermatology. 1997;1:35-39.
Berroeta L, Clark C, Ibbotson SH, et al. Narrow-band (TL-01) ultraviolet B phototherapy for chronic urticaria. Clin Exp Dermatol. 2004;29:91-99.
Engin B, Ozdemir M, Balevi A, et al. Treatment of chronic urticaria with narrowband ultraviolet B phototherapy: a randomized controlled trial. Acta Derm Venereol. 2008;3:247-251.
Meduri NB, Vandergriff T, Rasmussen H, et al. Phototherapy in the management of atopic dermatitis: a systemic review. Photodermatol Photoimmunol Photomed. 2007;23:106-112.
Nguyen T, Gattu S, Pugashetti R, et al. Practice of phototherapy in the treatment of moderate-to severe psoriasis. Curr Probl Dermatol. 2009;38:59-78.
Brazzelli V, Grassi S, Merante S, et al. Narrow-band UVB phototherapy and psoralen-ultraviolet A photochemotherapy in the treatment of cutaneous mastocytosis: a study in 20 patients. Photodermatol Photoimmunol Photomed. 2016;32:238-246.
Prignano F, Troiano M, Lotti T. Cutaneous mastocytosis: successful treatment with narrowband ultraviolet B phototherapy. Clin Exp Dermatol. 2010;35:914-915.
Brazzelli V, Grasso V, Manna G, et al. Indolent systemic mastocytosis treated with narrow-band UVB phototherapy: study of five cases [published online May 13, 2011]. J Eur Acad Dermatol Venereol. 2012;26:465-469.
Pardanani A, Lim KH, Lasho TL, et al. WHO subvariants of indolent mastocytosis: clinical details and prognostic evaluation in 159 consecutive adults. Blood. 2010;115:150-151.
Vardiman JW, Thiele J, Arber DA, et al. The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes [published online April 8, 2009]. Blood. 2009;114:937-951.
Wolff K, Komar M, Petzelbauer P. Clinical and histopathological aspects of cutaneous mastocytosis. Leuk Res. 2001;25:519-528.
Marone G, Spadaro G, Granata F, et al. Treatment of mastocytosis: pharmacologic basis and current concepts. Leuk Res. 2001;25:583-594.
Pardanani A. How I treat patients with indolent and smoldering mastocytosis (rare conditions but difficult to manage)[published online February 20, 2013]. Blood. 2013;121:3085-3094.
Hartmann K, Henz BM. Mastocytosis: recent advances in defining the disease. Br J Dermatol. 2001;144:682-695.
Vega-Ruiz A, Cortes JE, Sever M, et al. Phase II study of imatinib mesylate as therapy for patients with systemic mastocytosis. Leuk Res. 2009;33:1481-1484.
Lortholary O, Chandesris MO, Bulai Livideanu C, et al. Masitinib for treatment of severely symptomatic indolent systemic mastocytosis: a randomised, placebo-controlled, phase 3 study. Lancet. 2017;389:612-620.
Godt O, Proksch E, Streit V, et al. Short-and long-term effectiveness of oral and bath PUVA therapy in urticaria pigmentosa and systemic mastocytosis. Dermatology. 1997;1:35-39.
Berroeta L, Clark C, Ibbotson SH, et al. Narrow-band (TL-01) ultraviolet B phototherapy for chronic urticaria. Clin Exp Dermatol. 2004;29:91-99.
Engin B, Ozdemir M, Balevi A, et al. Treatment of chronic urticaria with narrowband ultraviolet B phototherapy: a randomized controlled trial. Acta Derm Venereol. 2008;3:247-251.
Meduri NB, Vandergriff T, Rasmussen H, et al. Phototherapy in the management of atopic dermatitis: a systemic review. Photodermatol Photoimmunol Photomed. 2007;23:106-112.
Nguyen T, Gattu S, Pugashetti R, et al. Practice of phototherapy in the treatment of moderate-to severe psoriasis. Curr Probl Dermatol. 2009;38:59-78.
Brazzelli V, Grassi S, Merante S, et al. Narrow-band UVB phototherapy and psoralen-ultraviolet A photochemotherapy in the treatment of cutaneous mastocytosis: a study in 20 patients. Photodermatol Photoimmunol Photomed. 2016;32:238-246.
Prignano F, Troiano M, Lotti T. Cutaneous mastocytosis: successful treatment with narrowband ultraviolet B phototherapy. Clin Exp Dermatol. 2010;35:914-915.
Despite standardization of diagnostic criteria by the MSIS for the diagnosis of PJI, some low-grade inflections create a diagnostic challenge for clinicians.
P acnes infection following TJA can be present despite patients having normal serum inflammatory marker levels and synovial fluid aspirations.
Patients with a PJI with low virulence organisms can present with painful, arthrofibrotic joints that do not appear to be clinically infected.
Biopsy for pathology and culture can aid in the diagnosis of suspected PJI in patients who fail to meet MSIS criteria.
If detected and accurately diagnosed, PJI with P acnes can be successfully eradicated with IV antibiotics and 2-stage revision arthroplasty with a good functional outcome.
Total joint arthroplasty (TJA) is a routinely performed, highly efficacious procedure for patients with degenerative osteoarthritis.1,2 In the United States in 2003, more than 450,000 total knee arthroplasties (TKAs) were performed, and this number is projected to increase by more than 673% by 2030, as America’s population continues to age.3 With the increase in primary TJAs has come an increase in revision TJAs. The most common cause of revision TJA is infection (25.2%), which has a rate of 1% to 4% after primary TJA.1,4 Despite advancements in implant technology, preoperative preventive strategies, perioperative techniques, and postoperative management, a recent meta-analysis of patient follow-up data revealed that 15% to 20% of patients remained dissatisfied after TJA, despite having technically well-placed implants.5,6
Recent studies have suggested that prosthetic joint infection (PJI) may be underreported because of the difficulty in diagnosis, which may be one of the reasons why patients remain dissatisfied after TJA.7 As a result, new efforts have been made to develop uniform criteria for PJI diagnosis.8 In 2011, the Musculoskeletal Infection Society (MSIS) developed a new definition for the PJI diagnosis, based on clinical and laboratory criteria, in order to increase diagnostic accuracy. However, MSIS acknowledged that PJI may be present even if these criteria are not met, particularly in the case of low-grade infections, as patients may not present with clinical signs of infection and may have normal inflammatory markers and joint aspirates. The biofilm-forming bacteria Propionibacterium acnes and Staphylococcus epidermidis are 2 such low-virulence organisms—once commonly considered contaminants but now recognized as potential pathogens for postoperative joint infections.9 In a review performed at a major orthopedic hospital, Bjerke-Kroll and colleagues10 found that the rate of PJI with P acnes has been increasing linearly over the past 14 years. According to reports in the literature,11-13P acnes has been isolated in 2% to 4% of all cases of PJI, and Zappe and colleagues13 found a P acnes PJI rate of 6% in a retrospective analysis performed at their institution. Given the high rate of P acnes colonization of the axilla, this organism is now increasingly recognized as a cause of infection after shoulder surgery, as found in a case series of 10 patients with P acnes PJI after total shoulder arthroplasty (TSA).14 However, there is still limited data on the role of P acnes in lower extremity PJI.
Although patients with P acnes PJI can present with overt signs of infection, more often they lack systemic or local signs of infection, making the diagnosis difficult.15 Surgeons may not consider PJI as a cause of TJA failure in patients who do not meet diagnostic criteria.7 In a case series of patients with P acnes PJI after TSA, Millett and colleagues14 concluded that erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) level are not always reliable indicators of infection with low-virulence organisms. Eighty percent of patients in their study had normal ESR and CRP level before surgery. Zappe and colleagues13 reported on P acnes PJI diagnoses in 4 total hip arthroplasties (THAs), 3 TKAs, and 1 TSA. Of the 8 patients, 6 (75%) had borderline elevated CRP levels, and 4 (50%) had normal synovial fluid analysis and cultures from joint aspirations. In a study using electron microscopy and fluorescence in situ hybridization (FISH) labeling, Stoodley and colleagues16 found, in 8 polyethylene liners removed from culture-negative THA patients for aseptic loosening, extensive biofilm colonization with S epidermidis.
Reports of PJI cases misdiagnosed as aseptic loosening also suggest that screening and diagnostic tools are not sensitive enough to detect all infections and that PJI likely is underdiagnosed. In a prospective cohort study, Portillo and colleagues17 categorized patients who were undergoing revision surgery after TJA by cause of failure: aseptic loosening, mechanical failure, or PJI based on current MSIS guidelines. Intraoperative cultures were taken during the revisions. P acnes was isolated in 2 (3%) of the 63 cases classified as PJI and in 12 (19%) of the 63 classified as aseptic loosening. Tsukayama and colleagues18 reported an 11% rate of positive intraoperative cultures for P acnes during revision surgery in cases that the operating surgeon considered aseptic, based on white blood cell (WBC) count, ESR, and CRP level. Rasouli and colleagues19 used an Ibis biosensor to perform polymerase chain reaction (PCR) on synovial fluid from 44 patients who underwent aseptic revision of TKA failures. The authors detected a pathogen in 17 (38%) of the 44 presumed aseptic patients and concluded some aseptic loosening cases are actually chronic low-grade organism PJIs not diagnosed according to current PJI criteria.
In this article, we present the case of a patient with a stiff, painful knee after TKA and with ESR, CRP level, and synovial fluid analysis within normal limits. Open biopsy for cultures showed P acnes PJI, which was successfully treated with 2-stage revision. The patient provided written informed consent for print and electronic publication of this case report.
Case Report
A 69-year-old man with a past medical history of hypertension underwent left primary TKA in 2012. In 2014, he presented to our office complaining of chronic left knee pain and stiffness that had developed insidiously over the first 3 months after surgery and never improved, despite rigorous physical therapy (Table).
With use of an assistive device, he could ambulate for a maximum of 1 city block, and he was on disability from his job as an electrician.
On presentation in 2014, radiographs of the left knee showed a well-seated, well-aligned TKA without any radiographic changes relative to the immediate postoperative radiographs (Figures 1A-1B, 2A-2B). Physical examination revealed no erythema or swelling of the joint. Skin was intact and incision well-healed. Left knee passive range of motion (ROM) was 10° to 30° of flexion and painful. A full infectious work-up was performed. Inflammatory markers were within normal limits: serum WBC count, 5.2 × 103/μL (normal, 4.0-10.5 × 103/uL); ESR, 9 mm/h (normal, <20 mm/h); and CRP, 0.29 mg/dL (normal, <0.8 mg/dL). Synovial fluid aspiration was performed for fluid analysis and cultures. Analysis revealed 422 WBCs/μL with 42% polymorphonuclear neutrophils (PMNs). MSIS criteria for using synovial fluid to diagnose PJI are >3000 WBC cells/uL with >65% PMNs. Cultures from synovial fluid were negative at 8 days of incubation.
Despite not meeting MSIS diagnostic criteria, the patient elected to undergo open biopsy for synovial culture as a last resort. During surgery, there was no purulence in the joint, and frozen section showed <5 neutrophils per high-power field. All cultures from 5 separate synovial tissue samples grew P acnes,confirming the PJI diagnosis. Cultures turned positive after being incubated an average of 12.2 days (range, 10-14 days). Sensitivities showed the organism was responsive to oxacillin. The risks and benefits of 2-stage revision surgery were discussed with the patient at the next office visit, and he decided on 2-stage revision. On November 4, 2014, he underwent open synovectomy, irrigation and débridement with iodine and Dakin solution, hardware removal, and cement antibiotic spacer placement without complication (Figures 3A, 3B).
Intravenous (IV) oxacillin was administered for 6 weeks, as directed by an infectious disease specialist, and the patient was monitored, both clinically and by ESR and CRP level, for signs of infection.
Just before stage 2 revision on January 6, 2015, preoperative inflammatory markers were within normal limits. During surgery, additional cultures were taken from synovial tissue. At 15 days, these cultures showed no growth, confirming eradication of the infection. The patient underwent reimplantation without complication and had an uneventful postoperative course with no wound-healing issues (Figures 4A, 4B).
At 1-month, 3-month, 6-month, and 1-year follow-up, he endorsed significantly improved pain and symptoms. ROM at 1-year follow-up was improved to 5° to 90° of flexion. The patient was ambulating pain-free, without an assistive device, and he had returned to work. He reported being satisfied with having undergone the 2-stage revision.
Discussion
Because PJIs with low-virulence organisms can present with normal levels of inflammatory markers and negative fluid analysis and culture from joint aspirations, they pose a diagnostic challenge for arthroplasty surgeons. In this case report, there was a low index of suspicion for PJI based on radiographic, physical examination, and laboratory findings. Our patient did not meet MSIS diagnostic criteria for PJI before undergoing open biopsy. Initial cultures from joint aspiration of synovial fluid were negative, and inflammatory markers were within normal limits. However, all 5 synovial tissue biopsy specimens that were cultured confirmed a low-grade periprosthetic infection with P acnes—likely the reason for the poor outcome. This case supports Zappe and colleagues13 and Millett and colleagues,14 who found that a subset of patients with a low-grade organism PJI had normal to mildly elevated inflammatory markers and negative fluid analysis and cultures from joint aspirations.
Hardware-involved orthopedic infections are often caused by bacteria that form a biofilm, which can be difficult to culture. Biofilm matrix binds cells into aggregates, which grow only a single colony on culture media, decreasing positive yield. Therefore, synovial fluid cultures are often negative, because of the low number of planktonic cells removed by aspirate. Using FISH and PCR, Stoodley and colleagues16 found biofilm on hardware removed for “culture-negative aseptic loosening.” This is especially important for low-grade organism infections that lack a strong inflammatory response in the joint and that may be missed with traditional screening. This may be one reason our patient’s synovial fluid cultures and inflammatory markers were negative.
Another reason these low-grade infections can be missed is that P acnes is notoriously difficult to culture—it may take up to 15 days to grow in a special medium.20 Intraoperative cultures may be read as false-negative if not incubated the right amount of time. In many hospitals, aerobic and anaerobic cultures are discarded if there is no growth after 3 to 5 days. In our patient’s case, the earliest that cultures turned positive was on day 10—which is consistent with other reports, including one by Butler-Wu and colleagues,15 who suggested a minimum incubation of 13 days for optimal recovery of organisms. Our case highlights the importance of lengthening incubation to allow for growth of low-virulent organisms. Given the different types of management used for PJI and aseptic loosening, it is imperative that surgeons take cultures during revision TJA and that cultures are held up to 14 days to allow enough time for low-virulence organisms to grow.
Fortunately, PJI with low-virulence organisms can be treated successfully. Treating P acnes PJI with exchange arthroplasty and IV antibiotics has documented success rates as high as 92%.21 Again, we emphasize the importance of obtaining intraoperative cultures to determine antibiotic sensitivities, which can guide treatment. Our patient’s infection was eradicated with 2-stage revision and IV antibiotics, and his symptoms, ROM, and function improved significantly.
Diagnosing PJI after TJA can be challenging, as there is no definitive test that is sensitive, specific, rapid, and minimally invasive. Researchers have looked for novel serum or synovial fluid biomarkers that may be elevated in PJI. Synovial interleukin 6 (IL-6) and synovial α-defensin show great promise. In 2 separate studies, elevated IL-6 levels strongly correlated with infection.22,23 Jacovides and colleagues23 found that a synovial IL-6 level higher than 4270 pg/mL had a 100% positive predictive value and a 91% negative predictive value for diagnosing PJI. In some trials, synovial α-defensin has shown up to 100% sensitivity and specificity for PJI diagnosis. Most notably, in a trial by Frangiamore and colleagues,24 α-defensin levels were elevated to statistically significant levels in P acnes PJI, indicating this test may help in diagnosing PJI with low-virulence organisms. Finally, PCR has also shown promise in detecting low-grade joint infections. PCR uses 16 primers that allow not only for the identification of pan-genomic bacterial markers, specific bacterial organisms, and Candida, but also for the presence of antibiotic resistance markers. Use of pan-genomic PCR also allows for detection of a wider variety of pathogens, including organisms commonly missed by conventional culture methods.25Early intervention can significantly improve outcomes in PJI. Therefore, we recommend maintaining a high index of suspicion for low-virulence PJI in patients with chronic pain and decreased functionality after TJA with well-placed implants, despite their not meeting current MSIS diagnostic criteria for PJI. As new microbiological tools for detecting PJI with low-grade organisms are developed, use of these technologies can be incorporated into the diagnosis algorithm. Screening tools more sensitive in detecting low-grade organisms can help avoid the morbidity associated with interoperative synovial biopsies for culture and can allow for more efficient surgical planning. These tools, along with increased clinical awareness of potential PJIs, ultimately will lead to earlier detection, accurate diagnosis, and optimal treatment.
Am J Orthop. 2017;46(3):E148-E153. Copyright Frontline Medical Communications Inc. 2017. All rights reserved.
References
1. Bozic KJ, Kurtz SM, Lau E, et al. The epidemiology of revision total knee arthroplasty in the United States. Clin Orthop Relat Res. 2010;468(1):45-51.
2. Kamath AF, Ong KL, Lau E, et al. Quantifying the burden of revision total joint arthroplasty for periprosthetic infection. J Arthroplasty. 2015;30(9):1492-1497.
3. Kurtz SM, Ong KL, Schmier J, et al. Future clinical and economic impact of revision total hip and knee arthroplasty. J Bone Joint Surg Am. 2007;89(suppl 3):144-151.
4. Zmistowski B, Restrepo C, Huang R, Hozack WJ, Parvizi J. Periprosthetic joint infection diagnosis: a complete understanding of white blood cell count and differential. J Arthroplasty. 2012;27(9):1589-1593.
5. Parvizi J, Adeli B, Zmistowski B, Restrepo C, Greenwald AS. Management of periprosthetic joint infection: the current knowledge: AAOS exhibit selection. J Bone Joint Surg Am. 2012;94(14):e104.
6. Djahani O, Rainer S, Pietsch M, Hofmann S. Systematic analysis of painful total knee prosthesis, a diagnostic algorithm. Arch Bone Jt Surg. 2013;1(2):48-52.
7. Parvizi J, Suh DH, Jafari SM, Mullan A, Purtill JJ. Aseptic loosening of total hip arthroplasty: infection always should be ruled out. Clin Orthop Relat Res. 2011;469(5):1401-1405.
8. Della Valle C, Parvizi J, Bauer TW, et al. Diagnosis of periprosthetic joint infections of the hip and knee. J Am Acad Orthop Surg. 2010;18(12):760-770.
9. Dramis A, Aldlyami E, Grimer RJ, Dunlop DJ, O’Connell N, Elliott T. What is the significance of a positive Propionibacterium acnes culture around a joint replacement? Int Orthop. 2009;33(3):829-833.
10. Bjerke-Kroll BT, Christ AB, Mclawhorn AS, Sculco PK, Jules-Elysée KM, Sculco TP. Periprosthetic joint infections treated with two-stage revision over 14 years: an evolving microbiology profile. J Arthroplasty. 2014;29(5):877-882.
11. Pandey R, Berendt AR, Athanasou NA. Histological and microbiological findings in non-infected and infected revision arthroplasty tissues. The OSIRIS Collaborative Study Group. Oxford Skeletal Infection Research and Intervention Service. Arch Orthop Trauma Surg. 2000;120(10):570-574.
12. Segawa H, Tsukayama DT, Kyle RF, Becker DA, Gustilo RB. Infection after total knee arthroplasty. A retrospective study of the treatment of eighty-one infections. J Bone Joint Surg Am. 1999;81(10):1434-1445.
13. Zappe B, Graf S, Ochsner PE, Zimmerli W, Sendi P. Propionibacterium spp. in prosthetic joint infections: a diagnostic challenge. Arch Orthop Trauma Surg. 2008;128(10):1039-1046.
14. Millett PJ, Yen YM, Price CS, Horan MP, van der Meijden OA, Elser F. Propionibacterium acnes infection as an occult cause of postoperative shoulder pain: a case series. Clin Orthop Relat Res. 2011;469(10):2824-2830.
15. Butler-Wu SM, Burns EM, Pottinger PS, et al. Optimization of periprosthetic culture for diagnosis of Propionibacterium acnes prosthetic joint infection. J Clin Microbiol. 2011;49(7):2490-2495.
17. Portillo ME, Salvadó M, Alier A, et al. Prosthesis failure within 2 years of implantation is highly predictive of infection. Clin Orthop Relat Res. 2013;471(11):3672-3678.
18. Tsukayama DT, Strada R, Gustilo RB. Infection after total hip arthroplasty. A study of the treatment of one hundred and six infections. J Bone Joint Surg Am. 1996;78(4):512-523.
19. Rasouli MR, Harandi AA, Adeli B, Purtill JJ, Parvizi J. Revision total knee arthroplasty: infection should be ruled out in all cases. J Arthroplasty. 2012;27(6):1239-1243.e1-e2.
20. Schäfer P, Fink B, Sandow D, Margull A, Berger I, Frommelt L. Prolonged bacterial culture to identify late periprosthetic joint infection: a promising strategy. Clin Infect Dis. 2008;47(11):1403-1409.
21. Zeller V, Ghorbani A, Strady C, Leonard P, Mamoudy P, Desplaces N. Propionibacterium acnes: an agent of prosthetic joint infection and colonization. J Infect. 2007;55(2):119-124.
22. Deirmengian C, Kardos K, Kilmartin P, Cameron A, Schiller K, Parvizi J. Diagnosing periprosthetic joint infection: has the era of the biomarker arrived? Clin Orthop Relat Res. 2014;472(11):3254-3262.
23. Jacovides CL, Parvizi J, Adeli B, Jung KA. Molecular markers for diagnosis of periprosthetic joint infection. J Arthroplasty. 2011;26(6 suppl):99-103.e1.
24. Frangiamore SJ, Gajewski ND, Saleh A, Farias-Kovac M, Barsoum WK, Higuera CA. α-Defensin accuracy to diagnose periprosthetic joint infection—best available test? J Arthroplasty. 2016;31(2):456-460.
25. Hartley JC, Harris KA. Molecular techniques for diagnosing prosthetic joint infections. J Antimicrob Chemother. 2014;69(suppl 1):i21-i24.
Despite standardization of diagnostic criteria by the MSIS for the diagnosis of PJI, some low-grade inflections create a diagnostic challenge for clinicians.
P acnes infection following TJA can be present despite patients having normal serum inflammatory marker levels and synovial fluid aspirations.
Patients with a PJI with low virulence organisms can present with painful, arthrofibrotic joints that do not appear to be clinically infected.
Biopsy for pathology and culture can aid in the diagnosis of suspected PJI in patients who fail to meet MSIS criteria.
If detected and accurately diagnosed, PJI with P acnes can be successfully eradicated with IV antibiotics and 2-stage revision arthroplasty with a good functional outcome.
Total joint arthroplasty (TJA) is a routinely performed, highly efficacious procedure for patients with degenerative osteoarthritis.1,2 In the United States in 2003, more than 450,000 total knee arthroplasties (TKAs) were performed, and this number is projected to increase by more than 673% by 2030, as America’s population continues to age.3 With the increase in primary TJAs has come an increase in revision TJAs. The most common cause of revision TJA is infection (25.2%), which has a rate of 1% to 4% after primary TJA.1,4 Despite advancements in implant technology, preoperative preventive strategies, perioperative techniques, and postoperative management, a recent meta-analysis of patient follow-up data revealed that 15% to 20% of patients remained dissatisfied after TJA, despite having technically well-placed implants.5,6
Recent studies have suggested that prosthetic joint infection (PJI) may be underreported because of the difficulty in diagnosis, which may be one of the reasons why patients remain dissatisfied after TJA.7 As a result, new efforts have been made to develop uniform criteria for PJI diagnosis.8 In 2011, the Musculoskeletal Infection Society (MSIS) developed a new definition for the PJI diagnosis, based on clinical and laboratory criteria, in order to increase diagnostic accuracy. However, MSIS acknowledged that PJI may be present even if these criteria are not met, particularly in the case of low-grade infections, as patients may not present with clinical signs of infection and may have normal inflammatory markers and joint aspirates. The biofilm-forming bacteria Propionibacterium acnes and Staphylococcus epidermidis are 2 such low-virulence organisms—once commonly considered contaminants but now recognized as potential pathogens for postoperative joint infections.9 In a review performed at a major orthopedic hospital, Bjerke-Kroll and colleagues10 found that the rate of PJI with P acnes has been increasing linearly over the past 14 years. According to reports in the literature,11-13P acnes has been isolated in 2% to 4% of all cases of PJI, and Zappe and colleagues13 found a P acnes PJI rate of 6% in a retrospective analysis performed at their institution. Given the high rate of P acnes colonization of the axilla, this organism is now increasingly recognized as a cause of infection after shoulder surgery, as found in a case series of 10 patients with P acnes PJI after total shoulder arthroplasty (TSA).14 However, there is still limited data on the role of P acnes in lower extremity PJI.
Although patients with P acnes PJI can present with overt signs of infection, more often they lack systemic or local signs of infection, making the diagnosis difficult.15 Surgeons may not consider PJI as a cause of TJA failure in patients who do not meet diagnostic criteria.7 In a case series of patients with P acnes PJI after TSA, Millett and colleagues14 concluded that erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) level are not always reliable indicators of infection with low-virulence organisms. Eighty percent of patients in their study had normal ESR and CRP level before surgery. Zappe and colleagues13 reported on P acnes PJI diagnoses in 4 total hip arthroplasties (THAs), 3 TKAs, and 1 TSA. Of the 8 patients, 6 (75%) had borderline elevated CRP levels, and 4 (50%) had normal synovial fluid analysis and cultures from joint aspirations. In a study using electron microscopy and fluorescence in situ hybridization (FISH) labeling, Stoodley and colleagues16 found, in 8 polyethylene liners removed from culture-negative THA patients for aseptic loosening, extensive biofilm colonization with S epidermidis.
Reports of PJI cases misdiagnosed as aseptic loosening also suggest that screening and diagnostic tools are not sensitive enough to detect all infections and that PJI likely is underdiagnosed. In a prospective cohort study, Portillo and colleagues17 categorized patients who were undergoing revision surgery after TJA by cause of failure: aseptic loosening, mechanical failure, or PJI based on current MSIS guidelines. Intraoperative cultures were taken during the revisions. P acnes was isolated in 2 (3%) of the 63 cases classified as PJI and in 12 (19%) of the 63 classified as aseptic loosening. Tsukayama and colleagues18 reported an 11% rate of positive intraoperative cultures for P acnes during revision surgery in cases that the operating surgeon considered aseptic, based on white blood cell (WBC) count, ESR, and CRP level. Rasouli and colleagues19 used an Ibis biosensor to perform polymerase chain reaction (PCR) on synovial fluid from 44 patients who underwent aseptic revision of TKA failures. The authors detected a pathogen in 17 (38%) of the 44 presumed aseptic patients and concluded some aseptic loosening cases are actually chronic low-grade organism PJIs not diagnosed according to current PJI criteria.
In this article, we present the case of a patient with a stiff, painful knee after TKA and with ESR, CRP level, and synovial fluid analysis within normal limits. Open biopsy for cultures showed P acnes PJI, which was successfully treated with 2-stage revision. The patient provided written informed consent for print and electronic publication of this case report.
Case Report
A 69-year-old man with a past medical history of hypertension underwent left primary TKA in 2012. In 2014, he presented to our office complaining of chronic left knee pain and stiffness that had developed insidiously over the first 3 months after surgery and never improved, despite rigorous physical therapy (Table).
With use of an assistive device, he could ambulate for a maximum of 1 city block, and he was on disability from his job as an electrician.
On presentation in 2014, radiographs of the left knee showed a well-seated, well-aligned TKA without any radiographic changes relative to the immediate postoperative radiographs (Figures 1A-1B, 2A-2B). Physical examination revealed no erythema or swelling of the joint. Skin was intact and incision well-healed. Left knee passive range of motion (ROM) was 10° to 30° of flexion and painful. A full infectious work-up was performed. Inflammatory markers were within normal limits: serum WBC count, 5.2 × 103/μL (normal, 4.0-10.5 × 103/uL); ESR, 9 mm/h (normal, <20 mm/h); and CRP, 0.29 mg/dL (normal, <0.8 mg/dL). Synovial fluid aspiration was performed for fluid analysis and cultures. Analysis revealed 422 WBCs/μL with 42% polymorphonuclear neutrophils (PMNs). MSIS criteria for using synovial fluid to diagnose PJI are >3000 WBC cells/uL with >65% PMNs. Cultures from synovial fluid were negative at 8 days of incubation.
Despite not meeting MSIS diagnostic criteria, the patient elected to undergo open biopsy for synovial culture as a last resort. During surgery, there was no purulence in the joint, and frozen section showed <5 neutrophils per high-power field. All cultures from 5 separate synovial tissue samples grew P acnes,confirming the PJI diagnosis. Cultures turned positive after being incubated an average of 12.2 days (range, 10-14 days). Sensitivities showed the organism was responsive to oxacillin. The risks and benefits of 2-stage revision surgery were discussed with the patient at the next office visit, and he decided on 2-stage revision. On November 4, 2014, he underwent open synovectomy, irrigation and débridement with iodine and Dakin solution, hardware removal, and cement antibiotic spacer placement without complication (Figures 3A, 3B).
Intravenous (IV) oxacillin was administered for 6 weeks, as directed by an infectious disease specialist, and the patient was monitored, both clinically and by ESR and CRP level, for signs of infection.
Just before stage 2 revision on January 6, 2015, preoperative inflammatory markers were within normal limits. During surgery, additional cultures were taken from synovial tissue. At 15 days, these cultures showed no growth, confirming eradication of the infection. The patient underwent reimplantation without complication and had an uneventful postoperative course with no wound-healing issues (Figures 4A, 4B).
At 1-month, 3-month, 6-month, and 1-year follow-up, he endorsed significantly improved pain and symptoms. ROM at 1-year follow-up was improved to 5° to 90° of flexion. The patient was ambulating pain-free, without an assistive device, and he had returned to work. He reported being satisfied with having undergone the 2-stage revision.
Discussion
Because PJIs with low-virulence organisms can present with normal levels of inflammatory markers and negative fluid analysis and culture from joint aspirations, they pose a diagnostic challenge for arthroplasty surgeons. In this case report, there was a low index of suspicion for PJI based on radiographic, physical examination, and laboratory findings. Our patient did not meet MSIS diagnostic criteria for PJI before undergoing open biopsy. Initial cultures from joint aspiration of synovial fluid were negative, and inflammatory markers were within normal limits. However, all 5 synovial tissue biopsy specimens that were cultured confirmed a low-grade periprosthetic infection with P acnes—likely the reason for the poor outcome. This case supports Zappe and colleagues13 and Millett and colleagues,14 who found that a subset of patients with a low-grade organism PJI had normal to mildly elevated inflammatory markers and negative fluid analysis and cultures from joint aspirations.
Hardware-involved orthopedic infections are often caused by bacteria that form a biofilm, which can be difficult to culture. Biofilm matrix binds cells into aggregates, which grow only a single colony on culture media, decreasing positive yield. Therefore, synovial fluid cultures are often negative, because of the low number of planktonic cells removed by aspirate. Using FISH and PCR, Stoodley and colleagues16 found biofilm on hardware removed for “culture-negative aseptic loosening.” This is especially important for low-grade organism infections that lack a strong inflammatory response in the joint and that may be missed with traditional screening. This may be one reason our patient’s synovial fluid cultures and inflammatory markers were negative.
Another reason these low-grade infections can be missed is that P acnes is notoriously difficult to culture—it may take up to 15 days to grow in a special medium.20 Intraoperative cultures may be read as false-negative if not incubated the right amount of time. In many hospitals, aerobic and anaerobic cultures are discarded if there is no growth after 3 to 5 days. In our patient’s case, the earliest that cultures turned positive was on day 10—which is consistent with other reports, including one by Butler-Wu and colleagues,15 who suggested a minimum incubation of 13 days for optimal recovery of organisms. Our case highlights the importance of lengthening incubation to allow for growth of low-virulent organisms. Given the different types of management used for PJI and aseptic loosening, it is imperative that surgeons take cultures during revision TJA and that cultures are held up to 14 days to allow enough time for low-virulence organisms to grow.
Fortunately, PJI with low-virulence organisms can be treated successfully. Treating P acnes PJI with exchange arthroplasty and IV antibiotics has documented success rates as high as 92%.21 Again, we emphasize the importance of obtaining intraoperative cultures to determine antibiotic sensitivities, which can guide treatment. Our patient’s infection was eradicated with 2-stage revision and IV antibiotics, and his symptoms, ROM, and function improved significantly.
Diagnosing PJI after TJA can be challenging, as there is no definitive test that is sensitive, specific, rapid, and minimally invasive. Researchers have looked for novel serum or synovial fluid biomarkers that may be elevated in PJI. Synovial interleukin 6 (IL-6) and synovial α-defensin show great promise. In 2 separate studies, elevated IL-6 levels strongly correlated with infection.22,23 Jacovides and colleagues23 found that a synovial IL-6 level higher than 4270 pg/mL had a 100% positive predictive value and a 91% negative predictive value for diagnosing PJI. In some trials, synovial α-defensin has shown up to 100% sensitivity and specificity for PJI diagnosis. Most notably, in a trial by Frangiamore and colleagues,24 α-defensin levels were elevated to statistically significant levels in P acnes PJI, indicating this test may help in diagnosing PJI with low-virulence organisms. Finally, PCR has also shown promise in detecting low-grade joint infections. PCR uses 16 primers that allow not only for the identification of pan-genomic bacterial markers, specific bacterial organisms, and Candida, but also for the presence of antibiotic resistance markers. Use of pan-genomic PCR also allows for detection of a wider variety of pathogens, including organisms commonly missed by conventional culture methods.25Early intervention can significantly improve outcomes in PJI. Therefore, we recommend maintaining a high index of suspicion for low-virulence PJI in patients with chronic pain and decreased functionality after TJA with well-placed implants, despite their not meeting current MSIS diagnostic criteria for PJI. As new microbiological tools for detecting PJI with low-grade organisms are developed, use of these technologies can be incorporated into the diagnosis algorithm. Screening tools more sensitive in detecting low-grade organisms can help avoid the morbidity associated with interoperative synovial biopsies for culture and can allow for more efficient surgical planning. These tools, along with increased clinical awareness of potential PJIs, ultimately will lead to earlier detection, accurate diagnosis, and optimal treatment.
Am J Orthop. 2017;46(3):E148-E153. Copyright Frontline Medical Communications Inc. 2017. All rights reserved.
Take-Home Points
Despite standardization of diagnostic criteria by the MSIS for the diagnosis of PJI, some low-grade inflections create a diagnostic challenge for clinicians.
P acnes infection following TJA can be present despite patients having normal serum inflammatory marker levels and synovial fluid aspirations.
Patients with a PJI with low virulence organisms can present with painful, arthrofibrotic joints that do not appear to be clinically infected.
Biopsy for pathology and culture can aid in the diagnosis of suspected PJI in patients who fail to meet MSIS criteria.
If detected and accurately diagnosed, PJI with P acnes can be successfully eradicated with IV antibiotics and 2-stage revision arthroplasty with a good functional outcome.
Total joint arthroplasty (TJA) is a routinely performed, highly efficacious procedure for patients with degenerative osteoarthritis.1,2 In the United States in 2003, more than 450,000 total knee arthroplasties (TKAs) were performed, and this number is projected to increase by more than 673% by 2030, as America’s population continues to age.3 With the increase in primary TJAs has come an increase in revision TJAs. The most common cause of revision TJA is infection (25.2%), which has a rate of 1% to 4% after primary TJA.1,4 Despite advancements in implant technology, preoperative preventive strategies, perioperative techniques, and postoperative management, a recent meta-analysis of patient follow-up data revealed that 15% to 20% of patients remained dissatisfied after TJA, despite having technically well-placed implants.5,6
Recent studies have suggested that prosthetic joint infection (PJI) may be underreported because of the difficulty in diagnosis, which may be one of the reasons why patients remain dissatisfied after TJA.7 As a result, new efforts have been made to develop uniform criteria for PJI diagnosis.8 In 2011, the Musculoskeletal Infection Society (MSIS) developed a new definition for the PJI diagnosis, based on clinical and laboratory criteria, in order to increase diagnostic accuracy. However, MSIS acknowledged that PJI may be present even if these criteria are not met, particularly in the case of low-grade infections, as patients may not present with clinical signs of infection and may have normal inflammatory markers and joint aspirates. The biofilm-forming bacteria Propionibacterium acnes and Staphylococcus epidermidis are 2 such low-virulence organisms—once commonly considered contaminants but now recognized as potential pathogens for postoperative joint infections.9 In a review performed at a major orthopedic hospital, Bjerke-Kroll and colleagues10 found that the rate of PJI with P acnes has been increasing linearly over the past 14 years. According to reports in the literature,11-13P acnes has been isolated in 2% to 4% of all cases of PJI, and Zappe and colleagues13 found a P acnes PJI rate of 6% in a retrospective analysis performed at their institution. Given the high rate of P acnes colonization of the axilla, this organism is now increasingly recognized as a cause of infection after shoulder surgery, as found in a case series of 10 patients with P acnes PJI after total shoulder arthroplasty (TSA).14 However, there is still limited data on the role of P acnes in lower extremity PJI.
Although patients with P acnes PJI can present with overt signs of infection, more often they lack systemic or local signs of infection, making the diagnosis difficult.15 Surgeons may not consider PJI as a cause of TJA failure in patients who do not meet diagnostic criteria.7 In a case series of patients with P acnes PJI after TSA, Millett and colleagues14 concluded that erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) level are not always reliable indicators of infection with low-virulence organisms. Eighty percent of patients in their study had normal ESR and CRP level before surgery. Zappe and colleagues13 reported on P acnes PJI diagnoses in 4 total hip arthroplasties (THAs), 3 TKAs, and 1 TSA. Of the 8 patients, 6 (75%) had borderline elevated CRP levels, and 4 (50%) had normal synovial fluid analysis and cultures from joint aspirations. In a study using electron microscopy and fluorescence in situ hybridization (FISH) labeling, Stoodley and colleagues16 found, in 8 polyethylene liners removed from culture-negative THA patients for aseptic loosening, extensive biofilm colonization with S epidermidis.
Reports of PJI cases misdiagnosed as aseptic loosening also suggest that screening and diagnostic tools are not sensitive enough to detect all infections and that PJI likely is underdiagnosed. In a prospective cohort study, Portillo and colleagues17 categorized patients who were undergoing revision surgery after TJA by cause of failure: aseptic loosening, mechanical failure, or PJI based on current MSIS guidelines. Intraoperative cultures were taken during the revisions. P acnes was isolated in 2 (3%) of the 63 cases classified as PJI and in 12 (19%) of the 63 classified as aseptic loosening. Tsukayama and colleagues18 reported an 11% rate of positive intraoperative cultures for P acnes during revision surgery in cases that the operating surgeon considered aseptic, based on white blood cell (WBC) count, ESR, and CRP level. Rasouli and colleagues19 used an Ibis biosensor to perform polymerase chain reaction (PCR) on synovial fluid from 44 patients who underwent aseptic revision of TKA failures. The authors detected a pathogen in 17 (38%) of the 44 presumed aseptic patients and concluded some aseptic loosening cases are actually chronic low-grade organism PJIs not diagnosed according to current PJI criteria.
In this article, we present the case of a patient with a stiff, painful knee after TKA and with ESR, CRP level, and synovial fluid analysis within normal limits. Open biopsy for cultures showed P acnes PJI, which was successfully treated with 2-stage revision. The patient provided written informed consent for print and electronic publication of this case report.
Case Report
A 69-year-old man with a past medical history of hypertension underwent left primary TKA in 2012. In 2014, he presented to our office complaining of chronic left knee pain and stiffness that had developed insidiously over the first 3 months after surgery and never improved, despite rigorous physical therapy (Table).
With use of an assistive device, he could ambulate for a maximum of 1 city block, and he was on disability from his job as an electrician.
On presentation in 2014, radiographs of the left knee showed a well-seated, well-aligned TKA without any radiographic changes relative to the immediate postoperative radiographs (Figures 1A-1B, 2A-2B). Physical examination revealed no erythema or swelling of the joint. Skin was intact and incision well-healed. Left knee passive range of motion (ROM) was 10° to 30° of flexion and painful. A full infectious work-up was performed. Inflammatory markers were within normal limits: serum WBC count, 5.2 × 103/μL (normal, 4.0-10.5 × 103/uL); ESR, 9 mm/h (normal, <20 mm/h); and CRP, 0.29 mg/dL (normal, <0.8 mg/dL). Synovial fluid aspiration was performed for fluid analysis and cultures. Analysis revealed 422 WBCs/μL with 42% polymorphonuclear neutrophils (PMNs). MSIS criteria for using synovial fluid to diagnose PJI are >3000 WBC cells/uL with >65% PMNs. Cultures from synovial fluid were negative at 8 days of incubation.
Despite not meeting MSIS diagnostic criteria, the patient elected to undergo open biopsy for synovial culture as a last resort. During surgery, there was no purulence in the joint, and frozen section showed <5 neutrophils per high-power field. All cultures from 5 separate synovial tissue samples grew P acnes,confirming the PJI diagnosis. Cultures turned positive after being incubated an average of 12.2 days (range, 10-14 days). Sensitivities showed the organism was responsive to oxacillin. The risks and benefits of 2-stage revision surgery were discussed with the patient at the next office visit, and he decided on 2-stage revision. On November 4, 2014, he underwent open synovectomy, irrigation and débridement with iodine and Dakin solution, hardware removal, and cement antibiotic spacer placement without complication (Figures 3A, 3B).
Intravenous (IV) oxacillin was administered for 6 weeks, as directed by an infectious disease specialist, and the patient was monitored, both clinically and by ESR and CRP level, for signs of infection.
Just before stage 2 revision on January 6, 2015, preoperative inflammatory markers were within normal limits. During surgery, additional cultures were taken from synovial tissue. At 15 days, these cultures showed no growth, confirming eradication of the infection. The patient underwent reimplantation without complication and had an uneventful postoperative course with no wound-healing issues (Figures 4A, 4B).
At 1-month, 3-month, 6-month, and 1-year follow-up, he endorsed significantly improved pain and symptoms. ROM at 1-year follow-up was improved to 5° to 90° of flexion. The patient was ambulating pain-free, without an assistive device, and he had returned to work. He reported being satisfied with having undergone the 2-stage revision.
Discussion
Because PJIs with low-virulence organisms can present with normal levels of inflammatory markers and negative fluid analysis and culture from joint aspirations, they pose a diagnostic challenge for arthroplasty surgeons. In this case report, there was a low index of suspicion for PJI based on radiographic, physical examination, and laboratory findings. Our patient did not meet MSIS diagnostic criteria for PJI before undergoing open biopsy. Initial cultures from joint aspiration of synovial fluid were negative, and inflammatory markers were within normal limits. However, all 5 synovial tissue biopsy specimens that were cultured confirmed a low-grade periprosthetic infection with P acnes—likely the reason for the poor outcome. This case supports Zappe and colleagues13 and Millett and colleagues,14 who found that a subset of patients with a low-grade organism PJI had normal to mildly elevated inflammatory markers and negative fluid analysis and cultures from joint aspirations.
Hardware-involved orthopedic infections are often caused by bacteria that form a biofilm, which can be difficult to culture. Biofilm matrix binds cells into aggregates, which grow only a single colony on culture media, decreasing positive yield. Therefore, synovial fluid cultures are often negative, because of the low number of planktonic cells removed by aspirate. Using FISH and PCR, Stoodley and colleagues16 found biofilm on hardware removed for “culture-negative aseptic loosening.” This is especially important for low-grade organism infections that lack a strong inflammatory response in the joint and that may be missed with traditional screening. This may be one reason our patient’s synovial fluid cultures and inflammatory markers were negative.
Another reason these low-grade infections can be missed is that P acnes is notoriously difficult to culture—it may take up to 15 days to grow in a special medium.20 Intraoperative cultures may be read as false-negative if not incubated the right amount of time. In many hospitals, aerobic and anaerobic cultures are discarded if there is no growth after 3 to 5 days. In our patient’s case, the earliest that cultures turned positive was on day 10—which is consistent with other reports, including one by Butler-Wu and colleagues,15 who suggested a minimum incubation of 13 days for optimal recovery of organisms. Our case highlights the importance of lengthening incubation to allow for growth of low-virulent organisms. Given the different types of management used for PJI and aseptic loosening, it is imperative that surgeons take cultures during revision TJA and that cultures are held up to 14 days to allow enough time for low-virulence organisms to grow.
Fortunately, PJI with low-virulence organisms can be treated successfully. Treating P acnes PJI with exchange arthroplasty and IV antibiotics has documented success rates as high as 92%.21 Again, we emphasize the importance of obtaining intraoperative cultures to determine antibiotic sensitivities, which can guide treatment. Our patient’s infection was eradicated with 2-stage revision and IV antibiotics, and his symptoms, ROM, and function improved significantly.
Diagnosing PJI after TJA can be challenging, as there is no definitive test that is sensitive, specific, rapid, and minimally invasive. Researchers have looked for novel serum or synovial fluid biomarkers that may be elevated in PJI. Synovial interleukin 6 (IL-6) and synovial α-defensin show great promise. In 2 separate studies, elevated IL-6 levels strongly correlated with infection.22,23 Jacovides and colleagues23 found that a synovial IL-6 level higher than 4270 pg/mL had a 100% positive predictive value and a 91% negative predictive value for diagnosing PJI. In some trials, synovial α-defensin has shown up to 100% sensitivity and specificity for PJI diagnosis. Most notably, in a trial by Frangiamore and colleagues,24 α-defensin levels were elevated to statistically significant levels in P acnes PJI, indicating this test may help in diagnosing PJI with low-virulence organisms. Finally, PCR has also shown promise in detecting low-grade joint infections. PCR uses 16 primers that allow not only for the identification of pan-genomic bacterial markers, specific bacterial organisms, and Candida, but also for the presence of antibiotic resistance markers. Use of pan-genomic PCR also allows for detection of a wider variety of pathogens, including organisms commonly missed by conventional culture methods.25Early intervention can significantly improve outcomes in PJI. Therefore, we recommend maintaining a high index of suspicion for low-virulence PJI in patients with chronic pain and decreased functionality after TJA with well-placed implants, despite their not meeting current MSIS diagnostic criteria for PJI. As new microbiological tools for detecting PJI with low-grade organisms are developed, use of these technologies can be incorporated into the diagnosis algorithm. Screening tools more sensitive in detecting low-grade organisms can help avoid the morbidity associated with interoperative synovial biopsies for culture and can allow for more efficient surgical planning. These tools, along with increased clinical awareness of potential PJIs, ultimately will lead to earlier detection, accurate diagnosis, and optimal treatment.
Am J Orthop. 2017;46(3):E148-E153. Copyright Frontline Medical Communications Inc. 2017. All rights reserved.
References
1. Bozic KJ, Kurtz SM, Lau E, et al. The epidemiology of revision total knee arthroplasty in the United States. Clin Orthop Relat Res. 2010;468(1):45-51.
2. Kamath AF, Ong KL, Lau E, et al. Quantifying the burden of revision total joint arthroplasty for periprosthetic infection. J Arthroplasty. 2015;30(9):1492-1497.
3. Kurtz SM, Ong KL, Schmier J, et al. Future clinical and economic impact of revision total hip and knee arthroplasty. J Bone Joint Surg Am. 2007;89(suppl 3):144-151.
4. Zmistowski B, Restrepo C, Huang R, Hozack WJ, Parvizi J. Periprosthetic joint infection diagnosis: a complete understanding of white blood cell count and differential. J Arthroplasty. 2012;27(9):1589-1593.
5. Parvizi J, Adeli B, Zmistowski B, Restrepo C, Greenwald AS. Management of periprosthetic joint infection: the current knowledge: AAOS exhibit selection. J Bone Joint Surg Am. 2012;94(14):e104.
6. Djahani O, Rainer S, Pietsch M, Hofmann S. Systematic analysis of painful total knee prosthesis, a diagnostic algorithm. Arch Bone Jt Surg. 2013;1(2):48-52.
7. Parvizi J, Suh DH, Jafari SM, Mullan A, Purtill JJ. Aseptic loosening of total hip arthroplasty: infection always should be ruled out. Clin Orthop Relat Res. 2011;469(5):1401-1405.
8. Della Valle C, Parvizi J, Bauer TW, et al. Diagnosis of periprosthetic joint infections of the hip and knee. J Am Acad Orthop Surg. 2010;18(12):760-770.
9. Dramis A, Aldlyami E, Grimer RJ, Dunlop DJ, O’Connell N, Elliott T. What is the significance of a positive Propionibacterium acnes culture around a joint replacement? Int Orthop. 2009;33(3):829-833.
10. Bjerke-Kroll BT, Christ AB, Mclawhorn AS, Sculco PK, Jules-Elysée KM, Sculco TP. Periprosthetic joint infections treated with two-stage revision over 14 years: an evolving microbiology profile. J Arthroplasty. 2014;29(5):877-882.
11. Pandey R, Berendt AR, Athanasou NA. Histological and microbiological findings in non-infected and infected revision arthroplasty tissues. The OSIRIS Collaborative Study Group. Oxford Skeletal Infection Research and Intervention Service. Arch Orthop Trauma Surg. 2000;120(10):570-574.
12. Segawa H, Tsukayama DT, Kyle RF, Becker DA, Gustilo RB. Infection after total knee arthroplasty. A retrospective study of the treatment of eighty-one infections. J Bone Joint Surg Am. 1999;81(10):1434-1445.
13. Zappe B, Graf S, Ochsner PE, Zimmerli W, Sendi P. Propionibacterium spp. in prosthetic joint infections: a diagnostic challenge. Arch Orthop Trauma Surg. 2008;128(10):1039-1046.
14. Millett PJ, Yen YM, Price CS, Horan MP, van der Meijden OA, Elser F. Propionibacterium acnes infection as an occult cause of postoperative shoulder pain: a case series. Clin Orthop Relat Res. 2011;469(10):2824-2830.
15. Butler-Wu SM, Burns EM, Pottinger PS, et al. Optimization of periprosthetic culture for diagnosis of Propionibacterium acnes prosthetic joint infection. J Clin Microbiol. 2011;49(7):2490-2495.
17. Portillo ME, Salvadó M, Alier A, et al. Prosthesis failure within 2 years of implantation is highly predictive of infection. Clin Orthop Relat Res. 2013;471(11):3672-3678.
18. Tsukayama DT, Strada R, Gustilo RB. Infection after total hip arthroplasty. A study of the treatment of one hundred and six infections. J Bone Joint Surg Am. 1996;78(4):512-523.
19. Rasouli MR, Harandi AA, Adeli B, Purtill JJ, Parvizi J. Revision total knee arthroplasty: infection should be ruled out in all cases. J Arthroplasty. 2012;27(6):1239-1243.e1-e2.
20. Schäfer P, Fink B, Sandow D, Margull A, Berger I, Frommelt L. Prolonged bacterial culture to identify late periprosthetic joint infection: a promising strategy. Clin Infect Dis. 2008;47(11):1403-1409.
21. Zeller V, Ghorbani A, Strady C, Leonard P, Mamoudy P, Desplaces N. Propionibacterium acnes: an agent of prosthetic joint infection and colonization. J Infect. 2007;55(2):119-124.
22. Deirmengian C, Kardos K, Kilmartin P, Cameron A, Schiller K, Parvizi J. Diagnosing periprosthetic joint infection: has the era of the biomarker arrived? Clin Orthop Relat Res. 2014;472(11):3254-3262.
23. Jacovides CL, Parvizi J, Adeli B, Jung KA. Molecular markers for diagnosis of periprosthetic joint infection. J Arthroplasty. 2011;26(6 suppl):99-103.e1.
24. Frangiamore SJ, Gajewski ND, Saleh A, Farias-Kovac M, Barsoum WK, Higuera CA. α-Defensin accuracy to diagnose periprosthetic joint infection—best available test? J Arthroplasty. 2016;31(2):456-460.
25. Hartley JC, Harris KA. Molecular techniques for diagnosing prosthetic joint infections. J Antimicrob Chemother. 2014;69(suppl 1):i21-i24.
References
1. Bozic KJ, Kurtz SM, Lau E, et al. The epidemiology of revision total knee arthroplasty in the United States. Clin Orthop Relat Res. 2010;468(1):45-51.
2. Kamath AF, Ong KL, Lau E, et al. Quantifying the burden of revision total joint arthroplasty for periprosthetic infection. J Arthroplasty. 2015;30(9):1492-1497.
3. Kurtz SM, Ong KL, Schmier J, et al. Future clinical and economic impact of revision total hip and knee arthroplasty. J Bone Joint Surg Am. 2007;89(suppl 3):144-151.
4. Zmistowski B, Restrepo C, Huang R, Hozack WJ, Parvizi J. Periprosthetic joint infection diagnosis: a complete understanding of white blood cell count and differential. J Arthroplasty. 2012;27(9):1589-1593.
5. Parvizi J, Adeli B, Zmistowski B, Restrepo C, Greenwald AS. Management of periprosthetic joint infection: the current knowledge: AAOS exhibit selection. J Bone Joint Surg Am. 2012;94(14):e104.
6. Djahani O, Rainer S, Pietsch M, Hofmann S. Systematic analysis of painful total knee prosthesis, a diagnostic algorithm. Arch Bone Jt Surg. 2013;1(2):48-52.
7. Parvizi J, Suh DH, Jafari SM, Mullan A, Purtill JJ. Aseptic loosening of total hip arthroplasty: infection always should be ruled out. Clin Orthop Relat Res. 2011;469(5):1401-1405.
8. Della Valle C, Parvizi J, Bauer TW, et al. Diagnosis of periprosthetic joint infections of the hip and knee. J Am Acad Orthop Surg. 2010;18(12):760-770.
9. Dramis A, Aldlyami E, Grimer RJ, Dunlop DJ, O’Connell N, Elliott T. What is the significance of a positive Propionibacterium acnes culture around a joint replacement? Int Orthop. 2009;33(3):829-833.
10. Bjerke-Kroll BT, Christ AB, Mclawhorn AS, Sculco PK, Jules-Elysée KM, Sculco TP. Periprosthetic joint infections treated with two-stage revision over 14 years: an evolving microbiology profile. J Arthroplasty. 2014;29(5):877-882.
11. Pandey R, Berendt AR, Athanasou NA. Histological and microbiological findings in non-infected and infected revision arthroplasty tissues. The OSIRIS Collaborative Study Group. Oxford Skeletal Infection Research and Intervention Service. Arch Orthop Trauma Surg. 2000;120(10):570-574.
12. Segawa H, Tsukayama DT, Kyle RF, Becker DA, Gustilo RB. Infection after total knee arthroplasty. A retrospective study of the treatment of eighty-one infections. J Bone Joint Surg Am. 1999;81(10):1434-1445.
13. Zappe B, Graf S, Ochsner PE, Zimmerli W, Sendi P. Propionibacterium spp. in prosthetic joint infections: a diagnostic challenge. Arch Orthop Trauma Surg. 2008;128(10):1039-1046.
14. Millett PJ, Yen YM, Price CS, Horan MP, van der Meijden OA, Elser F. Propionibacterium acnes infection as an occult cause of postoperative shoulder pain: a case series. Clin Orthop Relat Res. 2011;469(10):2824-2830.
15. Butler-Wu SM, Burns EM, Pottinger PS, et al. Optimization of periprosthetic culture for diagnosis of Propionibacterium acnes prosthetic joint infection. J Clin Microbiol. 2011;49(7):2490-2495.
17. Portillo ME, Salvadó M, Alier A, et al. Prosthesis failure within 2 years of implantation is highly predictive of infection. Clin Orthop Relat Res. 2013;471(11):3672-3678.
18. Tsukayama DT, Strada R, Gustilo RB. Infection after total hip arthroplasty. A study of the treatment of one hundred and six infections. J Bone Joint Surg Am. 1996;78(4):512-523.
19. Rasouli MR, Harandi AA, Adeli B, Purtill JJ, Parvizi J. Revision total knee arthroplasty: infection should be ruled out in all cases. J Arthroplasty. 2012;27(6):1239-1243.e1-e2.
20. Schäfer P, Fink B, Sandow D, Margull A, Berger I, Frommelt L. Prolonged bacterial culture to identify late periprosthetic joint infection: a promising strategy. Clin Infect Dis. 2008;47(11):1403-1409.
21. Zeller V, Ghorbani A, Strady C, Leonard P, Mamoudy P, Desplaces N. Propionibacterium acnes: an agent of prosthetic joint infection and colonization. J Infect. 2007;55(2):119-124.
22. Deirmengian C, Kardos K, Kilmartin P, Cameron A, Schiller K, Parvizi J. Diagnosing periprosthetic joint infection: has the era of the biomarker arrived? Clin Orthop Relat Res. 2014;472(11):3254-3262.
23. Jacovides CL, Parvizi J, Adeli B, Jung KA. Molecular markers for diagnosis of periprosthetic joint infection. J Arthroplasty. 2011;26(6 suppl):99-103.e1.
24. Frangiamore SJ, Gajewski ND, Saleh A, Farias-Kovac M, Barsoum WK, Higuera CA. α-Defensin accuracy to diagnose periprosthetic joint infection—best available test? J Arthroplasty. 2016;31(2):456-460.
25. Hartley JC, Harris KA. Molecular techniques for diagnosing prosthetic joint infections. J Antimicrob Chemother. 2014;69(suppl 1):i21-i24.
