Case Reports

Compared with monoarticular arthritis, polyarticular arthritis may yield an initially narrower differential diagnosis that focuses on systemic inflammatory conditions, such as rheumatoid arthritis (RA). Approximately 15% to 30% of septic arthritis is polyarticular, of which about 45% is associated with underlying RA.^1,2 Regardless of the number of joints involved, septic (infectious) arthritis is a valid consideration given the morbidity and mortality.

In a retrospective study in the United Kingdom (UK) between 1982 and 1991, the morbidity and mortality of septic arthritis was 31.6% and 11.5%, respectively, and 16% of the study population had RA.³ A review of the literature by Dubost and colleagues found that polyarticular septic arthritis (PASA) has a mortality of 31% to 42% compared with 4% to 8% for monoarticular septic arthritis, and RA was present in 67% of the PASA fatalities.¹

Related: The Golden Era of Treatment in Rheumatology

Rheumatoid arthritis and its treatment predispose patients to septic arthritis. Septic arthritis in the UK general population is 0.42 per 100 patient-years for patients with RA on antitumor necrosis factor therapy.^3,4 In a retrospective study in the U.S., the incidence of septic arthritis was 0.40 per 100 patient-years for patients with RA compared with 0.02 per 100 patient-years for patients without RA.⁵

Other complications of RA include infectious tenosynovitis and tendon rupture. The incidence and prevalence of infectious tenosynovitis and tendon rupture in RA are not firmly established in the literature.

We present a patient with RA and psoriasis who responded initially to acute management for RA but subsequently was diagnosed with culture-negative polyarticular arthritis and infectious tenosynovitis associated with beta hemolytic group G Streptococcus (GGS), a part of Streptococcus milleri (S. milleri). During surgery, he was also found to have bilateral extensor pollicus longus (EPL) tendon rupture. Given the possible morbidity, the authors believe this patient may be of interest to the medical community.

Case Presentation

A 69-year-old African American male presented with 3 to 4 days of swelling and pain of bilateral wrists, bilateral hands, and the left ankle with subjective, but resolved, fevers and chills. His medical history was significant for seropositive erosive RA, psoriasis, hypertension, hyperlipidemia, alcohol abuse, chronic tobacco use, osteoporosis, and glaucoma. He did not have diabetes, reported no IV drug abuse, and except for the immunosuppressive effects of his medications, was not otherwise immunocompromised.

For 2 years in the outpatient setting, the rheumatology clinic had been managing the patient’s rheumatoid factor (RF) positive and anti-cyclic citrullinated peptide (CCP) antibody positive erosive RA with etanercept 25 mg subcutaneously twice a week. The RA affected his hands, wrists, shoulders, and ankles bilaterally but was successfully controlled. The dermatology clinic was managing the patient’s psoriasis with calcipotriene cream 0.005% twice a week and clobetasol ointment 0.05% twice a week. Psoriatic plaques were noted on bilateral elbows, bilateral dorsal hands, and bilateral dorsal feet.

Initial Evaluation

At evaluation, the patient’s vital signs revealed a temperature of 36.3°C (97.3°F), pulse of 102 beats per minute, respiratory rate of 16 breaths per minute, oxygen saturation of 99% on room air, and blood pressure of 102/70 mm Hg. He was found to have edema, tenderness, and erythema of the wrists bilaterally and left metacarpophalangeal joints (MCPs) and edematous right MCPs and left medial ankle.

The patient had been nonadherent with etanercept for 5 monthsand restarted taking the medication only 2 weeks before presentation. He had noticed worsening arthritis for at least 1 month. His last RA flare was approximately 1 year before presentation. Additional symptoms included 4 days of nausea, nonbloody and nonbilious emesis, left lower quadrant pain, and diarrhea without melena or hematochezia.

Initial laboratory studies found 3.2 k/μL white blood cells (WBCs) with a differential of 11.9% lymphocytes, 4.2% monocytes, 83.3% neutrophils, 0.5% eosinophils, and 0.1% basophils; 165 k/μL platelets; 96 mm/h erythrocyte sedimentation rate (ESR); and 45 mg/dL C-reactive protein. The patient was diagnosed with viral gastroenteritis and RA flare and was admitted for inpatient management secondary to limited ability to care for himself.

Related: Infliximab-Induced Complications

The patient was started on prednisone 40 mg orally once a day (for 5 days) for empiric treatment of an RA flare and continued on etanercept. The inpatient rheumatology service was consulted. Further evaluation later that day found involvement of the proximal interphalangeal joints and elbows and tenderness of the tendons of the dorsal hand bilaterally. Over the next 2 days, the patient remained afebrile and WBCs were within normal limits. Edema, erythema, and tenderness of the involved joints somewhat improved, but tenderness along the tendons of the dorsal hand worsened, which concerned the managing teams for infectious tenosynovitis.

By day 4, the patient was afebrile and had a leukocytosis of 12.9 k/μLwith neutrophils 86.7%, but improvement of erythema, pain, and range of motion of involved joints and no tenderness to palpation of tendons was noted. The inpatient orthopedic surgery service evaluated the patient and did not find sufficient evidence necessitating surgical intervention.

Worsening Condition

On day 6, arthrocentesis of the left wrist was performed secondary to worsening of erythema and edema. The patient experienced new edema of the left shoulder and leukocytosis continued to trend upward (15.7 k/μL on day 6). Purulent aspirate (1.5 mL) was obtained from the fluctuance and tenosynovium of the left wrist. Empiric vancomycin 1 g IV twice daily and ceftriaxone 2 g IV daily were started and continued for 3 days. By this point in his hospital course, the patient had received 1 dose of etanercept. Prednisone and etanercept were previously discontinued because of the discovered infection. Blood cultures were drawn and had no growth (Table). Gastroenterology studies were limited to stool cultures and did not include colonoscopy. Leukocytosis began trending down.

On day 8, antibiotics were tailored to penicillin G 4 million units IV every 4 hours following growth of GGS from the sample of the left wrist. Subsequently, synovial fluid (3 mL) from the left shoulder was obtained following initiation of antibiotic therapy and had no growth. Magnetic resonance imaging (MRI) found tenosynovitis of the left ankle and right wrist.

On day 9, transthoracic echocardiography was performed and found no evidence of infectious endocarditis. Later that night, the patient was taken to surgery for incision and drainage/debridement of bilateral wrists and left ankle, synovectomy of right wrist, and aspiration of right shoulder. Findings included abscess in the left wrist and inflammatory synovitis and bilateral EPL tendon rupture consistent with RA. Pus from the left ankle had few gram-positive cocci in chains with no growth, and the specimens from both wrists grew GGS. Aspirate from the left ankle was an opaque yellow fluid with 14,900/mm³ WBC, 30,000/mm³ red blood cells (RBC), 97% neutrophils, 1% macrophages, 2% lymphocytes, and 0% monocytes. Aspirate from the right shoulder was an opaque bloody fluid with 10,100/mm³ WBC, 40,000/mm³ RBC, 95% neutrophils, 2% macrophages, 1% lymphocytes, and 1% monocytes. On day 10, sulfasalazine 500 mg twice a day was initiated for RA.

Following surgery and continued antibiotics, the patient’s leukocytosis resolved, and improvement was seen in all joints with decreased edema, erythema, and pain and increased range of motion. Postoperative recovery was complicated by ileus, urinary retention, and fungal (Candida albicans) urinary tract infection, all of which resolved without significant complications. The inpatient rheumatology service restarted prednisone at a lower dose of 20 mg. The patient became afebrile and sufficiently stable for transfer to a lower level of care with continued physical therapy and IV antibiotics for another 3 weeks.

Discussion

The patient had 2 underlying systemic inflammatory conditions: RA and psoriasis. The underlying chronic arthritis was likely caused by RA, not psoriatic arthritis (PsA). The patient met the 2010 American College of Rheumatology criteria but failed to meet the classification criteria for PsA.^6,7 However, the clinical features of RA and PsA overlap. Rheumatoid factor and CCP can be positive laboratory findings in both RA and PsA.^8-14 Tenosynovitis is found in about half of RA patients and PsA patients (P > .05).¹⁵ In its evaluation of the patient, the inpatient rheumatology service suspected that the patient may have had RA with components of PsA.

Rheumatoid arthritis complicates the diagnosis of septic arthritis. In a study by Nolla and colleagues, a mean of 7.3 days (range 3 to 18 days) elapsed before a diagnosis of septic arthritis was made in 10 patients with RA on corticosteroids.² Consideration of risk factors such as increasing age, male sex, tobacco use, extra-articular manifestations of RA, positive RF, rheumatoid nodules, poor functional capacity, high ESR, leukopenia, comorbidities (chronic lung disease, alcoholism, organic brain disease, and diabetes), and the use of corticosteroids may expedite the diagnosis of infections in patients with RA.¹⁶ In this case, the patient had some of these risk factors: age, male sex, alcoholism, chronic tobacco use, positive RF, high ESR, and leukopenia (at presentation).

Related: Trend Toward Concomitant Supplements and Medications

The history of medication nonadherence of etanercept with progressively worsening arthritis and early clinical improvement (reduction in erythema, edema, and pain and temporary loss of signs of tenosynovitis on examination) while on prednisone suggested that the patient had a RA flare. The prednisone likely alleviated the inflammatory process but created an immunosuppressed state that allowed GGS to invade and possibly disseminate. Alternately, the patient may have been infected before presentation. The lack of a definitive time line for his case prevented the authors from forming conclusions about a possible causal relationship between the infection and medications. The subjective fevers before admission were nonspecific and could have been caused by RA, presumed gastroenteritis, or other undiagnosed infectious processes. The observed leukocytosis may have been initially corticosteroid-induced.¹⁷

Septic Arthritis

The suspicion of septic arthritis and infectious tenosynovitis substantially increased on day 6 with worsening symptoms, involvement of additional joints, and spiking fevers. Group G Streptococcus was obtained from the aspirate of the left wrist and from the surgical specimens from the bilateral wrists. The clinical presentation, MRI imaging studies, and surgical and nonsurgical specimens supported a diagnosis of GGS tenosynovitis. However, there was no clear evidence (ie, positive culture with identified organism) of septic arthritis, likely secondary to early septic arthritis and initiation of antibiotics before joint aspirations. The aspirate from the left ankle was yellow and opaque, but the culture was negative.

The pathogenic organism in the patient was GGS. Group G Streptococcus is normal flora of the oral cavity, gastrointestinal (GI) tract, upper respiratory tract, genital tract, and skin, which were all possible sources of seeding.¹⁸ Streptococcal species account for about 20% of septic arthritis, and GGS arthritis accounts for 4% to 19% of streptococcal arthritis.^19-22 From a review of the literature, 2 cases of GGS tenosynovitis have been published.^23,24 However, in an ultrasound study and MRI study, 49% and 43%, respectively, of patients with RA had tenosynovitis of the tendons of the hands.^15,25

GGS Demographics

About three-quarters (71%) of patients with GGS arthritis are male.¹⁹ The analysis of the literature by Bronze and colleagues found that chronic joint disease and alcoholism are present in 34% and 14% of patients with GGS arthritis, respectively. One-quarter (23% from Dubost and colleagues) to one-third (32% from Schattner and colleagues) of patients with GGS arthritis have RA.^19,26

Fever is present in less than half (43%) of patients with GGS arthritis.¹⁹ Positive synovial fluid is expected in 90% of patients.¹⁹ Leukocytosis and elevated ESR need not be present.^27,28 The arthritis is polyarticular in one-quarter of patients (24% from Bronze and colleagues and 26% from Dubost and colleagues).^19,26

Positive blood cultures can be expected in one-fourth (26%) of patients with GGS arthritis.¹⁹ The patient’s blood cultures were negative. Blood cultures drawn before initiation of antibiotics yielded no growth, so if the spread was hematogenous, the bacteremia was transient or intermittent. Before and after initiation of antibiotics, specimens from the shoulders did not grow colonies, whereas specimens from the wrists did. If the shoulders were truly infected, these findings and the notably later involvement of the shoulders suggest that the shoulders may have been seeded later in the hospital course.

Trenkner and colleagues proposed that GI abnormalities provide a portal of entry for GGS, which is under the umbrella of S. milleri.²⁹S. milleri is associated with abscess formation, usually of the GI tract.^30-32 In the study patient, the possible gastroenteritis may have provided such a portal of entry and subsequent seeding to the joints, and an abscess was found in the left wrist.

Tendon Rupture

Additionally, bilateral EPL tendon rupture likely occurred as a consequence of the inflammatory process from RA and infectious tenosynovitis in the patient. According to Zheng and colleagues, tenosynovitis is an inflammatory process of the synovial tendon sheath that may result in degeneration and rupture of the tendons and may contribute to bone erosions, development of joint deformities, and loss of functional capacity.³³ In a histologic study of a ruptured EPL tendon from a patient with RA, Harris observed a chronic inflammatory cellular reaction.³⁴ Harris also described a male with RA with unconfirmed bilateral EPL rupture.³⁴ Björkman and colleague identified previous injury, RA, and local or systemic steroids as important etiologic factors for EPL tendon rupture.³⁵

As in the case of this patient, the utilization of both medical and surgical therapy is not uncommon for treating GGS infection. Antibiotic therapy typically consists of penicillin (74%).²⁶ Surgical intervention is necessary in 16% to 37% of patients.^19,26 This patient required both penicillin and incision and drainage/debridement before significant clinical improvement was noted. Prognosis of GGS arthritis is favorable with 5% mortality.²⁶

Conclusion

Septic arthritis and infectious tenosynovitis are readily treatable with low mortality if promptly identified. Identification can be masked by other medical conditions, such as RA and psoriasis, and their associated immunosuppressive treatment. Bilateral EPL tendon rupture may be a complication of RA, particularly with an underlying septic arthritis and infectious tenosynovitis.

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review the complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

Compared with monoarticular arthritis, polyarticular arthritis may yield an initially narrower differential diagnosis that focuses on systemic inflammatory conditions, such as rheumatoid arthritis (RA). Approximately 15% to 30% of septic arthritis is polyarticular, of which about 45% is associated with underlying RA.^1,2 Regardless of the number of joints involved, septic (infectious) arthritis is a valid consideration given the morbidity and mortality.

In a retrospective study in the United Kingdom (UK) between 1982 and 1991, the morbidity and mortality of septic arthritis was 31.6% and 11.5%, respectively, and 16% of the study population had RA.³ A review of the literature by Dubost and colleagues found that polyarticular septic arthritis (PASA) has a mortality of 31% to 42% compared with 4% to 8% for monoarticular septic arthritis, and RA was present in 67% of the PASA fatalities.¹

Related: The Golden Era of Treatment in Rheumatology

Rheumatoid arthritis and its treatment predispose patients to septic arthritis. Septic arthritis in the UK general population is 0.42 per 100 patient-years for patients with RA on antitumor necrosis factor therapy.^3,4 In a retrospective study in the U.S., the incidence of septic arthritis was 0.40 per 100 patient-years for patients with RA compared with 0.02 per 100 patient-years for patients without RA.⁵

Other complications of RA include infectious tenosynovitis and tendon rupture. The incidence and prevalence of infectious tenosynovitis and tendon rupture in RA are not firmly established in the literature.

We present a patient with RA and psoriasis who responded initially to acute management for RA but subsequently was diagnosed with culture-negative polyarticular arthritis and infectious tenosynovitis associated with beta hemolytic group G Streptococcus (GGS), a part of Streptococcus milleri (S. milleri). During surgery, he was also found to have bilateral extensor pollicus longus (EPL) tendon rupture. Given the possible morbidity, the authors believe this patient may be of interest to the medical community.

Case Presentation

A 69-year-old African American male presented with 3 to 4 days of swelling and pain of bilateral wrists, bilateral hands, and the left ankle with subjective, but resolved, fevers and chills. His medical history was significant for seropositive erosive RA, psoriasis, hypertension, hyperlipidemia, alcohol abuse, chronic tobacco use, osteoporosis, and glaucoma. He did not have diabetes, reported no IV drug abuse, and except for the immunosuppressive effects of his medications, was not otherwise immunocompromised.

For 2 years in the outpatient setting, the rheumatology clinic had been managing the patient’s rheumatoid factor (RF) positive and anti-cyclic citrullinated peptide (CCP) antibody positive erosive RA with etanercept 25 mg subcutaneously twice a week. The RA affected his hands, wrists, shoulders, and ankles bilaterally but was successfully controlled. The dermatology clinic was managing the patient’s psoriasis with calcipotriene cream 0.005% twice a week and clobetasol ointment 0.05% twice a week. Psoriatic plaques were noted on bilateral elbows, bilateral dorsal hands, and bilateral dorsal feet.

Initial Evaluation

At evaluation, the patient’s vital signs revealed a temperature of 36.3°C (97.3°F), pulse of 102 beats per minute, respiratory rate of 16 breaths per minute, oxygen saturation of 99% on room air, and blood pressure of 102/70 mm Hg. He was found to have edema, tenderness, and erythema of the wrists bilaterally and left metacarpophalangeal joints (MCPs) and edematous right MCPs and left medial ankle.

The patient had been nonadherent with etanercept for 5 monthsand restarted taking the medication only 2 weeks before presentation. He had noticed worsening arthritis for at least 1 month. His last RA flare was approximately 1 year before presentation. Additional symptoms included 4 days of nausea, nonbloody and nonbilious emesis, left lower quadrant pain, and diarrhea without melena or hematochezia.

Initial laboratory studies found 3.2 k/μL white blood cells (WBCs) with a differential of 11.9% lymphocytes, 4.2% monocytes, 83.3% neutrophils, 0.5% eosinophils, and 0.1% basophils; 165 k/μL platelets; 96 mm/h erythrocyte sedimentation rate (ESR); and 45 mg/dL C-reactive protein. The patient was diagnosed with viral gastroenteritis and RA flare and was admitted for inpatient management secondary to limited ability to care for himself.

Related: Infliximab-Induced Complications

The patient was started on prednisone 40 mg orally once a day (for 5 days) for empiric treatment of an RA flare and continued on etanercept. The inpatient rheumatology service was consulted. Further evaluation later that day found involvement of the proximal interphalangeal joints and elbows and tenderness of the tendons of the dorsal hand bilaterally. Over the next 2 days, the patient remained afebrile and WBCs were within normal limits. Edema, erythema, and tenderness of the involved joints somewhat improved, but tenderness along the tendons of the dorsal hand worsened, which concerned the managing teams for infectious tenosynovitis.

By day 4, the patient was afebrile and had a leukocytosis of 12.9 k/μLwith neutrophils 86.7%, but improvement of erythema, pain, and range of motion of involved joints and no tenderness to palpation of tendons was noted. The inpatient orthopedic surgery service evaluated the patient and did not find sufficient evidence necessitating surgical intervention.

Worsening Condition

On day 6, arthrocentesis of the left wrist was performed secondary to worsening of erythema and edema. The patient experienced new edema of the left shoulder and leukocytosis continued to trend upward (15.7 k/μL on day 6). Purulent aspirate (1.5 mL) was obtained from the fluctuance and tenosynovium of the left wrist. Empiric vancomycin 1 g IV twice daily and ceftriaxone 2 g IV daily were started and continued for 3 days. By this point in his hospital course, the patient had received 1 dose of etanercept. Prednisone and etanercept were previously discontinued because of the discovered infection. Blood cultures were drawn and had no growth (Table). Gastroenterology studies were limited to stool cultures and did not include colonoscopy. Leukocytosis began trending down.

On day 8, antibiotics were tailored to penicillin G 4 million units IV every 4 hours following growth of GGS from the sample of the left wrist. Subsequently, synovial fluid (3 mL) from the left shoulder was obtained following initiation of antibiotic therapy and had no growth. Magnetic resonance imaging (MRI) found tenosynovitis of the left ankle and right wrist.

On day 9, transthoracic echocardiography was performed and found no evidence of infectious endocarditis. Later that night, the patient was taken to surgery for incision and drainage/debridement of bilateral wrists and left ankle, synovectomy of right wrist, and aspiration of right shoulder. Findings included abscess in the left wrist and inflammatory synovitis and bilateral EPL tendon rupture consistent with RA. Pus from the left ankle had few gram-positive cocci in chains with no growth, and the specimens from both wrists grew GGS. Aspirate from the left ankle was an opaque yellow fluid with 14,900/mm³ WBC, 30,000/mm³ red blood cells (RBC), 97% neutrophils, 1% macrophages, 2% lymphocytes, and 0% monocytes. Aspirate from the right shoulder was an opaque bloody fluid with 10,100/mm³ WBC, 40,000/mm³ RBC, 95% neutrophils, 2% macrophages, 1% lymphocytes, and 1% monocytes. On day 10, sulfasalazine 500 mg twice a day was initiated for RA.

Following surgery and continued antibiotics, the patient’s leukocytosis resolved, and improvement was seen in all joints with decreased edema, erythema, and pain and increased range of motion. Postoperative recovery was complicated by ileus, urinary retention, and fungal (Candida albicans) urinary tract infection, all of which resolved without significant complications. The inpatient rheumatology service restarted prednisone at a lower dose of 20 mg. The patient became afebrile and sufficiently stable for transfer to a lower level of care with continued physical therapy and IV antibiotics for another 3 weeks.

Discussion

The patient had 2 underlying systemic inflammatory conditions: RA and psoriasis. The underlying chronic arthritis was likely caused by RA, not psoriatic arthritis (PsA). The patient met the 2010 American College of Rheumatology criteria but failed to meet the classification criteria for PsA.^6,7 However, the clinical features of RA and PsA overlap. Rheumatoid factor and CCP can be positive laboratory findings in both RA and PsA.^8-14 Tenosynovitis is found in about half of RA patients and PsA patients (P > .05).¹⁵ In its evaluation of the patient, the inpatient rheumatology service suspected that the patient may have had RA with components of PsA.

Rheumatoid arthritis complicates the diagnosis of septic arthritis. In a study by Nolla and colleagues, a mean of 7.3 days (range 3 to 18 days) elapsed before a diagnosis of septic arthritis was made in 10 patients with RA on corticosteroids.² Consideration of risk factors such as increasing age, male sex, tobacco use, extra-articular manifestations of RA, positive RF, rheumatoid nodules, poor functional capacity, high ESR, leukopenia, comorbidities (chronic lung disease, alcoholism, organic brain disease, and diabetes), and the use of corticosteroids may expedite the diagnosis of infections in patients with RA.¹⁶ In this case, the patient had some of these risk factors: age, male sex, alcoholism, chronic tobacco use, positive RF, high ESR, and leukopenia (at presentation).

Related: Trend Toward Concomitant Supplements and Medications

The history of medication nonadherence of etanercept with progressively worsening arthritis and early clinical improvement (reduction in erythema, edema, and pain and temporary loss of signs of tenosynovitis on examination) while on prednisone suggested that the patient had a RA flare. The prednisone likely alleviated the inflammatory process but created an immunosuppressed state that allowed GGS to invade and possibly disseminate. Alternately, the patient may have been infected before presentation. The lack of a definitive time line for his case prevented the authors from forming conclusions about a possible causal relationship between the infection and medications. The subjective fevers before admission were nonspecific and could have been caused by RA, presumed gastroenteritis, or other undiagnosed infectious processes. The observed leukocytosis may have been initially corticosteroid-induced.¹⁷

Septic Arthritis

The suspicion of septic arthritis and infectious tenosynovitis substantially increased on day 6 with worsening symptoms, involvement of additional joints, and spiking fevers. Group G Streptococcus was obtained from the aspirate of the left wrist and from the surgical specimens from the bilateral wrists. The clinical presentation, MRI imaging studies, and surgical and nonsurgical specimens supported a diagnosis of GGS tenosynovitis. However, there was no clear evidence (ie, positive culture with identified organism) of septic arthritis, likely secondary to early septic arthritis and initiation of antibiotics before joint aspirations. The aspirate from the left ankle was yellow and opaque, but the culture was negative.

The pathogenic organism in the patient was GGS. Group G Streptococcus is normal flora of the oral cavity, gastrointestinal (GI) tract, upper respiratory tract, genital tract, and skin, which were all possible sources of seeding.¹⁸ Streptococcal species account for about 20% of septic arthritis, and GGS arthritis accounts for 4% to 19% of streptococcal arthritis.^19-22 From a review of the literature, 2 cases of GGS tenosynovitis have been published.^23,24 However, in an ultrasound study and MRI study, 49% and 43%, respectively, of patients with RA had tenosynovitis of the tendons of the hands.^15,25

GGS Demographics

About three-quarters (71%) of patients with GGS arthritis are male.¹⁹ The analysis of the literature by Bronze and colleagues found that chronic joint disease and alcoholism are present in 34% and 14% of patients with GGS arthritis, respectively. One-quarter (23% from Dubost and colleagues) to one-third (32% from Schattner and colleagues) of patients with GGS arthritis have RA.^19,26

Fever is present in less than half (43%) of patients with GGS arthritis.¹⁹ Positive synovial fluid is expected in 90% of patients.¹⁹ Leukocytosis and elevated ESR need not be present.^27,28 The arthritis is polyarticular in one-quarter of patients (24% from Bronze and colleagues and 26% from Dubost and colleagues).^19,26

Positive blood cultures can be expected in one-fourth (26%) of patients with GGS arthritis.¹⁹ The patient’s blood cultures were negative. Blood cultures drawn before initiation of antibiotics yielded no growth, so if the spread was hematogenous, the bacteremia was transient or intermittent. Before and after initiation of antibiotics, specimens from the shoulders did not grow colonies, whereas specimens from the wrists did. If the shoulders were truly infected, these findings and the notably later involvement of the shoulders suggest that the shoulders may have been seeded later in the hospital course.

Trenkner and colleagues proposed that GI abnormalities provide a portal of entry for GGS, which is under the umbrella of S. milleri.²⁹S. milleri is associated with abscess formation, usually of the GI tract.^30-32 In the study patient, the possible gastroenteritis may have provided such a portal of entry and subsequent seeding to the joints, and an abscess was found in the left wrist.

Tendon Rupture

Additionally, bilateral EPL tendon rupture likely occurred as a consequence of the inflammatory process from RA and infectious tenosynovitis in the patient. According to Zheng and colleagues, tenosynovitis is an inflammatory process of the synovial tendon sheath that may result in degeneration and rupture of the tendons and may contribute to bone erosions, development of joint deformities, and loss of functional capacity.³³ In a histologic study of a ruptured EPL tendon from a patient with RA, Harris observed a chronic inflammatory cellular reaction.³⁴ Harris also described a male with RA with unconfirmed bilateral EPL rupture.³⁴ Björkman and colleague identified previous injury, RA, and local or systemic steroids as important etiologic factors for EPL tendon rupture.³⁵

As in the case of this patient, the utilization of both medical and surgical therapy is not uncommon for treating GGS infection. Antibiotic therapy typically consists of penicillin (74%).²⁶ Surgical intervention is necessary in 16% to 37% of patients.^19,26 This patient required both penicillin and incision and drainage/debridement before significant clinical improvement was noted. Prognosis of GGS arthritis is favorable with 5% mortality.²⁶

Conclusion

Septic arthritis and infectious tenosynovitis are readily treatable with low mortality if promptly identified. Identification can be masked by other medical conditions, such as RA and psoriasis, and their associated immunosuppressive treatment. Bilateral EPL tendon rupture may be a complication of RA, particularly with an underlying septic arthritis and infectious tenosynovitis.

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review the complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

Compared with monoarticular arthritis, polyarticular arthritis may yield an initially narrower differential diagnosis that focuses on systemic inflammatory conditions, such as rheumatoid arthritis (RA). Approximately 15% to 30% of septic arthritis is polyarticular, of which about 45% is associated with underlying RA.^1,2 Regardless of the number of joints involved, septic (infectious) arthritis is a valid consideration given the morbidity and mortality.

In a retrospective study in the United Kingdom (UK) between 1982 and 1991, the morbidity and mortality of septic arthritis was 31.6% and 11.5%, respectively, and 16% of the study population had RA.³ A review of the literature by Dubost and colleagues found that polyarticular septic arthritis (PASA) has a mortality of 31% to 42% compared with 4% to 8% for monoarticular septic arthritis, and RA was present in 67% of the PASA fatalities.¹

Related: The Golden Era of Treatment in Rheumatology

Rheumatoid arthritis and its treatment predispose patients to septic arthritis. Septic arthritis in the UK general population is 0.42 per 100 patient-years for patients with RA on antitumor necrosis factor therapy.^3,4 In a retrospective study in the U.S., the incidence of septic arthritis was 0.40 per 100 patient-years for patients with RA compared with 0.02 per 100 patient-years for patients without RA.⁵

Other complications of RA include infectious tenosynovitis and tendon rupture. The incidence and prevalence of infectious tenosynovitis and tendon rupture in RA are not firmly established in the literature.

We present a patient with RA and psoriasis who responded initially to acute management for RA but subsequently was diagnosed with culture-negative polyarticular arthritis and infectious tenosynovitis associated with beta hemolytic group G Streptococcus (GGS), a part of Streptococcus milleri (S. milleri). During surgery, he was also found to have bilateral extensor pollicus longus (EPL) tendon rupture. Given the possible morbidity, the authors believe this patient may be of interest to the medical community.

Case Presentation

A 69-year-old African American male presented with 3 to 4 days of swelling and pain of bilateral wrists, bilateral hands, and the left ankle with subjective, but resolved, fevers and chills. His medical history was significant for seropositive erosive RA, psoriasis, hypertension, hyperlipidemia, alcohol abuse, chronic tobacco use, osteoporosis, and glaucoma. He did not have diabetes, reported no IV drug abuse, and except for the immunosuppressive effects of his medications, was not otherwise immunocompromised.

For 2 years in the outpatient setting, the rheumatology clinic had been managing the patient’s rheumatoid factor (RF) positive and anti-cyclic citrullinated peptide (CCP) antibody positive erosive RA with etanercept 25 mg subcutaneously twice a week. The RA affected his hands, wrists, shoulders, and ankles bilaterally but was successfully controlled. The dermatology clinic was managing the patient’s psoriasis with calcipotriene cream 0.005% twice a week and clobetasol ointment 0.05% twice a week. Psoriatic plaques were noted on bilateral elbows, bilateral dorsal hands, and bilateral dorsal feet.

Initial Evaluation

At evaluation, the patient’s vital signs revealed a temperature of 36.3°C (97.3°F), pulse of 102 beats per minute, respiratory rate of 16 breaths per minute, oxygen saturation of 99% on room air, and blood pressure of 102/70 mm Hg. He was found to have edema, tenderness, and erythema of the wrists bilaterally and left metacarpophalangeal joints (MCPs) and edematous right MCPs and left medial ankle.

The patient had been nonadherent with etanercept for 5 monthsand restarted taking the medication only 2 weeks before presentation. He had noticed worsening arthritis for at least 1 month. His last RA flare was approximately 1 year before presentation. Additional symptoms included 4 days of nausea, nonbloody and nonbilious emesis, left lower quadrant pain, and diarrhea without melena or hematochezia.

Initial laboratory studies found 3.2 k/μL white blood cells (WBCs) with a differential of 11.9% lymphocytes, 4.2% monocytes, 83.3% neutrophils, 0.5% eosinophils, and 0.1% basophils; 165 k/μL platelets; 96 mm/h erythrocyte sedimentation rate (ESR); and 45 mg/dL C-reactive protein. The patient was diagnosed with viral gastroenteritis and RA flare and was admitted for inpatient management secondary to limited ability to care for himself.

Related: Infliximab-Induced Complications

The patient was started on prednisone 40 mg orally once a day (for 5 days) for empiric treatment of an RA flare and continued on etanercept. The inpatient rheumatology service was consulted. Further evaluation later that day found involvement of the proximal interphalangeal joints and elbows and tenderness of the tendons of the dorsal hand bilaterally. Over the next 2 days, the patient remained afebrile and WBCs were within normal limits. Edema, erythema, and tenderness of the involved joints somewhat improved, but tenderness along the tendons of the dorsal hand worsened, which concerned the managing teams for infectious tenosynovitis.

By day 4, the patient was afebrile and had a leukocytosis of 12.9 k/μLwith neutrophils 86.7%, but improvement of erythema, pain, and range of motion of involved joints and no tenderness to palpation of tendons was noted. The inpatient orthopedic surgery service evaluated the patient and did not find sufficient evidence necessitating surgical intervention.

Worsening Condition

On day 6, arthrocentesis of the left wrist was performed secondary to worsening of erythema and edema. The patient experienced new edema of the left shoulder and leukocytosis continued to trend upward (15.7 k/μL on day 6). Purulent aspirate (1.5 mL) was obtained from the fluctuance and tenosynovium of the left wrist. Empiric vancomycin 1 g IV twice daily and ceftriaxone 2 g IV daily were started and continued for 3 days. By this point in his hospital course, the patient had received 1 dose of etanercept. Prednisone and etanercept were previously discontinued because of the discovered infection. Blood cultures were drawn and had no growth (Table). Gastroenterology studies were limited to stool cultures and did not include colonoscopy. Leukocytosis began trending down.

On day 8, antibiotics were tailored to penicillin G 4 million units IV every 4 hours following growth of GGS from the sample of the left wrist. Subsequently, synovial fluid (3 mL) from the left shoulder was obtained following initiation of antibiotic therapy and had no growth. Magnetic resonance imaging (MRI) found tenosynovitis of the left ankle and right wrist.

On day 9, transthoracic echocardiography was performed and found no evidence of infectious endocarditis. Later that night, the patient was taken to surgery for incision and drainage/debridement of bilateral wrists and left ankle, synovectomy of right wrist, and aspiration of right shoulder. Findings included abscess in the left wrist and inflammatory synovitis and bilateral EPL tendon rupture consistent with RA. Pus from the left ankle had few gram-positive cocci in chains with no growth, and the specimens from both wrists grew GGS. Aspirate from the left ankle was an opaque yellow fluid with 14,900/mm³ WBC, 30,000/mm³ red blood cells (RBC), 97% neutrophils, 1% macrophages, 2% lymphocytes, and 0% monocytes. Aspirate from the right shoulder was an opaque bloody fluid with 10,100/mm³ WBC, 40,000/mm³ RBC, 95% neutrophils, 2% macrophages, 1% lymphocytes, and 1% monocytes. On day 10, sulfasalazine 500 mg twice a day was initiated for RA.

Following surgery and continued antibiotics, the patient’s leukocytosis resolved, and improvement was seen in all joints with decreased edema, erythema, and pain and increased range of motion. Postoperative recovery was complicated by ileus, urinary retention, and fungal (Candida albicans) urinary tract infection, all of which resolved without significant complications. The inpatient rheumatology service restarted prednisone at a lower dose of 20 mg. The patient became afebrile and sufficiently stable for transfer to a lower level of care with continued physical therapy and IV antibiotics for another 3 weeks.

Discussion

The patient had 2 underlying systemic inflammatory conditions: RA and psoriasis. The underlying chronic arthritis was likely caused by RA, not psoriatic arthritis (PsA). The patient met the 2010 American College of Rheumatology criteria but failed to meet the classification criteria for PsA.^6,7 However, the clinical features of RA and PsA overlap. Rheumatoid factor and CCP can be positive laboratory findings in both RA and PsA.^8-14 Tenosynovitis is found in about half of RA patients and PsA patients (P > .05).¹⁵ In its evaluation of the patient, the inpatient rheumatology service suspected that the patient may have had RA with components of PsA.

Rheumatoid arthritis complicates the diagnosis of septic arthritis. In a study by Nolla and colleagues, a mean of 7.3 days (range 3 to 18 days) elapsed before a diagnosis of septic arthritis was made in 10 patients with RA on corticosteroids.² Consideration of risk factors such as increasing age, male sex, tobacco use, extra-articular manifestations of RA, positive RF, rheumatoid nodules, poor functional capacity, high ESR, leukopenia, comorbidities (chronic lung disease, alcoholism, organic brain disease, and diabetes), and the use of corticosteroids may expedite the diagnosis of infections in patients with RA.¹⁶ In this case, the patient had some of these risk factors: age, male sex, alcoholism, chronic tobacco use, positive RF, high ESR, and leukopenia (at presentation).

Related: Trend Toward Concomitant Supplements and Medications

The history of medication nonadherence of etanercept with progressively worsening arthritis and early clinical improvement (reduction in erythema, edema, and pain and temporary loss of signs of tenosynovitis on examination) while on prednisone suggested that the patient had a RA flare. The prednisone likely alleviated the inflammatory process but created an immunosuppressed state that allowed GGS to invade and possibly disseminate. Alternately, the patient may have been infected before presentation. The lack of a definitive time line for his case prevented the authors from forming conclusions about a possible causal relationship between the infection and medications. The subjective fevers before admission were nonspecific and could have been caused by RA, presumed gastroenteritis, or other undiagnosed infectious processes. The observed leukocytosis may have been initially corticosteroid-induced.¹⁷

Septic Arthritis

The suspicion of septic arthritis and infectious tenosynovitis substantially increased on day 6 with worsening symptoms, involvement of additional joints, and spiking fevers. Group G Streptococcus was obtained from the aspirate of the left wrist and from the surgical specimens from the bilateral wrists. The clinical presentation, MRI imaging studies, and surgical and nonsurgical specimens supported a diagnosis of GGS tenosynovitis. However, there was no clear evidence (ie, positive culture with identified organism) of septic arthritis, likely secondary to early septic arthritis and initiation of antibiotics before joint aspirations. The aspirate from the left ankle was yellow and opaque, but the culture was negative.

The pathogenic organism in the patient was GGS. Group G Streptococcus is normal flora of the oral cavity, gastrointestinal (GI) tract, upper respiratory tract, genital tract, and skin, which were all possible sources of seeding.¹⁸ Streptococcal species account for about 20% of septic arthritis, and GGS arthritis accounts for 4% to 19% of streptococcal arthritis.^19-22 From a review of the literature, 2 cases of GGS tenosynovitis have been published.^23,24 However, in an ultrasound study and MRI study, 49% and 43%, respectively, of patients with RA had tenosynovitis of the tendons of the hands.^15,25

GGS Demographics

About three-quarters (71%) of patients with GGS arthritis are male.¹⁹ The analysis of the literature by Bronze and colleagues found that chronic joint disease and alcoholism are present in 34% and 14% of patients with GGS arthritis, respectively. One-quarter (23% from Dubost and colleagues) to one-third (32% from Schattner and colleagues) of patients with GGS arthritis have RA.^19,26

Fever is present in less than half (43%) of patients with GGS arthritis.¹⁹ Positive synovial fluid is expected in 90% of patients.¹⁹ Leukocytosis and elevated ESR need not be present.^27,28 The arthritis is polyarticular in one-quarter of patients (24% from Bronze and colleagues and 26% from Dubost and colleagues).^19,26

Positive blood cultures can be expected in one-fourth (26%) of patients with GGS arthritis.¹⁹ The patient’s blood cultures were negative. Blood cultures drawn before initiation of antibiotics yielded no growth, so if the spread was hematogenous, the bacteremia was transient or intermittent. Before and after initiation of antibiotics, specimens from the shoulders did not grow colonies, whereas specimens from the wrists did. If the shoulders were truly infected, these findings and the notably later involvement of the shoulders suggest that the shoulders may have been seeded later in the hospital course.

Trenkner and colleagues proposed that GI abnormalities provide a portal of entry for GGS, which is under the umbrella of S. milleri.²⁹S. milleri is associated with abscess formation, usually of the GI tract.^30-32 In the study patient, the possible gastroenteritis may have provided such a portal of entry and subsequent seeding to the joints, and an abscess was found in the left wrist.

Tendon Rupture

Additionally, bilateral EPL tendon rupture likely occurred as a consequence of the inflammatory process from RA and infectious tenosynovitis in the patient. According to Zheng and colleagues, tenosynovitis is an inflammatory process of the synovial tendon sheath that may result in degeneration and rupture of the tendons and may contribute to bone erosions, development of joint deformities, and loss of functional capacity.³³ In a histologic study of a ruptured EPL tendon from a patient with RA, Harris observed a chronic inflammatory cellular reaction.³⁴ Harris also described a male with RA with unconfirmed bilateral EPL rupture.³⁴ Björkman and colleague identified previous injury, RA, and local or systemic steroids as important etiologic factors for EPL tendon rupture.³⁵

As in the case of this patient, the utilization of both medical and surgical therapy is not uncommon for treating GGS infection. Antibiotic therapy typically consists of penicillin (74%).²⁶ Surgical intervention is necessary in 16% to 37% of patients.^19,26 This patient required both penicillin and incision and drainage/debridement before significant clinical improvement was noted. Prognosis of GGS arthritis is favorable with 5% mortality.²⁶

Conclusion

Septic arthritis and infectious tenosynovitis are readily treatable with low mortality if promptly identified. Identification can be masked by other medical conditions, such as RA and psoriasis, and their associated immunosuppressive treatment. Bilateral EPL tendon rupture may be a complication of RA, particularly with an underlying septic arthritis and infectious tenosynovitis.

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review the complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

Purpura fulminans is a hematologic emergency, with clinical skin necrosis and laboratory testing showing disseminated intravascular coagulation. The thrombotic occlusion usually affects small and medium-sized blood vessels and may involve any organ. Purpura fulminans has been implicated with sepsis, most commonly meningococcal infections; other infections such as Staphylococcus aureus, groups A and B β-hemolytic streptococci, Streptococcus pneumoniae, and Haemophilus influenzae; and as a sequela to benign childhood infections, such as varicella. Other associations with purpura fulminans include autoimmune disease and heritable or acquired deficiency of anticoagulant proteins, most commonly protein C. We present a rare case of purpura fulminans as the presenting sign of angioimmunoblastic T-cell lymphoma (AITL), an aggressive primary nodal peripheral T-cell lymphoma with a high mortality rate and nonspecific skin manifestations in roughly half of all patients involved.

Case Report

A 56-year-old woman presented with purpuric patches on the left foot (Figure 1A). Seven days after presentation the lesion progressed into ecchymotic geographic plaques and hemorrhagic bullae that spread upward and contralaterally, sparing the digits, trunk, head, neck, and mucous membranes. Ultimately, the involved skin became necrotic and involved 20% of the body surface area (Figure 1B). The lesions were painful with a burning sensation but were not pruritic. The patient also reported intermittent fevers, chills, myalgia, nausea, and shortness of breath. Enlarged lymph nodes were present in the right cervical chain. She denied new medications; stated she had been in good health prior to this episode; and had no history of spontaneous abortion, neurologic symptoms, or other serious illness.

Figure 1. Purpuric patches on the left foot (A). Several days later there were geographic plaques of noninflammatory purpura and ecchymoses with hemorrhagic bullae. There was a sharp demarcation between involved and uninvolved skin (B).

Computed tomography showed prominent diffuse mediastinal, mesenteric, retroperitoneal, and pelvic lymphadenopathy with involvement of the cervical and inguinal areas. Laboratory values showed thrombocytopenia and increased fibrin degradation products. Blood and tissue cultures were negative; the patient also had a negative viral serology, except for Epstein-Barr virus IgG titers (>1:2560). A skin biopsy of the left thigh demonstrated venules and capillaries in the mid and superficial dermis filled with fibrin thrombi without vasculitis (Figure 2). A lymph node biopsy was consistent with a diagnosis of AITL. The lymph node architecture was largely effaced by a polymorphous lymphoid infiltrate that predominantly expanded into paracortical areas and was associated with a prominent arborizing vascular proliferation. The infiltrate was composed of lymphocytes ranging in size from small to medium, with ample cytoplasm, coarsely clumped chromatin, and mildly irregular nuclear membranes. Large atypical lymphocytes with features of immunoblasts were easily identified. An associated inflammatory background composed of eosinophils, plasma cells, and histiocytes was present (Figure 3). The atypical lymphocytes stained positive for CD3and CD10 on immunohistochemistry. Additionally, a subset of large immunoblastlike lymphocytes was positive for Epstein-Barr–encoded small RNAs by in situ hybridization.

Figure 2. Fibrin thrombi filled the lumen of small arteries, arterioles, and capillaries. Red blood cell extravasation with paucicellular subepidermal bulla overlying a degenerative dermis also was seen (A)(H&E, original magnification ×100). A noninflammatory fibrin thrombus occluded a mid dermal vessel (B)(H&E, original magni-fication ×400).

The patient was started on rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone. She received 2 cycles with positive response based on subsequent computed tomography and positron emission tomography scans that showed regression of her disease as well as the lack of formation of new skin lesions. She was transferred to a burn unit where she had continuing treatment and skin grafts. Despite 2 cycles of chemotherapy, broad-spectrum antibiotics, and daily wound care management, the patient died secondary to sepsis 6 months after presentation.

Comment

Angioimmunoblastic T-cell lymphoma is a primary nodal lymphoma with occasional cutaneous involvement. Cutaneous manifestations occur in roughly half of all patients with AITL¹ and have mainly been described as erythematous macules and papules that can resemble a viral exanthem or a drug reaction.² However, other skin manifestations include urticaria, papulovesicular lesions, nodules, erythroderma,³ and to a lesser degree purpura.⁴ The lesions have been noted to occur prior to, concurrent with, or anytime during the disease.^3,5,6 This aggressive lymphoma has mortality rates ranging from 50% to 72%, and median survival ranges from 11 to 30 months.⁶

Figure 3. A high-power photomicrograph showed lymphoid cells admixed with immunoblasts (black arrowhead) and plasma cells. Vascular proliferation (red arrowhead) also was noted (H&E, original magnifi-cation ×400).

To arrive at the correct diagnosis of AITL, a nodal biopsy with immunochemistry is necessary. Classic findings on histopathology include effacement of normal architecture, marked vascular proliferation, and aggregates of atypical lymphoid cells. CD10 has been shown to be a good objective criterion for the diagnosis of AITL,4 with characteristic tumor cells expressing CD10. Nodal Epstein-Barr virus–positive lymphocytes often are present.² Other T-cell lymphomas with primarily nodal presentation along with peripheral T-cell lymphoma include peripheral T-cell lymphoma unspecified type and anaplastic large cell lymphoma, according to the World Health Organization classification.7 Anaplastic large cell lymphoma is easily distinguished from AITL based on histopathology, immunostaining, and clinical presentation. Until recently, peripheral T-cell lymphoma unspecified type and reactive lymphoid hyperplasia presented a challenge to differentiate from AITL, especially in the early phases of the disease; however, the introduction of CD10 as a phenotypic marker has been instrumental in distinguishing AITL from other T-cell lymphomas with primary nodal involvement.^1,4

The development of purpura fulminans and disseminated intravascular coagulation in a patient with AITL is rare. Although the exact mechanism for the thrombus formation in the skin has not been elucidated, purpura fulminans typically develops secondary to a severe infection. The exact incidence of purpura fulminans in the setting of AITL is unknown, but purpura as a cutaneous eruption has been associated as a clinical finding in AITL.⁶ Although our case may be a rare presentation of AITL, a prompt and accurate diagnosis can drastically change the prognosis of this aggressive disease.

Purpura fulminans is a hematologic emergency, with clinical skin necrosis and laboratory testing showing disseminated intravascular coagulation. The thrombotic occlusion usually affects small and medium-sized blood vessels and may involve any organ. Purpura fulminans has been implicated with sepsis, most commonly meningococcal infections; other infections such as Staphylococcus aureus, groups A and B β-hemolytic streptococci, Streptococcus pneumoniae, and Haemophilus influenzae; and as a sequela to benign childhood infections, such as varicella. Other associations with purpura fulminans include autoimmune disease and heritable or acquired deficiency of anticoagulant proteins, most commonly protein C. We present a rare case of purpura fulminans as the presenting sign of angioimmunoblastic T-cell lymphoma (AITL), an aggressive primary nodal peripheral T-cell lymphoma with a high mortality rate and nonspecific skin manifestations in roughly half of all patients involved.

Case Report

A 56-year-old woman presented with purpuric patches on the left foot (Figure 1A). Seven days after presentation the lesion progressed into ecchymotic geographic plaques and hemorrhagic bullae that spread upward and contralaterally, sparing the digits, trunk, head, neck, and mucous membranes. Ultimately, the involved skin became necrotic and involved 20% of the body surface area (Figure 1B). The lesions were painful with a burning sensation but were not pruritic. The patient also reported intermittent fevers, chills, myalgia, nausea, and shortness of breath. Enlarged lymph nodes were present in the right cervical chain. She denied new medications; stated she had been in good health prior to this episode; and had no history of spontaneous abortion, neurologic symptoms, or other serious illness.

Figure 1. Purpuric patches on the left foot (A). Several days later there were geographic plaques of noninflammatory purpura and ecchymoses with hemorrhagic bullae. There was a sharp demarcation between involved and uninvolved skin (B).

Computed tomography showed prominent diffuse mediastinal, mesenteric, retroperitoneal, and pelvic lymphadenopathy with involvement of the cervical and inguinal areas. Laboratory values showed thrombocytopenia and increased fibrin degradation products. Blood and tissue cultures were negative; the patient also had a negative viral serology, except for Epstein-Barr virus IgG titers (>1:2560). A skin biopsy of the left thigh demonstrated venules and capillaries in the mid and superficial dermis filled with fibrin thrombi without vasculitis (Figure 2). A lymph node biopsy was consistent with a diagnosis of AITL. The lymph node architecture was largely effaced by a polymorphous lymphoid infiltrate that predominantly expanded into paracortical areas and was associated with a prominent arborizing vascular proliferation. The infiltrate was composed of lymphocytes ranging in size from small to medium, with ample cytoplasm, coarsely clumped chromatin, and mildly irregular nuclear membranes. Large atypical lymphocytes with features of immunoblasts were easily identified. An associated inflammatory background composed of eosinophils, plasma cells, and histiocytes was present (Figure 3). The atypical lymphocytes stained positive for CD3and CD10 on immunohistochemistry. Additionally, a subset of large immunoblastlike lymphocytes was positive for Epstein-Barr–encoded small RNAs by in situ hybridization.

Figure 2. Fibrin thrombi filled the lumen of small arteries, arterioles, and capillaries. Red blood cell extravasation with paucicellular subepidermal bulla overlying a degenerative dermis also was seen (A)(H&E, original magnification ×100). A noninflammatory fibrin thrombus occluded a mid dermal vessel (B)(H&E, original magni-fication ×400).

The patient was started on rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone. She received 2 cycles with positive response based on subsequent computed tomography and positron emission tomography scans that showed regression of her disease as well as the lack of formation of new skin lesions. She was transferred to a burn unit where she had continuing treatment and skin grafts. Despite 2 cycles of chemotherapy, broad-spectrum antibiotics, and daily wound care management, the patient died secondary to sepsis 6 months after presentation.

Comment

Angioimmunoblastic T-cell lymphoma is a primary nodal lymphoma with occasional cutaneous involvement. Cutaneous manifestations occur in roughly half of all patients with AITL¹ and have mainly been described as erythematous macules and papules that can resemble a viral exanthem or a drug reaction.² However, other skin manifestations include urticaria, papulovesicular lesions, nodules, erythroderma,³ and to a lesser degree purpura.⁴ The lesions have been noted to occur prior to, concurrent with, or anytime during the disease.^3,5,6 This aggressive lymphoma has mortality rates ranging from 50% to 72%, and median survival ranges from 11 to 30 months.⁶

Figure 3. A high-power photomicrograph showed lymphoid cells admixed with immunoblasts (black arrowhead) and plasma cells. Vascular proliferation (red arrowhead) also was noted (H&E, original magnifi-cation ×400).

To arrive at the correct diagnosis of AITL, a nodal biopsy with immunochemistry is necessary. Classic findings on histopathology include effacement of normal architecture, marked vascular proliferation, and aggregates of atypical lymphoid cells. CD10 has been shown to be a good objective criterion for the diagnosis of AITL,4 with characteristic tumor cells expressing CD10. Nodal Epstein-Barr virus–positive lymphocytes often are present.² Other T-cell lymphomas with primarily nodal presentation along with peripheral T-cell lymphoma include peripheral T-cell lymphoma unspecified type and anaplastic large cell lymphoma, according to the World Health Organization classification.7 Anaplastic large cell lymphoma is easily distinguished from AITL based on histopathology, immunostaining, and clinical presentation. Until recently, peripheral T-cell lymphoma unspecified type and reactive lymphoid hyperplasia presented a challenge to differentiate from AITL, especially in the early phases of the disease; however, the introduction of CD10 as a phenotypic marker has been instrumental in distinguishing AITL from other T-cell lymphomas with primary nodal involvement.^1,4

The development of purpura fulminans and disseminated intravascular coagulation in a patient with AITL is rare. Although the exact mechanism for the thrombus formation in the skin has not been elucidated, purpura fulminans typically develops secondary to a severe infection. The exact incidence of purpura fulminans in the setting of AITL is unknown, but purpura as a cutaneous eruption has been associated as a clinical finding in AITL.⁶ Although our case may be a rare presentation of AITL, a prompt and accurate diagnosis can drastically change the prognosis of this aggressive disease.

Purpura fulminans is a hematologic emergency, with clinical skin necrosis and laboratory testing showing disseminated intravascular coagulation. The thrombotic occlusion usually affects small and medium-sized blood vessels and may involve any organ. Purpura fulminans has been implicated with sepsis, most commonly meningococcal infections; other infections such as Staphylococcus aureus, groups A and B β-hemolytic streptococci, Streptococcus pneumoniae, and Haemophilus influenzae; and as a sequela to benign childhood infections, such as varicella. Other associations with purpura fulminans include autoimmune disease and heritable or acquired deficiency of anticoagulant proteins, most commonly protein C. We present a rare case of purpura fulminans as the presenting sign of angioimmunoblastic T-cell lymphoma (AITL), an aggressive primary nodal peripheral T-cell lymphoma with a high mortality rate and nonspecific skin manifestations in roughly half of all patients involved.

Case Report

A 56-year-old woman presented with purpuric patches on the left foot (Figure 1A). Seven days after presentation the lesion progressed into ecchymotic geographic plaques and hemorrhagic bullae that spread upward and contralaterally, sparing the digits, trunk, head, neck, and mucous membranes. Ultimately, the involved skin became necrotic and involved 20% of the body surface area (Figure 1B). The lesions were painful with a burning sensation but were not pruritic. The patient also reported intermittent fevers, chills, myalgia, nausea, and shortness of breath. Enlarged lymph nodes were present in the right cervical chain. She denied new medications; stated she had been in good health prior to this episode; and had no history of spontaneous abortion, neurologic symptoms, or other serious illness.

Figure 1. Purpuric patches on the left foot (A). Several days later there were geographic plaques of noninflammatory purpura and ecchymoses with hemorrhagic bullae. There was a sharp demarcation between involved and uninvolved skin (B).

Computed tomography showed prominent diffuse mediastinal, mesenteric, retroperitoneal, and pelvic lymphadenopathy with involvement of the cervical and inguinal areas. Laboratory values showed thrombocytopenia and increased fibrin degradation products. Blood and tissue cultures were negative; the patient also had a negative viral serology, except for Epstein-Barr virus IgG titers (>1:2560). A skin biopsy of the left thigh demonstrated venules and capillaries in the mid and superficial dermis filled with fibrin thrombi without vasculitis (Figure 2). A lymph node biopsy was consistent with a diagnosis of AITL. The lymph node architecture was largely effaced by a polymorphous lymphoid infiltrate that predominantly expanded into paracortical areas and was associated with a prominent arborizing vascular proliferation. The infiltrate was composed of lymphocytes ranging in size from small to medium, with ample cytoplasm, coarsely clumped chromatin, and mildly irregular nuclear membranes. Large atypical lymphocytes with features of immunoblasts were easily identified. An associated inflammatory background composed of eosinophils, plasma cells, and histiocytes was present (Figure 3). The atypical lymphocytes stained positive for CD3and CD10 on immunohistochemistry. Additionally, a subset of large immunoblastlike lymphocytes was positive for Epstein-Barr–encoded small RNAs by in situ hybridization.

Figure 2. Fibrin thrombi filled the lumen of small arteries, arterioles, and capillaries. Red blood cell extravasation with paucicellular subepidermal bulla overlying a degenerative dermis also was seen (A)(H&E, original magnification ×100). A noninflammatory fibrin thrombus occluded a mid dermal vessel (B)(H&E, original magni-fication ×400).

The patient was started on rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone. She received 2 cycles with positive response based on subsequent computed tomography and positron emission tomography scans that showed regression of her disease as well as the lack of formation of new skin lesions. She was transferred to a burn unit where she had continuing treatment and skin grafts. Despite 2 cycles of chemotherapy, broad-spectrum antibiotics, and daily wound care management, the patient died secondary to sepsis 6 months after presentation.

Comment

Angioimmunoblastic T-cell lymphoma is a primary nodal lymphoma with occasional cutaneous involvement. Cutaneous manifestations occur in roughly half of all patients with AITL¹ and have mainly been described as erythematous macules and papules that can resemble a viral exanthem or a drug reaction.² However, other skin manifestations include urticaria, papulovesicular lesions, nodules, erythroderma,³ and to a lesser degree purpura.⁴ The lesions have been noted to occur prior to, concurrent with, or anytime during the disease.^3,5,6 This aggressive lymphoma has mortality rates ranging from 50% to 72%, and median survival ranges from 11 to 30 months.⁶

Figure 3. A high-power photomicrograph showed lymphoid cells admixed with immunoblasts (black arrowhead) and plasma cells. Vascular proliferation (red arrowhead) also was noted (H&E, original magnifi-cation ×400).

To arrive at the correct diagnosis of AITL, a nodal biopsy with immunochemistry is necessary. Classic findings on histopathology include effacement of normal architecture, marked vascular proliferation, and aggregates of atypical lymphoid cells. CD10 has been shown to be a good objective criterion for the diagnosis of AITL,4 with characteristic tumor cells expressing CD10. Nodal Epstein-Barr virus–positive lymphocytes often are present.² Other T-cell lymphomas with primarily nodal presentation along with peripheral T-cell lymphoma include peripheral T-cell lymphoma unspecified type and anaplastic large cell lymphoma, according to the World Health Organization classification.7 Anaplastic large cell lymphoma is easily distinguished from AITL based on histopathology, immunostaining, and clinical presentation. Until recently, peripheral T-cell lymphoma unspecified type and reactive lymphoid hyperplasia presented a challenge to differentiate from AITL, especially in the early phases of the disease; however, the introduction of CD10 as a phenotypic marker has been instrumental in distinguishing AITL from other T-cell lymphomas with primary nodal involvement.^1,4

The development of purpura fulminans and disseminated intravascular coagulation in a patient with AITL is rare. Although the exact mechanism for the thrombus formation in the skin has not been elucidated, purpura fulminans typically develops secondary to a severe infection. The exact incidence of purpura fulminans in the setting of AITL is unknown, but purpura as a cutaneous eruption has been associated as a clinical finding in AITL.⁶ Although our case may be a rare presentation of AITL, a prompt and accurate diagnosis can drastically change the prognosis of this aggressive disease.

Epithelioid sarcoma (ES) is a rare malignant soft tissue neoplasm that is most often encountered on the distal extremities of young adults.¹ Epithelioid sarcoma is notorious for its tendency to mimic palisading granulomatous processes such as granuloma annulare. We report a case of ES on the right hand of a 23-year-old man that resembled a benign fibrous histiocytoma (dermatofibroma) on incisional biopsy. The typical histopathologic features of ES were identified after amputation of the hand and evaluation of the deeper regions of the tumor. The tendency for ES to mimic granulomatous processes is a common diagnostic pitfall, but the potential for its close resemblance to benign fibrous histiocytoma is less recognized.

Figure 1. A 0.8×0.6-cm ulcerated nodule on the hypothenar region of the right hand (A). Four months after initial presentation the nodule measured 1.4×1 cm (B).

Case Report

A 23-year-old man presented with a nonhealing lesion on the right palm. His medical history was remarkable for a giant cell tumor of the tendon sheath involving the right fifth finger that had been treated via excision at an outside institution 2 years prior. Clinical examination revealed a 0.8×0.6-cm painful, firm, ulcerated dermal nodule with a hemorrhagic crust on the palmar surface of the right hand (Figure 1A). The clinical differential diagnosis included melanoma, traumatized verruca vulgaris, thrombosed pyogenic granuloma, and foreign body. A shave biopsy demonstrated verrucous epidermal hyperplasia, but the specimen did not include the dermis. Cultures of the lesion were positive for Staphylococcus aureus, and antibiotic therapy was initiated. In light of the clinical findings and the patient’s history of a giant cell tumor, imaging studies were performed. Magnetic resonance angiography showed abnormal masslike infiltrative enhancement throughout the soft tissues surrounding the right fifth metacarpal bone. The differential included a recurrent giant cell tumor, fibromatosis, and other soft tissue neoplasms.

After several missed appointments and surgery cancellations, the patient returned 4 months later for an incisional biopsy. Physical examination revealed a persistent palmar ulcer that had grown to 1.4×1 cm in size, along with an indurated purple plaque wrapping around the ulnar aspect of the right hand (Figure 1B). The biopsy demonstrated a proliferation of spindled and ovoid cells with scant cytoplasm that surrounded sclerotic collagen bundles resembling a dermatofibroma (Figure 2A). Cytologic atypia and mitotic activity were absent (Figure 2B). Glass slides of the original biopsy, which ultimately led to the diagnosis of the giant cell tumor of the tendon sheath more than 2 years earlier, were obtained and showed similar features. The proliferating cells were strongly and diffusely immunoreactive for vimentin, CD34, and cancer antigen 125 (CA 125). Scattered tumor cells strongly expressed cytokeratins (CKs) AE1/AE3 and cell adhesion molecule 5.2 (Figure 3). Staining for CD99 and epithelial membrane antigen was diffuse but weak. Factor XIIIa, S-100, CK7, smooth muscle actin, muscle-specific actin (HHF35), CD31, CD68, and B-cell lymphoma 2 were negative within the proliferating cells. Based on the clinical examination and results of the immunohistochemical staining, a diagnosis of ES was favored.

Figure 2. Low-power view of an incisional biopsy resembled a fibrohistiocytomalike neoplasm, as the tumor was composed of plump spindle cells that trapped sclerotic collagen bundles (A)(H&E, original magnification ×40). The tumor lacked significant cytologic atypia and mitotic figures were not seen (B)(H&E, original magnification ×200).

After a negative metastatic workup, amputation of the right hand was performed. The amputation specimen showed a tumor that extended through the entire hand with encasement of large vessels and tendons. Although the more superficial regions were cytologically bland, deep-seated regions of the tumor exhibited greater cellularity, nuclear pleomorphism, and mitotic activity (Figure 4). There was no bone involvement. Right axillary sentinel lymph nodes were negative for metastasis. Eighteen months later the patient developed chest and back pain with dyspnea. Thorascopic surgery was performed for a left pleural effusion and metastases to the left parietal pleura and adjacent soft tissue were identified. The patient was subsequently lost to follow-up.

Comment

First described by Enzinger¹ in 1970, ES is a rare malignant soft tissue neoplasm that most frequently arises on the hands, forearms, and pretibial soft tissues of young adults.^1-3 It is an aggressive tumor characterized by frequent recurrences and a high metastatic rate, with lung and regional lymph nodes being favored metastatic sites.^1-5 Periods of several months or even years often pass between the initial presentation and establishment of a correct diagnosis, as ES frequently is mistaken for other benign conditions. The tendency for ES to mimic granulomatous processes is a common diagnostic pitfall, but the potential for its close resemblance to benign fibrous histiocytoma is less recognized.^6,7 In his original series of 62 cases, Enzinger¹ noted that 17 patients were referred for treatment with a diagnosis of a benign fibrohistiocytic neoplasm, and other reports have described a resemblance to fibrous and fibrohistiocytic neoplasms.^8-11 Mirra et al¹⁰ designated these tumors as fibromalike variants of ES. Additional subtypes of ES have subsequently been recognized, including those described as angiomatoid or angiosarcomalike, reflecting the potential of ES to resemble vascular tumors.¹² A proximal type of ES also has been described. This lesion presents as a deep-seated tumor on the proximal limbs and is associated with more aggressive behavior. It lacks the granulomalike pattern and has more prominent epithelioid and rhabdoid histological presentation.^13-15

Epithelioid sarcoma is a mesenchymal tumor that can display multidirectional differentiation that is primarily epithelial.¹⁶ The precise histogenesis of ES remains unclear, but studies have demonstrated a spectrum of differentiation that ranges from primitive myofibroblast or fibrohistiocytelike cells to those with well-developed epithelial properties.^16,17 Epithelioid sarcoma characteristically coexpresses vimentin and low-molecular-weight CKs such as cell adhesion molecule 5.2. The tumor cells often are immunoreactive for epithelial membrane antigen and more than 50% of cases exhibit remarkable CD34 positivity.¹⁶ More recent studies have further refined the immunophenotype, demonstrating frequent expression of CK8 and CK19 but less commonly CK7, CK20, CK34bE12, and CK5/6.^18-20 Additional studies reported that in 10 of 11 cases, ES was positive for CA 125 on immunohistochemical staining, and 3 of 5 patients also had elevated serum CA 125 levels.^21,22 More recently, Hoshino et al²³ showed elevated serum CA 125 levels in 5 of 7 patients with ES. Cancer antigen 125 is a high-molecular-weight glycoprotein commonly used in the identification of epithelial ovarian carcinomas; however, it also has been described in a number of other neoplasms including carcinomas of the breast, lungs, and colon and lymphoma.^24-27 Although it appears that the addition of CA 125 to a panel of other immunohistochemical stains may be helpful in differentiating ES from other soft tissue sarcomas and serum CA 125 levels may help determine tumor burden, currently the number of cases studied is too small to definitively make that conclusion.^21,23 In our case, the tumor cells were strongly and diffusely positive for CA 125. Serum CA 125 levels were not available.

Figure 3. Tumor cells focally showed strong membranous staining for cytokeratin AE1/AE3 (original magnification ×400).

Figure 4. High-power view of the tumor from the amputation specimen showed sheets of epithelioid and polygonal cells displaying marked nuclear pleomorphism and scattered mitoses (H&E, original magnification ×400).

Cytogenetic studies have failed to identify a consistent chromosomal abnormality in ES.⁵ Some analyses performed by comparative genomic hybridization on isolated cases and small case series indicate that the most frequent alterations involve 8q, 18q11, and 22q11.^13,28,29 The tumor suppressor gene SMARCB1/INI1 (SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily B, member 1/integrase interactor 1) has been mapped to 22q11, and ES commonly shows absence of nuclear staining for this protein, indicating inactivation.^13-15

Conclusion

Benign fibrohistiocytic proliferations should be included in the differential of histological mimickers of ES. Deep biopsies are essential to differentiate these benign tumors from fibrous histiocytomalike or fibromalike lesions of ES because superficial portions of ES may be well differentiated.

Epithelioid sarcoma (ES) is a rare malignant soft tissue neoplasm that is most often encountered on the distal extremities of young adults.¹ Epithelioid sarcoma is notorious for its tendency to mimic palisading granulomatous processes such as granuloma annulare. We report a case of ES on the right hand of a 23-year-old man that resembled a benign fibrous histiocytoma (dermatofibroma) on incisional biopsy. The typical histopathologic features of ES were identified after amputation of the hand and evaluation of the deeper regions of the tumor. The tendency for ES to mimic granulomatous processes is a common diagnostic pitfall, but the potential for its close resemblance to benign fibrous histiocytoma is less recognized.

Figure 1. A 0.8×0.6-cm ulcerated nodule on the hypothenar region of the right hand (A). Four months after initial presentation the nodule measured 1.4×1 cm (B).

Case Report

A 23-year-old man presented with a nonhealing lesion on the right palm. His medical history was remarkable for a giant cell tumor of the tendon sheath involving the right fifth finger that had been treated via excision at an outside institution 2 years prior. Clinical examination revealed a 0.8×0.6-cm painful, firm, ulcerated dermal nodule with a hemorrhagic crust on the palmar surface of the right hand (Figure 1A). The clinical differential diagnosis included melanoma, traumatized verruca vulgaris, thrombosed pyogenic granuloma, and foreign body. A shave biopsy demonstrated verrucous epidermal hyperplasia, but the specimen did not include the dermis. Cultures of the lesion were positive for Staphylococcus aureus, and antibiotic therapy was initiated. In light of the clinical findings and the patient’s history of a giant cell tumor, imaging studies were performed. Magnetic resonance angiography showed abnormal masslike infiltrative enhancement throughout the soft tissues surrounding the right fifth metacarpal bone. The differential included a recurrent giant cell tumor, fibromatosis, and other soft tissue neoplasms.

After several missed appointments and surgery cancellations, the patient returned 4 months later for an incisional biopsy. Physical examination revealed a persistent palmar ulcer that had grown to 1.4×1 cm in size, along with an indurated purple plaque wrapping around the ulnar aspect of the right hand (Figure 1B). The biopsy demonstrated a proliferation of spindled and ovoid cells with scant cytoplasm that surrounded sclerotic collagen bundles resembling a dermatofibroma (Figure 2A). Cytologic atypia and mitotic activity were absent (Figure 2B). Glass slides of the original biopsy, which ultimately led to the diagnosis of the giant cell tumor of the tendon sheath more than 2 years earlier, were obtained and showed similar features. The proliferating cells were strongly and diffusely immunoreactive for vimentin, CD34, and cancer antigen 125 (CA 125). Scattered tumor cells strongly expressed cytokeratins (CKs) AE1/AE3 and cell adhesion molecule 5.2 (Figure 3). Staining for CD99 and epithelial membrane antigen was diffuse but weak. Factor XIIIa, S-100, CK7, smooth muscle actin, muscle-specific actin (HHF35), CD31, CD68, and B-cell lymphoma 2 were negative within the proliferating cells. Based on the clinical examination and results of the immunohistochemical staining, a diagnosis of ES was favored.

Figure 2. Low-power view of an incisional biopsy resembled a fibrohistiocytomalike neoplasm, as the tumor was composed of plump spindle cells that trapped sclerotic collagen bundles (A)(H&E, original magnification ×40). The tumor lacked significant cytologic atypia and mitotic figures were not seen (B)(H&E, original magnification ×200).

After a negative metastatic workup, amputation of the right hand was performed. The amputation specimen showed a tumor that extended through the entire hand with encasement of large vessels and tendons. Although the more superficial regions were cytologically bland, deep-seated regions of the tumor exhibited greater cellularity, nuclear pleomorphism, and mitotic activity (Figure 4). There was no bone involvement. Right axillary sentinel lymph nodes were negative for metastasis. Eighteen months later the patient developed chest and back pain with dyspnea. Thorascopic surgery was performed for a left pleural effusion and metastases to the left parietal pleura and adjacent soft tissue were identified. The patient was subsequently lost to follow-up.

Comment

First described by Enzinger¹ in 1970, ES is a rare malignant soft tissue neoplasm that most frequently arises on the hands, forearms, and pretibial soft tissues of young adults.^1-3 It is an aggressive tumor characterized by frequent recurrences and a high metastatic rate, with lung and regional lymph nodes being favored metastatic sites.^1-5 Periods of several months or even years often pass between the initial presentation and establishment of a correct diagnosis, as ES frequently is mistaken for other benign conditions. The tendency for ES to mimic granulomatous processes is a common diagnostic pitfall, but the potential for its close resemblance to benign fibrous histiocytoma is less recognized.^6,7 In his original series of 62 cases, Enzinger¹ noted that 17 patients were referred for treatment with a diagnosis of a benign fibrohistiocytic neoplasm, and other reports have described a resemblance to fibrous and fibrohistiocytic neoplasms.^8-11 Mirra et al¹⁰ designated these tumors as fibromalike variants of ES. Additional subtypes of ES have subsequently been recognized, including those described as angiomatoid or angiosarcomalike, reflecting the potential of ES to resemble vascular tumors.¹² A proximal type of ES also has been described. This lesion presents as a deep-seated tumor on the proximal limbs and is associated with more aggressive behavior. It lacks the granulomalike pattern and has more prominent epithelioid and rhabdoid histological presentation.^13-15

Epithelioid sarcoma is a mesenchymal tumor that can display multidirectional differentiation that is primarily epithelial.¹⁶ The precise histogenesis of ES remains unclear, but studies have demonstrated a spectrum of differentiation that ranges from primitive myofibroblast or fibrohistiocytelike cells to those with well-developed epithelial properties.^16,17 Epithelioid sarcoma characteristically coexpresses vimentin and low-molecular-weight CKs such as cell adhesion molecule 5.2. The tumor cells often are immunoreactive for epithelial membrane antigen and more than 50% of cases exhibit remarkable CD34 positivity.¹⁶ More recent studies have further refined the immunophenotype, demonstrating frequent expression of CK8 and CK19 but less commonly CK7, CK20, CK34bE12, and CK5/6.^18-20 Additional studies reported that in 10 of 11 cases, ES was positive for CA 125 on immunohistochemical staining, and 3 of 5 patients also had elevated serum CA 125 levels.^21,22 More recently, Hoshino et al²³ showed elevated serum CA 125 levels in 5 of 7 patients with ES. Cancer antigen 125 is a high-molecular-weight glycoprotein commonly used in the identification of epithelial ovarian carcinomas; however, it also has been described in a number of other neoplasms including carcinomas of the breast, lungs, and colon and lymphoma.^24-27 Although it appears that the addition of CA 125 to a panel of other immunohistochemical stains may be helpful in differentiating ES from other soft tissue sarcomas and serum CA 125 levels may help determine tumor burden, currently the number of cases studied is too small to definitively make that conclusion.^21,23 In our case, the tumor cells were strongly and diffusely positive for CA 125. Serum CA 125 levels were not available.

Figure 3. Tumor cells focally showed strong membranous staining for cytokeratin AE1/AE3 (original magnification ×400).

Figure 4. High-power view of the tumor from the amputation specimen showed sheets of epithelioid and polygonal cells displaying marked nuclear pleomorphism and scattered mitoses (H&E, original magnification ×400).

Cytogenetic studies have failed to identify a consistent chromosomal abnormality in ES.⁵ Some analyses performed by comparative genomic hybridization on isolated cases and small case series indicate that the most frequent alterations involve 8q, 18q11, and 22q11.^13,28,29 The tumor suppressor gene SMARCB1/INI1 (SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily B, member 1/integrase interactor 1) has been mapped to 22q11, and ES commonly shows absence of nuclear staining for this protein, indicating inactivation.^13-15

Conclusion

Benign fibrohistiocytic proliferations should be included in the differential of histological mimickers of ES. Deep biopsies are essential to differentiate these benign tumors from fibrous histiocytomalike or fibromalike lesions of ES because superficial portions of ES may be well differentiated.

Epithelioid sarcoma (ES) is a rare malignant soft tissue neoplasm that is most often encountered on the distal extremities of young adults.¹ Epithelioid sarcoma is notorious for its tendency to mimic palisading granulomatous processes such as granuloma annulare. We report a case of ES on the right hand of a 23-year-old man that resembled a benign fibrous histiocytoma (dermatofibroma) on incisional biopsy. The typical histopathologic features of ES were identified after amputation of the hand and evaluation of the deeper regions of the tumor. The tendency for ES to mimic granulomatous processes is a common diagnostic pitfall, but the potential for its close resemblance to benign fibrous histiocytoma is less recognized.

Figure 1. A 0.8×0.6-cm ulcerated nodule on the hypothenar region of the right hand (A). Four months after initial presentation the nodule measured 1.4×1 cm (B).

Case Report

A 23-year-old man presented with a nonhealing lesion on the right palm. His medical history was remarkable for a giant cell tumor of the tendon sheath involving the right fifth finger that had been treated via excision at an outside institution 2 years prior. Clinical examination revealed a 0.8×0.6-cm painful, firm, ulcerated dermal nodule with a hemorrhagic crust on the palmar surface of the right hand (Figure 1A). The clinical differential diagnosis included melanoma, traumatized verruca vulgaris, thrombosed pyogenic granuloma, and foreign body. A shave biopsy demonstrated verrucous epidermal hyperplasia, but the specimen did not include the dermis. Cultures of the lesion were positive for Staphylococcus aureus, and antibiotic therapy was initiated. In light of the clinical findings and the patient’s history of a giant cell tumor, imaging studies were performed. Magnetic resonance angiography showed abnormal masslike infiltrative enhancement throughout the soft tissues surrounding the right fifth metacarpal bone. The differential included a recurrent giant cell tumor, fibromatosis, and other soft tissue neoplasms.

After several missed appointments and surgery cancellations, the patient returned 4 months later for an incisional biopsy. Physical examination revealed a persistent palmar ulcer that had grown to 1.4×1 cm in size, along with an indurated purple plaque wrapping around the ulnar aspect of the right hand (Figure 1B). The biopsy demonstrated a proliferation of spindled and ovoid cells with scant cytoplasm that surrounded sclerotic collagen bundles resembling a dermatofibroma (Figure 2A). Cytologic atypia and mitotic activity were absent (Figure 2B). Glass slides of the original biopsy, which ultimately led to the diagnosis of the giant cell tumor of the tendon sheath more than 2 years earlier, were obtained and showed similar features. The proliferating cells were strongly and diffusely immunoreactive for vimentin, CD34, and cancer antigen 125 (CA 125). Scattered tumor cells strongly expressed cytokeratins (CKs) AE1/AE3 and cell adhesion molecule 5.2 (Figure 3). Staining for CD99 and epithelial membrane antigen was diffuse but weak. Factor XIIIa, S-100, CK7, smooth muscle actin, muscle-specific actin (HHF35), CD31, CD68, and B-cell lymphoma 2 were negative within the proliferating cells. Based on the clinical examination and results of the immunohistochemical staining, a diagnosis of ES was favored.

Figure 2. Low-power view of an incisional biopsy resembled a fibrohistiocytomalike neoplasm, as the tumor was composed of plump spindle cells that trapped sclerotic collagen bundles (A)(H&E, original magnification ×40). The tumor lacked significant cytologic atypia and mitotic figures were not seen (B)(H&E, original magnification ×200).

After a negative metastatic workup, amputation of the right hand was performed. The amputation specimen showed a tumor that extended through the entire hand with encasement of large vessels and tendons. Although the more superficial regions were cytologically bland, deep-seated regions of the tumor exhibited greater cellularity, nuclear pleomorphism, and mitotic activity (Figure 4). There was no bone involvement. Right axillary sentinel lymph nodes were negative for metastasis. Eighteen months later the patient developed chest and back pain with dyspnea. Thorascopic surgery was performed for a left pleural effusion and metastases to the left parietal pleura and adjacent soft tissue were identified. The patient was subsequently lost to follow-up.

Comment

First described by Enzinger¹ in 1970, ES is a rare malignant soft tissue neoplasm that most frequently arises on the hands, forearms, and pretibial soft tissues of young adults.^1-3 It is an aggressive tumor characterized by frequent recurrences and a high metastatic rate, with lung and regional lymph nodes being favored metastatic sites.^1-5 Periods of several months or even years often pass between the initial presentation and establishment of a correct diagnosis, as ES frequently is mistaken for other benign conditions. The tendency for ES to mimic granulomatous processes is a common diagnostic pitfall, but the potential for its close resemblance to benign fibrous histiocytoma is less recognized.^6,7 In his original series of 62 cases, Enzinger¹ noted that 17 patients were referred for treatment with a diagnosis of a benign fibrohistiocytic neoplasm, and other reports have described a resemblance to fibrous and fibrohistiocytic neoplasms.^8-11 Mirra et al¹⁰ designated these tumors as fibromalike variants of ES. Additional subtypes of ES have subsequently been recognized, including those described as angiomatoid or angiosarcomalike, reflecting the potential of ES to resemble vascular tumors.¹² A proximal type of ES also has been described. This lesion presents as a deep-seated tumor on the proximal limbs and is associated with more aggressive behavior. It lacks the granulomalike pattern and has more prominent epithelioid and rhabdoid histological presentation.^13-15

Epithelioid sarcoma is a mesenchymal tumor that can display multidirectional differentiation that is primarily epithelial.¹⁶ The precise histogenesis of ES remains unclear, but studies have demonstrated a spectrum of differentiation that ranges from primitive myofibroblast or fibrohistiocytelike cells to those with well-developed epithelial properties.^16,17 Epithelioid sarcoma characteristically coexpresses vimentin and low-molecular-weight CKs such as cell adhesion molecule 5.2. The tumor cells often are immunoreactive for epithelial membrane antigen and more than 50% of cases exhibit remarkable CD34 positivity.¹⁶ More recent studies have further refined the immunophenotype, demonstrating frequent expression of CK8 and CK19 but less commonly CK7, CK20, CK34bE12, and CK5/6.^18-20 Additional studies reported that in 10 of 11 cases, ES was positive for CA 125 on immunohistochemical staining, and 3 of 5 patients also had elevated serum CA 125 levels.^21,22 More recently, Hoshino et al²³ showed elevated serum CA 125 levels in 5 of 7 patients with ES. Cancer antigen 125 is a high-molecular-weight glycoprotein commonly used in the identification of epithelial ovarian carcinomas; however, it also has been described in a number of other neoplasms including carcinomas of the breast, lungs, and colon and lymphoma.^24-27 Although it appears that the addition of CA 125 to a panel of other immunohistochemical stains may be helpful in differentiating ES from other soft tissue sarcomas and serum CA 125 levels may help determine tumor burden, currently the number of cases studied is too small to definitively make that conclusion.^21,23 In our case, the tumor cells were strongly and diffusely positive for CA 125. Serum CA 125 levels were not available.

Figure 3. Tumor cells focally showed strong membranous staining for cytokeratin AE1/AE3 (original magnification ×400).

Figure 4. High-power view of the tumor from the amputation specimen showed sheets of epithelioid and polygonal cells displaying marked nuclear pleomorphism and scattered mitoses (H&E, original magnification ×400).

Cytogenetic studies have failed to identify a consistent chromosomal abnormality in ES.⁵ Some analyses performed by comparative genomic hybridization on isolated cases and small case series indicate that the most frequent alterations involve 8q, 18q11, and 22q11.^13,28,29 The tumor suppressor gene SMARCB1/INI1 (SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily B, member 1/integrase interactor 1) has been mapped to 22q11, and ES commonly shows absence of nuclear staining for this protein, indicating inactivation.^13-15

Conclusion

Benign fibrohistiocytic proliferations should be included in the differential of histological mimickers of ES. Deep biopsies are essential to differentiate these benign tumors from fibrous histiocytomalike or fibromalike lesions of ES because superficial portions of ES may be well differentiated.

Sun damage and chronic exposure to UV radiation have been recognized as causative factors for the development of squamous cell carcinoma (SCC), its precursor actinic keratosis (AK), and basal cell carcinoma (BCC). Although surgical treatment is necessary for most advanced cases of skin cancer, several other therapeutic approaches have been described including the use of topical chemotherapy agents such as 5-fluorouracil (5-FU) and topical immunomodulators such as imiquimod. Unlike surgery, these agents provide the added benefit of treating larger fields of photodamaged skin. With the increasing prevalence of nonmelanoma skin cancers (NMSCs), the use of multiple topical agents for treatment will continue to become more common.

We present the case of a patient who underwent field therapy with topical 5-FU for diffuse actinic damage and AKs. There was no subsequent inflammatory response within the perimeter of a BCC that had been treated with imiquimod 10 years prior.

Case Report

An otherwise healthy 58-year-old man with a history of long-standing diffuse sun damage and multiple prior NMSCs presented for treatment of a recurrent BCC on the right cheek. The patient reported that the BCC had initially been biopsied and excised by his primary care physician. Two months later local recurrence was noted by the primary care physician and the patient was subsequently referred to our dermatology office. A 2-month treatment course with daily imiquimod cream 5% was initiated. This treatment caused extensive inflammation of the right cheek but was otherwise well tolerated (Figure 1).

Figure 1. Extensive inflammation following application of imiquimod cream 5% for treatment of basal cell carcinoma. Figure 2. Right side of the patient’s face on day 1 (A) and day 30 (B) of treatment with 5-fluorouracil cream 0.5% as well as 15 days posttreatment (C), with no inflammatory response on the area that was previously treated with imiquimod.

During a routine skin cancer screening 10 years later, no recurrence of the BCC was noted on the right cheek; however, the patient had developed multiple AKs on the face. Therapeutic options were discussed with the patient; he agreed to topical field therapy with 5-FU cream 0.5%. The patient applied the 5-FU cream to the entire face nightly for 1 month. During this time he experienced a brisk inflammatory response with painful cracking and redness of the skin. On follow-up, it was noted that the area on the right cheek that had been treated with imiquimod 10 years prior showed no inflammatory response despite nightly application of 5-FU cream to the area (Figure 2). The patient denied any routine use of sunscreen or other sun-protective practices.

Comment

Basal cell carcinoma is the most common skin cancer in the United States with an incidence of 1.4% to 2% per year. It has become more prevalent in recent decades, likely due to genetic predisposition and increasing cumulative sun exposure.^1-4 A variety of treatment options are available. Surgical interventions include destruction via electrodesiccation and curettage, local excision, and Mohs micrographic surgery. One of the challenges in the management of BCC, as was the case in our patient, is the treatment of tumors that arise in cosmetically or functionally sensitive areas. Approaches that minimize the amount of tissue removed while ensuring the highest possible cure rate are favorable. In addition to surgery, topical imiquimod has been established as a potential treatment of BCC. Imiquimod, a nucleoside analogue of the imidazoquinoline family, is an agonist of toll-like receptors 7 and 8 that promotes cytokine-induced cell death via nuclear factor kB and a helper T cell T_H1-weighted antitumor inflammatory response.^5,6 Although clearance rates with imiquimod vary by drug regimen, success rates of 43% to 100% for superficial BCCs, 42% to 100% for nodular BCCs, and 56% to 63% for infiltrative BCCs have been reported.⁷ In a 2007 randomized study of imiquimod cream 5%, 5-FU ointment 5%, or cryosurgery for the treatment of AK, imiquimod resulted in superior and more reliable clearance with lower recurrence rates.⁸

Similar to BCC, AK is closely linked to lifetime cumulative sun exposure.⁹ Actinic keratoses have been well established as precursors to SCC, and some researchers advocate for their reclassification as early SCC in situ.¹⁰ The incidence of malignant conversion of AK to SCC has been estimated at 0.025% to 16% annually, with an estimated lifetime risk for malignant transformation of 8% per individual AK.^11,12 Cryotherapy has been a mainstay for the treatment of isolated AK, and alternative therapies including curettage, photodynamic therapy, and laser therapy have been employed. Field-directed therapy has become a popular alternative that targets multiple lesions and field cancerization.^8,13,14 Field cancerization implies that if one cell in the patient’s epidermis has been exposed to enough UV radiation to develop into a precancerous lesion or early skin cancer, then many other cells in the same environment likely have some degree of UV radiation–induced atypia.¹⁵ 5-Fluorouacil is a pyrimidine analogue chemotherapeutic agent that inhibits thymidylate synthase and interferes with DNA synthesis.¹⁶ This mechanism of 5-FU commonly causes an inflammatory response characterized by burning, dryness, and redness, but these effects rarely force early discontinuation of treatment. A randomized controlled trial comparing 5-FU cream 0.5% to a placebo found that complete clearance rates at 4 weeks posttreatment were significantly higher in the treatment group (47.5%) versus placebo (3.4%)(P<.001).¹³ Additional trials have established no significant superiority of 5-FU cream 5% over 5-FU cream 0.5%, with a decrease in side effects noted in patients treated with the lower concentration.¹⁷

Our patient had a history of a recurrent BCC and was previously treated with imiquimod. He showed no inflammatory response to field therapy with 5-FU within the perimeter of prior immunomodulatory therapy. Although no frank scaling or crusting papules consistent with AK were observed in the previously treated area prior to 5-FU therapy, subclinical field damage in that area was expected because 10 years of additional sun exposure had accumulated since imiquimod therapy was completed. Several conclusions can be drawn from this observation. Primarily, no new clinically significant actinic lesions occurred on the previously treated skin. This observation is consistent with 12-month follow-up data on AKs treated with either 5-FU, imiquimod, or cryosurgery that identified imiquimod as having the lowest recurrence rate.⁸ Thus, a photoprotective effect may be ascribed to imiquimod therapy that extends beyond its drug effects on atypical keratinocytes. It has been one author’s personal experience (M.Q.) that patients treated with 5-FU experience recurrence of AKs within 3 to 5 years versus 10 years of remission with imiquimod. In our patient, imiquimod therapy seemed to reset the patient’s skin at the location of the prior BCC and surrounding field cancerization.

Studies with long-term follow-up are needed to investigate the need for re-treatment with imiquimod or 5-FU. The longevity of imiquimod treatment may be of importance beyond the treatment of AKs or NMSCs. For instance, during the treatment of lentigo maligna with imiquimod, Metcalf et al¹⁸ found a significant reduction in solar elastosis (P=.0036), normalization of epidermal thickness (P=.0073), and increased papillary dermal fibroplasia in pre- and posttreatment biopsies (P<.0001), which have been described as antiaging effects in the laypress. Some of these mechanisms appear to be implicated in the observations noted in our patient. The 10-year period between the 2 courses of therapy in our patient suggests that imiquimod may cause sustained healing of skin that was previously classified both clinically and microscopically as UV damaged.

Conclusion

Both topical immunomodulators such as imiquimod and topical chemotherapeutic agents such as 5-FU have a role in the field treatment of AK and the focal treatment of superficial BCC and SCC. As multiple topical immunomodulators continue to be evaluated, long-term studies assessing the need for re-treatment as well as the degree of sustained remission of sun damage will be necessary. We expect that their individual roles will continue to become more precisely defined and distinct in the coming years.

Sun damage and chronic exposure to UV radiation have been recognized as causative factors for the development of squamous cell carcinoma (SCC), its precursor actinic keratosis (AK), and basal cell carcinoma (BCC). Although surgical treatment is necessary for most advanced cases of skin cancer, several other therapeutic approaches have been described including the use of topical chemotherapy agents such as 5-fluorouracil (5-FU) and topical immunomodulators such as imiquimod. Unlike surgery, these agents provide the added benefit of treating larger fields of photodamaged skin. With the increasing prevalence of nonmelanoma skin cancers (NMSCs), the use of multiple topical agents for treatment will continue to become more common.

We present the case of a patient who underwent field therapy with topical 5-FU for diffuse actinic damage and AKs. There was no subsequent inflammatory response within the perimeter of a BCC that had been treated with imiquimod 10 years prior.

Case Report

An otherwise healthy 58-year-old man with a history of long-standing diffuse sun damage and multiple prior NMSCs presented for treatment of a recurrent BCC on the right cheek. The patient reported that the BCC had initially been biopsied and excised by his primary care physician. Two months later local recurrence was noted by the primary care physician and the patient was subsequently referred to our dermatology office. A 2-month treatment course with daily imiquimod cream 5% was initiated. This treatment caused extensive inflammation of the right cheek but was otherwise well tolerated (Figure 1).

Figure 1. Extensive inflammation following application of imiquimod cream 5% for treatment of basal cell carcinoma. Figure 2. Right side of the patient’s face on day 1 (A) and day 30 (B) of treatment with 5-fluorouracil cream 0.5% as well as 15 days posttreatment (C), with no inflammatory response on the area that was previously treated with imiquimod.

During a routine skin cancer screening 10 years later, no recurrence of the BCC was noted on the right cheek; however, the patient had developed multiple AKs on the face. Therapeutic options were discussed with the patient; he agreed to topical field therapy with 5-FU cream 0.5%. The patient applied the 5-FU cream to the entire face nightly for 1 month. During this time he experienced a brisk inflammatory response with painful cracking and redness of the skin. On follow-up, it was noted that the area on the right cheek that had been treated with imiquimod 10 years prior showed no inflammatory response despite nightly application of 5-FU cream to the area (Figure 2). The patient denied any routine use of sunscreen or other sun-protective practices.

Comment

Basal cell carcinoma is the most common skin cancer in the United States with an incidence of 1.4% to 2% per year. It has become more prevalent in recent decades, likely due to genetic predisposition and increasing cumulative sun exposure.^1-4 A variety of treatment options are available. Surgical interventions include destruction via electrodesiccation and curettage, local excision, and Mohs micrographic surgery. One of the challenges in the management of BCC, as was the case in our patient, is the treatment of tumors that arise in cosmetically or functionally sensitive areas. Approaches that minimize the amount of tissue removed while ensuring the highest possible cure rate are favorable. In addition to surgery, topical imiquimod has been established as a potential treatment of BCC. Imiquimod, a nucleoside analogue of the imidazoquinoline family, is an agonist of toll-like receptors 7 and 8 that promotes cytokine-induced cell death via nuclear factor kB and a helper T cell T_H1-weighted antitumor inflammatory response.^5,6 Although clearance rates with imiquimod vary by drug regimen, success rates of 43% to 100% for superficial BCCs, 42% to 100% for nodular BCCs, and 56% to 63% for infiltrative BCCs have been reported.⁷ In a 2007 randomized study of imiquimod cream 5%, 5-FU ointment 5%, or cryosurgery for the treatment of AK, imiquimod resulted in superior and more reliable clearance with lower recurrence rates.⁸

Similar to BCC, AK is closely linked to lifetime cumulative sun exposure.⁹ Actinic keratoses have been well established as precursors to SCC, and some researchers advocate for their reclassification as early SCC in situ.¹⁰ The incidence of malignant conversion of AK to SCC has been estimated at 0.025% to 16% annually, with an estimated lifetime risk for malignant transformation of 8% per individual AK.^11,12 Cryotherapy has been a mainstay for the treatment of isolated AK, and alternative therapies including curettage, photodynamic therapy, and laser therapy have been employed. Field-directed therapy has become a popular alternative that targets multiple lesions and field cancerization.^8,13,14 Field cancerization implies that if one cell in the patient’s epidermis has been exposed to enough UV radiation to develop into a precancerous lesion or early skin cancer, then many other cells in the same environment likely have some degree of UV radiation–induced atypia.¹⁵ 5-Fluorouacil is a pyrimidine analogue chemotherapeutic agent that inhibits thymidylate synthase and interferes with DNA synthesis.¹⁶ This mechanism of 5-FU commonly causes an inflammatory response characterized by burning, dryness, and redness, but these effects rarely force early discontinuation of treatment. A randomized controlled trial comparing 5-FU cream 0.5% to a placebo found that complete clearance rates at 4 weeks posttreatment were significantly higher in the treatment group (47.5%) versus placebo (3.4%)(P<.001).¹³ Additional trials have established no significant superiority of 5-FU cream 5% over 5-FU cream 0.5%, with a decrease in side effects noted in patients treated with the lower concentration.¹⁷

Our patient had a history of a recurrent BCC and was previously treated with imiquimod. He showed no inflammatory response to field therapy with 5-FU within the perimeter of prior immunomodulatory therapy. Although no frank scaling or crusting papules consistent with AK were observed in the previously treated area prior to 5-FU therapy, subclinical field damage in that area was expected because 10 years of additional sun exposure had accumulated since imiquimod therapy was completed. Several conclusions can be drawn from this observation. Primarily, no new clinically significant actinic lesions occurred on the previously treated skin. This observation is consistent with 12-month follow-up data on AKs treated with either 5-FU, imiquimod, or cryosurgery that identified imiquimod as having the lowest recurrence rate.⁸ Thus, a photoprotective effect may be ascribed to imiquimod therapy that extends beyond its drug effects on atypical keratinocytes. It has been one author’s personal experience (M.Q.) that patients treated with 5-FU experience recurrence of AKs within 3 to 5 years versus 10 years of remission with imiquimod. In our patient, imiquimod therapy seemed to reset the patient’s skin at the location of the prior BCC and surrounding field cancerization.

Studies with long-term follow-up are needed to investigate the need for re-treatment with imiquimod or 5-FU. The longevity of imiquimod treatment may be of importance beyond the treatment of AKs or NMSCs. For instance, during the treatment of lentigo maligna with imiquimod, Metcalf et al¹⁸ found a significant reduction in solar elastosis (P=.0036), normalization of epidermal thickness (P=.0073), and increased papillary dermal fibroplasia in pre- and posttreatment biopsies (P<.0001), which have been described as antiaging effects in the laypress. Some of these mechanisms appear to be implicated in the observations noted in our patient. The 10-year period between the 2 courses of therapy in our patient suggests that imiquimod may cause sustained healing of skin that was previously classified both clinically and microscopically as UV damaged.

Conclusion

Both topical immunomodulators such as imiquimod and topical chemotherapeutic agents such as 5-FU have a role in the field treatment of AK and the focal treatment of superficial BCC and SCC. As multiple topical immunomodulators continue to be evaluated, long-term studies assessing the need for re-treatment as well as the degree of sustained remission of sun damage will be necessary. We expect that their individual roles will continue to become more precisely defined and distinct in the coming years.

Sun damage and chronic exposure to UV radiation have been recognized as causative factors for the development of squamous cell carcinoma (SCC), its precursor actinic keratosis (AK), and basal cell carcinoma (BCC). Although surgical treatment is necessary for most advanced cases of skin cancer, several other therapeutic approaches have been described including the use of topical chemotherapy agents such as 5-fluorouracil (5-FU) and topical immunomodulators such as imiquimod. Unlike surgery, these agents provide the added benefit of treating larger fields of photodamaged skin. With the increasing prevalence of nonmelanoma skin cancers (NMSCs), the use of multiple topical agents for treatment will continue to become more common.

We present the case of a patient who underwent field therapy with topical 5-FU for diffuse actinic damage and AKs. There was no subsequent inflammatory response within the perimeter of a BCC that had been treated with imiquimod 10 years prior.

Case Report

An otherwise healthy 58-year-old man with a history of long-standing diffuse sun damage and multiple prior NMSCs presented for treatment of a recurrent BCC on the right cheek. The patient reported that the BCC had initially been biopsied and excised by his primary care physician. Two months later local recurrence was noted by the primary care physician and the patient was subsequently referred to our dermatology office. A 2-month treatment course with daily imiquimod cream 5% was initiated. This treatment caused extensive inflammation of the right cheek but was otherwise well tolerated (Figure 1).

Figure 1. Extensive inflammation following application of imiquimod cream 5% for treatment of basal cell carcinoma. Figure 2. Right side of the patient’s face on day 1 (A) and day 30 (B) of treatment with 5-fluorouracil cream 0.5% as well as 15 days posttreatment (C), with no inflammatory response on the area that was previously treated with imiquimod.

During a routine skin cancer screening 10 years later, no recurrence of the BCC was noted on the right cheek; however, the patient had developed multiple AKs on the face. Therapeutic options were discussed with the patient; he agreed to topical field therapy with 5-FU cream 0.5%. The patient applied the 5-FU cream to the entire face nightly for 1 month. During this time he experienced a brisk inflammatory response with painful cracking and redness of the skin. On follow-up, it was noted that the area on the right cheek that had been treated with imiquimod 10 years prior showed no inflammatory response despite nightly application of 5-FU cream to the area (Figure 2). The patient denied any routine use of sunscreen or other sun-protective practices.

Comment

Basal cell carcinoma is the most common skin cancer in the United States with an incidence of 1.4% to 2% per year. It has become more prevalent in recent decades, likely due to genetic predisposition and increasing cumulative sun exposure.^1-4 A variety of treatment options are available. Surgical interventions include destruction via electrodesiccation and curettage, local excision, and Mohs micrographic surgery. One of the challenges in the management of BCC, as was the case in our patient, is the treatment of tumors that arise in cosmetically or functionally sensitive areas. Approaches that minimize the amount of tissue removed while ensuring the highest possible cure rate are favorable. In addition to surgery, topical imiquimod has been established as a potential treatment of BCC. Imiquimod, a nucleoside analogue of the imidazoquinoline family, is an agonist of toll-like receptors 7 and 8 that promotes cytokine-induced cell death via nuclear factor kB and a helper T cell T_H1-weighted antitumor inflammatory response.^5,6 Although clearance rates with imiquimod vary by drug regimen, success rates of 43% to 100% for superficial BCCs, 42% to 100% for nodular BCCs, and 56% to 63% for infiltrative BCCs have been reported.⁷ In a 2007 randomized study of imiquimod cream 5%, 5-FU ointment 5%, or cryosurgery for the treatment of AK, imiquimod resulted in superior and more reliable clearance with lower recurrence rates.⁸

Similar to BCC, AK is closely linked to lifetime cumulative sun exposure.⁹ Actinic keratoses have been well established as precursors to SCC, and some researchers advocate for their reclassification as early SCC in situ.¹⁰ The incidence of malignant conversion of AK to SCC has been estimated at 0.025% to 16% annually, with an estimated lifetime risk for malignant transformation of 8% per individual AK.^11,12 Cryotherapy has been a mainstay for the treatment of isolated AK, and alternative therapies including curettage, photodynamic therapy, and laser therapy have been employed. Field-directed therapy has become a popular alternative that targets multiple lesions and field cancerization.^8,13,14 Field cancerization implies that if one cell in the patient’s epidermis has been exposed to enough UV radiation to develop into a precancerous lesion or early skin cancer, then many other cells in the same environment likely have some degree of UV radiation–induced atypia.¹⁵ 5-Fluorouacil is a pyrimidine analogue chemotherapeutic agent that inhibits thymidylate synthase and interferes with DNA synthesis.¹⁶ This mechanism of 5-FU commonly causes an inflammatory response characterized by burning, dryness, and redness, but these effects rarely force early discontinuation of treatment. A randomized controlled trial comparing 5-FU cream 0.5% to a placebo found that complete clearance rates at 4 weeks posttreatment were significantly higher in the treatment group (47.5%) versus placebo (3.4%)(P<.001).¹³ Additional trials have established no significant superiority of 5-FU cream 5% over 5-FU cream 0.5%, with a decrease in side effects noted in patients treated with the lower concentration.¹⁷

Our patient had a history of a recurrent BCC and was previously treated with imiquimod. He showed no inflammatory response to field therapy with 5-FU within the perimeter of prior immunomodulatory therapy. Although no frank scaling or crusting papules consistent with AK were observed in the previously treated area prior to 5-FU therapy, subclinical field damage in that area was expected because 10 years of additional sun exposure had accumulated since imiquimod therapy was completed. Several conclusions can be drawn from this observation. Primarily, no new clinically significant actinic lesions occurred on the previously treated skin. This observation is consistent with 12-month follow-up data on AKs treated with either 5-FU, imiquimod, or cryosurgery that identified imiquimod as having the lowest recurrence rate.⁸ Thus, a photoprotective effect may be ascribed to imiquimod therapy that extends beyond its drug effects on atypical keratinocytes. It has been one author’s personal experience (M.Q.) that patients treated with 5-FU experience recurrence of AKs within 3 to 5 years versus 10 years of remission with imiquimod. In our patient, imiquimod therapy seemed to reset the patient’s skin at the location of the prior BCC and surrounding field cancerization.

Studies with long-term follow-up are needed to investigate the need for re-treatment with imiquimod or 5-FU. The longevity of imiquimod treatment may be of importance beyond the treatment of AKs or NMSCs. For instance, during the treatment of lentigo maligna with imiquimod, Metcalf et al¹⁸ found a significant reduction in solar elastosis (P=.0036), normalization of epidermal thickness (P=.0073), and increased papillary dermal fibroplasia in pre- and posttreatment biopsies (P<.0001), which have been described as antiaging effects in the laypress. Some of these mechanisms appear to be implicated in the observations noted in our patient. The 10-year period between the 2 courses of therapy in our patient suggests that imiquimod may cause sustained healing of skin that was previously classified both clinically and microscopically as UV damaged.

Conclusion

Both topical immunomodulators such as imiquimod and topical chemotherapeutic agents such as 5-FU have a role in the field treatment of AK and the focal treatment of superficial BCC and SCC. As multiple topical immunomodulators continue to be evaluated, long-term studies assessing the need for re-treatment as well as the degree of sustained remission of sun damage will be necessary. We expect that their individual roles will continue to become more precisely defined and distinct in the coming years.

First described by Fetsch et al¹ in 2001, superficial acral fibromyxoma (SAFM) is a rare fibromyxoid mesenchymal tumor that typically affects the fingers and toes with frequent involvement of the nail unit. It is not widely recognized and remains poorly understood. We describe a series of 3 cases of SAFM encountered at our institution and provide a review of the literature on this unique tumor.

Case Reports

Patient 1

A 35-year-old man presented for treatment of a “wart” on the right fifth toe that had increased in size over the last year. He reported that the lesion was mildly painful and occasionally bled or drained clear fluid. He also noted cracking of the nail plate on the same toe. Physical examination revealed a firm, flesh-colored, 3-mm dermal papule on the proximal nail fold of the right fifth toe with subtle flattening of the underlying nail plate (Figure 1). The patient underwent biopsy of the involved proximal nail fold. Histopathology revealed a proliferation of small oval and spindle cells arranged in fascicles and bundles in the dermis (Figure 2). There was extensive mucin deposition associated with the spindle cell proliferation. Additionally, spindle cells and mucin surrounded and entrapped collagen bundles on the periphery of the lesion. Lesional cells were diffusely positive for CD34 and extended to the deep surgical margin (Figure 3). S-100 and factor XIIIa stains were negative. The diagnosis of SAFM was made based on the acral location, histopathologic appearance, and immunohistochemical profile of the tumor.

Figure 1. Firm dermal papule on the proximal nail fold of the right fifth toe with associated nail plate dystrophy. Figure 2. Small oval and spindle cells arranged in fascicles and bundles in the dermis, with extensive mucin deposition and collagen trapping (H&E, original magnification ×100). Figure 3. Tumor cells were positive on CD34 staining (original magnification ×40). Figure 4. Dermal stellate spindle cells arranged in a loose fascicular pattern with marked mucin deposition (H&E, original magnification ×400).

Patient 2

A 47-year-old man presented with an asymptomatic growth on the left fourth toe that had increased in size over the last year. Physical examination revealed an 8-mm, firm, fleshy, flesh-colored, smooth and slightly pedunculated papule on the distal aspect of the left fourth toe. The nail plate and periungual region were not involved. A shave biopsy of the papule was obtained. Histopathology demonstrated dermal stellate spindle cells arranged in a loose fascicular pattern with marked mucin deposition throughout the dermis (Figure 4). Lesional cells were positive for CD34. An S-100 stain highlighted dermal dendritic cells, but lesional cells were negative. No further excision was undertaken, and there was no evidence of recurrence at 1-year follow-up. The diagnosis of SAFM was made based on the acral location, histopathologic appearance, and immunohistochemical profile of the tumor.

Patient 3

A 45-year-old woman presented with asymptomatic distal onycholysis of the right thumbnail of 1 year’s duration. She denied any history of trauma, and no bleeding or pigmentary changes were noted. Physical examination revealed a 5-mm flesh-colored papule on the hyponychium of the right thumb with focal onycholysis (Figure 5). A wedge biopsy of the lesion was performed. Histopathology showed an intradermal nodular proliferation of bland spindle cells arranged in loose fascicles and bundles and embedded in a myxoid stroma (Figure 6). CD34 staining strongly highlighted lesional cells. S-100 and neurofilament stains were negative. The diagnosis of SAFM was made based on the acral location, histopathologic appearance, and immunohistochemical profile of the tumor.

Comment

Clinically, SAFM typically presents as a slow-growing solitary nodule on the distal fingers or toes. The great toe is the most commonly affected digit, and the tumor may be subungual in up to two-thirds of cases.¹ Unusual locations, such as the heel, also have been reported.² Onset typically occurs in the fifth or sixth decade, and there is an approximately 2-fold higher incidence in men than women.^1-3

Histopathologically, SAFM is a characteristically well-circumscribed but unencapsulated dermal tumor composed of spindle and stellate cells in a loose storiform or fascicular arrangement embedded in a myxoid, myxocollagenous, or collagenous stroma.⁴ The tumor often occupies the entire dermis and may extend into the subcutis or occasionally the underlying fascia and bone.^4,5 Mast cells often are prominent, and microvascular accentuation also may be seen. Inflammatory infiltrates and multinucleated giant cells typically are not seen.⁶ Although 2 cases of atypical SAFM have been described,² cellular atypia is not a characteristic feature of SAFM.

The immunohistochemical profile of SAFM is characterized by diffuse or focal expression of CD34, focal expression of epithelial membrane antigen (EMA), CD99 expression, and varying numbers of factor XIIIa–positive histiocytes.^2,3 Positive staining for vimentin also is common. Staining typically is negative for S-100, human melanoma black 45, keratin, smooth muscle actin, and desmin.

The standard treatment of SAFM is complete local resection of the tumor, though some patients have been treated with partial excision or biopsy and partial or complete digital amputation.¹ Local recurrence may occur in up to 20% of cases; however, approximately two-thirds of the reported recurrences in the literature occurred after incomplete tumor excision.^1,2 It may be more appropriate to consider these cases as persistent rather than recurrent tumors. Superficial acral fibromyxoma is considered a benign tumor, with no known cases of metastases.⁴

Figure 5. A firm flesh-colored papule on the hyponychium of the right thumb prior to biopsy. Figure 6. Intradermal nodular proliferation of bland spindle cells arranged in loose fascicles and bundles and embedded in a myxoid stroma (H&E, original magnification ×40).

A broad differential diagnosis exists for SAFM and it can be difficult to differentiate it from a wide variety of benign and malignant tumors that may be seen on the nail unit and distal extremities (Table). Myxoid neurofibromas typically present as solitary lesions on the hands and feet. Similar to SAFM, myxoid neurofibromas are unencapsulated dermal tumors composed of spindle-shaped cells in which mast cells often are conspicuous.^2,7 However, tumor cells in myxoid neurofibromas are S-100 positive, and the lesions typically do not show vasculature accentuation.^4,7

Sclerosing perineuriomas are benign fibrous tumors of the fingers and palms. Histopathologically, bland spindle cells arranged in fascicles and whorls are observed in a hyalinized collagen matrix.⁸ Immunohistochemically, sclerosing perineuriomas are positive for EMA and negative for S-100, but unlike SAFM, these tumors usually are CD34 negative.⁸

Superficial angiomyxomas typically are located on the head and neck but also may be found in other locations such as the trunk. They present as cutaneous papules or polypoid lesions. Histopathologically, superficial angiomyxomas are poorly circumscribed with a lobular pattern. Spindle-shaped fibroblasts exist in a myxoid matrix with neutrophils and thin-walled capillaries. The fibroblasts are variably positive for CD34 but also are S-100 positive.^1,9

Myxoid dermatofibrosarcoma protuberans is a rare, locally aggressive, mesenchymal tumor of the skin and subcutis² that typically presents on the trunk, proximal extremities, or head and neck; occurrence on the fingers or toes is exceedingly rare.^2,10 Histopathologically, a myxoid stroma contains sheets of bland spindle-shaped cells with minimal to no atypia, sometimes arranged in a storiform pattern. The tumor characteristically invades deeply into the subcutaneous tissues. CD34 is characteristically positive and S-100 is negative.^2,10

Low-grade myxofibrosarcoma is a soft tissue sarcoma easily confused with other spindle cell tumors. It is one of the most common sarcomas in adults but rarely arises in acral areas.² It is characterized by a nodular growth pattern with marked nuclear atypia and perivascular clustering of tumor cells. CD34 staining may be positive in some cases.¹¹

Similar to SAFM, myxoinflammatory fibroblastic sarcoma has a predilection for the extremities.⁴ However, it typically presents as a subcutaneous mass and has no documented tendency for nail bed involvement. Also unlike SAFM, it has a remarkable inflammatory infiltrate and characteristic virocyte or Reed-Sternberg cells.¹²

Acquired digital fibrokeratomas are benign neoplasms that occur on fingers and toes; the classic clinical presentation is a solitary smooth nodule or dome, often with a characteristic projecting configuration and horn shape.¹ Histopathologically, these tumors are paucicellular with thick, vertically oriented, interwoven collagen bundles; cells may be positive for CD34 but are negative for EMA.^1,13 Related to acquired digital fibrokeratomas are Koenen tumors, which share a similar histology but are distinguished by their clinical characteristics. For example, Koenen tumors tend to be multifocal and are strongly associated with tuberous sclerosis. These tumors also have a tendency to recur.¹

Conclusion

Our report of 3 typical cases of SAFM highlights the need to keep this increasingly recognized and well-defined clinicopathological entity in the differential for slow-growing tumors in acral locations, particularly those in the periungual and subungual regions.

First described by Fetsch et al¹ in 2001, superficial acral fibromyxoma (SAFM) is a rare fibromyxoid mesenchymal tumor that typically affects the fingers and toes with frequent involvement of the nail unit. It is not widely recognized and remains poorly understood. We describe a series of 3 cases of SAFM encountered at our institution and provide a review of the literature on this unique tumor.

Case Reports

Patient 1

A 35-year-old man presented for treatment of a “wart” on the right fifth toe that had increased in size over the last year. He reported that the lesion was mildly painful and occasionally bled or drained clear fluid. He also noted cracking of the nail plate on the same toe. Physical examination revealed a firm, flesh-colored, 3-mm dermal papule on the proximal nail fold of the right fifth toe with subtle flattening of the underlying nail plate (Figure 1). The patient underwent biopsy of the involved proximal nail fold. Histopathology revealed a proliferation of small oval and spindle cells arranged in fascicles and bundles in the dermis (Figure 2). There was extensive mucin deposition associated with the spindle cell proliferation. Additionally, spindle cells and mucin surrounded and entrapped collagen bundles on the periphery of the lesion. Lesional cells were diffusely positive for CD34 and extended to the deep surgical margin (Figure 3). S-100 and factor XIIIa stains were negative. The diagnosis of SAFM was made based on the acral location, histopathologic appearance, and immunohistochemical profile of the tumor.

Figure 1. Firm dermal papule on the proximal nail fold of the right fifth toe with associated nail plate dystrophy. Figure 2. Small oval and spindle cells arranged in fascicles and bundles in the dermis, with extensive mucin deposition and collagen trapping (H&E, original magnification ×100). Figure 3. Tumor cells were positive on CD34 staining (original magnification ×40). Figure 4. Dermal stellate spindle cells arranged in a loose fascicular pattern with marked mucin deposition (H&E, original magnification ×400).

Patient 2

A 47-year-old man presented with an asymptomatic growth on the left fourth toe that had increased in size over the last year. Physical examination revealed an 8-mm, firm, fleshy, flesh-colored, smooth and slightly pedunculated papule on the distal aspect of the left fourth toe. The nail plate and periungual region were not involved. A shave biopsy of the papule was obtained. Histopathology demonstrated dermal stellate spindle cells arranged in a loose fascicular pattern with marked mucin deposition throughout the dermis (Figure 4). Lesional cells were positive for CD34. An S-100 stain highlighted dermal dendritic cells, but lesional cells were negative. No further excision was undertaken, and there was no evidence of recurrence at 1-year follow-up. The diagnosis of SAFM was made based on the acral location, histopathologic appearance, and immunohistochemical profile of the tumor.

Patient 3

A 45-year-old woman presented with asymptomatic distal onycholysis of the right thumbnail of 1 year’s duration. She denied any history of trauma, and no bleeding or pigmentary changes were noted. Physical examination revealed a 5-mm flesh-colored papule on the hyponychium of the right thumb with focal onycholysis (Figure 5). A wedge biopsy of the lesion was performed. Histopathology showed an intradermal nodular proliferation of bland spindle cells arranged in loose fascicles and bundles and embedded in a myxoid stroma (Figure 6). CD34 staining strongly highlighted lesional cells. S-100 and neurofilament stains were negative. The diagnosis of SAFM was made based on the acral location, histopathologic appearance, and immunohistochemical profile of the tumor.

Comment

Clinically, SAFM typically presents as a slow-growing solitary nodule on the distal fingers or toes. The great toe is the most commonly affected digit, and the tumor may be subungual in up to two-thirds of cases.¹ Unusual locations, such as the heel, also have been reported.² Onset typically occurs in the fifth or sixth decade, and there is an approximately 2-fold higher incidence in men than women.^1-3

Histopathologically, SAFM is a characteristically well-circumscribed but unencapsulated dermal tumor composed of spindle and stellate cells in a loose storiform or fascicular arrangement embedded in a myxoid, myxocollagenous, or collagenous stroma.⁴ The tumor often occupies the entire dermis and may extend into the subcutis or occasionally the underlying fascia and bone.^4,5 Mast cells often are prominent, and microvascular accentuation also may be seen. Inflammatory infiltrates and multinucleated giant cells typically are not seen.⁶ Although 2 cases of atypical SAFM have been described,² cellular atypia is not a characteristic feature of SAFM.

The immunohistochemical profile of SAFM is characterized by diffuse or focal expression of CD34, focal expression of epithelial membrane antigen (EMA), CD99 expression, and varying numbers of factor XIIIa–positive histiocytes.^2,3 Positive staining for vimentin also is common. Staining typically is negative for S-100, human melanoma black 45, keratin, smooth muscle actin, and desmin.

The standard treatment of SAFM is complete local resection of the tumor, though some patients have been treated with partial excision or biopsy and partial or complete digital amputation.¹ Local recurrence may occur in up to 20% of cases; however, approximately two-thirds of the reported recurrences in the literature occurred after incomplete tumor excision.^1,2 It may be more appropriate to consider these cases as persistent rather than recurrent tumors. Superficial acral fibromyxoma is considered a benign tumor, with no known cases of metastases.⁴

Figure 5. A firm flesh-colored papule on the hyponychium of the right thumb prior to biopsy. Figure 6. Intradermal nodular proliferation of bland spindle cells arranged in loose fascicles and bundles and embedded in a myxoid stroma (H&E, original magnification ×40).

A broad differential diagnosis exists for SAFM and it can be difficult to differentiate it from a wide variety of benign and malignant tumors that may be seen on the nail unit and distal extremities (Table). Myxoid neurofibromas typically present as solitary lesions on the hands and feet. Similar to SAFM, myxoid neurofibromas are unencapsulated dermal tumors composed of spindle-shaped cells in which mast cells often are conspicuous.^2,7 However, tumor cells in myxoid neurofibromas are S-100 positive, and the lesions typically do not show vasculature accentuation.^4,7

Sclerosing perineuriomas are benign fibrous tumors of the fingers and palms. Histopathologically, bland spindle cells arranged in fascicles and whorls are observed in a hyalinized collagen matrix.⁸ Immunohistochemically, sclerosing perineuriomas are positive for EMA and negative for S-100, but unlike SAFM, these tumors usually are CD34 negative.⁸

Superficial angiomyxomas typically are located on the head and neck but also may be found in other locations such as the trunk. They present as cutaneous papules or polypoid lesions. Histopathologically, superficial angiomyxomas are poorly circumscribed with a lobular pattern. Spindle-shaped fibroblasts exist in a myxoid matrix with neutrophils and thin-walled capillaries. The fibroblasts are variably positive for CD34 but also are S-100 positive.^1,9

Myxoid dermatofibrosarcoma protuberans is a rare, locally aggressive, mesenchymal tumor of the skin and subcutis² that typically presents on the trunk, proximal extremities, or head and neck; occurrence on the fingers or toes is exceedingly rare.^2,10 Histopathologically, a myxoid stroma contains sheets of bland spindle-shaped cells with minimal to no atypia, sometimes arranged in a storiform pattern. The tumor characteristically invades deeply into the subcutaneous tissues. CD34 is characteristically positive and S-100 is negative.^2,10

Low-grade myxofibrosarcoma is a soft tissue sarcoma easily confused with other spindle cell tumors. It is one of the most common sarcomas in adults but rarely arises in acral areas.² It is characterized by a nodular growth pattern with marked nuclear atypia and perivascular clustering of tumor cells. CD34 staining may be positive in some cases.¹¹

Similar to SAFM, myxoinflammatory fibroblastic sarcoma has a predilection for the extremities.⁴ However, it typically presents as a subcutaneous mass and has no documented tendency for nail bed involvement. Also unlike SAFM, it has a remarkable inflammatory infiltrate and characteristic virocyte or Reed-Sternberg cells.¹²

Acquired digital fibrokeratomas are benign neoplasms that occur on fingers and toes; the classic clinical presentation is a solitary smooth nodule or dome, often with a characteristic projecting configuration and horn shape.¹ Histopathologically, these tumors are paucicellular with thick, vertically oriented, interwoven collagen bundles; cells may be positive for CD34 but are negative for EMA.^1,13 Related to acquired digital fibrokeratomas are Koenen tumors, which share a similar histology but are distinguished by their clinical characteristics. For example, Koenen tumors tend to be multifocal and are strongly associated with tuberous sclerosis. These tumors also have a tendency to recur.¹

Conclusion

Our report of 3 typical cases of SAFM highlights the need to keep this increasingly recognized and well-defined clinicopathological entity in the differential for slow-growing tumors in acral locations, particularly those in the periungual and subungual regions.

First described by Fetsch et al¹ in 2001, superficial acral fibromyxoma (SAFM) is a rare fibromyxoid mesenchymal tumor that typically affects the fingers and toes with frequent involvement of the nail unit. It is not widely recognized and remains poorly understood. We describe a series of 3 cases of SAFM encountered at our institution and provide a review of the literature on this unique tumor.

Case Reports

Patient 1

A 35-year-old man presented for treatment of a “wart” on the right fifth toe that had increased in size over the last year. He reported that the lesion was mildly painful and occasionally bled or drained clear fluid. He also noted cracking of the nail plate on the same toe. Physical examination revealed a firm, flesh-colored, 3-mm dermal papule on the proximal nail fold of the right fifth toe with subtle flattening of the underlying nail plate (Figure 1). The patient underwent biopsy of the involved proximal nail fold. Histopathology revealed a proliferation of small oval and spindle cells arranged in fascicles and bundles in the dermis (Figure 2). There was extensive mucin deposition associated with the spindle cell proliferation. Additionally, spindle cells and mucin surrounded and entrapped collagen bundles on the periphery of the lesion. Lesional cells were diffusely positive for CD34 and extended to the deep surgical margin (Figure 3). S-100 and factor XIIIa stains were negative. The diagnosis of SAFM was made based on the acral location, histopathologic appearance, and immunohistochemical profile of the tumor.

Figure 1. Firm dermal papule on the proximal nail fold of the right fifth toe with associated nail plate dystrophy. Figure 2. Small oval and spindle cells arranged in fascicles and bundles in the dermis, with extensive mucin deposition and collagen trapping (H&E, original magnification ×100). Figure 3. Tumor cells were positive on CD34 staining (original magnification ×40). Figure 4. Dermal stellate spindle cells arranged in a loose fascicular pattern with marked mucin deposition (H&E, original magnification ×400).

Patient 2

A 47-year-old man presented with an asymptomatic growth on the left fourth toe that had increased in size over the last year. Physical examination revealed an 8-mm, firm, fleshy, flesh-colored, smooth and slightly pedunculated papule on the distal aspect of the left fourth toe. The nail plate and periungual region were not involved. A shave biopsy of the papule was obtained. Histopathology demonstrated dermal stellate spindle cells arranged in a loose fascicular pattern with marked mucin deposition throughout the dermis (Figure 4). Lesional cells were positive for CD34. An S-100 stain highlighted dermal dendritic cells, but lesional cells were negative. No further excision was undertaken, and there was no evidence of recurrence at 1-year follow-up. The diagnosis of SAFM was made based on the acral location, histopathologic appearance, and immunohistochemical profile of the tumor.

Patient 3

A 45-year-old woman presented with asymptomatic distal onycholysis of the right thumbnail of 1 year’s duration. She denied any history of trauma, and no bleeding or pigmentary changes were noted. Physical examination revealed a 5-mm flesh-colored papule on the hyponychium of the right thumb with focal onycholysis (Figure 5). A wedge biopsy of the lesion was performed. Histopathology showed an intradermal nodular proliferation of bland spindle cells arranged in loose fascicles and bundles and embedded in a myxoid stroma (Figure 6). CD34 staining strongly highlighted lesional cells. S-100 and neurofilament stains were negative. The diagnosis of SAFM was made based on the acral location, histopathologic appearance, and immunohistochemical profile of the tumor.

Comment

Clinically, SAFM typically presents as a slow-growing solitary nodule on the distal fingers or toes. The great toe is the most commonly affected digit, and the tumor may be subungual in up to two-thirds of cases.¹ Unusual locations, such as the heel, also have been reported.² Onset typically occurs in the fifth or sixth decade, and there is an approximately 2-fold higher incidence in men than women.^1-3

Histopathologically, SAFM is a characteristically well-circumscribed but unencapsulated dermal tumor composed of spindle and stellate cells in a loose storiform or fascicular arrangement embedded in a myxoid, myxocollagenous, or collagenous stroma.⁴ The tumor often occupies the entire dermis and may extend into the subcutis or occasionally the underlying fascia and bone.^4,5 Mast cells often are prominent, and microvascular accentuation also may be seen. Inflammatory infiltrates and multinucleated giant cells typically are not seen.⁶ Although 2 cases of atypical SAFM have been described,² cellular atypia is not a characteristic feature of SAFM.

The immunohistochemical profile of SAFM is characterized by diffuse or focal expression of CD34, focal expression of epithelial membrane antigen (EMA), CD99 expression, and varying numbers of factor XIIIa–positive histiocytes.^2,3 Positive staining for vimentin also is common. Staining typically is negative for S-100, human melanoma black 45, keratin, smooth muscle actin, and desmin.

The standard treatment of SAFM is complete local resection of the tumor, though some patients have been treated with partial excision or biopsy and partial or complete digital amputation.¹ Local recurrence may occur in up to 20% of cases; however, approximately two-thirds of the reported recurrences in the literature occurred after incomplete tumor excision.^1,2 It may be more appropriate to consider these cases as persistent rather than recurrent tumors. Superficial acral fibromyxoma is considered a benign tumor, with no known cases of metastases.⁴

Figure 5. A firm flesh-colored papule on the hyponychium of the right thumb prior to biopsy. Figure 6. Intradermal nodular proliferation of bland spindle cells arranged in loose fascicles and bundles and embedded in a myxoid stroma (H&E, original magnification ×40).

A broad differential diagnosis exists for SAFM and it can be difficult to differentiate it from a wide variety of benign and malignant tumors that may be seen on the nail unit and distal extremities (Table). Myxoid neurofibromas typically present as solitary lesions on the hands and feet. Similar to SAFM, myxoid neurofibromas are unencapsulated dermal tumors composed of spindle-shaped cells in which mast cells often are conspicuous.^2,7 However, tumor cells in myxoid neurofibromas are S-100 positive, and the lesions typically do not show vasculature accentuation.^4,7

Sclerosing perineuriomas are benign fibrous tumors of the fingers and palms. Histopathologically, bland spindle cells arranged in fascicles and whorls are observed in a hyalinized collagen matrix.⁸ Immunohistochemically, sclerosing perineuriomas are positive for EMA and negative for S-100, but unlike SAFM, these tumors usually are CD34 negative.⁸

Superficial angiomyxomas typically are located on the head and neck but also may be found in other locations such as the trunk. They present as cutaneous papules or polypoid lesions. Histopathologically, superficial angiomyxomas are poorly circumscribed with a lobular pattern. Spindle-shaped fibroblasts exist in a myxoid matrix with neutrophils and thin-walled capillaries. The fibroblasts are variably positive for CD34 but also are S-100 positive.^1,9

Myxoid dermatofibrosarcoma protuberans is a rare, locally aggressive, mesenchymal tumor of the skin and subcutis² that typically presents on the trunk, proximal extremities, or head and neck; occurrence on the fingers or toes is exceedingly rare.^2,10 Histopathologically, a myxoid stroma contains sheets of bland spindle-shaped cells with minimal to no atypia, sometimes arranged in a storiform pattern. The tumor characteristically invades deeply into the subcutaneous tissues. CD34 is characteristically positive and S-100 is negative.^2,10

Low-grade myxofibrosarcoma is a soft tissue sarcoma easily confused with other spindle cell tumors. It is one of the most common sarcomas in adults but rarely arises in acral areas.² It is characterized by a nodular growth pattern with marked nuclear atypia and perivascular clustering of tumor cells. CD34 staining may be positive in some cases.¹¹

Similar to SAFM, myxoinflammatory fibroblastic sarcoma has a predilection for the extremities.⁴ However, it typically presents as a subcutaneous mass and has no documented tendency for nail bed involvement. Also unlike SAFM, it has a remarkable inflammatory infiltrate and characteristic virocyte or Reed-Sternberg cells.¹²

Acquired digital fibrokeratomas are benign neoplasms that occur on fingers and toes; the classic clinical presentation is a solitary smooth nodule or dome, often with a characteristic projecting configuration and horn shape.¹ Histopathologically, these tumors are paucicellular with thick, vertically oriented, interwoven collagen bundles; cells may be positive for CD34 but are negative for EMA.^1,13 Related to acquired digital fibrokeratomas are Koenen tumors, which share a similar histology but are distinguished by their clinical characteristics. For example, Koenen tumors tend to be multifocal and are strongly associated with tuberous sclerosis. These tumors also have a tendency to recur.¹

Conclusion

Our report of 3 typical cases of SAFM highlights the need to keep this increasingly recognized and well-defined clinicopathological entity in the differential for slow-growing tumors in acral locations, particularly those in the periungual and subungual regions.