Nonmelanoma Skin Cancer

Basal cell carcinoma (BCC) is the most common of all malignant neoplasms; approximately 1 million new cases occur annually in the United States, with increasing incidence.¹ Although BCC is locally invasive, the occurrence of BCC metastasis is exceedingly rare, with an average rate of approximately 0.03%,² typically involving a large, long-standing, locally destructive, recalcitrant tumor of the head or neck.³ BCC metastasis is rare because of the early recognition of the disease, current treatment, and the noninvasive character of the tumor. In the event of metastatic spread, the most commonly involved sites (in descending order of frequency) include regional lymph nodes, the lungs, and bone, but also may involve the pleura and abdominal viscera.⁴ Criteria used to establish the diagnosis of metastatic BCC were put forth in 1951 by Lattes and Kessler⁵ and include: (1) the neoplasm must originate from skin, not mucous membranes; (2) direct invasion of the neoplasm to the presumed metastatic site must be ruled out; and (3) primary and metastatic lesions must show identical histologic features consistent with BCC.

Bone is involved in approximately 20% to 30% of metastatic BCCs.^3,6 In addition to the above guidelines, other objective findings in BCC metastatic to bone have been reported in the literature, such as increased skeletal uptake on bone scintigraphy, elevated serum levels of alkaline phosphatase, and radiographic imaging studies that demonstrate lytic bone lesions.⁷ We report a case of BCC with probable extensive metastases to the axial skeleton above the pelvis. Results of a physical examination, as well as x-ray and bone scintigraphy findings, were consistent with extensive skeletal involvement by metastatic tumor. Histologic confirmation of bone metastasis was not possible due to the patient's family's refusal of a postmortem biopsy of the bone specimen.

Case Report

A 56-year-old white male veteran presented to a Midwestern United States veterans affairs medical center with 2 prominent skin lesions of unknown duration. The patient stated that the lesions began as small boils on his upper back and right arm many years ago and subsequently enlarged. He had not been seen by a physician for many years. Results of a physical examination revealed the patient was a cachectic man in no apparent distress; he had no fever and his vital signs were within reference range. His skin examination revealed an extensive, ulcerated, weeping lesion with rolled borders on his upper back extending to the posterior neck, and another similar lesion on his right arm. The lesion on his back measured 26X15 cm, and the lesion on his arm measured 12X6 cm (Figure 1). No mucous membrane involvement was noted. Biopsies of skin specimens were obtained from both lesions for histologic diagnosis, which confirmed the presence of BCC (Figure 2). Because of the lesions' proximity to bone, bone radiographs were performed on the patient's chest, bilateral shoulders, and right arm, revealing punched-out lytic bone lesions in the ribs, left clavicle, scapulae, and right humerus (Figure 3A). Next, a bone scintigraphy scan was performed to survey the extent of disease, revealing a "superscan," with increased bony uptake in most of the axial skeleton above the pelvis along with other discrete areas of increased uptake in the upper extremities (Figure 3B). Additional laboratory data were not available. The patient was admitted to the medical center for improvement of his nutritional status and for the management of his skin lesions. On the seventh day of hospitalization, the patient unexpectedly died, and his family refused an autopsy.

Please refer to the PDF to view the figures

Comment

The first case of BCC metastatic to a submandibular lymph node was reported by Beadles⁸ in 1894. Few cases have been described in the literature since then, and rates of metastasis have been reported to be from 0.0028% to 0.4%, depending on the study protocol used.⁹ Although histologic confirmation of bone involvement is lacking, in the absence of other detectable malignancies, our objective clinical and radiographic findings point toward bone metastasis in our patient. A review of several case reports of BCC metastatic to bone demonstrates clinical and radiographic similarities with those of our patient (Table).

Please refer to the PDF to view the table

In contrast to nonmetastatic BCC, the age of onset of metastatic lesions is approximately 45 to 59 years, with an interval of approximately 9 to 11 years between primary tumor onset and spread.¹ However, cases of metastasis have been reported after latency periods of up to 23,²⁰ 26,²¹ and even 45³ years following diagnosis of primary lesions. Men are more often affected, and tumors generally are large, long-standing, and refractory to treatment.³ No significantly different histologic characteristics in metastatic tumors were identified by Wermuth and Fajardo²²; however, other authors have concluded that metatypical BCC, or BCC with foci of squamous differentiation, demonstrates more aggressive behavior and increased potential to metastasize.^9-11,16,19 Factors noted to be associated with an increased incidence of metastasis include long duration of a large primary lesion on the head or neck,²³ recalcitrance to treatment,¹ immunodeficiency combined with stromal independence of the tumor,²⁴ inadequate excision followed by immediate wound closure,²⁵ and lesion depth.²⁶ Farmer and Helwig¹⁶ noted a paucity of inflammatory cells in the vicinity of recurrent tumors, implicating the possibility of a defective cellular immune response as a contributing factor. Our patient's evolving history, however, was unclear due to his inability to provide an accurate account.

Total excision of primary tumors following recommended treatment guidelines does not tend to halt metastatic spread,⁴ and prior to discovery of metastases, lesions generally tend to recur locally following excision and/or radiation therapy.^1,4,9 Approximately equal rates of hematogenous and lymphatic spread are observed, and the lung is the most likely distant organ to be involved, followed by bone, liver, and pleura.³ Cases of bone metastasis may present with symptoms of spinal cord compression⁶ or anemia,¹⁵ as well as bone pain¹⁷ and pathologic fractures,^7,15 and tend to involve the lumbar spine more frequently than the thoracic and cervical regions.¹⁰ Our patient did not complain of any such symptoms indicative of osseous lesions, even with extensive bony involvement.

von Domarus and Stevens³ noted a slightly better survival rate among patients with lymphatic metastases versus those patients whose tumors disseminated hematogenously. Patients with metastatic BCC have a 5-year survival rate of approximately 10%; patients with distant spread typically survive only 10 to 14 months.¹ Prognosis is especially poor with metastases to the lungs, bone, or liver,^12,16 and palliative treatment generally is used in these cases.

Aggressive treatment should be pursued if BCC metastasis has been detected. Unfortunately, once distant metastasis occurs, cure is not possible and survival generally is short.¹² Excision of the primary lesion with free margins is the initial objective, but it may not always be possible due to the size or extent of the tumor. Therapeutic options for bone metastases include chemotherapy with agents such as cyclophosphamide, etoposide, fluorouracil, methotrexate, cisplatin, bleomycin, and doxorubicin.¹¹ Radiation therapy is an effective palliative treatment, but its use has not demonstrated increased survival benefit.¹² Laminectomy has been used for vertebral involvement.^10,12 Because of the rare nature of metastatic BCC, appropriate treatment protocols have not been formulated, and combination therapy with the above modalities generally is employed. Nevertheless, therapeutic response to treatment usually is poor. Because of our patient's untimely death, no treatment options were sought. 

Basal cell carcinoma (BCC) is the most common of all malignant neoplasms; approximately 1 million new cases occur annually in the United States, with increasing incidence.¹ Although BCC is locally invasive, the occurrence of BCC metastasis is exceedingly rare, with an average rate of approximately 0.03%,² typically involving a large, long-standing, locally destructive, recalcitrant tumor of the head or neck.³ BCC metastasis is rare because of the early recognition of the disease, current treatment, and the noninvasive character of the tumor. In the event of metastatic spread, the most commonly involved sites (in descending order of frequency) include regional lymph nodes, the lungs, and bone, but also may involve the pleura and abdominal viscera.⁴ Criteria used to establish the diagnosis of metastatic BCC were put forth in 1951 by Lattes and Kessler⁵ and include: (1) the neoplasm must originate from skin, not mucous membranes; (2) direct invasion of the neoplasm to the presumed metastatic site must be ruled out; and (3) primary and metastatic lesions must show identical histologic features consistent with BCC.

Bone is involved in approximately 20% to 30% of metastatic BCCs.^3,6 In addition to the above guidelines, other objective findings in BCC metastatic to bone have been reported in the literature, such as increased skeletal uptake on bone scintigraphy, elevated serum levels of alkaline phosphatase, and radiographic imaging studies that demonstrate lytic bone lesions.⁷ We report a case of BCC with probable extensive metastases to the axial skeleton above the pelvis. Results of a physical examination, as well as x-ray and bone scintigraphy findings, were consistent with extensive skeletal involvement by metastatic tumor. Histologic confirmation of bone metastasis was not possible due to the patient's family's refusal of a postmortem biopsy of the bone specimen.

Case Report

A 56-year-old white male veteran presented to a Midwestern United States veterans affairs medical center with 2 prominent skin lesions of unknown duration. The patient stated that the lesions began as small boils on his upper back and right arm many years ago and subsequently enlarged. He had not been seen by a physician for many years. Results of a physical examination revealed the patient was a cachectic man in no apparent distress; he had no fever and his vital signs were within reference range. His skin examination revealed an extensive, ulcerated, weeping lesion with rolled borders on his upper back extending to the posterior neck, and another similar lesion on his right arm. The lesion on his back measured 26X15 cm, and the lesion on his arm measured 12X6 cm (Figure 1). No mucous membrane involvement was noted. Biopsies of skin specimens were obtained from both lesions for histologic diagnosis, which confirmed the presence of BCC (Figure 2). Because of the lesions' proximity to bone, bone radiographs were performed on the patient's chest, bilateral shoulders, and right arm, revealing punched-out lytic bone lesions in the ribs, left clavicle, scapulae, and right humerus (Figure 3A). Next, a bone scintigraphy scan was performed to survey the extent of disease, revealing a "superscan," with increased bony uptake in most of the axial skeleton above the pelvis along with other discrete areas of increased uptake in the upper extremities (Figure 3B). Additional laboratory data were not available. The patient was admitted to the medical center for improvement of his nutritional status and for the management of his skin lesions. On the seventh day of hospitalization, the patient unexpectedly died, and his family refused an autopsy.

Please refer to the PDF to view the figures

Comment

The first case of BCC metastatic to a submandibular lymph node was reported by Beadles⁸ in 1894. Few cases have been described in the literature since then, and rates of metastasis have been reported to be from 0.0028% to 0.4%, depending on the study protocol used.⁹ Although histologic confirmation of bone involvement is lacking, in the absence of other detectable malignancies, our objective clinical and radiographic findings point toward bone metastasis in our patient. A review of several case reports of BCC metastatic to bone demonstrates clinical and radiographic similarities with those of our patient (Table).

Please refer to the PDF to view the table

In contrast to nonmetastatic BCC, the age of onset of metastatic lesions is approximately 45 to 59 years, with an interval of approximately 9 to 11 years between primary tumor onset and spread.¹ However, cases of metastasis have been reported after latency periods of up to 23,²⁰ 26,²¹ and even 45³ years following diagnosis of primary lesions. Men are more often affected, and tumors generally are large, long-standing, and refractory to treatment.³ No significantly different histologic characteristics in metastatic tumors were identified by Wermuth and Fajardo²²; however, other authors have concluded that metatypical BCC, or BCC with foci of squamous differentiation, demonstrates more aggressive behavior and increased potential to metastasize.^9-11,16,19 Factors noted to be associated with an increased incidence of metastasis include long duration of a large primary lesion on the head or neck,²³ recalcitrance to treatment,¹ immunodeficiency combined with stromal independence of the tumor,²⁴ inadequate excision followed by immediate wound closure,²⁵ and lesion depth.²⁶ Farmer and Helwig¹⁶ noted a paucity of inflammatory cells in the vicinity of recurrent tumors, implicating the possibility of a defective cellular immune response as a contributing factor. Our patient's evolving history, however, was unclear due to his inability to provide an accurate account.

Total excision of primary tumors following recommended treatment guidelines does not tend to halt metastatic spread,⁴ and prior to discovery of metastases, lesions generally tend to recur locally following excision and/or radiation therapy.^1,4,9 Approximately equal rates of hematogenous and lymphatic spread are observed, and the lung is the most likely distant organ to be involved, followed by bone, liver, and pleura.³ Cases of bone metastasis may present with symptoms of spinal cord compression⁶ or anemia,¹⁵ as well as bone pain¹⁷ and pathologic fractures,^7,15 and tend to involve the lumbar spine more frequently than the thoracic and cervical regions.¹⁰ Our patient did not complain of any such symptoms indicative of osseous lesions, even with extensive bony involvement.

von Domarus and Stevens³ noted a slightly better survival rate among patients with lymphatic metastases versus those patients whose tumors disseminated hematogenously. Patients with metastatic BCC have a 5-year survival rate of approximately 10%; patients with distant spread typically survive only 10 to 14 months.¹ Prognosis is especially poor with metastases to the lungs, bone, or liver,^12,16 and palliative treatment generally is used in these cases.

Aggressive treatment should be pursued if BCC metastasis has been detected. Unfortunately, once distant metastasis occurs, cure is not possible and survival generally is short.¹² Excision of the primary lesion with free margins is the initial objective, but it may not always be possible due to the size or extent of the tumor. Therapeutic options for bone metastases include chemotherapy with agents such as cyclophosphamide, etoposide, fluorouracil, methotrexate, cisplatin, bleomycin, and doxorubicin.¹¹ Radiation therapy is an effective palliative treatment, but its use has not demonstrated increased survival benefit.¹² Laminectomy has been used for vertebral involvement.^10,12 Because of the rare nature of metastatic BCC, appropriate treatment protocols have not been formulated, and combination therapy with the above modalities generally is employed. Nevertheless, therapeutic response to treatment usually is poor. Because of our patient's untimely death, no treatment options were sought. 

Basal cell carcinoma (BCC) is the most common of all malignant neoplasms; approximately 1 million new cases occur annually in the United States, with increasing incidence.¹ Although BCC is locally invasive, the occurrence of BCC metastasis is exceedingly rare, with an average rate of approximately 0.03%,² typically involving a large, long-standing, locally destructive, recalcitrant tumor of the head or neck.³ BCC metastasis is rare because of the early recognition of the disease, current treatment, and the noninvasive character of the tumor. In the event of metastatic spread, the most commonly involved sites (in descending order of frequency) include regional lymph nodes, the lungs, and bone, but also may involve the pleura and abdominal viscera.⁴ Criteria used to establish the diagnosis of metastatic BCC were put forth in 1951 by Lattes and Kessler⁵ and include: (1) the neoplasm must originate from skin, not mucous membranes; (2) direct invasion of the neoplasm to the presumed metastatic site must be ruled out; and (3) primary and metastatic lesions must show identical histologic features consistent with BCC.

Bone is involved in approximately 20% to 30% of metastatic BCCs.^3,6 In addition to the above guidelines, other objective findings in BCC metastatic to bone have been reported in the literature, such as increased skeletal uptake on bone scintigraphy, elevated serum levels of alkaline phosphatase, and radiographic imaging studies that demonstrate lytic bone lesions.⁷ We report a case of BCC with probable extensive metastases to the axial skeleton above the pelvis. Results of a physical examination, as well as x-ray and bone scintigraphy findings, were consistent with extensive skeletal involvement by metastatic tumor. Histologic confirmation of bone metastasis was not possible due to the patient's family's refusal of a postmortem biopsy of the bone specimen.

Case Report

A 56-year-old white male veteran presented to a Midwestern United States veterans affairs medical center with 2 prominent skin lesions of unknown duration. The patient stated that the lesions began as small boils on his upper back and right arm many years ago and subsequently enlarged. He had not been seen by a physician for many years. Results of a physical examination revealed the patient was a cachectic man in no apparent distress; he had no fever and his vital signs were within reference range. His skin examination revealed an extensive, ulcerated, weeping lesion with rolled borders on his upper back extending to the posterior neck, and another similar lesion on his right arm. The lesion on his back measured 26X15 cm, and the lesion on his arm measured 12X6 cm (Figure 1). No mucous membrane involvement was noted. Biopsies of skin specimens were obtained from both lesions for histologic diagnosis, which confirmed the presence of BCC (Figure 2). Because of the lesions' proximity to bone, bone radiographs were performed on the patient's chest, bilateral shoulders, and right arm, revealing punched-out lytic bone lesions in the ribs, left clavicle, scapulae, and right humerus (Figure 3A). Next, a bone scintigraphy scan was performed to survey the extent of disease, revealing a "superscan," with increased bony uptake in most of the axial skeleton above the pelvis along with other discrete areas of increased uptake in the upper extremities (Figure 3B). Additional laboratory data were not available. The patient was admitted to the medical center for improvement of his nutritional status and for the management of his skin lesions. On the seventh day of hospitalization, the patient unexpectedly died, and his family refused an autopsy.

Please refer to the PDF to view the figures

Comment

The first case of BCC metastatic to a submandibular lymph node was reported by Beadles⁸ in 1894. Few cases have been described in the literature since then, and rates of metastasis have been reported to be from 0.0028% to 0.4%, depending on the study protocol used.⁹ Although histologic confirmation of bone involvement is lacking, in the absence of other detectable malignancies, our objective clinical and radiographic findings point toward bone metastasis in our patient. A review of several case reports of BCC metastatic to bone demonstrates clinical and radiographic similarities with those of our patient (Table).

Please refer to the PDF to view the table

In contrast to nonmetastatic BCC, the age of onset of metastatic lesions is approximately 45 to 59 years, with an interval of approximately 9 to 11 years between primary tumor onset and spread.¹ However, cases of metastasis have been reported after latency periods of up to 23,²⁰ 26,²¹ and even 45³ years following diagnosis of primary lesions. Men are more often affected, and tumors generally are large, long-standing, and refractory to treatment.³ No significantly different histologic characteristics in metastatic tumors were identified by Wermuth and Fajardo²²; however, other authors have concluded that metatypical BCC, or BCC with foci of squamous differentiation, demonstrates more aggressive behavior and increased potential to metastasize.^9-11,16,19 Factors noted to be associated with an increased incidence of metastasis include long duration of a large primary lesion on the head or neck,²³ recalcitrance to treatment,¹ immunodeficiency combined with stromal independence of the tumor,²⁴ inadequate excision followed by immediate wound closure,²⁵ and lesion depth.²⁶ Farmer and Helwig¹⁶ noted a paucity of inflammatory cells in the vicinity of recurrent tumors, implicating the possibility of a defective cellular immune response as a contributing factor. Our patient's evolving history, however, was unclear due to his inability to provide an accurate account.

Total excision of primary tumors following recommended treatment guidelines does not tend to halt metastatic spread,⁴ and prior to discovery of metastases, lesions generally tend to recur locally following excision and/or radiation therapy.^1,4,9 Approximately equal rates of hematogenous and lymphatic spread are observed, and the lung is the most likely distant organ to be involved, followed by bone, liver, and pleura.³ Cases of bone metastasis may present with symptoms of spinal cord compression⁶ or anemia,¹⁵ as well as bone pain¹⁷ and pathologic fractures,^7,15 and tend to involve the lumbar spine more frequently than the thoracic and cervical regions.¹⁰ Our patient did not complain of any such symptoms indicative of osseous lesions, even with extensive bony involvement.

von Domarus and Stevens³ noted a slightly better survival rate among patients with lymphatic metastases versus those patients whose tumors disseminated hematogenously. Patients with metastatic BCC have a 5-year survival rate of approximately 10%; patients with distant spread typically survive only 10 to 14 months.¹ Prognosis is especially poor with metastases to the lungs, bone, or liver,^12,16 and palliative treatment generally is used in these cases.

Aggressive treatment should be pursued if BCC metastasis has been detected. Unfortunately, once distant metastasis occurs, cure is not possible and survival generally is short.¹² Excision of the primary lesion with free margins is the initial objective, but it may not always be possible due to the size or extent of the tumor. Therapeutic options for bone metastases include chemotherapy with agents such as cyclophosphamide, etoposide, fluorouracil, methotrexate, cisplatin, bleomycin, and doxorubicin.¹¹ Radiation therapy is an effective palliative treatment, but its use has not demonstrated increased survival benefit.¹² Laminectomy has been used for vertebral involvement.^10,12 Because of the rare nature of metastatic BCC, appropriate treatment protocols have not been formulated, and combination therapy with the above modalities generally is employed. Nevertheless, therapeutic response to treatment usually is poor. Because of our patient's untimely death, no treatment options were sought. 

Case Report

An otherwise healthy 54-year-old woman presented with a 6-month history of multiple asymptomatic papules on her nose. The patient's past medical history included hypertension and hyperlipidemia. Her medications included atenolol, hydrochlorothiazide, and gemfibrozil. She denied prior infection suggestive of Borrelia species or molluscum contagiosum. Results of a physical examination revealed 4 firm, skin-colored to pink, dome-shaped papules on the right nasal ala (Figure 1) and dorsum. A shave biopsy of a lesion on the right nasal ala was performed. Results of a routine histologic evaluation revealed a diffuse basophilic infiltrate in the dermis (Figure 2). The infiltrate consisted of polyclonal B and T cells (Figure 3). The B cells were CD20+ and T cells were CD4+ and CD8+. In addition, there was a mixed expression of κ and λ chains within the infiltrate. The patient was diagnosed with cutaneous lymphoid hyperplasia (CLH).

Please refer to the PDF to view the figures

For cosmetic reasons, numerous treatment modalities were attempted. The lesions initially were treated with a variety of topical steroids and immunomodulators, with minimal success. In addition, cryotherapy and intralesional steroids were used, with some short-lived response. However, the treated lesions never completely regressed and returned to their pretreatment size within 10 to 14 days after therapy. The lesions did respond well to shave removal, but the patient's personal fear of needles prevented her from continuing this treatment option. She subsequently was lost to follow-up.

Comment

The term cutaneous lymphoid hyperplasia was coined by Caro and Helwig¹ in 1969. The disease also has been called lymphadenosis benigna cutis, Spiegler-Fendt pseudolymphoma, lymphocytoma cutis, and cutaneous lymphoplasia.² Although the pathogenesis of CLH remains unknown and most cases are idiopathic, certain drugs and long-term antigenic stimulation are implicated in many cases.³ Anticonvulsant medications (ie, phenytoin, phenobarbital, carbamazepine, sodium valproate) appear to be the most common pharmaceutical agents to cause CLH. Losartan, gemcitabine, bromocriptine, fluoxetine, amitriptyline, and injected silicone also have been associated with this disease.^4-8 Rarely, infectious agents such as Borrelia species and molluscum contagiosum have been linked with CLH.^9-11 Additionally, CLH has occurred following exposure to various foreign antigens, including tattoos, trauma, body piercing jewelry, cobalt, leeches, and arthropod bites and stings.^9,12-14 Appearance of multiple lesions has been reported following injection of allergen for hyposensitization.^15,16 May et al³ described CLH localized to the site of influenza vaccination.

CLH is seen in both adults and pediatric patients and is 2 to 3 times more likely to occur in females.⁹ Morphologically, CLH appears as clusters of firm pink-colored to plum-colored papules, plaques, nodules, or tumors that occur on any skin surface but most commonly on the face. Although patients usually are asymptomatic, many seek treatment for cosmesis. CLH can be associated with regional lymphadenopathy, though most cases are not associated with other physical findings. The clinical differential diagnosis includes cutaneous lymphomas.^10,17

On histologic examination, lesions of CLH may display multiple lymphoid follicles and dense superficial to deep infiltration of mostly mature lymphocytes.^2,9 Lymphocytes often are admixed with histiocytes and occasional eosinophils and plasma cells.1 Germinal centers with tingible body macrophages often are apparent.^9,10,18 Because these features also may be seen in lymphomas, determination of polyclonality by immunophenotyping with either polymerase chain reaction or other techniques is helpful in the evaluation of CLH. Lesions of CLH may consist of an infiltrate that mostly consists of mixed CD4⁺ and CD8⁺ T lymphocytes in the periphery, with B lymphocytes predominating within germinal centers. Mixed expression of κ and λ chains also has been suggested as a marker for CLH because most lymphomas demonstrate restricted expression of κ or λ chains.^3,10 Despite the general rule of polyclonality with CLH and monoclonality with lymphomas, there have been reports of CLH in the presence of a monoclonal lymphocyte population and clinically malignant cutaneous B-cell lymphomas without evidence of monoclonality.^9,19

Although the characteristic lymphocytic proliferation appears to be reactive and polyclonal, the literature suggests that some cases of CLH have the potential to become malignant.^9,20 A study by Nihal et al⁹ identified several cases of CLH that harbored monoclonal B-cell populations that eventually progressed to overt lymphomas. During follow-up of these patients, polymerase chain reaction analysis of their lymphomas revealed malignant lymphocytes from the same cell lineage noted in the original CLH lesion. Although the molecular pathogenesis of B-cell proliferations in CLH is poorly understood, recent literature has shown that a B-cell chemoattractant, BCA-1 (B-cell attracting chemokine 1), and its receptor, CXCR5 (chemokine receptor 5), are expressed by lymphocytes in moderate quantities in lesions of CLH.²⁰ The same lesions also have shown expression of BCA-1 on dendritic cells within lymphoid follicles. Low-grade and high-grade B-cell lymphomas also express both BCA-1 and its receptor, but expression is restricted to neoplastic B cells.²⁰ Neither BCA-1 nor CXCR5 are expressed in healthy skin.

Lesions of CLH often regress spontaneously, though some cases become chronic and others recur locally.¹⁹ Rarely, some lesions progress to cutaneous lymphoma. However, it is uncertain if this represents true progression of a benign lesion along a continuum leading to lymphoma or a failure to diagnose a lesion that was malignant from the start.^2,9,21

For CLH that results from known stimuli, the first step in treatment is removal of the causative agent. Antibiotic therapy has been effective in cases related to infective causes.^10,18 Reported therapies for persistent or idiopathic cases include topical or intralesional corticosteroids, cryosurgery, local radiation, excision, interferon alfa, and laser ablation.^19,22,23 Good response to thalidomide has been documented in one small study.²⁴ 

Conclusion

CLH is a benign lymphoid proliferation resulting from various antigenic stimuli and may have the potential for progression to overt lymphoma. Lesions may closely resemble lymphoma both clinically and histologically, highlighting the importance of immunophenotyping in establishing a diagnosis. Treatment of this benign disease entity needs to be individualized for each patient. Although there are numerous treatment options for CLH, none are consistently effective. 

Case Report

An otherwise healthy 54-year-old woman presented with a 6-month history of multiple asymptomatic papules on her nose. The patient's past medical history included hypertension and hyperlipidemia. Her medications included atenolol, hydrochlorothiazide, and gemfibrozil. She denied prior infection suggestive of Borrelia species or molluscum contagiosum. Results of a physical examination revealed 4 firm, skin-colored to pink, dome-shaped papules on the right nasal ala (Figure 1) and dorsum. A shave biopsy of a lesion on the right nasal ala was performed. Results of a routine histologic evaluation revealed a diffuse basophilic infiltrate in the dermis (Figure 2). The infiltrate consisted of polyclonal B and T cells (Figure 3). The B cells were CD20+ and T cells were CD4+ and CD8+. In addition, there was a mixed expression of κ and λ chains within the infiltrate. The patient was diagnosed with cutaneous lymphoid hyperplasia (CLH).

Please refer to the PDF to view the figures

For cosmetic reasons, numerous treatment modalities were attempted. The lesions initially were treated with a variety of topical steroids and immunomodulators, with minimal success. In addition, cryotherapy and intralesional steroids were used, with some short-lived response. However, the treated lesions never completely regressed and returned to their pretreatment size within 10 to 14 days after therapy. The lesions did respond well to shave removal, but the patient's personal fear of needles prevented her from continuing this treatment option. She subsequently was lost to follow-up.

Comment

The term cutaneous lymphoid hyperplasia was coined by Caro and Helwig¹ in 1969. The disease also has been called lymphadenosis benigna cutis, Spiegler-Fendt pseudolymphoma, lymphocytoma cutis, and cutaneous lymphoplasia.² Although the pathogenesis of CLH remains unknown and most cases are idiopathic, certain drugs and long-term antigenic stimulation are implicated in many cases.³ Anticonvulsant medications (ie, phenytoin, phenobarbital, carbamazepine, sodium valproate) appear to be the most common pharmaceutical agents to cause CLH. Losartan, gemcitabine, bromocriptine, fluoxetine, amitriptyline, and injected silicone also have been associated with this disease.^4-8 Rarely, infectious agents such as Borrelia species and molluscum contagiosum have been linked with CLH.^9-11 Additionally, CLH has occurred following exposure to various foreign antigens, including tattoos, trauma, body piercing jewelry, cobalt, leeches, and arthropod bites and stings.^9,12-14 Appearance of multiple lesions has been reported following injection of allergen for hyposensitization.^15,16 May et al³ described CLH localized to the site of influenza vaccination.

CLH is seen in both adults and pediatric patients and is 2 to 3 times more likely to occur in females.⁹ Morphologically, CLH appears as clusters of firm pink-colored to plum-colored papules, plaques, nodules, or tumors that occur on any skin surface but most commonly on the face. Although patients usually are asymptomatic, many seek treatment for cosmesis. CLH can be associated with regional lymphadenopathy, though most cases are not associated with other physical findings. The clinical differential diagnosis includes cutaneous lymphomas.^10,17

On histologic examination, lesions of CLH may display multiple lymphoid follicles and dense superficial to deep infiltration of mostly mature lymphocytes.^2,9 Lymphocytes often are admixed with histiocytes and occasional eosinophils and plasma cells.1 Germinal centers with tingible body macrophages often are apparent.^9,10,18 Because these features also may be seen in lymphomas, determination of polyclonality by immunophenotyping with either polymerase chain reaction or other techniques is helpful in the evaluation of CLH. Lesions of CLH may consist of an infiltrate that mostly consists of mixed CD4⁺ and CD8⁺ T lymphocytes in the periphery, with B lymphocytes predominating within germinal centers. Mixed expression of κ and λ chains also has been suggested as a marker for CLH because most lymphomas demonstrate restricted expression of κ or λ chains.^3,10 Despite the general rule of polyclonality with CLH and monoclonality with lymphomas, there have been reports of CLH in the presence of a monoclonal lymphocyte population and clinically malignant cutaneous B-cell lymphomas without evidence of monoclonality.^9,19

Although the characteristic lymphocytic proliferation appears to be reactive and polyclonal, the literature suggests that some cases of CLH have the potential to become malignant.^9,20 A study by Nihal et al⁹ identified several cases of CLH that harbored monoclonal B-cell populations that eventually progressed to overt lymphomas. During follow-up of these patients, polymerase chain reaction analysis of their lymphomas revealed malignant lymphocytes from the same cell lineage noted in the original CLH lesion. Although the molecular pathogenesis of B-cell proliferations in CLH is poorly understood, recent literature has shown that a B-cell chemoattractant, BCA-1 (B-cell attracting chemokine 1), and its receptor, CXCR5 (chemokine receptor 5), are expressed by lymphocytes in moderate quantities in lesions of CLH.²⁰ The same lesions also have shown expression of BCA-1 on dendritic cells within lymphoid follicles. Low-grade and high-grade B-cell lymphomas also express both BCA-1 and its receptor, but expression is restricted to neoplastic B cells.²⁰ Neither BCA-1 nor CXCR5 are expressed in healthy skin.

Lesions of CLH often regress spontaneously, though some cases become chronic and others recur locally.¹⁹ Rarely, some lesions progress to cutaneous lymphoma. However, it is uncertain if this represents true progression of a benign lesion along a continuum leading to lymphoma or a failure to diagnose a lesion that was malignant from the start.^2,9,21

For CLH that results from known stimuli, the first step in treatment is removal of the causative agent. Antibiotic therapy has been effective in cases related to infective causes.^10,18 Reported therapies for persistent or idiopathic cases include topical or intralesional corticosteroids, cryosurgery, local radiation, excision, interferon alfa, and laser ablation.^19,22,23 Good response to thalidomide has been documented in one small study.²⁴ 

Conclusion

CLH is a benign lymphoid proliferation resulting from various antigenic stimuli and may have the potential for progression to overt lymphoma. Lesions may closely resemble lymphoma both clinically and histologically, highlighting the importance of immunophenotyping in establishing a diagnosis. Treatment of this benign disease entity needs to be individualized for each patient. Although there are numerous treatment options for CLH, none are consistently effective. 

Case Report

An otherwise healthy 54-year-old woman presented with a 6-month history of multiple asymptomatic papules on her nose. The patient's past medical history included hypertension and hyperlipidemia. Her medications included atenolol, hydrochlorothiazide, and gemfibrozil. She denied prior infection suggestive of Borrelia species or molluscum contagiosum. Results of a physical examination revealed 4 firm, skin-colored to pink, dome-shaped papules on the right nasal ala (Figure 1) and dorsum. A shave biopsy of a lesion on the right nasal ala was performed. Results of a routine histologic evaluation revealed a diffuse basophilic infiltrate in the dermis (Figure 2). The infiltrate consisted of polyclonal B and T cells (Figure 3). The B cells were CD20+ and T cells were CD4+ and CD8+. In addition, there was a mixed expression of κ and λ chains within the infiltrate. The patient was diagnosed with cutaneous lymphoid hyperplasia (CLH).

Please refer to the PDF to view the figures

For cosmetic reasons, numerous treatment modalities were attempted. The lesions initially were treated with a variety of topical steroids and immunomodulators, with minimal success. In addition, cryotherapy and intralesional steroids were used, with some short-lived response. However, the treated lesions never completely regressed and returned to their pretreatment size within 10 to 14 days after therapy. The lesions did respond well to shave removal, but the patient's personal fear of needles prevented her from continuing this treatment option. She subsequently was lost to follow-up.

Comment

The term cutaneous lymphoid hyperplasia was coined by Caro and Helwig¹ in 1969. The disease also has been called lymphadenosis benigna cutis, Spiegler-Fendt pseudolymphoma, lymphocytoma cutis, and cutaneous lymphoplasia.² Although the pathogenesis of CLH remains unknown and most cases are idiopathic, certain drugs and long-term antigenic stimulation are implicated in many cases.³ Anticonvulsant medications (ie, phenytoin, phenobarbital, carbamazepine, sodium valproate) appear to be the most common pharmaceutical agents to cause CLH. Losartan, gemcitabine, bromocriptine, fluoxetine, amitriptyline, and injected silicone also have been associated with this disease.^4-8 Rarely, infectious agents such as Borrelia species and molluscum contagiosum have been linked with CLH.^9-11 Additionally, CLH has occurred following exposure to various foreign antigens, including tattoos, trauma, body piercing jewelry, cobalt, leeches, and arthropod bites and stings.^9,12-14 Appearance of multiple lesions has been reported following injection of allergen for hyposensitization.^15,16 May et al³ described CLH localized to the site of influenza vaccination.

CLH is seen in both adults and pediatric patients and is 2 to 3 times more likely to occur in females.⁹ Morphologically, CLH appears as clusters of firm pink-colored to plum-colored papules, plaques, nodules, or tumors that occur on any skin surface but most commonly on the face. Although patients usually are asymptomatic, many seek treatment for cosmesis. CLH can be associated with regional lymphadenopathy, though most cases are not associated with other physical findings. The clinical differential diagnosis includes cutaneous lymphomas.^10,17

On histologic examination, lesions of CLH may display multiple lymphoid follicles and dense superficial to deep infiltration of mostly mature lymphocytes.^2,9 Lymphocytes often are admixed with histiocytes and occasional eosinophils and plasma cells.1 Germinal centers with tingible body macrophages often are apparent.^9,10,18 Because these features also may be seen in lymphomas, determination of polyclonality by immunophenotyping with either polymerase chain reaction or other techniques is helpful in the evaluation of CLH. Lesions of CLH may consist of an infiltrate that mostly consists of mixed CD4⁺ and CD8⁺ T lymphocytes in the periphery, with B lymphocytes predominating within germinal centers. Mixed expression of κ and λ chains also has been suggested as a marker for CLH because most lymphomas demonstrate restricted expression of κ or λ chains.^3,10 Despite the general rule of polyclonality with CLH and monoclonality with lymphomas, there have been reports of CLH in the presence of a monoclonal lymphocyte population and clinically malignant cutaneous B-cell lymphomas without evidence of monoclonality.^9,19

Although the characteristic lymphocytic proliferation appears to be reactive and polyclonal, the literature suggests that some cases of CLH have the potential to become malignant.^9,20 A study by Nihal et al⁹ identified several cases of CLH that harbored monoclonal B-cell populations that eventually progressed to overt lymphomas. During follow-up of these patients, polymerase chain reaction analysis of their lymphomas revealed malignant lymphocytes from the same cell lineage noted in the original CLH lesion. Although the molecular pathogenesis of B-cell proliferations in CLH is poorly understood, recent literature has shown that a B-cell chemoattractant, BCA-1 (B-cell attracting chemokine 1), and its receptor, CXCR5 (chemokine receptor 5), are expressed by lymphocytes in moderate quantities in lesions of CLH.²⁰ The same lesions also have shown expression of BCA-1 on dendritic cells within lymphoid follicles. Low-grade and high-grade B-cell lymphomas also express both BCA-1 and its receptor, but expression is restricted to neoplastic B cells.²⁰ Neither BCA-1 nor CXCR5 are expressed in healthy skin.

Lesions of CLH often regress spontaneously, though some cases become chronic and others recur locally.¹⁹ Rarely, some lesions progress to cutaneous lymphoma. However, it is uncertain if this represents true progression of a benign lesion along a continuum leading to lymphoma or a failure to diagnose a lesion that was malignant from the start.^2,9,21

For CLH that results from known stimuli, the first step in treatment is removal of the causative agent. Antibiotic therapy has been effective in cases related to infective causes.^10,18 Reported therapies for persistent or idiopathic cases include topical or intralesional corticosteroids, cryosurgery, local radiation, excision, interferon alfa, and laser ablation.^19,22,23 Good response to thalidomide has been documented in one small study.²⁴ 

Conclusion

CLH is a benign lymphoid proliferation resulting from various antigenic stimuli and may have the potential for progression to overt lymphoma. Lesions may closely resemble lymphoma both clinically and histologically, highlighting the importance of immunophenotyping in establishing a diagnosis. Treatment of this benign disease entity needs to be individualized for each patient. Although there are numerous treatment options for CLH, none are consistently effective. 

Microcystic adnexal carcinoma (MAC) is a relatively uncommon adnexal neoplasm that can demonstrate locally aggressive behavior; rare instances of metastatic lesions have been reported. We report a case of a 34-year-old black man with multiple primary MACs.

Case Report
An otherwise healthy 34-year-old black man presented for evaluation of a progressive lesion on the left thigh that had been diagnosed as lichen simplex chronicus 15 years earlier. The patient stated that the lesion had been there for approximately 19 years and had gotten progressively but not rapidly larger. Results of a physical examination revealed a 3-cm indurated hyperpigmented plaque with prominent scale (Figure 1). There were approximately 21 other lesions (of varying age by patient report); the most prominent lesion was located on the right shoulder (Figure 2). Other clinically similar lesions, ranging from less than 1 cm to about 10 cm, were noted on the hands, arms, shoulders, back, abdomen, thighs, and lower legs in both sun-exposed and non–sun-exposed areas. There were no lesions on the face.

Biopsy results revealed a microcystic adnexal carcinoma (MAC). Subsequent workup, including computed tomography, revealed 3 small areas of pleural thickening but no evidence of internal metastatic disease. The patient had no other significant medical history, and he reported no prior radiation therapy. He reported that none of his family members had a history of MAC. Eighteen months after the patient's lesions were first biopsied, no subsequent lesions had developed, and no substantial clinical progression of current lesions was noted; the patient remained in good health. Histology—Punch biopsy specimens were obtained of lesions in the upper left lateral thigh, lower left inner leg, and left web space between the thumb and index finger. An excisional specimen was available for the lesion from the left thigh. Biopsies of all 3 lesions showed similar histology (Figure 3). Examination results from the specimens at low power revealed mild to moderate psoriasiform epidermal hyperplasia with acanthosis, hyperkeratosis, and basilar hyperpigmentation, changes similarly encountered in lichen simplex chronicus. Larger cystic structures were immediately subadjacent in the superficial dermis, with follicular differentiation and cyst formation. Admixed were ductal structures consisting of basaloid cells, with eccrine differentiation consisting of cells with a moderate amount of pale ill-defined eosinophilic cytoplasm and oval hyperchromatic nuclei. Cytologic pleomorphism was not encountered.

Overall, the tumors demonstrated a stratified appearance, with larger cystic structures in the superficial dermis being replaced by smaller cysts and cords and nests of cells in the deeper dermis (Figure 4). In all specimens, there was extension into the subcutis. Perineural invasion was identified focally. In the superficial dermis of some of the specimens, the follicular cystic structures showed evidence of rupture, with keratin debris in the adjacent dermis and subsequent foreign body giant cell reaction. Results of immunoperoxidase tests on paraffin tissue showed the epithelial cells to be diffusely positive for cytokeratins (AE1/AE3) and carcinoembryonic antigen. Evaluations for the presence of estrogen and progesterone receptors both had negative results.

Comment
MAC is an uncommon adnexal malignancy with locally aggressive and infrequently metastatic behavior. Originally described by Goldstein et al,1 this lesion has a propensity for the centrofrontal area. Clinically, this neoplasm usually presents with an indurated plaque or nodule averaging 2 cm. MAC has been reported as long-standing in some patients, with an inclination for recurrence despite extensive surgical therapy. The lesions are infiltrative, and perineural invasion is frequent.2,3 Locoregional metastasis is an infrequent occurrence,4-8 and widespread metastasis has been described in only one case.9 Although MACs can arise in virtually any age group, most MACs occur in older individuals, with a reported average age of incidence between 44 and 64 years and an overall range of 11 to 90 years.3,10 Although a slight female predominance has been noted in some case series, overall the sexes are equally affected.11 A review of the cases of MAC in the slide files of our laboratory revealed a similar distribution, with an average age of 63 years and a 1:1 male-female ratio. Most of our cases also involved the face or neck, with this patient as the only case of MACs occurring elsewhere anatomically. The principle underlying risk factors for and etiologic influences of MAC are largely unknown. Several studies have noted that MACs are found predominantly on the left side of the face. The exact reason for this anatomic distribution is unclear, but it could be indicative of the fact that MAC has a tendency to develop in UV-exposed areas. A prior review has postulated that this distribution could be caused by sun exposure while driving; however, this theory has not been adequately tested because no comparisons have been made between incidence in the United States versus Australia or England where driving, and thereby sun exposure, occur on the right side.12 Prior radiation exposure also has been implicated as a potential risk factor, and several cases have described MAC occurring in an area of previous radiation therapy.13,14 Similarly, a potential explanation for a portion of these lesions occurring on the face is that several patients with MAC have had prior radiation therapy for facial acne.10,15 There also is a report in the literature of MACs occurring in the axilla in patients who received radiation therapy for breast cancer.3 Additionally, immunodeficiency has been implicated as an etiologic influence,4 and there is one report of documenting a familial influence with occurrence in 2 sisters.10 MAC is a rare tumor, and the lack of physician familiarity with it and limited biopsy sampling can frequently lead to misdiagnosis. As described in the current case, MAC clinically can present as a plaquelike, nodular, or cystlike tumor existing for many years and occasionally for decades. The overlying skin may appear unaffected or have slight lichenification, and ulceration is extremely uncommon. Often, the tumor is biopsied numerous times during several years before a correct diagnosis is made. As infrequent as MAC is, it is fleetingly rare in the black population. Only 3 case reports exist in the literature, and these lesions were all solitary.16-18 One of the cases was similar to ours in that the lesion was very large and long-standing; the lesion was present on the scalp for at least 31 years. The other 2 reported cases involved the scalp and upper lip, and the lesions in both cases were smaller than 2 cm.16-18 The histologic similarities of MAC with other basaloid tumors, combined with its indistinct clinical appearance, can lead to misdiagnosis. MACs typically demonstrate histology results similar to our case. The Table lists both benign and malignant tumors that share histologic features with MAC. The histologic features that are most helpful in distinguishing MAC from these benign and malignant entities are a stratified histologic appearance with ductal differentiation and the presence of perineural involvement with deep dermal infiltration. Although a desmoplastic trichoepithelioma will commonly show similar 2-tier histology results, with the presence of superficial keratocysts and a deeper basaloid infiltrative cell population, the condition will not have deep dermal involvement, ductal differentiation, or perineural involvement. Perineural involvement also will not be demonstrated in syringoma or trichoadenoma. Although deep dermal involvement and perineural invasion can be seen in the 3 malignant entities included in the Table, the histology results of these conditions typically will not show a stratified appearance. Basal cell carcinoma, in addition, rarely demonstrates ductal differentiation in the morpheic or infiltrative form.11

To our knowledge, no case reports of patients with multiple primary cutaneous lesions existed prior to the presentation of this patient. Martin et al¹⁹ describe an 8-year-old patient with multiple carcinomas on the lower extremities arising within systemized compound epithelial lesions; however, only one of these lesions was MAC, and the remainder showed divergent differentiation. Multiple primary lesions in our current case are manifested by the stratified histologic appearance of the tumor at the primary sites and are supported by the lack of metastatic disease elsewhere, which was demonstrated by extensive clinical examination and the absence of additional clinical symptoms or suspicious lesions on computed tomography. Reports of metastasis in MACs also are infrequent and represent only 6 cases in the medical literature worldwide3-5,7-9; 4 of these cases possibly do not describe true metastases3-5,7—one in the axilla that arguably represented tumor extension.3 Two of the others showed metastatic disease in ipsilateral lymph nodes, with a primary lesion on the right posterior scalp4 and the upper forehead,7 respectively. The fourth case illustrated cutaneous metastases in transit, possibly representing recurrence and not metastasis.5 A recent report described a patient with lung metastases,8 and a single case exists in the literature of a patient with widely metastatic MAC of long-standing duration.6 For this reason, and despite its aggressive local behavior, MAC is considered to be a tumor with excellent overall prognosis. Of the more than 300 cases from the medical literature worldwide, only the group of aforementioned lesions demonstrated metastatic potential, which represents an incidence rate of only 2% (probably overrepresented because reported cases only are a fraction of cases in existence). The death rate of reported cases, 0.3%, is an overestimate for similar reasons.21 Because MAC demonstrates its greatest morbidity from local invasion and destruction with locoregional recurrence, the optimal therapeutic approach generally consists of Mohs micrographic surgery (MMS) or primary surgical excision (intraoperative frozen section).12 Local recurrence following surgical excision, however, is not uncommon. In a comprehensive study using MMS, it was found that the extent of these lesions generally is 4-fold larger than the initially clinically evident lesion. Hence, intraoperative assessment of marginal status is paramount.12 In a study of 48 cases, 22 cases were treated with MMS, 23 cases were treated with simple excision, and 3 cases were untreated.12 Only 2 of the cases treated with MMS recurred after a single procedure. In those cases treated with excision, 7 cases (30%) had to have at least one additional surgical procedure before excision was deemed complete, and 1 case experienced recurrence. The overall recurrence rate was similar between the 2 groups (1.98% per patient-year), but fewer procedures were required.12 Although a small number of cases have been treated with adjuvant modalities, including radiation and chemotherapy, the effectiveness of this protocol, in addition to surgical excision, is most likely minimal.22 Our case represents a therapeutic problem in that the number and size of the lesions would be a monumental task to undertake surgically. The indolent course of these lesions might require a conservative clinical approach, such as surgical therapy reserved for problematic or aesthetically displeasing lesions. Systemic therapy was proposed in this patient, possibly using currently known biologic adjunctive therapy such as tamoxifen citrate and trastuzumab. Given that this tumor tested negative for both estrogen and progesterone receptors, as well as HER2/neu, biologic therapy was not undertaken. In addition, the indolent nature and low proliferative rate of these neoplasms most likely would make them poorly responsive to radiation or chemotherapy. A recent case report by Eisen and Zloty21 described a 58-year-old woman with a 12X12-cm MAC involving a large portion of the face. Similar to our case, this patient presented a difficult therapeutic problem because surgical intervention would involve substantial facial disfigurement. The authors opted, as we did, for close clinical surveillance; 2 years after initial diagnosis, the patient continued to do well, with no reported evidence of metastatic disease.21 Radiation therapy has been advocated for palliation in elderly or debilitated individuals; however, this therapy is less than ideal because these lesions generally are radioresistant, and recurrence following this therapy is not infrequent. In addition, radiation has been implicated as a causative mechanism. Comparing treatment methods for a tumor for which no randomized prospective studies exist is difficult, but because the tumor can be locally aggressive, surgical therapy should be pursued if feasible.

Comment
Our case of multiple primary cutaneous MAC in a black patient appears to represent a unique presentation of MAC. Therapeutic options, particularly in a patient with multiple lesions, represent a difficult clinical problem; however, close clinical follow-up without surgical intervention, except for those cases in which MMS is feasible, remains a reasonable alternative.

Microcystic adnexal carcinoma (MAC) is a relatively uncommon adnexal neoplasm that can demonstrate locally aggressive behavior; rare instances of metastatic lesions have been reported. We report a case of a 34-year-old black man with multiple primary MACs.

Case Report
An otherwise healthy 34-year-old black man presented for evaluation of a progressive lesion on the left thigh that had been diagnosed as lichen simplex chronicus 15 years earlier. The patient stated that the lesion had been there for approximately 19 years and had gotten progressively but not rapidly larger. Results of a physical examination revealed a 3-cm indurated hyperpigmented plaque with prominent scale (Figure 1). There were approximately 21 other lesions (of varying age by patient report); the most prominent lesion was located on the right shoulder (Figure 2). Other clinically similar lesions, ranging from less than 1 cm to about 10 cm, were noted on the hands, arms, shoulders, back, abdomen, thighs, and lower legs in both sun-exposed and non–sun-exposed areas. There were no lesions on the face.

Biopsy results revealed a microcystic adnexal carcinoma (MAC). Subsequent workup, including computed tomography, revealed 3 small areas of pleural thickening but no evidence of internal metastatic disease. The patient had no other significant medical history, and he reported no prior radiation therapy. He reported that none of his family members had a history of MAC. Eighteen months after the patient's lesions were first biopsied, no subsequent lesions had developed, and no substantial clinical progression of current lesions was noted; the patient remained in good health. Histology—Punch biopsy specimens were obtained of lesions in the upper left lateral thigh, lower left inner leg, and left web space between the thumb and index finger. An excisional specimen was available for the lesion from the left thigh. Biopsies of all 3 lesions showed similar histology (Figure 3). Examination results from the specimens at low power revealed mild to moderate psoriasiform epidermal hyperplasia with acanthosis, hyperkeratosis, and basilar hyperpigmentation, changes similarly encountered in lichen simplex chronicus. Larger cystic structures were immediately subadjacent in the superficial dermis, with follicular differentiation and cyst formation. Admixed were ductal structures consisting of basaloid cells, with eccrine differentiation consisting of cells with a moderate amount of pale ill-defined eosinophilic cytoplasm and oval hyperchromatic nuclei. Cytologic pleomorphism was not encountered.

Overall, the tumors demonstrated a stratified appearance, with larger cystic structures in the superficial dermis being replaced by smaller cysts and cords and nests of cells in the deeper dermis (Figure 4). In all specimens, there was extension into the subcutis. Perineural invasion was identified focally. In the superficial dermis of some of the specimens, the follicular cystic structures showed evidence of rupture, with keratin debris in the adjacent dermis and subsequent foreign body giant cell reaction. Results of immunoperoxidase tests on paraffin tissue showed the epithelial cells to be diffusely positive for cytokeratins (AE1/AE3) and carcinoembryonic antigen. Evaluations for the presence of estrogen and progesterone receptors both had negative results.

Comment
MAC is an uncommon adnexal malignancy with locally aggressive and infrequently metastatic behavior. Originally described by Goldstein et al,1 this lesion has a propensity for the centrofrontal area. Clinically, this neoplasm usually presents with an indurated plaque or nodule averaging 2 cm. MAC has been reported as long-standing in some patients, with an inclination for recurrence despite extensive surgical therapy. The lesions are infiltrative, and perineural invasion is frequent.2,3 Locoregional metastasis is an infrequent occurrence,4-8 and widespread metastasis has been described in only one case.9 Although MACs can arise in virtually any age group, most MACs occur in older individuals, with a reported average age of incidence between 44 and 64 years and an overall range of 11 to 90 years.3,10 Although a slight female predominance has been noted in some case series, overall the sexes are equally affected.11 A review of the cases of MAC in the slide files of our laboratory revealed a similar distribution, with an average age of 63 years and a 1:1 male-female ratio. Most of our cases also involved the face or neck, with this patient as the only case of MACs occurring elsewhere anatomically. The principle underlying risk factors for and etiologic influences of MAC are largely unknown. Several studies have noted that MACs are found predominantly on the left side of the face. The exact reason for this anatomic distribution is unclear, but it could be indicative of the fact that MAC has a tendency to develop in UV-exposed areas. A prior review has postulated that this distribution could be caused by sun exposure while driving; however, this theory has not been adequately tested because no comparisons have been made between incidence in the United States versus Australia or England where driving, and thereby sun exposure, occur on the right side.12 Prior radiation exposure also has been implicated as a potential risk factor, and several cases have described MAC occurring in an area of previous radiation therapy.13,14 Similarly, a potential explanation for a portion of these lesions occurring on the face is that several patients with MAC have had prior radiation therapy for facial acne.10,15 There also is a report in the literature of MACs occurring in the axilla in patients who received radiation therapy for breast cancer.3 Additionally, immunodeficiency has been implicated as an etiologic influence,4 and there is one report of documenting a familial influence with occurrence in 2 sisters.10 MAC is a rare tumor, and the lack of physician familiarity with it and limited biopsy sampling can frequently lead to misdiagnosis. As described in the current case, MAC clinically can present as a plaquelike, nodular, or cystlike tumor existing for many years and occasionally for decades. The overlying skin may appear unaffected or have slight lichenification, and ulceration is extremely uncommon. Often, the tumor is biopsied numerous times during several years before a correct diagnosis is made. As infrequent as MAC is, it is fleetingly rare in the black population. Only 3 case reports exist in the literature, and these lesions were all solitary.16-18 One of the cases was similar to ours in that the lesion was very large and long-standing; the lesion was present on the scalp for at least 31 years. The other 2 reported cases involved the scalp and upper lip, and the lesions in both cases were smaller than 2 cm.16-18 The histologic similarities of MAC with other basaloid tumors, combined with its indistinct clinical appearance, can lead to misdiagnosis. MACs typically demonstrate histology results similar to our case. The Table lists both benign and malignant tumors that share histologic features with MAC. The histologic features that are most helpful in distinguishing MAC from these benign and malignant entities are a stratified histologic appearance with ductal differentiation and the presence of perineural involvement with deep dermal infiltration. Although a desmoplastic trichoepithelioma will commonly show similar 2-tier histology results, with the presence of superficial keratocysts and a deeper basaloid infiltrative cell population, the condition will not have deep dermal involvement, ductal differentiation, or perineural involvement. Perineural involvement also will not be demonstrated in syringoma or trichoadenoma. Although deep dermal involvement and perineural invasion can be seen in the 3 malignant entities included in the Table, the histology results of these conditions typically will not show a stratified appearance. Basal cell carcinoma, in addition, rarely demonstrates ductal differentiation in the morpheic or infiltrative form.11

To our knowledge, no case reports of patients with multiple primary cutaneous lesions existed prior to the presentation of this patient. Martin et al¹⁹ describe an 8-year-old patient with multiple carcinomas on the lower extremities arising within systemized compound epithelial lesions; however, only one of these lesions was MAC, and the remainder showed divergent differentiation. Multiple primary lesions in our current case are manifested by the stratified histologic appearance of the tumor at the primary sites and are supported by the lack of metastatic disease elsewhere, which was demonstrated by extensive clinical examination and the absence of additional clinical symptoms or suspicious lesions on computed tomography. Reports of metastasis in MACs also are infrequent and represent only 6 cases in the medical literature worldwide3-5,7-9; 4 of these cases possibly do not describe true metastases3-5,7—one in the axilla that arguably represented tumor extension.3 Two of the others showed metastatic disease in ipsilateral lymph nodes, with a primary lesion on the right posterior scalp4 and the upper forehead,7 respectively. The fourth case illustrated cutaneous metastases in transit, possibly representing recurrence and not metastasis.5 A recent report described a patient with lung metastases,8 and a single case exists in the literature of a patient with widely metastatic MAC of long-standing duration.6 For this reason, and despite its aggressive local behavior, MAC is considered to be a tumor with excellent overall prognosis. Of the more than 300 cases from the medical literature worldwide, only the group of aforementioned lesions demonstrated metastatic potential, which represents an incidence rate of only 2% (probably overrepresented because reported cases only are a fraction of cases in existence). The death rate of reported cases, 0.3%, is an overestimate for similar reasons.21 Because MAC demonstrates its greatest morbidity from local invasion and destruction with locoregional recurrence, the optimal therapeutic approach generally consists of Mohs micrographic surgery (MMS) or primary surgical excision (intraoperative frozen section).12 Local recurrence following surgical excision, however, is not uncommon. In a comprehensive study using MMS, it was found that the extent of these lesions generally is 4-fold larger than the initially clinically evident lesion. Hence, intraoperative assessment of marginal status is paramount.12 In a study of 48 cases, 22 cases were treated with MMS, 23 cases were treated with simple excision, and 3 cases were untreated.12 Only 2 of the cases treated with MMS recurred after a single procedure. In those cases treated with excision, 7 cases (30%) had to have at least one additional surgical procedure before excision was deemed complete, and 1 case experienced recurrence. The overall recurrence rate was similar between the 2 groups (1.98% per patient-year), but fewer procedures were required.12 Although a small number of cases have been treated with adjuvant modalities, including radiation and chemotherapy, the effectiveness of this protocol, in addition to surgical excision, is most likely minimal.22 Our case represents a therapeutic problem in that the number and size of the lesions would be a monumental task to undertake surgically. The indolent course of these lesions might require a conservative clinical approach, such as surgical therapy reserved for problematic or aesthetically displeasing lesions. Systemic therapy was proposed in this patient, possibly using currently known biologic adjunctive therapy such as tamoxifen citrate and trastuzumab. Given that this tumor tested negative for both estrogen and progesterone receptors, as well as HER2/neu, biologic therapy was not undertaken. In addition, the indolent nature and low proliferative rate of these neoplasms most likely would make them poorly responsive to radiation or chemotherapy. A recent case report by Eisen and Zloty21 described a 58-year-old woman with a 12X12-cm MAC involving a large portion of the face. Similar to our case, this patient presented a difficult therapeutic problem because surgical intervention would involve substantial facial disfigurement. The authors opted, as we did, for close clinical surveillance; 2 years after initial diagnosis, the patient continued to do well, with no reported evidence of metastatic disease.21 Radiation therapy has been advocated for palliation in elderly or debilitated individuals; however, this therapy is less than ideal because these lesions generally are radioresistant, and recurrence following this therapy is not infrequent. In addition, radiation has been implicated as a causative mechanism. Comparing treatment methods for a tumor for which no randomized prospective studies exist is difficult, but because the tumor can be locally aggressive, surgical therapy should be pursued if feasible.

Comment
Our case of multiple primary cutaneous MAC in a black patient appears to represent a unique presentation of MAC. Therapeutic options, particularly in a patient with multiple lesions, represent a difficult clinical problem; however, close clinical follow-up without surgical intervention, except for those cases in which MMS is feasible, remains a reasonable alternative.

Microcystic adnexal carcinoma (MAC) is a relatively uncommon adnexal neoplasm that can demonstrate locally aggressive behavior; rare instances of metastatic lesions have been reported. We report a case of a 34-year-old black man with multiple primary MACs.

Case Report
An otherwise healthy 34-year-old black man presented for evaluation of a progressive lesion on the left thigh that had been diagnosed as lichen simplex chronicus 15 years earlier. The patient stated that the lesion had been there for approximately 19 years and had gotten progressively but not rapidly larger. Results of a physical examination revealed a 3-cm indurated hyperpigmented plaque with prominent scale (Figure 1). There were approximately 21 other lesions (of varying age by patient report); the most prominent lesion was located on the right shoulder (Figure 2). Other clinically similar lesions, ranging from less than 1 cm to about 10 cm, were noted on the hands, arms, shoulders, back, abdomen, thighs, and lower legs in both sun-exposed and non–sun-exposed areas. There were no lesions on the face.

Biopsy results revealed a microcystic adnexal carcinoma (MAC). Subsequent workup, including computed tomography, revealed 3 small areas of pleural thickening but no evidence of internal metastatic disease. The patient had no other significant medical history, and he reported no prior radiation therapy. He reported that none of his family members had a history of MAC. Eighteen months after the patient's lesions were first biopsied, no subsequent lesions had developed, and no substantial clinical progression of current lesions was noted; the patient remained in good health. Histology—Punch biopsy specimens were obtained of lesions in the upper left lateral thigh, lower left inner leg, and left web space between the thumb and index finger. An excisional specimen was available for the lesion from the left thigh. Biopsies of all 3 lesions showed similar histology (Figure 3). Examination results from the specimens at low power revealed mild to moderate psoriasiform epidermal hyperplasia with acanthosis, hyperkeratosis, and basilar hyperpigmentation, changes similarly encountered in lichen simplex chronicus. Larger cystic structures were immediately subadjacent in the superficial dermis, with follicular differentiation and cyst formation. Admixed were ductal structures consisting of basaloid cells, with eccrine differentiation consisting of cells with a moderate amount of pale ill-defined eosinophilic cytoplasm and oval hyperchromatic nuclei. Cytologic pleomorphism was not encountered.

Overall, the tumors demonstrated a stratified appearance, with larger cystic structures in the superficial dermis being replaced by smaller cysts and cords and nests of cells in the deeper dermis (Figure 4). In all specimens, there was extension into the subcutis. Perineural invasion was identified focally. In the superficial dermis of some of the specimens, the follicular cystic structures showed evidence of rupture, with keratin debris in the adjacent dermis and subsequent foreign body giant cell reaction. Results of immunoperoxidase tests on paraffin tissue showed the epithelial cells to be diffusely positive for cytokeratins (AE1/AE3) and carcinoembryonic antigen. Evaluations for the presence of estrogen and progesterone receptors both had negative results.

Comment
MAC is an uncommon adnexal malignancy with locally aggressive and infrequently metastatic behavior. Originally described by Goldstein et al,1 this lesion has a propensity for the centrofrontal area. Clinically, this neoplasm usually presents with an indurated plaque or nodule averaging 2 cm. MAC has been reported as long-standing in some patients, with an inclination for recurrence despite extensive surgical therapy. The lesions are infiltrative, and perineural invasion is frequent.2,3 Locoregional metastasis is an infrequent occurrence,4-8 and widespread metastasis has been described in only one case.9 Although MACs can arise in virtually any age group, most MACs occur in older individuals, with a reported average age of incidence between 44 and 64 years and an overall range of 11 to 90 years.3,10 Although a slight female predominance has been noted in some case series, overall the sexes are equally affected.11 A review of the cases of MAC in the slide files of our laboratory revealed a similar distribution, with an average age of 63 years and a 1:1 male-female ratio. Most of our cases also involved the face or neck, with this patient as the only case of MACs occurring elsewhere anatomically. The principle underlying risk factors for and etiologic influences of MAC are largely unknown. Several studies have noted that MACs are found predominantly on the left side of the face. The exact reason for this anatomic distribution is unclear, but it could be indicative of the fact that MAC has a tendency to develop in UV-exposed areas. A prior review has postulated that this distribution could be caused by sun exposure while driving; however, this theory has not been adequately tested because no comparisons have been made between incidence in the United States versus Australia or England where driving, and thereby sun exposure, occur on the right side.12 Prior radiation exposure also has been implicated as a potential risk factor, and several cases have described MAC occurring in an area of previous radiation therapy.13,14 Similarly, a potential explanation for a portion of these lesions occurring on the face is that several patients with MAC have had prior radiation therapy for facial acne.10,15 There also is a report in the literature of MACs occurring in the axilla in patients who received radiation therapy for breast cancer.3 Additionally, immunodeficiency has been implicated as an etiologic influence,4 and there is one report of documenting a familial influence with occurrence in 2 sisters.10 MAC is a rare tumor, and the lack of physician familiarity with it and limited biopsy sampling can frequently lead to misdiagnosis. As described in the current case, MAC clinically can present as a plaquelike, nodular, or cystlike tumor existing for many years and occasionally for decades. The overlying skin may appear unaffected or have slight lichenification, and ulceration is extremely uncommon. Often, the tumor is biopsied numerous times during several years before a correct diagnosis is made. As infrequent as MAC is, it is fleetingly rare in the black population. Only 3 case reports exist in the literature, and these lesions were all solitary.16-18 One of the cases was similar to ours in that the lesion was very large and long-standing; the lesion was present on the scalp for at least 31 years. The other 2 reported cases involved the scalp and upper lip, and the lesions in both cases were smaller than 2 cm.16-18 The histologic similarities of MAC with other basaloid tumors, combined with its indistinct clinical appearance, can lead to misdiagnosis. MACs typically demonstrate histology results similar to our case. The Table lists both benign and malignant tumors that share histologic features with MAC. The histologic features that are most helpful in distinguishing MAC from these benign and malignant entities are a stratified histologic appearance with ductal differentiation and the presence of perineural involvement with deep dermal infiltration. Although a desmoplastic trichoepithelioma will commonly show similar 2-tier histology results, with the presence of superficial keratocysts and a deeper basaloid infiltrative cell population, the condition will not have deep dermal involvement, ductal differentiation, or perineural involvement. Perineural involvement also will not be demonstrated in syringoma or trichoadenoma. Although deep dermal involvement and perineural invasion can be seen in the 3 malignant entities included in the Table, the histology results of these conditions typically will not show a stratified appearance. Basal cell carcinoma, in addition, rarely demonstrates ductal differentiation in the morpheic or infiltrative form.11

To our knowledge, no case reports of patients with multiple primary cutaneous lesions existed prior to the presentation of this patient. Martin et al¹⁹ describe an 8-year-old patient with multiple carcinomas on the lower extremities arising within systemized compound epithelial lesions; however, only one of these lesions was MAC, and the remainder showed divergent differentiation. Multiple primary lesions in our current case are manifested by the stratified histologic appearance of the tumor at the primary sites and are supported by the lack of metastatic disease elsewhere, which was demonstrated by extensive clinical examination and the absence of additional clinical symptoms or suspicious lesions on computed tomography. Reports of metastasis in MACs also are infrequent and represent only 6 cases in the medical literature worldwide3-5,7-9; 4 of these cases possibly do not describe true metastases3-5,7—one in the axilla that arguably represented tumor extension.3 Two of the others showed metastatic disease in ipsilateral lymph nodes, with a primary lesion on the right posterior scalp4 and the upper forehead,7 respectively. The fourth case illustrated cutaneous metastases in transit, possibly representing recurrence and not metastasis.5 A recent report described a patient with lung metastases,8 and a single case exists in the literature of a patient with widely metastatic MAC of long-standing duration.6 For this reason, and despite its aggressive local behavior, MAC is considered to be a tumor with excellent overall prognosis. Of the more than 300 cases from the medical literature worldwide, only the group of aforementioned lesions demonstrated metastatic potential, which represents an incidence rate of only 2% (probably overrepresented because reported cases only are a fraction of cases in existence). The death rate of reported cases, 0.3%, is an overestimate for similar reasons.21 Because MAC demonstrates its greatest morbidity from local invasion and destruction with locoregional recurrence, the optimal therapeutic approach generally consists of Mohs micrographic surgery (MMS) or primary surgical excision (intraoperative frozen section).12 Local recurrence following surgical excision, however, is not uncommon. In a comprehensive study using MMS, it was found that the extent of these lesions generally is 4-fold larger than the initially clinically evident lesion. Hence, intraoperative assessment of marginal status is paramount.12 In a study of 48 cases, 22 cases were treated with MMS, 23 cases were treated with simple excision, and 3 cases were untreated.12 Only 2 of the cases treated with MMS recurred after a single procedure. In those cases treated with excision, 7 cases (30%) had to have at least one additional surgical procedure before excision was deemed complete, and 1 case experienced recurrence. The overall recurrence rate was similar between the 2 groups (1.98% per patient-year), but fewer procedures were required.12 Although a small number of cases have been treated with adjuvant modalities, including radiation and chemotherapy, the effectiveness of this protocol, in addition to surgical excision, is most likely minimal.22 Our case represents a therapeutic problem in that the number and size of the lesions would be a monumental task to undertake surgically. The indolent course of these lesions might require a conservative clinical approach, such as surgical therapy reserved for problematic or aesthetically displeasing lesions. Systemic therapy was proposed in this patient, possibly using currently known biologic adjunctive therapy such as tamoxifen citrate and trastuzumab. Given that this tumor tested negative for both estrogen and progesterone receptors, as well as HER2/neu, biologic therapy was not undertaken. In addition, the indolent nature and low proliferative rate of these neoplasms most likely would make them poorly responsive to radiation or chemotherapy. A recent case report by Eisen and Zloty21 described a 58-year-old woman with a 12X12-cm MAC involving a large portion of the face. Similar to our case, this patient presented a difficult therapeutic problem because surgical intervention would involve substantial facial disfigurement. The authors opted, as we did, for close clinical surveillance; 2 years after initial diagnosis, the patient continued to do well, with no reported evidence of metastatic disease.21 Radiation therapy has been advocated for palliation in elderly or debilitated individuals; however, this therapy is less than ideal because these lesions generally are radioresistant, and recurrence following this therapy is not infrequent. In addition, radiation has been implicated as a causative mechanism. Comparing treatment methods for a tumor for which no randomized prospective studies exist is difficult, but because the tumor can be locally aggressive, surgical therapy should be pursued if feasible.

Comment
Our case of multiple primary cutaneous MAC in a black patient appears to represent a unique presentation of MAC. Therapeutic options, particularly in a patient with multiple lesions, represent a difficult clinical problem; however, close clinical follow-up without surgical intervention, except for those cases in which MMS is feasible, remains a reasonable alternative.