Nonmelanoma Skin Cancer

Angiosarcoma is an aggressive neoplasm that predominantly affects elderly patients. Most cases appear on the scalp and face de novo; however, trauma, longstanding lymphedema, and irradiation are predisposing factors. Management includes a multidisciplinary team and may involve a combination of surgery, radiation, and chemotherapy tailored to the patient’s age and associated comorbidities.

Bruiselike patches on the face and scalp of elderly patients should raise the index of suspicion for angiosarcoma. A biopsy of the lesion and a workup for other organ involvement should be considered. We present the case of an elderly patient with an angiosarcoma and discuss the management and follow-up along with a brief review of the current literature. 

Case Report
In February 2002, an 80-year-old white man presented with approximately a 3-month history of a growing raised area on the nose (Figure). The patient first noticed a sudden onset of redness on the right side of his nose in December 2001. The redness gradually darkened over the next 3 months.

Examination revealed a 30-X20-mm purplish red plaque on the right side of the patient's nose. Results of a 4-mm punch biopsy showed an angiosarcoma. The patient was referred to an ear, nose, and throat physician with a special interest in oncology. He also was evaluated by an oncologist. Results of the patient's physical examination were unremarkable except for the skin lesion on his nose. Results of a complete blood count, x-ray, and computed tomography of the chest, as well as an abdominal ultrasound and magnetic resonance imaging of the head and neck, were unremarkable for masses, lymphadenopathy, or other significant findings. In March 2002, the patient underwent excision of the tumor followed by skin grafting. Six weeks after the operation, the patient was started on external beam radiation therapy. He was treated with 98 Gy over 49 days (2.0 Gy daily). Results of follow-up physical examinations by the multidisciplinary team did not reveal any signs or symptoms of tumor recurrence. On the patient's last follow-up visit in April 2005, he showed no evidence of recurrence of the lesion or metastasis. No follow-up photographs were taken. 

Comment

Cutaneous angiosarcoma of the face and scalp is a distinct entity among the angiosarcomas. It was first described in detail by Jones1 in 1964 as malignant angioendothelioma of the skin.2 This aggressive vascular neoplasm predominantly affects elderly patients (average age, 70 years).3 Men are affected twice as frequently as women. Men also tend to develop the disease at an earlier age. The tumor is localized mostly to the upper half of the face and the scalp.3 Predisposing factors in the onset of angiosarcoma include trauma, longstanding lymphedema, and irradiation of benign vascular lesions; however, most cases present with no obvious etiology.4 The clinical presentation of angiosarcoma is variable. Ill-defined bruiselike areas or facial edema with minimal erythema are the initial signs. Progressively more indurated plaques appear with nodular or ulcerated components. The neoplasm spreads quickly, centrifugally, and transdermally.5,6 Multifocality also is possible. The original clinical size of the tumor rarely correlates to the degree of microscopic tissue invasion.7 Unusual presentations have included yellowish plaques over the upper eyelids that resemble xanthelasma and cause ptosis,8 rosacealike lesions,9 and lesions presenting with scarring alopecia.10 Angiosarcoma presenting with intermittent angioedema of the face that comes and goes is another uncommon manifestation.11 Rhinophymalike features also should be considered as an unusual clinical manifestation of cutaneous angiosarcoma.12 Diagnosis often is delayed by the variable presentation and the benign appearance of the lesion, which simulates a bruise or a hemangioma. Retrospective studies show that clinical diagnosis of cutaneous angiosarcomas often is difficult.13 Other lesions that may need to be differentiated from angiosarcoma on the face include hemangiomas, Kaposi sarcomas, malignant melanomas, metastases, and vascular venous malformations. A summary of the characteristic features is included in the Table.

Pathologically, 2 main patterns of angiomas are recognized: angiomatous and solid.9 The angiomatous pattern is characterized by irregular, anastomosing vascular channels that dissect through the collagen. The vessels are lined by endothelial cells with features that range from normal-appearing endothelial cells to pleomorphic, hyperchromatic cells that exhibit multi-layering. Papillary processes may be present within the lumen. Numerous normal or abnormal mitotic figures are present as well. A dense mononuclear cell infiltrate is present and correlates with a better prognosis. In the solid form of angiosarcoma, tumor cells may be spindle or polygonal shaped. Vascular architecture may not be identified in the poorly differentiated areas. Reticulin staining highlights the vascular channels.9 Possible immunohistochemical markers for angiosarcoma include ulex europaeus 1 lectin (sensitive marker; used in conjunction with epithelial membrane antigen and cytokeratin to exclude epithelial tumor); factor VIII antigen (highly specific; low detection sensitivity); CD34 cells (highly sensitive; stains dermal dendrocytes, sweat gland basement membrane, and hematopoietic progenitor cells); and CD31 cells (highly sensitive; good specificity).7,19 Several differential diagnoses should be considered on pathology.20 Unlike benign vascular lesions, the well-differentiated angiomatous areas in angiosarcoma display cytologic atypia; multilayering, papillary structures; and irregular anastomosing blood vessels. In Kaposi sarcoma, cytologic atypia is less prominent and there is no endothelial multilayering.20 The optimal treatment of cutaneous angiosarcoma has not been defined.21 Generally, radical surgery and postoperative radiotherapy are advocated to treat patients with these tumors. In many patients, surgery often is not feasible because of the tumor's multifocal nature and local spread pattern.21 Therefore, the results have been poor. In a study by Mark et al,22 only 1 of 12 patients had the disease locally controlled. Holden et al23 reported 1 cure in 7 patients treated with surgery alone. The surgical aim is to resect all clinically identifiable disease.24 In areas of doubt, microscopic control of surgical margins may have a role in guiding the extent of resection. Achieving a negative margin frequently is difficult in angiosarcoma patients because of the extensive microscopic spread that is so common in this disease. Therefore, in trying to achieve a negative margin, a wound is created that almost never can be closed primarily. The reconstructive surgeon has a number of options for initial temporary coverage, as well as definitive reconstruction, including homograft skin, autologous skin graft, rotation flaps, and free flaps.24 Angiosarcomas usually respond to radiotherapy to some degree and most studies suggest that a combination of surgery and radiotherapy offers the best chance for long-term control.3,21 In 1 series of 28 angiosarcomas of the head and neck, Mark et al22 reported better survival after a median 32 months with combined surgery and radiotherapy compared with surgery alone. In cases unsuited for surgery, radiotherapy alone may be considered; however, usually only partial responses are achieved. Morrison et al21 suggested that moderate doses of radiation could control subclinical disease. Because angiosarcoma is a systemic disease, chemotherapy may be useful in its management.25 The efficacy of chemotherapy is undefined, with some studies reporting a beneficial effect and others suggesting no survival benefit. Chemotherapeutic agents used have included doxorubicin, cyclophosphamide, dacarbazine, actinomycin D, methotrexate, and vincristine.25 Systemic paclitaxel therapy has been used with encouraging results in 3 patients with angiosarcoma with regression of the lesions.26 Spieth and colleagues27 reported the effectiveness of 13-cis-retinoic acid and interferon alfa-2a combination therapy in a patient with recurring cutaneous angiosarcoma of the head after radical radiation treatment. There is no optimal treatment for angiosarcoma and the search for effective systemic treatment is needed. The prognosis in angiosarcoma is poor because of its high potential for metastasis.28 The 5-year survival rate is about 12%. Prognostic factors include the size of the tumor and mitotic counts, with tumors less than 10 cm in diameter and those with low mitotic counts having a better prognosis.28

Conclusion

Angiosarcomas are rare, aggressive tumors of vascular origin. They occur most often in areas of long-term sun-exposed skin in elderly patients, patients with longstanding lymphedema, or patients who have completed radiation therapy. The prognosis is poor and radical surgery is often required. In addition, radiation or chemotherapy may be considered as therapeutic options.

Angiosarcoma is an aggressive neoplasm that predominantly affects elderly patients. Most cases appear on the scalp and face de novo; however, trauma, longstanding lymphedema, and irradiation are predisposing factors. Management includes a multidisciplinary team and may involve a combination of surgery, radiation, and chemotherapy tailored to the patient’s age and associated comorbidities.

Bruiselike patches on the face and scalp of elderly patients should raise the index of suspicion for angiosarcoma. A biopsy of the lesion and a workup for other organ involvement should be considered. We present the case of an elderly patient with an angiosarcoma and discuss the management and follow-up along with a brief review of the current literature. 

Case Report
In February 2002, an 80-year-old white man presented with approximately a 3-month history of a growing raised area on the nose (Figure). The patient first noticed a sudden onset of redness on the right side of his nose in December 2001. The redness gradually darkened over the next 3 months.

Examination revealed a 30-X20-mm purplish red plaque on the right side of the patient's nose. Results of a 4-mm punch biopsy showed an angiosarcoma. The patient was referred to an ear, nose, and throat physician with a special interest in oncology. He also was evaluated by an oncologist. Results of the patient's physical examination were unremarkable except for the skin lesion on his nose. Results of a complete blood count, x-ray, and computed tomography of the chest, as well as an abdominal ultrasound and magnetic resonance imaging of the head and neck, were unremarkable for masses, lymphadenopathy, or other significant findings. In March 2002, the patient underwent excision of the tumor followed by skin grafting. Six weeks after the operation, the patient was started on external beam radiation therapy. He was treated with 98 Gy over 49 days (2.0 Gy daily). Results of follow-up physical examinations by the multidisciplinary team did not reveal any signs or symptoms of tumor recurrence. On the patient's last follow-up visit in April 2005, he showed no evidence of recurrence of the lesion or metastasis. No follow-up photographs were taken. 

Comment

Cutaneous angiosarcoma of the face and scalp is a distinct entity among the angiosarcomas. It was first described in detail by Jones1 in 1964 as malignant angioendothelioma of the skin.2 This aggressive vascular neoplasm predominantly affects elderly patients (average age, 70 years).3 Men are affected twice as frequently as women. Men also tend to develop the disease at an earlier age. The tumor is localized mostly to the upper half of the face and the scalp.3 Predisposing factors in the onset of angiosarcoma include trauma, longstanding lymphedema, and irradiation of benign vascular lesions; however, most cases present with no obvious etiology.4 The clinical presentation of angiosarcoma is variable. Ill-defined bruiselike areas or facial edema with minimal erythema are the initial signs. Progressively more indurated plaques appear with nodular or ulcerated components. The neoplasm spreads quickly, centrifugally, and transdermally.5,6 Multifocality also is possible. The original clinical size of the tumor rarely correlates to the degree of microscopic tissue invasion.7 Unusual presentations have included yellowish plaques over the upper eyelids that resemble xanthelasma and cause ptosis,8 rosacealike lesions,9 and lesions presenting with scarring alopecia.10 Angiosarcoma presenting with intermittent angioedema of the face that comes and goes is another uncommon manifestation.11 Rhinophymalike features also should be considered as an unusual clinical manifestation of cutaneous angiosarcoma.12 Diagnosis often is delayed by the variable presentation and the benign appearance of the lesion, which simulates a bruise or a hemangioma. Retrospective studies show that clinical diagnosis of cutaneous angiosarcomas often is difficult.13 Other lesions that may need to be differentiated from angiosarcoma on the face include hemangiomas, Kaposi sarcomas, malignant melanomas, metastases, and vascular venous malformations. A summary of the characteristic features is included in the Table.

Pathologically, 2 main patterns of angiomas are recognized: angiomatous and solid.9 The angiomatous pattern is characterized by irregular, anastomosing vascular channels that dissect through the collagen. The vessels are lined by endothelial cells with features that range from normal-appearing endothelial cells to pleomorphic, hyperchromatic cells that exhibit multi-layering. Papillary processes may be present within the lumen. Numerous normal or abnormal mitotic figures are present as well. A dense mononuclear cell infiltrate is present and correlates with a better prognosis. In the solid form of angiosarcoma, tumor cells may be spindle or polygonal shaped. Vascular architecture may not be identified in the poorly differentiated areas. Reticulin staining highlights the vascular channels.9 Possible immunohistochemical markers for angiosarcoma include ulex europaeus 1 lectin (sensitive marker; used in conjunction with epithelial membrane antigen and cytokeratin to exclude epithelial tumor); factor VIII antigen (highly specific; low detection sensitivity); CD34 cells (highly sensitive; stains dermal dendrocytes, sweat gland basement membrane, and hematopoietic progenitor cells); and CD31 cells (highly sensitive; good specificity).7,19 Several differential diagnoses should be considered on pathology.20 Unlike benign vascular lesions, the well-differentiated angiomatous areas in angiosarcoma display cytologic atypia; multilayering, papillary structures; and irregular anastomosing blood vessels. In Kaposi sarcoma, cytologic atypia is less prominent and there is no endothelial multilayering.20 The optimal treatment of cutaneous angiosarcoma has not been defined.21 Generally, radical surgery and postoperative radiotherapy are advocated to treat patients with these tumors. In many patients, surgery often is not feasible because of the tumor's multifocal nature and local spread pattern.21 Therefore, the results have been poor. In a study by Mark et al,22 only 1 of 12 patients had the disease locally controlled. Holden et al23 reported 1 cure in 7 patients treated with surgery alone. The surgical aim is to resect all clinically identifiable disease.24 In areas of doubt, microscopic control of surgical margins may have a role in guiding the extent of resection. Achieving a negative margin frequently is difficult in angiosarcoma patients because of the extensive microscopic spread that is so common in this disease. Therefore, in trying to achieve a negative margin, a wound is created that almost never can be closed primarily. The reconstructive surgeon has a number of options for initial temporary coverage, as well as definitive reconstruction, including homograft skin, autologous skin graft, rotation flaps, and free flaps.24 Angiosarcomas usually respond to radiotherapy to some degree and most studies suggest that a combination of surgery and radiotherapy offers the best chance for long-term control.3,21 In 1 series of 28 angiosarcomas of the head and neck, Mark et al22 reported better survival after a median 32 months with combined surgery and radiotherapy compared with surgery alone. In cases unsuited for surgery, radiotherapy alone may be considered; however, usually only partial responses are achieved. Morrison et al21 suggested that moderate doses of radiation could control subclinical disease. Because angiosarcoma is a systemic disease, chemotherapy may be useful in its management.25 The efficacy of chemotherapy is undefined, with some studies reporting a beneficial effect and others suggesting no survival benefit. Chemotherapeutic agents used have included doxorubicin, cyclophosphamide, dacarbazine, actinomycin D, methotrexate, and vincristine.25 Systemic paclitaxel therapy has been used with encouraging results in 3 patients with angiosarcoma with regression of the lesions.26 Spieth and colleagues27 reported the effectiveness of 13-cis-retinoic acid and interferon alfa-2a combination therapy in a patient with recurring cutaneous angiosarcoma of the head after radical radiation treatment. There is no optimal treatment for angiosarcoma and the search for effective systemic treatment is needed. The prognosis in angiosarcoma is poor because of its high potential for metastasis.28 The 5-year survival rate is about 12%. Prognostic factors include the size of the tumor and mitotic counts, with tumors less than 10 cm in diameter and those with low mitotic counts having a better prognosis.28

Conclusion

Angiosarcomas are rare, aggressive tumors of vascular origin. They occur most often in areas of long-term sun-exposed skin in elderly patients, patients with longstanding lymphedema, or patients who have completed radiation therapy. The prognosis is poor and radical surgery is often required. In addition, radiation or chemotherapy may be considered as therapeutic options.

Angiosarcoma is an aggressive neoplasm that predominantly affects elderly patients. Most cases appear on the scalp and face de novo; however, trauma, longstanding lymphedema, and irradiation are predisposing factors. Management includes a multidisciplinary team and may involve a combination of surgery, radiation, and chemotherapy tailored to the patient’s age and associated comorbidities.

Bruiselike patches on the face and scalp of elderly patients should raise the index of suspicion for angiosarcoma. A biopsy of the lesion and a workup for other organ involvement should be considered. We present the case of an elderly patient with an angiosarcoma and discuss the management and follow-up along with a brief review of the current literature. 

Case Report
In February 2002, an 80-year-old white man presented with approximately a 3-month history of a growing raised area on the nose (Figure). The patient first noticed a sudden onset of redness on the right side of his nose in December 2001. The redness gradually darkened over the next 3 months.

Examination revealed a 30-X20-mm purplish red plaque on the right side of the patient's nose. Results of a 4-mm punch biopsy showed an angiosarcoma. The patient was referred to an ear, nose, and throat physician with a special interest in oncology. He also was evaluated by an oncologist. Results of the patient's physical examination were unremarkable except for the skin lesion on his nose. Results of a complete blood count, x-ray, and computed tomography of the chest, as well as an abdominal ultrasound and magnetic resonance imaging of the head and neck, were unremarkable for masses, lymphadenopathy, or other significant findings. In March 2002, the patient underwent excision of the tumor followed by skin grafting. Six weeks after the operation, the patient was started on external beam radiation therapy. He was treated with 98 Gy over 49 days (2.0 Gy daily). Results of follow-up physical examinations by the multidisciplinary team did not reveal any signs or symptoms of tumor recurrence. On the patient's last follow-up visit in April 2005, he showed no evidence of recurrence of the lesion or metastasis. No follow-up photographs were taken. 

Comment

Cutaneous angiosarcoma of the face and scalp is a distinct entity among the angiosarcomas. It was first described in detail by Jones1 in 1964 as malignant angioendothelioma of the skin.2 This aggressive vascular neoplasm predominantly affects elderly patients (average age, 70 years).3 Men are affected twice as frequently as women. Men also tend to develop the disease at an earlier age. The tumor is localized mostly to the upper half of the face and the scalp.3 Predisposing factors in the onset of angiosarcoma include trauma, longstanding lymphedema, and irradiation of benign vascular lesions; however, most cases present with no obvious etiology.4 The clinical presentation of angiosarcoma is variable. Ill-defined bruiselike areas or facial edema with minimal erythema are the initial signs. Progressively more indurated plaques appear with nodular or ulcerated components. The neoplasm spreads quickly, centrifugally, and transdermally.5,6 Multifocality also is possible. The original clinical size of the tumor rarely correlates to the degree of microscopic tissue invasion.7 Unusual presentations have included yellowish plaques over the upper eyelids that resemble xanthelasma and cause ptosis,8 rosacealike lesions,9 and lesions presenting with scarring alopecia.10 Angiosarcoma presenting with intermittent angioedema of the face that comes and goes is another uncommon manifestation.11 Rhinophymalike features also should be considered as an unusual clinical manifestation of cutaneous angiosarcoma.12 Diagnosis often is delayed by the variable presentation and the benign appearance of the lesion, which simulates a bruise or a hemangioma. Retrospective studies show that clinical diagnosis of cutaneous angiosarcomas often is difficult.13 Other lesions that may need to be differentiated from angiosarcoma on the face include hemangiomas, Kaposi sarcomas, malignant melanomas, metastases, and vascular venous malformations. A summary of the characteristic features is included in the Table.

Pathologically, 2 main patterns of angiomas are recognized: angiomatous and solid.9 The angiomatous pattern is characterized by irregular, anastomosing vascular channels that dissect through the collagen. The vessels are lined by endothelial cells with features that range from normal-appearing endothelial cells to pleomorphic, hyperchromatic cells that exhibit multi-layering. Papillary processes may be present within the lumen. Numerous normal or abnormal mitotic figures are present as well. A dense mononuclear cell infiltrate is present and correlates with a better prognosis. In the solid form of angiosarcoma, tumor cells may be spindle or polygonal shaped. Vascular architecture may not be identified in the poorly differentiated areas. Reticulin staining highlights the vascular channels.9 Possible immunohistochemical markers for angiosarcoma include ulex europaeus 1 lectin (sensitive marker; used in conjunction with epithelial membrane antigen and cytokeratin to exclude epithelial tumor); factor VIII antigen (highly specific; low detection sensitivity); CD34 cells (highly sensitive; stains dermal dendrocytes, sweat gland basement membrane, and hematopoietic progenitor cells); and CD31 cells (highly sensitive; good specificity).7,19 Several differential diagnoses should be considered on pathology.20 Unlike benign vascular lesions, the well-differentiated angiomatous areas in angiosarcoma display cytologic atypia; multilayering, papillary structures; and irregular anastomosing blood vessels. In Kaposi sarcoma, cytologic atypia is less prominent and there is no endothelial multilayering.20 The optimal treatment of cutaneous angiosarcoma has not been defined.21 Generally, radical surgery and postoperative radiotherapy are advocated to treat patients with these tumors. In many patients, surgery often is not feasible because of the tumor's multifocal nature and local spread pattern.21 Therefore, the results have been poor. In a study by Mark et al,22 only 1 of 12 patients had the disease locally controlled. Holden et al23 reported 1 cure in 7 patients treated with surgery alone. The surgical aim is to resect all clinically identifiable disease.24 In areas of doubt, microscopic control of surgical margins may have a role in guiding the extent of resection. Achieving a negative margin frequently is difficult in angiosarcoma patients because of the extensive microscopic spread that is so common in this disease. Therefore, in trying to achieve a negative margin, a wound is created that almost never can be closed primarily. The reconstructive surgeon has a number of options for initial temporary coverage, as well as definitive reconstruction, including homograft skin, autologous skin graft, rotation flaps, and free flaps.24 Angiosarcomas usually respond to radiotherapy to some degree and most studies suggest that a combination of surgery and radiotherapy offers the best chance for long-term control.3,21 In 1 series of 28 angiosarcomas of the head and neck, Mark et al22 reported better survival after a median 32 months with combined surgery and radiotherapy compared with surgery alone. In cases unsuited for surgery, radiotherapy alone may be considered; however, usually only partial responses are achieved. Morrison et al21 suggested that moderate doses of radiation could control subclinical disease. Because angiosarcoma is a systemic disease, chemotherapy may be useful in its management.25 The efficacy of chemotherapy is undefined, with some studies reporting a beneficial effect and others suggesting no survival benefit. Chemotherapeutic agents used have included doxorubicin, cyclophosphamide, dacarbazine, actinomycin D, methotrexate, and vincristine.25 Systemic paclitaxel therapy has been used with encouraging results in 3 patients with angiosarcoma with regression of the lesions.26 Spieth and colleagues27 reported the effectiveness of 13-cis-retinoic acid and interferon alfa-2a combination therapy in a patient with recurring cutaneous angiosarcoma of the head after radical radiation treatment. There is no optimal treatment for angiosarcoma and the search for effective systemic treatment is needed. The prognosis in angiosarcoma is poor because of its high potential for metastasis.28 The 5-year survival rate is about 12%. Prognostic factors include the size of the tumor and mitotic counts, with tumors less than 10 cm in diameter and those with low mitotic counts having a better prognosis.28

Conclusion

Angiosarcomas are rare, aggressive tumors of vascular origin. They occur most often in areas of long-term sun-exposed skin in elderly patients, patients with longstanding lymphedema, or patients who have completed radiation therapy. The prognosis is poor and radical surgery is often required. In addition, radiation or chemotherapy may be considered as therapeutic options.

Case Report

A 35-year-old white man visited our Sector of Dermatology complaining about a feeling of increased weight and volume in his arms and legs that had started 2 months previously. The symptoms had begun 48 hours after a vigorous and unusual physical effort—carrying 30- to 40-kg boxes during a more than 2.5-hour period. When the patient sought medical assistance, his problem was diagnosed as rheumatism. He was prescribed a nonsteroidal anti-inflammatory drug, with partial improvement. A few days later, his condition evolved to hand and wrist joint induration lasting more than 2 hours that was associated with a discrete disturbance to his normal way of walking.

The patient did not exercise regularly and denied the use of medication containing L-tryptophan. He did not report any systemic signs and symptoms such as fever, reduced weight, hyporexia, dyspnea, difficulty swallowing solids and liquids, previous upper respiratory tract infections, recent history of hepatitis, diabetes mellitus, or similar cases in the family.

Results of a physical examination showed loss of weight and skin blushing. The patient was hydrated, acyanotic, anicteric, feverless, and eupneic. His arterial pressure was 120x80 mm Hg, with ample peripheral pulses. The patient showed atypical facies without edema, with normal wrinkling for his gender and age and a mouth opening of 4.5 cm. His thorax and abdomen were without abnormalities. His upper and lower limbs had increased volume with infiltration varying from discrete to moderate, without sustained depressions at finger pressure except on the extremities. There was absence of Raynaud phenomenon. Results of an examination of articulations showed absence of edema or synovitis of the knees, ankles, wrists, and hands; mobility was free and painless.

Results of a dermatologic examination revealed visible sclerosis of limb skin, which was more evident at the extremities and diminished in intensity in the direction of the proximal region; in addition, the affected area had a discrete yellowish color, scarcity of hair, and telangiectasia (Figures 1 and 2).

Please refer to the PDF to view the figures

Results of laboratory tests showed intense eosinophilia (28%: a blood count of 2500 eosinophils in 8900 leukocytes); an increased erythrocyte sedimentation rate; and hypergammaglobulinemia (35.7%). His immunologic profile was evaluated for antinuclear factor, anti-DNA, antitopoisomerase, and anticentromere antibodies; all test results were negative. Antibodies for human immunodeficiency virus and indicators for hepatitis also were negative. Urine sediment and parasitologic stool examinations, as well as an x-ray of the thorax, did not reveal alterations. An incisional biopsy down to the muscular fascia was performed with a scalpel on the anterior surface of the right forearm.

Results of a histopathologic examination with hematoxylin-eosin stain revealed an inflammatory infiltrate of lymphocytes, plasma cells, and eosinophils around dermal vessels, mostly at the muscular fascia and adjacent adipose tissue (Figures 3 and 4). Results of direct immunofluorescence showed immunoreactivity to fibrinogen in some vessels of the superficial dermis; however, the results were negative for IgG, IgM, IgA, and C3, configuring an unspecific pattern of vascular reaction.

Please refer to the PDF to view the figures

The patient was diagnosed with eosinophilic fasciitis (Shulman syndrome), prescribed a therapeutic regimen of prednisone 20 mg/d (0.3 mg/kg) and diclofenac potassium 100 mg/d, and advised to avoid exercise and to rest. The patient's condition progressively improved, as did the cutaneous sclerosis, which improved faster in the upper limbs. After 6 months of prednisone with gradual withdrawal, examination results showed only a discrete sclerosis of the arms, forearms, thighs, and legs. 

Comment

Shulman syndrome, first described in 1974 by Shulman,¹ is characterized by a sudden onset of a symmetrical edema with induration at the extremities. In 1975, Rodnan et al² proposed the name eosinophilic fasciitis after evaluating a laboratorial aspect of the disease. At that time, more than 200 cases were reported, some in nonhuman primates such as the rhesus monkey.³

Eosinophilic fasciitis is an inflammatory disease of unknown etiology that affects the muscular fascia and is characterized by a considerable increase of serous and tissue eosinophils, with hypergammaglobulinemia.^4-6 This sclerodermiform syndrome presents clinical and histopathologic characteristics that allow a clinical distinction from scleroderma, despite that in some cases such differentiation may be difficult. Eosinophilic fasciitis mostly affects white men aged 30 to 70 years, frequently after the performance of vigorous and unusual physical effort. Patients complain about pain and edema with sudden onset and centripetal evolution starting at the extremities, evolving to induration that leads to limitation of hand and feet mobility.^7,8 Occasionally, the face and abdomen also may be involved.⁹ An important dermatologic sign for the diagnosis is called the valley signal, which can be observed during extension and abduction of the arms, and corresponds to the linear depression following the vascular path of the area involved. The description of 6 cases in the presence of hematologic neoplasia has led some authors to believe that eosinophilic fasciitis is a manifestation of a paraneoplastic syndrome.¹⁰

Since the first description of Shulman syndrome in the literature, the condition has appeared in more than 100 articles, mostly of Anglo-Saxon origin. These articles have generated much debate regarding the condition's relation to scleroderma or its existence as an autonomous entity.¹¹ The condition should be set apart from all other sclerodermiform states. Scleredema adultorum (Buschke disease) is related to respiratory infection or to diabetes mellitus of long evolution. Scleredema adultorum presents a centrifugal evolution, beginning at the cervical region and root of the upper limbs, with half of the cases occurring during childhood or adolescence, and is twice as frequent in women.⁸ Mucin is generally evident at the beginning of the disease.¹² Myalgia-eosinophilia syndrome presents respiratory and neurologic symptoms associated with myalgia of sudden onset and is accompanied by a temporary cutaneous eruption that varies from maculopapular to urticarial. Myalgia-eosinophilia syndrome may present intense itching, and is related to the ingestion of the amino acid L-tryptophan.^13-16 Systemic scleroderma presents a universal induration of the skin accompanied by vasospastic phenomena in several organs with a variety of symptoms. Patients with acroesclerosis, a form of systemic scleroderma, present with calcinosis, Raynaud phenomenon, esophageal alterations, sclerodactyly, and telangiectasis (also known as CREST syndrome) on the face and upper trunk. The circumscribed forms are characterized by several types of cutaneous lesions, which are localized and seldom accompanied by other alterations.^17-20

Peripheral eosinophilia is a common finding in patients with eosinophilic fasciitis, presenting in more than 80% of cases; it also may occur in different forms in systemic sclerosis (7%) and in localized scleroderma (31%).^17,21 In nonmedicated patients with eosinophilic fasciitis, peripheral eosinophilia was a consistent finding, even in those who had the disease for more than 30 months. Most authors define eosinophilia as an eosinophil count of more than 600 cells/cm³; however, others have defined it as 400 or even 300 cells/cm³, with existence of a relationship between the peripheral and tissue count of eosinophils in most cases. In one study, eosinophilia above 1000 cells/mm³ was found in 61% of patients, but only 1% had systemic sclerosis and 8% had the localized form, indicating that peripheral eosinophilia is not only more frequent and intense but also guides the diagnosis.^17,21 Tissue eosinophilia is more variable than peripheral eosinophilia.

In some cases, the peripheral eosinophils are present in numbers within reference range in a certain blood sample, showing that the finding may be temporary. It is important to make the differential diagnosis between systemic sclerosis, morphea, and eosinophilic fasciitis because they not only have different prognoses but also have different treatments.^21,22 Eosinophilic fasciitis responds well to systemic corticoid therapy; in scleroderma, steroids are not always useful, and morphea can remit spontaneously. Absence of Raynaud phenomenon and induration of the limbs after intense and unusual exercise help to establish the diagnosis of eosinophilic fasciitis. Fascia damage can be found, though rarely, in the late phases of systemic sclerosis. Proliferative fasciitis represents a pseudosarcomatous reaction involving the muscular fascia and the subcutaneous fibrous septum; in addition, despite not presenting eosinophilia, proliferative fasciitis affects the extremities of adults and may have trauma as an etiological factor.¹⁹

The diagnosis of eosinophilic fasciitis may be confirmed by histopathologic examination, results of which show an inflammatory infiltrate with eosinophils extending to the muscular fascia.¹⁹ Tissue eosinophilia is defined as the presence of 3 or more cells in the microscopic field.¹⁶ The eosinophils are present in the entire damaged area from disease onset; however, this must not be confused with disseminated eosinophilic collagenosis, in which the cells infiltrate several organs, leading to focal necrosis and necrotizing endarteritis. When the biopsy result does not reach a diagnosis of hypodermis and fascia, the sclerotic aspect prevails, which is not characteristic of eosinophilic fasciitis. In the initial phases of eosinophilic fasciitis, there are no significant epidermal and dermal alterations; in scleroderma, there are variable degrees of edema and sclerosis, and the inflammatory process, when present, occurs in the dermis and in the upper portion of the subcutaneous cell tissue.^8,19,20 

Case Report

A 35-year-old white man visited our Sector of Dermatology complaining about a feeling of increased weight and volume in his arms and legs that had started 2 months previously. The symptoms had begun 48 hours after a vigorous and unusual physical effort—carrying 30- to 40-kg boxes during a more than 2.5-hour period. When the patient sought medical assistance, his problem was diagnosed as rheumatism. He was prescribed a nonsteroidal anti-inflammatory drug, with partial improvement. A few days later, his condition evolved to hand and wrist joint induration lasting more than 2 hours that was associated with a discrete disturbance to his normal way of walking.

The patient did not exercise regularly and denied the use of medication containing L-tryptophan. He did not report any systemic signs and symptoms such as fever, reduced weight, hyporexia, dyspnea, difficulty swallowing solids and liquids, previous upper respiratory tract infections, recent history of hepatitis, diabetes mellitus, or similar cases in the family.

Results of a physical examination showed loss of weight and skin blushing. The patient was hydrated, acyanotic, anicteric, feverless, and eupneic. His arterial pressure was 120x80 mm Hg, with ample peripheral pulses. The patient showed atypical facies without edema, with normal wrinkling for his gender and age and a mouth opening of 4.5 cm. His thorax and abdomen were without abnormalities. His upper and lower limbs had increased volume with infiltration varying from discrete to moderate, without sustained depressions at finger pressure except on the extremities. There was absence of Raynaud phenomenon. Results of an examination of articulations showed absence of edema or synovitis of the knees, ankles, wrists, and hands; mobility was free and painless.

Results of a dermatologic examination revealed visible sclerosis of limb skin, which was more evident at the extremities and diminished in intensity in the direction of the proximal region; in addition, the affected area had a discrete yellowish color, scarcity of hair, and telangiectasia (Figures 1 and 2).

Please refer to the PDF to view the figures

Results of laboratory tests showed intense eosinophilia (28%: a blood count of 2500 eosinophils in 8900 leukocytes); an increased erythrocyte sedimentation rate; and hypergammaglobulinemia (35.7%). His immunologic profile was evaluated for antinuclear factor, anti-DNA, antitopoisomerase, and anticentromere antibodies; all test results were negative. Antibodies for human immunodeficiency virus and indicators for hepatitis also were negative. Urine sediment and parasitologic stool examinations, as well as an x-ray of the thorax, did not reveal alterations. An incisional biopsy down to the muscular fascia was performed with a scalpel on the anterior surface of the right forearm.

Results of a histopathologic examination with hematoxylin-eosin stain revealed an inflammatory infiltrate of lymphocytes, plasma cells, and eosinophils around dermal vessels, mostly at the muscular fascia and adjacent adipose tissue (Figures 3 and 4). Results of direct immunofluorescence showed immunoreactivity to fibrinogen in some vessels of the superficial dermis; however, the results were negative for IgG, IgM, IgA, and C3, configuring an unspecific pattern of vascular reaction.

Please refer to the PDF to view the figures

The patient was diagnosed with eosinophilic fasciitis (Shulman syndrome), prescribed a therapeutic regimen of prednisone 20 mg/d (0.3 mg/kg) and diclofenac potassium 100 mg/d, and advised to avoid exercise and to rest. The patient's condition progressively improved, as did the cutaneous sclerosis, which improved faster in the upper limbs. After 6 months of prednisone with gradual withdrawal, examination results showed only a discrete sclerosis of the arms, forearms, thighs, and legs. 

Comment

Shulman syndrome, first described in 1974 by Shulman,¹ is characterized by a sudden onset of a symmetrical edema with induration at the extremities. In 1975, Rodnan et al² proposed the name eosinophilic fasciitis after evaluating a laboratorial aspect of the disease. At that time, more than 200 cases were reported, some in nonhuman primates such as the rhesus monkey.³

Eosinophilic fasciitis is an inflammatory disease of unknown etiology that affects the muscular fascia and is characterized by a considerable increase of serous and tissue eosinophils, with hypergammaglobulinemia.^4-6 This sclerodermiform syndrome presents clinical and histopathologic characteristics that allow a clinical distinction from scleroderma, despite that in some cases such differentiation may be difficult. Eosinophilic fasciitis mostly affects white men aged 30 to 70 years, frequently after the performance of vigorous and unusual physical effort. Patients complain about pain and edema with sudden onset and centripetal evolution starting at the extremities, evolving to induration that leads to limitation of hand and feet mobility.^7,8 Occasionally, the face and abdomen also may be involved.⁹ An important dermatologic sign for the diagnosis is called the valley signal, which can be observed during extension and abduction of the arms, and corresponds to the linear depression following the vascular path of the area involved. The description of 6 cases in the presence of hematologic neoplasia has led some authors to believe that eosinophilic fasciitis is a manifestation of a paraneoplastic syndrome.¹⁰

Since the first description of Shulman syndrome in the literature, the condition has appeared in more than 100 articles, mostly of Anglo-Saxon origin. These articles have generated much debate regarding the condition's relation to scleroderma or its existence as an autonomous entity.¹¹ The condition should be set apart from all other sclerodermiform states. Scleredema adultorum (Buschke disease) is related to respiratory infection or to diabetes mellitus of long evolution. Scleredema adultorum presents a centrifugal evolution, beginning at the cervical region and root of the upper limbs, with half of the cases occurring during childhood or adolescence, and is twice as frequent in women.⁸ Mucin is generally evident at the beginning of the disease.¹² Myalgia-eosinophilia syndrome presents respiratory and neurologic symptoms associated with myalgia of sudden onset and is accompanied by a temporary cutaneous eruption that varies from maculopapular to urticarial. Myalgia-eosinophilia syndrome may present intense itching, and is related to the ingestion of the amino acid L-tryptophan.^13-16 Systemic scleroderma presents a universal induration of the skin accompanied by vasospastic phenomena in several organs with a variety of symptoms. Patients with acroesclerosis, a form of systemic scleroderma, present with calcinosis, Raynaud phenomenon, esophageal alterations, sclerodactyly, and telangiectasis (also known as CREST syndrome) on the face and upper trunk. The circumscribed forms are characterized by several types of cutaneous lesions, which are localized and seldom accompanied by other alterations.^17-20

Peripheral eosinophilia is a common finding in patients with eosinophilic fasciitis, presenting in more than 80% of cases; it also may occur in different forms in systemic sclerosis (7%) and in localized scleroderma (31%).^17,21 In nonmedicated patients with eosinophilic fasciitis, peripheral eosinophilia was a consistent finding, even in those who had the disease for more than 30 months. Most authors define eosinophilia as an eosinophil count of more than 600 cells/cm³; however, others have defined it as 400 or even 300 cells/cm³, with existence of a relationship between the peripheral and tissue count of eosinophils in most cases. In one study, eosinophilia above 1000 cells/mm³ was found in 61% of patients, but only 1% had systemic sclerosis and 8% had the localized form, indicating that peripheral eosinophilia is not only more frequent and intense but also guides the diagnosis.^17,21 Tissue eosinophilia is more variable than peripheral eosinophilia.

In some cases, the peripheral eosinophils are present in numbers within reference range in a certain blood sample, showing that the finding may be temporary. It is important to make the differential diagnosis between systemic sclerosis, morphea, and eosinophilic fasciitis because they not only have different prognoses but also have different treatments.^21,22 Eosinophilic fasciitis responds well to systemic corticoid therapy; in scleroderma, steroids are not always useful, and morphea can remit spontaneously. Absence of Raynaud phenomenon and induration of the limbs after intense and unusual exercise help to establish the diagnosis of eosinophilic fasciitis. Fascia damage can be found, though rarely, in the late phases of systemic sclerosis. Proliferative fasciitis represents a pseudosarcomatous reaction involving the muscular fascia and the subcutaneous fibrous septum; in addition, despite not presenting eosinophilia, proliferative fasciitis affects the extremities of adults and may have trauma as an etiological factor.¹⁹

The diagnosis of eosinophilic fasciitis may be confirmed by histopathologic examination, results of which show an inflammatory infiltrate with eosinophils extending to the muscular fascia.¹⁹ Tissue eosinophilia is defined as the presence of 3 or more cells in the microscopic field.¹⁶ The eosinophils are present in the entire damaged area from disease onset; however, this must not be confused with disseminated eosinophilic collagenosis, in which the cells infiltrate several organs, leading to focal necrosis and necrotizing endarteritis. When the biopsy result does not reach a diagnosis of hypodermis and fascia, the sclerotic aspect prevails, which is not characteristic of eosinophilic fasciitis. In the initial phases of eosinophilic fasciitis, there are no significant epidermal and dermal alterations; in scleroderma, there are variable degrees of edema and sclerosis, and the inflammatory process, when present, occurs in the dermis and in the upper portion of the subcutaneous cell tissue.^8,19,20 

Case Report

A 35-year-old white man visited our Sector of Dermatology complaining about a feeling of increased weight and volume in his arms and legs that had started 2 months previously. The symptoms had begun 48 hours after a vigorous and unusual physical effort—carrying 30- to 40-kg boxes during a more than 2.5-hour period. When the patient sought medical assistance, his problem was diagnosed as rheumatism. He was prescribed a nonsteroidal anti-inflammatory drug, with partial improvement. A few days later, his condition evolved to hand and wrist joint induration lasting more than 2 hours that was associated with a discrete disturbance to his normal way of walking.

The patient did not exercise regularly and denied the use of medication containing L-tryptophan. He did not report any systemic signs and symptoms such as fever, reduced weight, hyporexia, dyspnea, difficulty swallowing solids and liquids, previous upper respiratory tract infections, recent history of hepatitis, diabetes mellitus, or similar cases in the family.

Results of a physical examination showed loss of weight and skin blushing. The patient was hydrated, acyanotic, anicteric, feverless, and eupneic. His arterial pressure was 120x80 mm Hg, with ample peripheral pulses. The patient showed atypical facies without edema, with normal wrinkling for his gender and age and a mouth opening of 4.5 cm. His thorax and abdomen were without abnormalities. His upper and lower limbs had increased volume with infiltration varying from discrete to moderate, without sustained depressions at finger pressure except on the extremities. There was absence of Raynaud phenomenon. Results of an examination of articulations showed absence of edema or synovitis of the knees, ankles, wrists, and hands; mobility was free and painless.

Results of a dermatologic examination revealed visible sclerosis of limb skin, which was more evident at the extremities and diminished in intensity in the direction of the proximal region; in addition, the affected area had a discrete yellowish color, scarcity of hair, and telangiectasia (Figures 1 and 2).

Please refer to the PDF to view the figures

Results of laboratory tests showed intense eosinophilia (28%: a blood count of 2500 eosinophils in 8900 leukocytes); an increased erythrocyte sedimentation rate; and hypergammaglobulinemia (35.7%). His immunologic profile was evaluated for antinuclear factor, anti-DNA, antitopoisomerase, and anticentromere antibodies; all test results were negative. Antibodies for human immunodeficiency virus and indicators for hepatitis also were negative. Urine sediment and parasitologic stool examinations, as well as an x-ray of the thorax, did not reveal alterations. An incisional biopsy down to the muscular fascia was performed with a scalpel on the anterior surface of the right forearm.

Results of a histopathologic examination with hematoxylin-eosin stain revealed an inflammatory infiltrate of lymphocytes, plasma cells, and eosinophils around dermal vessels, mostly at the muscular fascia and adjacent adipose tissue (Figures 3 and 4). Results of direct immunofluorescence showed immunoreactivity to fibrinogen in some vessels of the superficial dermis; however, the results were negative for IgG, IgM, IgA, and C3, configuring an unspecific pattern of vascular reaction.

Please refer to the PDF to view the figures

The patient was diagnosed with eosinophilic fasciitis (Shulman syndrome), prescribed a therapeutic regimen of prednisone 20 mg/d (0.3 mg/kg) and diclofenac potassium 100 mg/d, and advised to avoid exercise and to rest. The patient's condition progressively improved, as did the cutaneous sclerosis, which improved faster in the upper limbs. After 6 months of prednisone with gradual withdrawal, examination results showed only a discrete sclerosis of the arms, forearms, thighs, and legs. 

Comment

Shulman syndrome, first described in 1974 by Shulman,¹ is characterized by a sudden onset of a symmetrical edema with induration at the extremities. In 1975, Rodnan et al² proposed the name eosinophilic fasciitis after evaluating a laboratorial aspect of the disease. At that time, more than 200 cases were reported, some in nonhuman primates such as the rhesus monkey.³

Eosinophilic fasciitis is an inflammatory disease of unknown etiology that affects the muscular fascia and is characterized by a considerable increase of serous and tissue eosinophils, with hypergammaglobulinemia.^4-6 This sclerodermiform syndrome presents clinical and histopathologic characteristics that allow a clinical distinction from scleroderma, despite that in some cases such differentiation may be difficult. Eosinophilic fasciitis mostly affects white men aged 30 to 70 years, frequently after the performance of vigorous and unusual physical effort. Patients complain about pain and edema with sudden onset and centripetal evolution starting at the extremities, evolving to induration that leads to limitation of hand and feet mobility.^7,8 Occasionally, the face and abdomen also may be involved.⁹ An important dermatologic sign for the diagnosis is called the valley signal, which can be observed during extension and abduction of the arms, and corresponds to the linear depression following the vascular path of the area involved. The description of 6 cases in the presence of hematologic neoplasia has led some authors to believe that eosinophilic fasciitis is a manifestation of a paraneoplastic syndrome.¹⁰

Since the first description of Shulman syndrome in the literature, the condition has appeared in more than 100 articles, mostly of Anglo-Saxon origin. These articles have generated much debate regarding the condition's relation to scleroderma or its existence as an autonomous entity.¹¹ The condition should be set apart from all other sclerodermiform states. Scleredema adultorum (Buschke disease) is related to respiratory infection or to diabetes mellitus of long evolution. Scleredema adultorum presents a centrifugal evolution, beginning at the cervical region and root of the upper limbs, with half of the cases occurring during childhood or adolescence, and is twice as frequent in women.⁸ Mucin is generally evident at the beginning of the disease.¹² Myalgia-eosinophilia syndrome presents respiratory and neurologic symptoms associated with myalgia of sudden onset and is accompanied by a temporary cutaneous eruption that varies from maculopapular to urticarial. Myalgia-eosinophilia syndrome may present intense itching, and is related to the ingestion of the amino acid L-tryptophan.^13-16 Systemic scleroderma presents a universal induration of the skin accompanied by vasospastic phenomena in several organs with a variety of symptoms. Patients with acroesclerosis, a form of systemic scleroderma, present with calcinosis, Raynaud phenomenon, esophageal alterations, sclerodactyly, and telangiectasis (also known as CREST syndrome) on the face and upper trunk. The circumscribed forms are characterized by several types of cutaneous lesions, which are localized and seldom accompanied by other alterations.^17-20

Peripheral eosinophilia is a common finding in patients with eosinophilic fasciitis, presenting in more than 80% of cases; it also may occur in different forms in systemic sclerosis (7%) and in localized scleroderma (31%).^17,21 In nonmedicated patients with eosinophilic fasciitis, peripheral eosinophilia was a consistent finding, even in those who had the disease for more than 30 months. Most authors define eosinophilia as an eosinophil count of more than 600 cells/cm³; however, others have defined it as 400 or even 300 cells/cm³, with existence of a relationship between the peripheral and tissue count of eosinophils in most cases. In one study, eosinophilia above 1000 cells/mm³ was found in 61% of patients, but only 1% had systemic sclerosis and 8% had the localized form, indicating that peripheral eosinophilia is not only more frequent and intense but also guides the diagnosis.^17,21 Tissue eosinophilia is more variable than peripheral eosinophilia.

In some cases, the peripheral eosinophils are present in numbers within reference range in a certain blood sample, showing that the finding may be temporary. It is important to make the differential diagnosis between systemic sclerosis, morphea, and eosinophilic fasciitis because they not only have different prognoses but also have different treatments.^21,22 Eosinophilic fasciitis responds well to systemic corticoid therapy; in scleroderma, steroids are not always useful, and morphea can remit spontaneously. Absence of Raynaud phenomenon and induration of the limbs after intense and unusual exercise help to establish the diagnosis of eosinophilic fasciitis. Fascia damage can be found, though rarely, in the late phases of systemic sclerosis. Proliferative fasciitis represents a pseudosarcomatous reaction involving the muscular fascia and the subcutaneous fibrous septum; in addition, despite not presenting eosinophilia, proliferative fasciitis affects the extremities of adults and may have trauma as an etiological factor.¹⁹

The diagnosis of eosinophilic fasciitis may be confirmed by histopathologic examination, results of which show an inflammatory infiltrate with eosinophils extending to the muscular fascia.¹⁹ Tissue eosinophilia is defined as the presence of 3 or more cells in the microscopic field.¹⁶ The eosinophils are present in the entire damaged area from disease onset; however, this must not be confused with disseminated eosinophilic collagenosis, in which the cells infiltrate several organs, leading to focal necrosis and necrotizing endarteritis. When the biopsy result does not reach a diagnosis of hypodermis and fascia, the sclerotic aspect prevails, which is not characteristic of eosinophilic fasciitis. In the initial phases of eosinophilic fasciitis, there are no significant epidermal and dermal alterations; in scleroderma, there are variable degrees of edema and sclerosis, and the inflammatory process, when present, occurs in the dermis and in the upper portion of the subcutaneous cell tissue.^8,19,20 

Merkel cell carcinoma (MCC) is a rare primary cutaneous neoplasm known for its propensity to develop early regional and distant metastasis. Fewer than 400 cases occur annually in the United States. MCC ranks as the most deadly of cutaneous malignancies, with a fatality rate of approximately 25%. Because of its aggressive nature, MCC is often resistant to surgery, radiation, and chemotherapy regimens. Standardized treatment patterns have not been established, and difficulty arises finding appropriate treatment for the elderly, who comprise the majority of patients with MCC.

Merkel cell carcinoma (MCC) is a neuroendocrine tumor that has been described as a primary neuroendocrine carcinoma of the skin or "cutaneous APUDoma." Alternatively, MCC has been called a primary small cell carcinoma of the skin1 because of its morphologic and behavioral similarities to small cell carcinoma of the lung.

Merkel cells are slowly adapting mechanoreceptors in epidermal nerve endings. Although they are found in ectoderm-derived skin and mucosa, recent evidence places their origin as neural crest.2 Merkel cells contain cytokeratins and neuropeptide-containing eosinophilic granules. These cells combine with nerve terminals to form mechanoreceptors. It remains unclear if MCC originates from the same developmental lineage as Merkel cells. Recent research suggests these tumors originate from epidermal epithelial cells that are not in contact with nerve terminals but that have similar cytoskeletal filaments and a neuroendocrine origin.2 Although the pathogenesis of MCC has not been completely illuminated, it is agreed that UV exposure is an important risk factor. UVB-induced C · T transitions have been found, as well as p53 missense mutations. For this reason, risks include fair skin (as evidenced by the higher incidence in Caucasian populations), advanced age, and previous or concurrent sun-related skin malignancies such as squamous cell carcinoma and basal cell carcinoma.3 MCC also is linked to immunosuppression, with a higher incidence in transplant recipients and patients receiving chemotherapy.4 In addition, there is an increased incidence in patients with psoriasis who were treated with psoralen-UVA. Reports link MCC to a history of prolonged arsenic exposure,1 as well as to congenital dysplasia syndrome and chronic lymphocytic leukemia.5 MCC most often presents in fair-skinned patients 65 years and older as a solitary firm nodule on the head or neck. Its gross appearance is often nonspecific, being misdiagnosed as basal cell carcinoma or metastasis of a small cell carcinoma elsewhere.2 Even when diagnosed at its earliest stage, MCC has a 2-year fatality rate of 10%. Its 5-year survival rate is 50% to 68%. Regional metastasis occurs in 50% to 60% of patients. When metastasis does occur, regional lymph nodes are involved 65% of the time,6 with the majority (70%) occurring within 2 years of diagnosis. Nearly 40% will develop distant metastasis.7 Metastases most commonly involve the skin, lymph nodes, liver, lung, and bone.1 A primary lesion larger than 2 cm denotes a poor prognosis. There have been rare reports of spontaneous regression. 

Histopathology Microscopically, MCC can be difficult to identify. The epidermis may show bowenoid or squamous cell carcinoma-like changes, but they are not characteristic. Under low power microscopy, small round blue cells are evident in the dermis; the cells appear uniform and are often arranged to form either sheets or clusters that create a trabecular appearance or that of a group of grapes. On high power, the cells will appear to be pale and empty. Numerous mitoses can be identified, and evidence of metastasis can be found in the lymphatic or blood vessels. Neurosecretory granules that range from 80 to 120 nm and look like small blue dots5 are membrane bound in the paranuclear regions. Because traditional hematoxylin-eosin (H&E) staining demonstrates morphologic features of both epithelial and neuroendocrine tumors, H&E results cannot distinguish MCC from other small round blue cell tumors such as melanoma, lymphoma, neuroblastoma, and metastatic small cell lung carcinoma.7 Cytokeratin staining and immunohistologic markers are required to make the definitive diagnosis; cytokeratin 20, chromogranin A, and synaptophysin are among those used. Other markers include neuron-specific enolase and, most recently, CD56, a marker for neural cell adhesion molecule.8 

Case Report

In August 2002, an 86-year-old white man presented for evaluation of an 8-mm friable pink nodule on the right ear of uncertain duration (Figure 1). No cervical or peripheral adenopathy was appreciated. The man had an extensive history of prior basal cell carcinoma and squamous cell carcinoma on sun-exposed areas, having undergone excisions and Mohs micrographic surgery for many of these lesions.

An excisional biopsy was performed, and the pathology results revealed aggregates of neoplastic cells with indistinct nucleoli with granular nucleoplasms and scant cytoplasms separated by fibrous septa or trabeculae (Figure 2). Also, numerous mitotic figures and areas of focal necrosis were present. In our patient, cytokeratin 20 and chromogranin A results were strongly positive (Figures 3 and 4); although other entities can demonstrate either of these markers, when found together they confirm the diagnosis of MCC. Our patient also demonstrated CD56 positivity and a weakly positive reaction to synaptophysin (Figure 4). Cytokeratin 7 and CD45 results were negative, which also confirmed the diagnosis of MCC (Figure 5).

Staging by computed tomography scan of the neck, chest, and upper abdomen ruled out systemic spread. Because of the patient's advanced age, frail health status, and his adamant opposition, chemotherapy was deferred. Instead, he was referred to radiation oncology for a course of regional electron beam therapy. It was believed that radiation therapy might adequately control his disease and would not present the morbidity risks involved with chemotherapy and/or a more aggressive wide excision.9 Six MeV radiation was used to deliver a 60-Gy surface dose to the ear area and 50 Gy to deep upper cervical nodes, facial nodes, and adjacent skin to the level of the larynx. The patient tolerated the 5 weeks of radiation treatment well, with mild skin erythema to the region. The patient was followed closely; at a routine follow-up in February 2003, examination revealed a new 1-cm, right-sided preauricular pearly nodule. The patient revealed that the lesion had been present for 10 days. The new lesion appeared to be outside the previously treated radiation field. Excision was done using Mohs micrographic surgery, and the pathology results revealed clusters of undifferentiated neoplastic cells, some of which appeared to be within the lymphatics. This outcome, along with the immunohistochemistry results, confirmed that the lesion was the same histologic type as the primary lesion. Shortly thereafter, the patient developed 2 new lesions on the right temple (0.8- and 1.3-cm irregular subcutaneous nodules). Pathology of these nodules also was consistent with MCC, with lymphatic and vascular involvement and positive margins of the resected area. The new lesions were then treated with a second course of electron beam therapy with a generous field that included some overlap with the previously irradiated area. Chemotherapy was again discussed with the patient, who strongly declined this option despite disease progression. His age and ability to tolerate the chemotherapeutic side effects involved were considerations in the patient's decision. In October 2003, a second course of 6 MeV radiation to the right temple and anterior right cheek over 25 treatment sessions was completed. Despite the widened field of radiation, several new nodules developed during its course. These involved the superior aspect of the right ear, right nasolabial fold, upper left temple, left preauricular regions, and posterior neck. In November 2003, a magnetic resonance image of the spine demonstrated systemic spread with bone metastasis involving the C2 and C3 vertebral bodies. A third round of radiation, now considered palliative, was directed to the cervical spine. With the patient finally concurring, a mild chemotherapeutic regimen of pamidronate and capecitabine also was planned. These treatments were discontinued after 2 courses because of failure to thrive. Bone metastases and cutaneous involvement continued to progress. Despite the unfavorable prognosis, the patient requested further treatment, and a single regimen of oral etoposide was chosen.

Comment

Treatment of a primary lesion without evidence of spread, or stage I disease, has historically been wide excision; however, acceptable margins have been debated, ranging from 1 to 3 cm. The addition of postsurgical irradiation of 50 to 60 Gy to the area of the lesion and all draining lymph node basins has been found to decrease local recurrence but has not been found to have a major impact on survival rates, given the frequency of distant metastasis in MCC.10 Mortier et al9 recently reported similar outcomes with radiation therapy alone and with wide excision followed by radiation for inoperable stage I disease. Prophylactic radiation (40–60 Gy) to the draining lymph node basin also has been proposed for stage I, though it has not been thoroughly investigated. Mohs micrographic surgery may have a significant impact on the primary treatment of MCC. Local recurrence rates with Mohs micrographic surgery are lower than with wide excision because thorough histologic evaluation of margins is best.11,12 Radiation at the primary site is indicated when clear margins cannot be achieved.12 In the case of successful excision by Mohs micrographic surgery, adjuvant radiation therapy has not been shown to lower the rates of recurrence. However, irradiation of the lesion, including the draining lymph node basin, may improve regional control and increase the disease-free interval.9 MCC spreads to regional lymph nodes within 2 years in 70% of cases.13 When lymph nodes are affected, 5-year survival is approximately 50%. Historically, regional lymphadenectomy was used in those patients with confirmed or suspected lymph node spread. Due to the morbidity risks of this procedure, this technique has fallen out of favor.14 A newer alternative is sentinel lymph node biopsy. The usefulness of this modality for the overall impact on survival is debated.6 Given the morphologic and immunohistologic similarities to small cell carcinoma, MCC also is similarly chemosensitive. Although there is no doubt about the efficacy of adjuvant chemotherapy in vitro, its benefit in preventing recurrence is debated. It is most widely accepted as a last-line effort in stage II disease to prevent progression to distant metastasis, and in stage III disease as a palliative effort.15 In the limited studies of chemotherapy for cases of MCC, the response rate to first-line therapy approached only 65%. Dose-response figures have not been established.11 In the investigation into the use of chemotherapy as a first-line therapy, chemotherapy regimens employed in small cell lung carcinoma (cyclophosamide, doxorubicin, vincristine, or etoposide-cisplatin) may provide a useful guide. Although combinations such as cisplatin-doxorubicin are acceptable in patients younger than 65 years, elderly patients are often poor candidates given their comorbidities. Some monotherapy regimens, such as oral etoposide, have been successful.10 Risks, including neutropenia and peripheral neuropathy, are magnified by the pharmacodynamic changes in absorption and metabolism that occur with age. Human growth factors such as granulocyte colony-stimulating factor, macrophage-macrophage colony-stimulating factor, and recombinant human erythropoietin have been supplemented in more elderly patients in an attempt to reduce morbidity and increase dose escalations.11 The lack of data on chemotherapy in the elderly population is not unique to MCC; rather, it is a common problem in cancer research. Most cancers occur in patients 65 years and older, yet there is a paucity of data on the effects of chemotherapy because elderly patients are poor candidates for phase 1 and phase 2 trials. Therefore, existing knowledge of the pharmacophysiology of aging must be used to extrapolate the most appropriate dosing and drug combinations. New treatment modalities are being explored. Immunotherapy has shown some results for early stage MCC. Interferon alfa 2b and tumor necrosis factor have shown some promise. The antigens mucin 1 and epithelial cell adhesion molecule are expressed in 85% and 70% of MCC cases, respectively.16 Current research is directed at developing antibodies to these antigens. Somatostatin receptor scintigraphy along with sentinel lymph node biopsy might become another tool with which to detect micrometastasis. Reverse transcription polymerase chain reaction can be used to find markers such as cytokeratin 20 on MCC cells circulating in the peripheral blood pool.17 This would allow identification of patients at high risk for systemic spread and relapse. To date, no treatment has been found to successfully arrest distant metastases.

Conclusion

Given the early dissemination of MCC and the poor prognosis once metastasis has occurred, aggressive treatment for stage I disease must be considered. Radiation therapy may be palliative and may have an increasing role as prophylactic protection in early disease. Chemotherapy has been employed in regional spread of disease (stage II). Will chemotherapy utilized in earlier stages of disease be a possible solution? Could combined chemoimmunotherapy be a useful compliment to the modest success of radiation treatment? These modalities are only as good as their practical use in the typical elderly patient with MCC, and addressing this challenge will be crucial in future research. back to top

Merkel cell carcinoma (MCC) is a rare primary cutaneous neoplasm known for its propensity to develop early regional and distant metastasis. Fewer than 400 cases occur annually in the United States. MCC ranks as the most deadly of cutaneous malignancies, with a fatality rate of approximately 25%. Because of its aggressive nature, MCC is often resistant to surgery, radiation, and chemotherapy regimens. Standardized treatment patterns have not been established, and difficulty arises finding appropriate treatment for the elderly, who comprise the majority of patients with MCC.

Merkel cell carcinoma (MCC) is a neuroendocrine tumor that has been described as a primary neuroendocrine carcinoma of the skin or "cutaneous APUDoma." Alternatively, MCC has been called a primary small cell carcinoma of the skin1 because of its morphologic and behavioral similarities to small cell carcinoma of the lung.

Merkel cells are slowly adapting mechanoreceptors in epidermal nerve endings. Although they are found in ectoderm-derived skin and mucosa, recent evidence places their origin as neural crest.2 Merkel cells contain cytokeratins and neuropeptide-containing eosinophilic granules. These cells combine with nerve terminals to form mechanoreceptors. It remains unclear if MCC originates from the same developmental lineage as Merkel cells. Recent research suggests these tumors originate from epidermal epithelial cells that are not in contact with nerve terminals but that have similar cytoskeletal filaments and a neuroendocrine origin.2 Although the pathogenesis of MCC has not been completely illuminated, it is agreed that UV exposure is an important risk factor. UVB-induced C · T transitions have been found, as well as p53 missense mutations. For this reason, risks include fair skin (as evidenced by the higher incidence in Caucasian populations), advanced age, and previous or concurrent sun-related skin malignancies such as squamous cell carcinoma and basal cell carcinoma.3 MCC also is linked to immunosuppression, with a higher incidence in transplant recipients and patients receiving chemotherapy.4 In addition, there is an increased incidence in patients with psoriasis who were treated with psoralen-UVA. Reports link MCC to a history of prolonged arsenic exposure,1 as well as to congenital dysplasia syndrome and chronic lymphocytic leukemia.5 MCC most often presents in fair-skinned patients 65 years and older as a solitary firm nodule on the head or neck. Its gross appearance is often nonspecific, being misdiagnosed as basal cell carcinoma or metastasis of a small cell carcinoma elsewhere.2 Even when diagnosed at its earliest stage, MCC has a 2-year fatality rate of 10%. Its 5-year survival rate is 50% to 68%. Regional metastasis occurs in 50% to 60% of patients. When metastasis does occur, regional lymph nodes are involved 65% of the time,6 with the majority (70%) occurring within 2 years of diagnosis. Nearly 40% will develop distant metastasis.7 Metastases most commonly involve the skin, lymph nodes, liver, lung, and bone.1 A primary lesion larger than 2 cm denotes a poor prognosis. There have been rare reports of spontaneous regression. 

Histopathology Microscopically, MCC can be difficult to identify. The epidermis may show bowenoid or squamous cell carcinoma-like changes, but they are not characteristic. Under low power microscopy, small round blue cells are evident in the dermis; the cells appear uniform and are often arranged to form either sheets or clusters that create a trabecular appearance or that of a group of grapes. On high power, the cells will appear to be pale and empty. Numerous mitoses can be identified, and evidence of metastasis can be found in the lymphatic or blood vessels. Neurosecretory granules that range from 80 to 120 nm and look like small blue dots5 are membrane bound in the paranuclear regions. Because traditional hematoxylin-eosin (H&E) staining demonstrates morphologic features of both epithelial and neuroendocrine tumors, H&E results cannot distinguish MCC from other small round blue cell tumors such as melanoma, lymphoma, neuroblastoma, and metastatic small cell lung carcinoma.7 Cytokeratin staining and immunohistologic markers are required to make the definitive diagnosis; cytokeratin 20, chromogranin A, and synaptophysin are among those used. Other markers include neuron-specific enolase and, most recently, CD56, a marker for neural cell adhesion molecule.8 

Case Report

In August 2002, an 86-year-old white man presented for evaluation of an 8-mm friable pink nodule on the right ear of uncertain duration (Figure 1). No cervical or peripheral adenopathy was appreciated. The man had an extensive history of prior basal cell carcinoma and squamous cell carcinoma on sun-exposed areas, having undergone excisions and Mohs micrographic surgery for many of these lesions.

An excisional biopsy was performed, and the pathology results revealed aggregates of neoplastic cells with indistinct nucleoli with granular nucleoplasms and scant cytoplasms separated by fibrous septa or trabeculae (Figure 2). Also, numerous mitotic figures and areas of focal necrosis were present. In our patient, cytokeratin 20 and chromogranin A results were strongly positive (Figures 3 and 4); although other entities can demonstrate either of these markers, when found together they confirm the diagnosis of MCC. Our patient also demonstrated CD56 positivity and a weakly positive reaction to synaptophysin (Figure 4). Cytokeratin 7 and CD45 results were negative, which also confirmed the diagnosis of MCC (Figure 5).

Staging by computed tomography scan of the neck, chest, and upper abdomen ruled out systemic spread. Because of the patient's advanced age, frail health status, and his adamant opposition, chemotherapy was deferred. Instead, he was referred to radiation oncology for a course of regional electron beam therapy. It was believed that radiation therapy might adequately control his disease and would not present the morbidity risks involved with chemotherapy and/or a more aggressive wide excision.9 Six MeV radiation was used to deliver a 60-Gy surface dose to the ear area and 50 Gy to deep upper cervical nodes, facial nodes, and adjacent skin to the level of the larynx. The patient tolerated the 5 weeks of radiation treatment well, with mild skin erythema to the region. The patient was followed closely; at a routine follow-up in February 2003, examination revealed a new 1-cm, right-sided preauricular pearly nodule. The patient revealed that the lesion had been present for 10 days. The new lesion appeared to be outside the previously treated radiation field. Excision was done using Mohs micrographic surgery, and the pathology results revealed clusters of undifferentiated neoplastic cells, some of which appeared to be within the lymphatics. This outcome, along with the immunohistochemistry results, confirmed that the lesion was the same histologic type as the primary lesion. Shortly thereafter, the patient developed 2 new lesions on the right temple (0.8- and 1.3-cm irregular subcutaneous nodules). Pathology of these nodules also was consistent with MCC, with lymphatic and vascular involvement and positive margins of the resected area. The new lesions were then treated with a second course of electron beam therapy with a generous field that included some overlap with the previously irradiated area. Chemotherapy was again discussed with the patient, who strongly declined this option despite disease progression. His age and ability to tolerate the chemotherapeutic side effects involved were considerations in the patient's decision. In October 2003, a second course of 6 MeV radiation to the right temple and anterior right cheek over 25 treatment sessions was completed. Despite the widened field of radiation, several new nodules developed during its course. These involved the superior aspect of the right ear, right nasolabial fold, upper left temple, left preauricular regions, and posterior neck. In November 2003, a magnetic resonance image of the spine demonstrated systemic spread with bone metastasis involving the C2 and C3 vertebral bodies. A third round of radiation, now considered palliative, was directed to the cervical spine. With the patient finally concurring, a mild chemotherapeutic regimen of pamidronate and capecitabine also was planned. These treatments were discontinued after 2 courses because of failure to thrive. Bone metastases and cutaneous involvement continued to progress. Despite the unfavorable prognosis, the patient requested further treatment, and a single regimen of oral etoposide was chosen.

Comment

Treatment of a primary lesion without evidence of spread, or stage I disease, has historically been wide excision; however, acceptable margins have been debated, ranging from 1 to 3 cm. The addition of postsurgical irradiation of 50 to 60 Gy to the area of the lesion and all draining lymph node basins has been found to decrease local recurrence but has not been found to have a major impact on survival rates, given the frequency of distant metastasis in MCC.10 Mortier et al9 recently reported similar outcomes with radiation therapy alone and with wide excision followed by radiation for inoperable stage I disease. Prophylactic radiation (40–60 Gy) to the draining lymph node basin also has been proposed for stage I, though it has not been thoroughly investigated. Mohs micrographic surgery may have a significant impact on the primary treatment of MCC. Local recurrence rates with Mohs micrographic surgery are lower than with wide excision because thorough histologic evaluation of margins is best.11,12 Radiation at the primary site is indicated when clear margins cannot be achieved.12 In the case of successful excision by Mohs micrographic surgery, adjuvant radiation therapy has not been shown to lower the rates of recurrence. However, irradiation of the lesion, including the draining lymph node basin, may improve regional control and increase the disease-free interval.9 MCC spreads to regional lymph nodes within 2 years in 70% of cases.13 When lymph nodes are affected, 5-year survival is approximately 50%. Historically, regional lymphadenectomy was used in those patients with confirmed or suspected lymph node spread. Due to the morbidity risks of this procedure, this technique has fallen out of favor.14 A newer alternative is sentinel lymph node biopsy. The usefulness of this modality for the overall impact on survival is debated.6 Given the morphologic and immunohistologic similarities to small cell carcinoma, MCC also is similarly chemosensitive. Although there is no doubt about the efficacy of adjuvant chemotherapy in vitro, its benefit in preventing recurrence is debated. It is most widely accepted as a last-line effort in stage II disease to prevent progression to distant metastasis, and in stage III disease as a palliative effort.15 In the limited studies of chemotherapy for cases of MCC, the response rate to first-line therapy approached only 65%. Dose-response figures have not been established.11 In the investigation into the use of chemotherapy as a first-line therapy, chemotherapy regimens employed in small cell lung carcinoma (cyclophosamide, doxorubicin, vincristine, or etoposide-cisplatin) may provide a useful guide. Although combinations such as cisplatin-doxorubicin are acceptable in patients younger than 65 years, elderly patients are often poor candidates given their comorbidities. Some monotherapy regimens, such as oral etoposide, have been successful.10 Risks, including neutropenia and peripheral neuropathy, are magnified by the pharmacodynamic changes in absorption and metabolism that occur with age. Human growth factors such as granulocyte colony-stimulating factor, macrophage-macrophage colony-stimulating factor, and recombinant human erythropoietin have been supplemented in more elderly patients in an attempt to reduce morbidity and increase dose escalations.11 The lack of data on chemotherapy in the elderly population is not unique to MCC; rather, it is a common problem in cancer research. Most cancers occur in patients 65 years and older, yet there is a paucity of data on the effects of chemotherapy because elderly patients are poor candidates for phase 1 and phase 2 trials. Therefore, existing knowledge of the pharmacophysiology of aging must be used to extrapolate the most appropriate dosing and drug combinations. New treatment modalities are being explored. Immunotherapy has shown some results for early stage MCC. Interferon alfa 2b and tumor necrosis factor have shown some promise. The antigens mucin 1 and epithelial cell adhesion molecule are expressed in 85% and 70% of MCC cases, respectively.16 Current research is directed at developing antibodies to these antigens. Somatostatin receptor scintigraphy along with sentinel lymph node biopsy might become another tool with which to detect micrometastasis. Reverse transcription polymerase chain reaction can be used to find markers such as cytokeratin 20 on MCC cells circulating in the peripheral blood pool.17 This would allow identification of patients at high risk for systemic spread and relapse. To date, no treatment has been found to successfully arrest distant metastases.

Conclusion

Given the early dissemination of MCC and the poor prognosis once metastasis has occurred, aggressive treatment for stage I disease must be considered. Radiation therapy may be palliative and may have an increasing role as prophylactic protection in early disease. Chemotherapy has been employed in regional spread of disease (stage II). Will chemotherapy utilized in earlier stages of disease be a possible solution? Could combined chemoimmunotherapy be a useful compliment to the modest success of radiation treatment? These modalities are only as good as their practical use in the typical elderly patient with MCC, and addressing this challenge will be crucial in future research. back to top

Merkel cell carcinoma (MCC) is a rare primary cutaneous neoplasm known for its propensity to develop early regional and distant metastasis. Fewer than 400 cases occur annually in the United States. MCC ranks as the most deadly of cutaneous malignancies, with a fatality rate of approximately 25%. Because of its aggressive nature, MCC is often resistant to surgery, radiation, and chemotherapy regimens. Standardized treatment patterns have not been established, and difficulty arises finding appropriate treatment for the elderly, who comprise the majority of patients with MCC.

Merkel cell carcinoma (MCC) is a neuroendocrine tumor that has been described as a primary neuroendocrine carcinoma of the skin or "cutaneous APUDoma." Alternatively, MCC has been called a primary small cell carcinoma of the skin1 because of its morphologic and behavioral similarities to small cell carcinoma of the lung.

Merkel cells are slowly adapting mechanoreceptors in epidermal nerve endings. Although they are found in ectoderm-derived skin and mucosa, recent evidence places their origin as neural crest.2 Merkel cells contain cytokeratins and neuropeptide-containing eosinophilic granules. These cells combine with nerve terminals to form mechanoreceptors. It remains unclear if MCC originates from the same developmental lineage as Merkel cells. Recent research suggests these tumors originate from epidermal epithelial cells that are not in contact with nerve terminals but that have similar cytoskeletal filaments and a neuroendocrine origin.2 Although the pathogenesis of MCC has not been completely illuminated, it is agreed that UV exposure is an important risk factor. UVB-induced C · T transitions have been found, as well as p53 missense mutations. For this reason, risks include fair skin (as evidenced by the higher incidence in Caucasian populations), advanced age, and previous or concurrent sun-related skin malignancies such as squamous cell carcinoma and basal cell carcinoma.3 MCC also is linked to immunosuppression, with a higher incidence in transplant recipients and patients receiving chemotherapy.4 In addition, there is an increased incidence in patients with psoriasis who were treated with psoralen-UVA. Reports link MCC to a history of prolonged arsenic exposure,1 as well as to congenital dysplasia syndrome and chronic lymphocytic leukemia.5 MCC most often presents in fair-skinned patients 65 years and older as a solitary firm nodule on the head or neck. Its gross appearance is often nonspecific, being misdiagnosed as basal cell carcinoma or metastasis of a small cell carcinoma elsewhere.2 Even when diagnosed at its earliest stage, MCC has a 2-year fatality rate of 10%. Its 5-year survival rate is 50% to 68%. Regional metastasis occurs in 50% to 60% of patients. When metastasis does occur, regional lymph nodes are involved 65% of the time,6 with the majority (70%) occurring within 2 years of diagnosis. Nearly 40% will develop distant metastasis.7 Metastases most commonly involve the skin, lymph nodes, liver, lung, and bone.1 A primary lesion larger than 2 cm denotes a poor prognosis. There have been rare reports of spontaneous regression. 

Histopathology Microscopically, MCC can be difficult to identify. The epidermis may show bowenoid or squamous cell carcinoma-like changes, but they are not characteristic. Under low power microscopy, small round blue cells are evident in the dermis; the cells appear uniform and are often arranged to form either sheets or clusters that create a trabecular appearance or that of a group of grapes. On high power, the cells will appear to be pale and empty. Numerous mitoses can be identified, and evidence of metastasis can be found in the lymphatic or blood vessels. Neurosecretory granules that range from 80 to 120 nm and look like small blue dots5 are membrane bound in the paranuclear regions. Because traditional hematoxylin-eosin (H&E) staining demonstrates morphologic features of both epithelial and neuroendocrine tumors, H&E results cannot distinguish MCC from other small round blue cell tumors such as melanoma, lymphoma, neuroblastoma, and metastatic small cell lung carcinoma.7 Cytokeratin staining and immunohistologic markers are required to make the definitive diagnosis; cytokeratin 20, chromogranin A, and synaptophysin are among those used. Other markers include neuron-specific enolase and, most recently, CD56, a marker for neural cell adhesion molecule.8 

Case Report

In August 2002, an 86-year-old white man presented for evaluation of an 8-mm friable pink nodule on the right ear of uncertain duration (Figure 1). No cervical or peripheral adenopathy was appreciated. The man had an extensive history of prior basal cell carcinoma and squamous cell carcinoma on sun-exposed areas, having undergone excisions and Mohs micrographic surgery for many of these lesions.

An excisional biopsy was performed, and the pathology results revealed aggregates of neoplastic cells with indistinct nucleoli with granular nucleoplasms and scant cytoplasms separated by fibrous septa or trabeculae (Figure 2). Also, numerous mitotic figures and areas of focal necrosis were present. In our patient, cytokeratin 20 and chromogranin A results were strongly positive (Figures 3 and 4); although other entities can demonstrate either of these markers, when found together they confirm the diagnosis of MCC. Our patient also demonstrated CD56 positivity and a weakly positive reaction to synaptophysin (Figure 4). Cytokeratin 7 and CD45 results were negative, which also confirmed the diagnosis of MCC (Figure 5).

Staging by computed tomography scan of the neck, chest, and upper abdomen ruled out systemic spread. Because of the patient's advanced age, frail health status, and his adamant opposition, chemotherapy was deferred. Instead, he was referred to radiation oncology for a course of regional electron beam therapy. It was believed that radiation therapy might adequately control his disease and would not present the morbidity risks involved with chemotherapy and/or a more aggressive wide excision.9 Six MeV radiation was used to deliver a 60-Gy surface dose to the ear area and 50 Gy to deep upper cervical nodes, facial nodes, and adjacent skin to the level of the larynx. The patient tolerated the 5 weeks of radiation treatment well, with mild skin erythema to the region. The patient was followed closely; at a routine follow-up in February 2003, examination revealed a new 1-cm, right-sided preauricular pearly nodule. The patient revealed that the lesion had been present for 10 days. The new lesion appeared to be outside the previously treated radiation field. Excision was done using Mohs micrographic surgery, and the pathology results revealed clusters of undifferentiated neoplastic cells, some of which appeared to be within the lymphatics. This outcome, along with the immunohistochemistry results, confirmed that the lesion was the same histologic type as the primary lesion. Shortly thereafter, the patient developed 2 new lesions on the right temple (0.8- and 1.3-cm irregular subcutaneous nodules). Pathology of these nodules also was consistent with MCC, with lymphatic and vascular involvement and positive margins of the resected area. The new lesions were then treated with a second course of electron beam therapy with a generous field that included some overlap with the previously irradiated area. Chemotherapy was again discussed with the patient, who strongly declined this option despite disease progression. His age and ability to tolerate the chemotherapeutic side effects involved were considerations in the patient's decision. In October 2003, a second course of 6 MeV radiation to the right temple and anterior right cheek over 25 treatment sessions was completed. Despite the widened field of radiation, several new nodules developed during its course. These involved the superior aspect of the right ear, right nasolabial fold, upper left temple, left preauricular regions, and posterior neck. In November 2003, a magnetic resonance image of the spine demonstrated systemic spread with bone metastasis involving the C2 and C3 vertebral bodies. A third round of radiation, now considered palliative, was directed to the cervical spine. With the patient finally concurring, a mild chemotherapeutic regimen of pamidronate and capecitabine also was planned. These treatments were discontinued after 2 courses because of failure to thrive. Bone metastases and cutaneous involvement continued to progress. Despite the unfavorable prognosis, the patient requested further treatment, and a single regimen of oral etoposide was chosen.

Comment

Treatment of a primary lesion without evidence of spread, or stage I disease, has historically been wide excision; however, acceptable margins have been debated, ranging from 1 to 3 cm. The addition of postsurgical irradiation of 50 to 60 Gy to the area of the lesion and all draining lymph node basins has been found to decrease local recurrence but has not been found to have a major impact on survival rates, given the frequency of distant metastasis in MCC.10 Mortier et al9 recently reported similar outcomes with radiation therapy alone and with wide excision followed by radiation for inoperable stage I disease. Prophylactic radiation (40–60 Gy) to the draining lymph node basin also has been proposed for stage I, though it has not been thoroughly investigated. Mohs micrographic surgery may have a significant impact on the primary treatment of MCC. Local recurrence rates with Mohs micrographic surgery are lower than with wide excision because thorough histologic evaluation of margins is best.11,12 Radiation at the primary site is indicated when clear margins cannot be achieved.12 In the case of successful excision by Mohs micrographic surgery, adjuvant radiation therapy has not been shown to lower the rates of recurrence. However, irradiation of the lesion, including the draining lymph node basin, may improve regional control and increase the disease-free interval.9 MCC spreads to regional lymph nodes within 2 years in 70% of cases.13 When lymph nodes are affected, 5-year survival is approximately 50%. Historically, regional lymphadenectomy was used in those patients with confirmed or suspected lymph node spread. Due to the morbidity risks of this procedure, this technique has fallen out of favor.14 A newer alternative is sentinel lymph node biopsy. The usefulness of this modality for the overall impact on survival is debated.6 Given the morphologic and immunohistologic similarities to small cell carcinoma, MCC also is similarly chemosensitive. Although there is no doubt about the efficacy of adjuvant chemotherapy in vitro, its benefit in preventing recurrence is debated. It is most widely accepted as a last-line effort in stage II disease to prevent progression to distant metastasis, and in stage III disease as a palliative effort.15 In the limited studies of chemotherapy for cases of MCC, the response rate to first-line therapy approached only 65%. Dose-response figures have not been established.11 In the investigation into the use of chemotherapy as a first-line therapy, chemotherapy regimens employed in small cell lung carcinoma (cyclophosamide, doxorubicin, vincristine, or etoposide-cisplatin) may provide a useful guide. Although combinations such as cisplatin-doxorubicin are acceptable in patients younger than 65 years, elderly patients are often poor candidates given their comorbidities. Some monotherapy regimens, such as oral etoposide, have been successful.10 Risks, including neutropenia and peripheral neuropathy, are magnified by the pharmacodynamic changes in absorption and metabolism that occur with age. Human growth factors such as granulocyte colony-stimulating factor, macrophage-macrophage colony-stimulating factor, and recombinant human erythropoietin have been supplemented in more elderly patients in an attempt to reduce morbidity and increase dose escalations.11 The lack of data on chemotherapy in the elderly population is not unique to MCC; rather, it is a common problem in cancer research. Most cancers occur in patients 65 years and older, yet there is a paucity of data on the effects of chemotherapy because elderly patients are poor candidates for phase 1 and phase 2 trials. Therefore, existing knowledge of the pharmacophysiology of aging must be used to extrapolate the most appropriate dosing and drug combinations. New treatment modalities are being explored. Immunotherapy has shown some results for early stage MCC. Interferon alfa 2b and tumor necrosis factor have shown some promise. The antigens mucin 1 and epithelial cell adhesion molecule are expressed in 85% and 70% of MCC cases, respectively.16 Current research is directed at developing antibodies to these antigens. Somatostatin receptor scintigraphy along with sentinel lymph node biopsy might become another tool with which to detect micrometastasis. Reverse transcription polymerase chain reaction can be used to find markers such as cytokeratin 20 on MCC cells circulating in the peripheral blood pool.17 This would allow identification of patients at high risk for systemic spread and relapse. To date, no treatment has been found to successfully arrest distant metastases.

Conclusion

Given the early dissemination of MCC and the poor prognosis once metastasis has occurred, aggressive treatment for stage I disease must be considered. Radiation therapy may be palliative and may have an increasing role as prophylactic protection in early disease. Chemotherapy has been employed in regional spread of disease (stage II). Will chemotherapy utilized in earlier stages of disease be a possible solution? Could combined chemoimmunotherapy be a useful compliment to the modest success of radiation treatment? These modalities are only as good as their practical use in the typical elderly patient with MCC, and addressing this challenge will be crucial in future research. back to top

Dermatofibrosarcoma protuberans (DFSP) is an uncommon cutaneous tumor of intermediate malignancy that is known to be locally aggressive.1 It is thought to be of fibrohistiocytic origin and accounts for 1% of all soft tissue malignancies.2 DFSP occurs in men and women with equal incidence, mostly on the trunk and less commonly on the proximal extremities, with a higher incidence in Caucasians. Most patients present between the second and fifth decades, though the disease can be noted in any age group and any anatomic location.3

Four clinical variants of early DFSP are thought to exist: confluent nodular lesions forming a sclerotic plaque, keloidlike sclerotic plaque, tumor, and atrophic plaque.4,5 The usual clinical appearance of DFSP at an early stage is as a slow-growing, asymptomatic plaque or nodule. The tumor's gross pathology is of a gray-white mass involving the dermis and subcutis; histologically, it is a poorly circumscribed infiltrative spindle cell tumor. The spindle cells, which are CD34+, are arranged in a storiform pattern described as a dense, poorly circumscribed, monomorphic cell proliferation arranged in fascicles that often reach and infiltrate the hypodermis.6,7 The 3 recognized histologic variants of DFSP are fibrosarcomatous, plaquelike, and myxoid forms.8 The infiltrating pattern accounts for the tumor's common recurrence after excision and the need for wide excision or Mohs micrographic surgery for curative removal.2,3,9-11 One recent review of atrophic DFSP implicated chromosomal translocations or the formation of supernumerary ring chromosomes in the pathogenesis of DFSP.12 These chromosomal events result in the fusion of the collagen type 1α1 gene with the platelet-derived growth factor-β chain gene. How this mutation could contribute to the atrophic phenotype is unknown.12 This review documents only 25 cases of atrophic DFSP in the literature. We present a case involving a woman who had an atrophic DFSP treated successfully with Mohs micrographic surgery and review 35 cases in the literature regarding this rare presentation of DFSP. 

Case Report

A 41-year-old white woman presented with a 12-year history of a well-demarcated, scalloped, markedly depressed, reddish brown, slightly firm, 4x5-cm plaque on the right chest (Figure 1). On initial evaluation, the patient denied prior trauma to the area or any past manipulation of the lesion. The patient's preoperative clinical differential diagnosis included atrophoderma of Pasini and Pierini, anetoderma, morphea, and lipoatrophy.

A punch biopsy of the lesion was performed. Results revealed a spindle cell neoplasm that was thought to be a dermatofibroma. The entire lesion was subsequently excised. Histopathology results of the excision specimen demonstrated atrophy of the dermis and a permeative spindle cell neoplasm with scattered multinucleated giant cells involving the dermis and underlying soft tissue with a few areas of a storiform growth pattern (Figure 2). The lesion also was diffusely immunoreactive for CD34 and extended to the margins of the specimen. A diagnosis of DFSP was made, and the patient was treated with Mohs micrographic surgery. Three stages of surgery were performed, and the final defect was 7.0x8.5 cm. The patient elected to allow the wound to heal by secondary intention. There was no evidence of recurrence 12 months after the procedure.

Comment

The atrophic presentation of DFSP is the rarest variant of this infrequent neoplasm. Although this subject was recently reviewed, there are several other important issues in the literature that need to be clarified regarding this unusual phenotype.12 For a lesion to be classified as atrophic, there should be both clinical and histologic evidence of atrophy. When the epidermis is atrophic, the result is shiny smooth skin clinically and flattening of the rete ridges histopathologically. Conversely, when the dermis or subcutaneous tissue is atrophic, the result is a loss in skin thickness and a corresponding loss of collagen bundles or subcutaneous fat histopathologically.13

Epidermal atrophy is commonly noted histologically in DFSP cases that present in the usual fashion.14,15 Only rarely has DFSP presented as a clinically depressed lesion.16-20 Even more rare is a documentation of dermal atrophy.12,21 We report a case of DFSP in which the initial lesion was an atrophic depression of the skin lacking nodularity and histologically demonstrating significant dermal atrophy.

A number of cases have been reported describing atrophic presentations of DFSP (Table 1).4,5,8,12,16-26 However, as Davis and Sanchez8 noted, rarely does a so-called atrophic DFSP present as a visible depression in the skin.16-21 Clearly, there is some discrepancy in the literature as to the nature of atrophy in relation to the clinical presentation of DFSP. Some authors have even speculated that the atrophic variant of DFSP is nothing more than an early presentation of the more usual DFSP prior to the formation of nodules.4 However, the fact that our patient had her lesion for 12 years prior to treatment without the formation of a nodular component indicates that the atrophic variant of DFSP is a real entity.

Table 2 demonstrates the sex and anatomic location of the patients in the 35 reported cases of DFSP described as atrophic or morpheaform, including the present case. The majority (20/35) of cases have been in female patients, and the most common location in both sexes has been the trunk (24/35). The next most common location was the lower extremity (7/35).

Table 3 documents the age and anatomic location of the 9 cases clinically described as resembling lipoatrophy, atrophoderma or anetoderma, or that were significantly clinically depressed based on clinical photographs, ie, the cases most similar to the one we now present.4,16,19-21,25 Three of the 9 cases were on the trunks of females aged 16 to 41 years. Interestingly, 4 of the remaining 6 cases were on the lower extremities of children aged 18 months to 16 years.

A number of conclusions can be drawn from this data. First, atrophic variants of DFSP tend to occur most often on the trunk, as do the usual variants of DFSP. However, the atrophic variants tend to occur more often in females as opposed to the standard presentation of DFSP, which occurs with equal frequency in males and females. In addition, a distinction exists in the presentation of atrophic lesions, which can have either a morpheaform or a more clinically depressed appearance, mimicking such disorders as anetoderma, atrophoderma, or lipoatrophy. We report such a case mimicking atrophoderma, and we contend that this is the rarest presentation of atrophic DFSP.

One final entity in the differential diagnosis of a depressed plaque on the trunk would be an atrophic dermatofibroma. The dermatofibroma, a well-known and benign cousin of DFSP, is often noted to have some dermal atrophy grossly with lateral pressure, described as a dimple sign.27 As Requena and Reichel28 pointed out, even when there is a central depression over a dermatofibroma without lateral pressure, no true loss of the dermis is seen histopathologically. As such, this central depression doesn't represent true dermal atrophy.28 However, the dermatofibroma also can present as a depressed lesion demonstrating thinning of the dermis histologically, and this variety of dermatofibroma has been described as atrophic.28-31 Although a recently published article recommended considering a diagnosis of atrophic dermatofibroma in the case of "atrophic, depressed lesions on the upper body of middle-aged women,"31 we would maintain that atrophic DFSP also should be considered in the differential diagnosis.

One possibility to clarify the imprecision in the literature in relation to the clinical presentation of DFSP would be to eliminate protuberans from the name, thereby recognizing that some lesions that are histologically proven to be DFSP can present without nodularity and with epidermal or dermal atrophy. This change in the nomenclature was first proposed by Lambert et al23 and was reiterated by Page and Assaad.16 Perhaps a greater awareness that DFSP can present as atrophic lesions without nodules could lead to earlier diagnosis and decreased morbidity with smaller curative surgeries when the lesions are recognized at an earlier stage. The atrophic variant of DFSP does not carry a different prognosis compared with the traditional variant; Mohs micrographic surgery is still the treatment of choice, providing a low rate of recurrence. Atrophic DFSP should be kept in the differential diagnosis for atrophic, depressed lesions, particularly those seen on the trunks of women or on the lower extremities of children. 

Dermatofibrosarcoma protuberans (DFSP) is an uncommon cutaneous tumor of intermediate malignancy that is known to be locally aggressive.1 It is thought to be of fibrohistiocytic origin and accounts for 1% of all soft tissue malignancies.2 DFSP occurs in men and women with equal incidence, mostly on the trunk and less commonly on the proximal extremities, with a higher incidence in Caucasians. Most patients present between the second and fifth decades, though the disease can be noted in any age group and any anatomic location.3

Four clinical variants of early DFSP are thought to exist: confluent nodular lesions forming a sclerotic plaque, keloidlike sclerotic plaque, tumor, and atrophic plaque.4,5 The usual clinical appearance of DFSP at an early stage is as a slow-growing, asymptomatic plaque or nodule. The tumor's gross pathology is of a gray-white mass involving the dermis and subcutis; histologically, it is a poorly circumscribed infiltrative spindle cell tumor. The spindle cells, which are CD34+, are arranged in a storiform pattern described as a dense, poorly circumscribed, monomorphic cell proliferation arranged in fascicles that often reach and infiltrate the hypodermis.6,7 The 3 recognized histologic variants of DFSP are fibrosarcomatous, plaquelike, and myxoid forms.8 The infiltrating pattern accounts for the tumor's common recurrence after excision and the need for wide excision or Mohs micrographic surgery for curative removal.2,3,9-11 One recent review of atrophic DFSP implicated chromosomal translocations or the formation of supernumerary ring chromosomes in the pathogenesis of DFSP.12 These chromosomal events result in the fusion of the collagen type 1α1 gene with the platelet-derived growth factor-β chain gene. How this mutation could contribute to the atrophic phenotype is unknown.12 This review documents only 25 cases of atrophic DFSP in the literature. We present a case involving a woman who had an atrophic DFSP treated successfully with Mohs micrographic surgery and review 35 cases in the literature regarding this rare presentation of DFSP. 

Case Report

A 41-year-old white woman presented with a 12-year history of a well-demarcated, scalloped, markedly depressed, reddish brown, slightly firm, 4x5-cm plaque on the right chest (Figure 1). On initial evaluation, the patient denied prior trauma to the area or any past manipulation of the lesion. The patient's preoperative clinical differential diagnosis included atrophoderma of Pasini and Pierini, anetoderma, morphea, and lipoatrophy.

A punch biopsy of the lesion was performed. Results revealed a spindle cell neoplasm that was thought to be a dermatofibroma. The entire lesion was subsequently excised. Histopathology results of the excision specimen demonstrated atrophy of the dermis and a permeative spindle cell neoplasm with scattered multinucleated giant cells involving the dermis and underlying soft tissue with a few areas of a storiform growth pattern (Figure 2). The lesion also was diffusely immunoreactive for CD34 and extended to the margins of the specimen. A diagnosis of DFSP was made, and the patient was treated with Mohs micrographic surgery. Three stages of surgery were performed, and the final defect was 7.0x8.5 cm. The patient elected to allow the wound to heal by secondary intention. There was no evidence of recurrence 12 months after the procedure.

Comment

The atrophic presentation of DFSP is the rarest variant of this infrequent neoplasm. Although this subject was recently reviewed, there are several other important issues in the literature that need to be clarified regarding this unusual phenotype.12 For a lesion to be classified as atrophic, there should be both clinical and histologic evidence of atrophy. When the epidermis is atrophic, the result is shiny smooth skin clinically and flattening of the rete ridges histopathologically. Conversely, when the dermis or subcutaneous tissue is atrophic, the result is a loss in skin thickness and a corresponding loss of collagen bundles or subcutaneous fat histopathologically.13

Epidermal atrophy is commonly noted histologically in DFSP cases that present in the usual fashion.14,15 Only rarely has DFSP presented as a clinically depressed lesion.16-20 Even more rare is a documentation of dermal atrophy.12,21 We report a case of DFSP in which the initial lesion was an atrophic depression of the skin lacking nodularity and histologically demonstrating significant dermal atrophy.

A number of cases have been reported describing atrophic presentations of DFSP (Table 1).4,5,8,12,16-26 However, as Davis and Sanchez8 noted, rarely does a so-called atrophic DFSP present as a visible depression in the skin.16-21 Clearly, there is some discrepancy in the literature as to the nature of atrophy in relation to the clinical presentation of DFSP. Some authors have even speculated that the atrophic variant of DFSP is nothing more than an early presentation of the more usual DFSP prior to the formation of nodules.4 However, the fact that our patient had her lesion for 12 years prior to treatment without the formation of a nodular component indicates that the atrophic variant of DFSP is a real entity.

Table 2 demonstrates the sex and anatomic location of the patients in the 35 reported cases of DFSP described as atrophic or morpheaform, including the present case. The majority (20/35) of cases have been in female patients, and the most common location in both sexes has been the trunk (24/35). The next most common location was the lower extremity (7/35).

Table 3 documents the age and anatomic location of the 9 cases clinically described as resembling lipoatrophy, atrophoderma or anetoderma, or that were significantly clinically depressed based on clinical photographs, ie, the cases most similar to the one we now present.4,16,19-21,25 Three of the 9 cases were on the trunks of females aged 16 to 41 years. Interestingly, 4 of the remaining 6 cases were on the lower extremities of children aged 18 months to 16 years.

A number of conclusions can be drawn from this data. First, atrophic variants of DFSP tend to occur most often on the trunk, as do the usual variants of DFSP. However, the atrophic variants tend to occur more often in females as opposed to the standard presentation of DFSP, which occurs with equal frequency in males and females. In addition, a distinction exists in the presentation of atrophic lesions, which can have either a morpheaform or a more clinically depressed appearance, mimicking such disorders as anetoderma, atrophoderma, or lipoatrophy. We report such a case mimicking atrophoderma, and we contend that this is the rarest presentation of atrophic DFSP.

One final entity in the differential diagnosis of a depressed plaque on the trunk would be an atrophic dermatofibroma. The dermatofibroma, a well-known and benign cousin of DFSP, is often noted to have some dermal atrophy grossly with lateral pressure, described as a dimple sign.27 As Requena and Reichel28 pointed out, even when there is a central depression over a dermatofibroma without lateral pressure, no true loss of the dermis is seen histopathologically. As such, this central depression doesn't represent true dermal atrophy.28 However, the dermatofibroma also can present as a depressed lesion demonstrating thinning of the dermis histologically, and this variety of dermatofibroma has been described as atrophic.28-31 Although a recently published article recommended considering a diagnosis of atrophic dermatofibroma in the case of "atrophic, depressed lesions on the upper body of middle-aged women,"31 we would maintain that atrophic DFSP also should be considered in the differential diagnosis.

One possibility to clarify the imprecision in the literature in relation to the clinical presentation of DFSP would be to eliminate protuberans from the name, thereby recognizing that some lesions that are histologically proven to be DFSP can present without nodularity and with epidermal or dermal atrophy. This change in the nomenclature was first proposed by Lambert et al23 and was reiterated by Page and Assaad.16 Perhaps a greater awareness that DFSP can present as atrophic lesions without nodules could lead to earlier diagnosis and decreased morbidity with smaller curative surgeries when the lesions are recognized at an earlier stage. The atrophic variant of DFSP does not carry a different prognosis compared with the traditional variant; Mohs micrographic surgery is still the treatment of choice, providing a low rate of recurrence. Atrophic DFSP should be kept in the differential diagnosis for atrophic, depressed lesions, particularly those seen on the trunks of women or on the lower extremities of children. 

Dermatofibrosarcoma protuberans (DFSP) is an uncommon cutaneous tumor of intermediate malignancy that is known to be locally aggressive.1 It is thought to be of fibrohistiocytic origin and accounts for 1% of all soft tissue malignancies.2 DFSP occurs in men and women with equal incidence, mostly on the trunk and less commonly on the proximal extremities, with a higher incidence in Caucasians. Most patients present between the second and fifth decades, though the disease can be noted in any age group and any anatomic location.3

Four clinical variants of early DFSP are thought to exist: confluent nodular lesions forming a sclerotic plaque, keloidlike sclerotic plaque, tumor, and atrophic plaque.4,5 The usual clinical appearance of DFSP at an early stage is as a slow-growing, asymptomatic plaque or nodule. The tumor's gross pathology is of a gray-white mass involving the dermis and subcutis; histologically, it is a poorly circumscribed infiltrative spindle cell tumor. The spindle cells, which are CD34+, are arranged in a storiform pattern described as a dense, poorly circumscribed, monomorphic cell proliferation arranged in fascicles that often reach and infiltrate the hypodermis.6,7 The 3 recognized histologic variants of DFSP are fibrosarcomatous, plaquelike, and myxoid forms.8 The infiltrating pattern accounts for the tumor's common recurrence after excision and the need for wide excision or Mohs micrographic surgery for curative removal.2,3,9-11 One recent review of atrophic DFSP implicated chromosomal translocations or the formation of supernumerary ring chromosomes in the pathogenesis of DFSP.12 These chromosomal events result in the fusion of the collagen type 1α1 gene with the platelet-derived growth factor-β chain gene. How this mutation could contribute to the atrophic phenotype is unknown.12 This review documents only 25 cases of atrophic DFSP in the literature. We present a case involving a woman who had an atrophic DFSP treated successfully with Mohs micrographic surgery and review 35 cases in the literature regarding this rare presentation of DFSP. 

Case Report

A 41-year-old white woman presented with a 12-year history of a well-demarcated, scalloped, markedly depressed, reddish brown, slightly firm, 4x5-cm plaque on the right chest (Figure 1). On initial evaluation, the patient denied prior trauma to the area or any past manipulation of the lesion. The patient's preoperative clinical differential diagnosis included atrophoderma of Pasini and Pierini, anetoderma, morphea, and lipoatrophy.

A punch biopsy of the lesion was performed. Results revealed a spindle cell neoplasm that was thought to be a dermatofibroma. The entire lesion was subsequently excised. Histopathology results of the excision specimen demonstrated atrophy of the dermis and a permeative spindle cell neoplasm with scattered multinucleated giant cells involving the dermis and underlying soft tissue with a few areas of a storiform growth pattern (Figure 2). The lesion also was diffusely immunoreactive for CD34 and extended to the margins of the specimen. A diagnosis of DFSP was made, and the patient was treated with Mohs micrographic surgery. Three stages of surgery were performed, and the final defect was 7.0x8.5 cm. The patient elected to allow the wound to heal by secondary intention. There was no evidence of recurrence 12 months after the procedure.

Comment

The atrophic presentation of DFSP is the rarest variant of this infrequent neoplasm. Although this subject was recently reviewed, there are several other important issues in the literature that need to be clarified regarding this unusual phenotype.12 For a lesion to be classified as atrophic, there should be both clinical and histologic evidence of atrophy. When the epidermis is atrophic, the result is shiny smooth skin clinically and flattening of the rete ridges histopathologically. Conversely, when the dermis or subcutaneous tissue is atrophic, the result is a loss in skin thickness and a corresponding loss of collagen bundles or subcutaneous fat histopathologically.13

Epidermal atrophy is commonly noted histologically in DFSP cases that present in the usual fashion.14,15 Only rarely has DFSP presented as a clinically depressed lesion.16-20 Even more rare is a documentation of dermal atrophy.12,21 We report a case of DFSP in which the initial lesion was an atrophic depression of the skin lacking nodularity and histologically demonstrating significant dermal atrophy.

A number of cases have been reported describing atrophic presentations of DFSP (Table 1).4,5,8,12,16-26 However, as Davis and Sanchez8 noted, rarely does a so-called atrophic DFSP present as a visible depression in the skin.16-21 Clearly, there is some discrepancy in the literature as to the nature of atrophy in relation to the clinical presentation of DFSP. Some authors have even speculated that the atrophic variant of DFSP is nothing more than an early presentation of the more usual DFSP prior to the formation of nodules.4 However, the fact that our patient had her lesion for 12 years prior to treatment without the formation of a nodular component indicates that the atrophic variant of DFSP is a real entity.

Table 2 demonstrates the sex and anatomic location of the patients in the 35 reported cases of DFSP described as atrophic or morpheaform, including the present case. The majority (20/35) of cases have been in female patients, and the most common location in both sexes has been the trunk (24/35). The next most common location was the lower extremity (7/35).

Table 3 documents the age and anatomic location of the 9 cases clinically described as resembling lipoatrophy, atrophoderma or anetoderma, or that were significantly clinically depressed based on clinical photographs, ie, the cases most similar to the one we now present.4,16,19-21,25 Three of the 9 cases were on the trunks of females aged 16 to 41 years. Interestingly, 4 of the remaining 6 cases were on the lower extremities of children aged 18 months to 16 years.

A number of conclusions can be drawn from this data. First, atrophic variants of DFSP tend to occur most often on the trunk, as do the usual variants of DFSP. However, the atrophic variants tend to occur more often in females as opposed to the standard presentation of DFSP, which occurs with equal frequency in males and females. In addition, a distinction exists in the presentation of atrophic lesions, which can have either a morpheaform or a more clinically depressed appearance, mimicking such disorders as anetoderma, atrophoderma, or lipoatrophy. We report such a case mimicking atrophoderma, and we contend that this is the rarest presentation of atrophic DFSP.

One final entity in the differential diagnosis of a depressed plaque on the trunk would be an atrophic dermatofibroma. The dermatofibroma, a well-known and benign cousin of DFSP, is often noted to have some dermal atrophy grossly with lateral pressure, described as a dimple sign.27 As Requena and Reichel28 pointed out, even when there is a central depression over a dermatofibroma without lateral pressure, no true loss of the dermis is seen histopathologically. As such, this central depression doesn't represent true dermal atrophy.28 However, the dermatofibroma also can present as a depressed lesion demonstrating thinning of the dermis histologically, and this variety of dermatofibroma has been described as atrophic.28-31 Although a recently published article recommended considering a diagnosis of atrophic dermatofibroma in the case of "atrophic, depressed lesions on the upper body of middle-aged women,"31 we would maintain that atrophic DFSP also should be considered in the differential diagnosis.

One possibility to clarify the imprecision in the literature in relation to the clinical presentation of DFSP would be to eliminate protuberans from the name, thereby recognizing that some lesions that are histologically proven to be DFSP can present without nodularity and with epidermal or dermal atrophy. This change in the nomenclature was first proposed by Lambert et al23 and was reiterated by Page and Assaad.16 Perhaps a greater awareness that DFSP can present as atrophic lesions without nodules could lead to earlier diagnosis and decreased morbidity with smaller curative surgeries when the lesions are recognized at an earlier stage. The atrophic variant of DFSP does not carry a different prognosis compared with the traditional variant; Mohs micrographic surgery is still the treatment of choice, providing a low rate of recurrence. Atrophic DFSP should be kept in the differential diagnosis for atrophic, depressed lesions, particularly those seen on the trunks of women or on the lower extremities of children. 

A keratoacanthoma centrifugum marginatum (KACM) may pose a diagnostic and therapeutic challenge. Clinically and histologically, it may resemble mycobacterial or deep fungal infection or halogenoderma. Therapy can be challenging because the lesion can expand to a great size. We report on a patient with multiple lesions of KACM. The diagnostic difficulty and the therapeutic failure of imiquimod, intralesional methotrexate (MTX), and isotretinoin, as well as the therapeutic success of 5-fluorouracil (5-FU) cream, are discussed.

Although Belisario first referred to the large annular keratoacanthoma (KA) as keratoacanthoma centrifugum marginatum (KACM) in 1965, a variety of names have been applied to this entity, including squamous cell pseudoepithelioma, aggregated KA, coral-reef KA, nodulo-vegetating KA, KA centrifugum, and multinodular KA.1,2 KACM is characterized by central regression with concomitant growth and expansion of the periphery but no tendencies toward complete regression in contrast to other types of KAs. A proper diagnosis can be challenging because clinically and histologically the lesions may resemble halogenoderma or infections such as verrucous tuberculosis or deep fungal infection. Therapy can be challenging because the lesions can reach a great size. The present case illustrates this diagnostic and therapeutic conundrum in a patient with multiple KACM. 

Case Report

A 78-year-old man being treated for more than 9 years for multiple KAs on his upper and lower extremities presented with an annular plaque with an elevated crusted keratotic border on the right ankle. Over the course of a year, the plaque enlarged to measure 20 cm (Figure 1). Additional annular and arciform plaques ranging from 13 to 16 cm developed on both legs over this period. The patient's medical history included type 2 diabetes mellitus, peripheral vascular disease, hyperlipidemia, coronary artery disease, and benign prostatic hypertrophy. There was no history of internal malignancy or family history of KAs. Chromoblastomycosis, verrucous tuberculosis, and KACM were considered in the differential diagnosis. No fungi or mycobacteria were isolated in any of the several skin biopsies or cultures performed. There were frequent secondary bacterial infections of the lesions, which were treated with appropriate antibiotics.

A wedge biopsy of the large annular plaque was performed. The area of regression showed fibrosis with an overlying flattened epidermis. The peripheral expanding area showed aggregations of large epithelial cells with abundant pink cytoplasm emanating from the epidermis (Figure 2), while the trailing clearing areas showed fibrosis. Some of the aggregations had jagged outlines that were lined by atypical epithelial cells (Figure 3). Within the aggregations, there were varying degrees of keratinization with presence of parakeratotic cornified cells and neutrophils centrally (Figure 3). Although the histopathologic changes were compatible for KACM, the differential diagnosis included halogenoderma and infectious etiology such as deep fungal or mycobacterial infection. The clinical and histopathologic findings, the lack of halogen exposure, the history of multiple KAs, and the absence of organisms in tissue biopsy and culture results led to the diagnosis of multiple KACM.

Once the frequent secondary bacterial infections were under control, the patient was treated with several therapeutic agents including imiquimod cream, intralesional methotrexate (MTX), and 5-fluorouracil (5-FU) cream. Because the lesions were multiple and large, surgery was not performed. As chemoprophylaxis, isotretinoin was initiated at 40 mg/d and then increased to 60 mg/d after 4 months. The total duration of isotretinoin therapy was 13 months. Along with the usual mucocutaneous side effects, the patient experienced back pain and mild mood alteration after the dose was increased. His complete blood count, liver function tests, and serum triglyceride levels all remained within reference range throughout the duration of therapy.

At the time of initiation of isotretinoin, MTX was injected into 2 different areas of the peripheral border of the largest lesion 3 weeks apart. The doses totaled 68 mg and 60 mg at each site, respectively. In addition, imiquimod under occlusion was applied every night to several of the lesions for the next 7 months. None of the lesions treated with either intralesional MTX or imiquimod resolved. Subsequent to the failure of imiquimod and MTX, 5-FU cream was applied to all of the annular lesions while the patient was still receiving isotretinoin therapy. Clinical response to 5-FU was apparent after 2 months. A complete clinical resolution, however, occurred over a period of 11 months (Figure 4). Isotretinoin was discontinued 5 months prior to the completion of the course of 5-FU cream.

While receiving isotretinoin therapy, the patient developed several more solitary KAs, and the annular lesions enlarged to varying sizes. The solitary KAs were managed either surgically or with liquid nitrogen, depending on the size. The new annular lesions were promptly eradicated with 5-FU cream. 

Comment

Some of the largest lesions of KACM (measuring ≥20 cm) have been reported to occur on the lower extremities.3-6 The lesions enlarged over a period of 10 months to several years with no tendency to regress completely, similar to our patient. All of these reported large lesions of the legs were successfully treated surgically. The diagnostic difficulty was not addressed in these previously reported cases; in our case, however, the initial lack of the characteristic exophytic rolled and shiny peripheral border and the frequent secondary bacterial infections contributed to the difficulty in accurate diagnosis. Initially, an infectious etiology such as chromoblastomycosis and verrucous tuberculosis was suspected. Histopathologically, the distinguishing exoendophytic architecture present at the periphery of KACM was not present; instead, the pathologic changes were confined to the superficial dermis, which consisted of jagged outlined epithelial aggregations that were difficult to distinguish from pseuodoepitheliomatous hyperplasia secondary to deep fungal or mycobacterial infection or halogenoderma. The history, clinicopathologic correlation, and negative culture results eventually led to the diagnosis of KACM.

A variety of treatment modalities have been employed successfully for KAs, including surgical excision, intralesional MTX, intralesional and topical 5-FU, intralesional bleomycin, and isotretinoin.2 Isotretinoin has been advocated as both a prophylactic and therapeutic agent for skin cancers, especially in the setting of multiple lesions.7-9 A relatively high dose (1–3 mg/kg) is required, even for prophylactic outcome. A low dose, in the range of 5 to 10 mg/d, is neither prophylactic nor therapeutic.10,11 The side effects, which include elevated triglyceride levels, mucocutaneous reactions, and hyperostotic axial skeletal changes, limit the use of isotretinoin. The efficacy of retinoids in the prophylaxis and treatment of KA and KACM also has been reported by several authors.12-15 The dosage of isotretinoin ranged from 1 to 3 mg/kg per day with a response observed as early as within one week to several months. In our case, despite adequate duration and relative high doses of isotretinoin, there was no prophylactic or therapeutic effect as evidenced by the patient's continual development of nodular KAs without any of the existing KAs regressing while he was receiving isotretinoin therapy. The patient experienced the usual mucocutaneous side effects. His backache and the changes in his mood were suspected to be the side effects of isotretinoin, as well.

Intralesional MTX for the treatment of KAs has been reported to be effective with a regimen of 1 to 3 injections not exceeding a total dose of 100 mg, resulting in resolution of the KAs in 2 to 4 weeks.16-18 In our patient, although the 2 sites were injected with adequate amounts of MTX, the treatment was unsuccessful. In retrospect, intralesional therapy was unreasonable because of the large amounts of MTX that would have been required. The 2 treated sites accounted for less than 10% of the surface area of the lesions.

The rationale for imiquimod therapy in our patient was 2-fold. First, imiquimod is an immune response modifier emerging as an effective therapy for superficial carcinomas of the skin.19-22 Most therapies available for superficial skin carcinomas also have been applied to KAs. Second, because human papillomavirus has been found to be present in KA, though not consistently,23-26 we were hopeful that imiquimod would have a therapeutic effect for KACM similar to that for condyloma. Despite daily application of the cream for 7 months to some of the lesions, far beyond the 6 to 12 weeks' duration recommended for basal cell carcinomas,19,27 imiquimod had no effect.

Both topical and intralesional 5-FU, a thymine analog, have been reported to be effective therapies for solitary and multiple KAs, though there is no reported case of KACM treated with either topical or intralesional 5-FU. A dramatic resolution has been observed as early as one week after treatment using topical 5-FU, but the usual duration of therapy was 3 to 4 weeks.28-30 In contrast to these reports, encouraging signs of resolution were present in our patient after 2 months of therapy, and complete resolution occurred over a period of many months, not weeks. Despite the apparent efficacy of 5-FU, we cannot exclude the possibility that the regression of the lesions was the natural course of the neoplasm, especially when KAs are known to regress without any therapeutic intervention. The evidence supporting topical 5-FU being efficacious is that there was prompt resolution when the cream was applied to the new lesions.

The nature of KA and KACM, whether or not the neoplasm is a squamous cell carcinoma (SCC), has been controversial. A few authors assert that a KA is an SCC.5,31,32 We consider KA and its variants, including KACM, as one type of SCC encountered in the skin. A few well-documented cases of metastases of KAs to the lymph nodes have been reported.31,33 At the molecular level, KA has been shown to overexpress p53,34 a tumor suppressor gene that has been associated with a variety of malignant neoplasms. In contrast to other types of SCC, a complete regression, believed to be an immune-mediated process by some,35,36 is a unique characteristic of KA. The exact mechanism by which a KA regresses, however, remains largely a mystery. LeBoit37 has hinted that solving this mystery may have far-reaching applications. We agree.

A keratoacanthoma centrifugum marginatum (KACM) may pose a diagnostic and therapeutic challenge. Clinically and histologically, it may resemble mycobacterial or deep fungal infection or halogenoderma. Therapy can be challenging because the lesion can expand to a great size. We report on a patient with multiple lesions of KACM. The diagnostic difficulty and the therapeutic failure of imiquimod, intralesional methotrexate (MTX), and isotretinoin, as well as the therapeutic success of 5-fluorouracil (5-FU) cream, are discussed.

Although Belisario first referred to the large annular keratoacanthoma (KA) as keratoacanthoma centrifugum marginatum (KACM) in 1965, a variety of names have been applied to this entity, including squamous cell pseudoepithelioma, aggregated KA, coral-reef KA, nodulo-vegetating KA, KA centrifugum, and multinodular KA.1,2 KACM is characterized by central regression with concomitant growth and expansion of the periphery but no tendencies toward complete regression in contrast to other types of KAs. A proper diagnosis can be challenging because clinically and histologically the lesions may resemble halogenoderma or infections such as verrucous tuberculosis or deep fungal infection. Therapy can be challenging because the lesions can reach a great size. The present case illustrates this diagnostic and therapeutic conundrum in a patient with multiple KACM. 

Case Report

A 78-year-old man being treated for more than 9 years for multiple KAs on his upper and lower extremities presented with an annular plaque with an elevated crusted keratotic border on the right ankle. Over the course of a year, the plaque enlarged to measure 20 cm (Figure 1). Additional annular and arciform plaques ranging from 13 to 16 cm developed on both legs over this period. The patient's medical history included type 2 diabetes mellitus, peripheral vascular disease, hyperlipidemia, coronary artery disease, and benign prostatic hypertrophy. There was no history of internal malignancy or family history of KAs. Chromoblastomycosis, verrucous tuberculosis, and KACM were considered in the differential diagnosis. No fungi or mycobacteria were isolated in any of the several skin biopsies or cultures performed. There were frequent secondary bacterial infections of the lesions, which were treated with appropriate antibiotics.

A wedge biopsy of the large annular plaque was performed. The area of regression showed fibrosis with an overlying flattened epidermis. The peripheral expanding area showed aggregations of large epithelial cells with abundant pink cytoplasm emanating from the epidermis (Figure 2), while the trailing clearing areas showed fibrosis. Some of the aggregations had jagged outlines that were lined by atypical epithelial cells (Figure 3). Within the aggregations, there were varying degrees of keratinization with presence of parakeratotic cornified cells and neutrophils centrally (Figure 3). Although the histopathologic changes were compatible for KACM, the differential diagnosis included halogenoderma and infectious etiology such as deep fungal or mycobacterial infection. The clinical and histopathologic findings, the lack of halogen exposure, the history of multiple KAs, and the absence of organisms in tissue biopsy and culture results led to the diagnosis of multiple KACM.

Once the frequent secondary bacterial infections were under control, the patient was treated with several therapeutic agents including imiquimod cream, intralesional methotrexate (MTX), and 5-fluorouracil (5-FU) cream. Because the lesions were multiple and large, surgery was not performed. As chemoprophylaxis, isotretinoin was initiated at 40 mg/d and then increased to 60 mg/d after 4 months. The total duration of isotretinoin therapy was 13 months. Along with the usual mucocutaneous side effects, the patient experienced back pain and mild mood alteration after the dose was increased. His complete blood count, liver function tests, and serum triglyceride levels all remained within reference range throughout the duration of therapy.

At the time of initiation of isotretinoin, MTX was injected into 2 different areas of the peripheral border of the largest lesion 3 weeks apart. The doses totaled 68 mg and 60 mg at each site, respectively. In addition, imiquimod under occlusion was applied every night to several of the lesions for the next 7 months. None of the lesions treated with either intralesional MTX or imiquimod resolved. Subsequent to the failure of imiquimod and MTX, 5-FU cream was applied to all of the annular lesions while the patient was still receiving isotretinoin therapy. Clinical response to 5-FU was apparent after 2 months. A complete clinical resolution, however, occurred over a period of 11 months (Figure 4). Isotretinoin was discontinued 5 months prior to the completion of the course of 5-FU cream.

While receiving isotretinoin therapy, the patient developed several more solitary KAs, and the annular lesions enlarged to varying sizes. The solitary KAs were managed either surgically or with liquid nitrogen, depending on the size. The new annular lesions were promptly eradicated with 5-FU cream. 

Comment

Some of the largest lesions of KACM (measuring ≥20 cm) have been reported to occur on the lower extremities.3-6 The lesions enlarged over a period of 10 months to several years with no tendency to regress completely, similar to our patient. All of these reported large lesions of the legs were successfully treated surgically. The diagnostic difficulty was not addressed in these previously reported cases; in our case, however, the initial lack of the characteristic exophytic rolled and shiny peripheral border and the frequent secondary bacterial infections contributed to the difficulty in accurate diagnosis. Initially, an infectious etiology such as chromoblastomycosis and verrucous tuberculosis was suspected. Histopathologically, the distinguishing exoendophytic architecture present at the periphery of KACM was not present; instead, the pathologic changes were confined to the superficial dermis, which consisted of jagged outlined epithelial aggregations that were difficult to distinguish from pseuodoepitheliomatous hyperplasia secondary to deep fungal or mycobacterial infection or halogenoderma. The history, clinicopathologic correlation, and negative culture results eventually led to the diagnosis of KACM.

A variety of treatment modalities have been employed successfully for KAs, including surgical excision, intralesional MTX, intralesional and topical 5-FU, intralesional bleomycin, and isotretinoin.2 Isotretinoin has been advocated as both a prophylactic and therapeutic agent for skin cancers, especially in the setting of multiple lesions.7-9 A relatively high dose (1–3 mg/kg) is required, even for prophylactic outcome. A low dose, in the range of 5 to 10 mg/d, is neither prophylactic nor therapeutic.10,11 The side effects, which include elevated triglyceride levels, mucocutaneous reactions, and hyperostotic axial skeletal changes, limit the use of isotretinoin. The efficacy of retinoids in the prophylaxis and treatment of KA and KACM also has been reported by several authors.12-15 The dosage of isotretinoin ranged from 1 to 3 mg/kg per day with a response observed as early as within one week to several months. In our case, despite adequate duration and relative high doses of isotretinoin, there was no prophylactic or therapeutic effect as evidenced by the patient's continual development of nodular KAs without any of the existing KAs regressing while he was receiving isotretinoin therapy. The patient experienced the usual mucocutaneous side effects. His backache and the changes in his mood were suspected to be the side effects of isotretinoin, as well.

Intralesional MTX for the treatment of KAs has been reported to be effective with a regimen of 1 to 3 injections not exceeding a total dose of 100 mg, resulting in resolution of the KAs in 2 to 4 weeks.16-18 In our patient, although the 2 sites were injected with adequate amounts of MTX, the treatment was unsuccessful. In retrospect, intralesional therapy was unreasonable because of the large amounts of MTX that would have been required. The 2 treated sites accounted for less than 10% of the surface area of the lesions.

The rationale for imiquimod therapy in our patient was 2-fold. First, imiquimod is an immune response modifier emerging as an effective therapy for superficial carcinomas of the skin.19-22 Most therapies available for superficial skin carcinomas also have been applied to KAs. Second, because human papillomavirus has been found to be present in KA, though not consistently,23-26 we were hopeful that imiquimod would have a therapeutic effect for KACM similar to that for condyloma. Despite daily application of the cream for 7 months to some of the lesions, far beyond the 6 to 12 weeks' duration recommended for basal cell carcinomas,19,27 imiquimod had no effect.

Both topical and intralesional 5-FU, a thymine analog, have been reported to be effective therapies for solitary and multiple KAs, though there is no reported case of KACM treated with either topical or intralesional 5-FU. A dramatic resolution has been observed as early as one week after treatment using topical 5-FU, but the usual duration of therapy was 3 to 4 weeks.28-30 In contrast to these reports, encouraging signs of resolution were present in our patient after 2 months of therapy, and complete resolution occurred over a period of many months, not weeks. Despite the apparent efficacy of 5-FU, we cannot exclude the possibility that the regression of the lesions was the natural course of the neoplasm, especially when KAs are known to regress without any therapeutic intervention. The evidence supporting topical 5-FU being efficacious is that there was prompt resolution when the cream was applied to the new lesions.

The nature of KA and KACM, whether or not the neoplasm is a squamous cell carcinoma (SCC), has been controversial. A few authors assert that a KA is an SCC.5,31,32 We consider KA and its variants, including KACM, as one type of SCC encountered in the skin. A few well-documented cases of metastases of KAs to the lymph nodes have been reported.31,33 At the molecular level, KA has been shown to overexpress p53,34 a tumor suppressor gene that has been associated with a variety of malignant neoplasms. In contrast to other types of SCC, a complete regression, believed to be an immune-mediated process by some,35,36 is a unique characteristic of KA. The exact mechanism by which a KA regresses, however, remains largely a mystery. LeBoit37 has hinted that solving this mystery may have far-reaching applications. We agree.

A keratoacanthoma centrifugum marginatum (KACM) may pose a diagnostic and therapeutic challenge. Clinically and histologically, it may resemble mycobacterial or deep fungal infection or halogenoderma. Therapy can be challenging because the lesion can expand to a great size. We report on a patient with multiple lesions of KACM. The diagnostic difficulty and the therapeutic failure of imiquimod, intralesional methotrexate (MTX), and isotretinoin, as well as the therapeutic success of 5-fluorouracil (5-FU) cream, are discussed.

Although Belisario first referred to the large annular keratoacanthoma (KA) as keratoacanthoma centrifugum marginatum (KACM) in 1965, a variety of names have been applied to this entity, including squamous cell pseudoepithelioma, aggregated KA, coral-reef KA, nodulo-vegetating KA, KA centrifugum, and multinodular KA.1,2 KACM is characterized by central regression with concomitant growth and expansion of the periphery but no tendencies toward complete regression in contrast to other types of KAs. A proper diagnosis can be challenging because clinically and histologically the lesions may resemble halogenoderma or infections such as verrucous tuberculosis or deep fungal infection. Therapy can be challenging because the lesions can reach a great size. The present case illustrates this diagnostic and therapeutic conundrum in a patient with multiple KACM. 

Case Report

A 78-year-old man being treated for more than 9 years for multiple KAs on his upper and lower extremities presented with an annular plaque with an elevated crusted keratotic border on the right ankle. Over the course of a year, the plaque enlarged to measure 20 cm (Figure 1). Additional annular and arciform plaques ranging from 13 to 16 cm developed on both legs over this period. The patient's medical history included type 2 diabetes mellitus, peripheral vascular disease, hyperlipidemia, coronary artery disease, and benign prostatic hypertrophy. There was no history of internal malignancy or family history of KAs. Chromoblastomycosis, verrucous tuberculosis, and KACM were considered in the differential diagnosis. No fungi or mycobacteria were isolated in any of the several skin biopsies or cultures performed. There were frequent secondary bacterial infections of the lesions, which were treated with appropriate antibiotics.

A wedge biopsy of the large annular plaque was performed. The area of regression showed fibrosis with an overlying flattened epidermis. The peripheral expanding area showed aggregations of large epithelial cells with abundant pink cytoplasm emanating from the epidermis (Figure 2), while the trailing clearing areas showed fibrosis. Some of the aggregations had jagged outlines that were lined by atypical epithelial cells (Figure 3). Within the aggregations, there were varying degrees of keratinization with presence of parakeratotic cornified cells and neutrophils centrally (Figure 3). Although the histopathologic changes were compatible for KACM, the differential diagnosis included halogenoderma and infectious etiology such as deep fungal or mycobacterial infection. The clinical and histopathologic findings, the lack of halogen exposure, the history of multiple KAs, and the absence of organisms in tissue biopsy and culture results led to the diagnosis of multiple KACM.

Once the frequent secondary bacterial infections were under control, the patient was treated with several therapeutic agents including imiquimod cream, intralesional methotrexate (MTX), and 5-fluorouracil (5-FU) cream. Because the lesions were multiple and large, surgery was not performed. As chemoprophylaxis, isotretinoin was initiated at 40 mg/d and then increased to 60 mg/d after 4 months. The total duration of isotretinoin therapy was 13 months. Along with the usual mucocutaneous side effects, the patient experienced back pain and mild mood alteration after the dose was increased. His complete blood count, liver function tests, and serum triglyceride levels all remained within reference range throughout the duration of therapy.

At the time of initiation of isotretinoin, MTX was injected into 2 different areas of the peripheral border of the largest lesion 3 weeks apart. The doses totaled 68 mg and 60 mg at each site, respectively. In addition, imiquimod under occlusion was applied every night to several of the lesions for the next 7 months. None of the lesions treated with either intralesional MTX or imiquimod resolved. Subsequent to the failure of imiquimod and MTX, 5-FU cream was applied to all of the annular lesions while the patient was still receiving isotretinoin therapy. Clinical response to 5-FU was apparent after 2 months. A complete clinical resolution, however, occurred over a period of 11 months (Figure 4). Isotretinoin was discontinued 5 months prior to the completion of the course of 5-FU cream.

While receiving isotretinoin therapy, the patient developed several more solitary KAs, and the annular lesions enlarged to varying sizes. The solitary KAs were managed either surgically or with liquid nitrogen, depending on the size. The new annular lesions were promptly eradicated with 5-FU cream. 

Comment

Some of the largest lesions of KACM (measuring ≥20 cm) have been reported to occur on the lower extremities.3-6 The lesions enlarged over a period of 10 months to several years with no tendency to regress completely, similar to our patient. All of these reported large lesions of the legs were successfully treated surgically. The diagnostic difficulty was not addressed in these previously reported cases; in our case, however, the initial lack of the characteristic exophytic rolled and shiny peripheral border and the frequent secondary bacterial infections contributed to the difficulty in accurate diagnosis. Initially, an infectious etiology such as chromoblastomycosis and verrucous tuberculosis was suspected. Histopathologically, the distinguishing exoendophytic architecture present at the periphery of KACM was not present; instead, the pathologic changes were confined to the superficial dermis, which consisted of jagged outlined epithelial aggregations that were difficult to distinguish from pseuodoepitheliomatous hyperplasia secondary to deep fungal or mycobacterial infection or halogenoderma. The history, clinicopathologic correlation, and negative culture results eventually led to the diagnosis of KACM.

A variety of treatment modalities have been employed successfully for KAs, including surgical excision, intralesional MTX, intralesional and topical 5-FU, intralesional bleomycin, and isotretinoin.2 Isotretinoin has been advocated as both a prophylactic and therapeutic agent for skin cancers, especially in the setting of multiple lesions.7-9 A relatively high dose (1–3 mg/kg) is required, even for prophylactic outcome. A low dose, in the range of 5 to 10 mg/d, is neither prophylactic nor therapeutic.10,11 The side effects, which include elevated triglyceride levels, mucocutaneous reactions, and hyperostotic axial skeletal changes, limit the use of isotretinoin. The efficacy of retinoids in the prophylaxis and treatment of KA and KACM also has been reported by several authors.12-15 The dosage of isotretinoin ranged from 1 to 3 mg/kg per day with a response observed as early as within one week to several months. In our case, despite adequate duration and relative high doses of isotretinoin, there was no prophylactic or therapeutic effect as evidenced by the patient's continual development of nodular KAs without any of the existing KAs regressing while he was receiving isotretinoin therapy. The patient experienced the usual mucocutaneous side effects. His backache and the changes in his mood were suspected to be the side effects of isotretinoin, as well.

Intralesional MTX for the treatment of KAs has been reported to be effective with a regimen of 1 to 3 injections not exceeding a total dose of 100 mg, resulting in resolution of the KAs in 2 to 4 weeks.16-18 In our patient, although the 2 sites were injected with adequate amounts of MTX, the treatment was unsuccessful. In retrospect, intralesional therapy was unreasonable because of the large amounts of MTX that would have been required. The 2 treated sites accounted for less than 10% of the surface area of the lesions.

The rationale for imiquimod therapy in our patient was 2-fold. First, imiquimod is an immune response modifier emerging as an effective therapy for superficial carcinomas of the skin.19-22 Most therapies available for superficial skin carcinomas also have been applied to KAs. Second, because human papillomavirus has been found to be present in KA, though not consistently,23-26 we were hopeful that imiquimod would have a therapeutic effect for KACM similar to that for condyloma. Despite daily application of the cream for 7 months to some of the lesions, far beyond the 6 to 12 weeks' duration recommended for basal cell carcinomas,19,27 imiquimod had no effect.

Both topical and intralesional 5-FU, a thymine analog, have been reported to be effective therapies for solitary and multiple KAs, though there is no reported case of KACM treated with either topical or intralesional 5-FU. A dramatic resolution has been observed as early as one week after treatment using topical 5-FU, but the usual duration of therapy was 3 to 4 weeks.28-30 In contrast to these reports, encouraging signs of resolution were present in our patient after 2 months of therapy, and complete resolution occurred over a period of many months, not weeks. Despite the apparent efficacy of 5-FU, we cannot exclude the possibility that the regression of the lesions was the natural course of the neoplasm, especially when KAs are known to regress without any therapeutic intervention. The evidence supporting topical 5-FU being efficacious is that there was prompt resolution when the cream was applied to the new lesions.

The nature of KA and KACM, whether or not the neoplasm is a squamous cell carcinoma (SCC), has been controversial. A few authors assert that a KA is an SCC.5,31,32 We consider KA and its variants, including KACM, as one type of SCC encountered in the skin. A few well-documented cases of metastases of KAs to the lymph nodes have been reported.31,33 At the molecular level, KA has been shown to overexpress p53,34 a tumor suppressor gene that has been associated with a variety of malignant neoplasms. In contrast to other types of SCC, a complete regression, believed to be an immune-mediated process by some,35,36 is a unique characteristic of KA. The exact mechanism by which a KA regresses, however, remains largely a mystery. LeBoit37 has hinted that solving this mystery may have far-reaching applications. We agree.

We report the case of a 6-week-old girl who presented with a pedunculated embryonal rhabdomyosarcoma arising in a giant congenital melanocytic nevus (GCMN) on her lower back. There was no associated leptomeningeal involvement. The patient underwent surgical resection of the rhabdomyosarcoma at age 2 months, with subsequent chemotherapy consisting of actinomycin D and vincristine. No recurrences of metastases of tumor have been noted at 5 months of age.

Giant congenital melanocytic nevus (GCMN), defined as measuring or predicted to measure greater than 20 cm in diameter by adulthood, uncommonly occurs in newborns.1 Concerns arise regarding malignant degeneration, with melanoma developing in 4.5% to 8.5% of cases.2,3 Other malignancies rarely have been reported in a GCMN, including rhabdomyosarcoma, melanosarcoma, undifferentiated spindle cell tumor, neuroblastoma, melanoblastoma, myoblastic sarcoma, liposarcoma, and malignant peripheral nerve sheath tumor.1,4 We report a case of rhabdomyosarcoma arising in a GCMN. 

CASE REPORT

A 6-week-old infant girl presented with an 18x13-cm pigmented hairy nevus extending from the lower back onto the abdomen. A rapidly enlarging, soft pink pedunculated polyp measuring 3 cm in diameter had been present centrally at birth (Figure 1). An ultrasound of the spine revealed no abnormalities.

The polyp was surgically resected, along with a portion of the GCMN. Results of the histologic examination disclosed a rhabdomyosarcoma, embryonal type, located superficially within the dermis (Figure 2). The deep and lateral margins showed no evidence of tumor. Immunohistochemistry results of the neoplastic cells showed marked positivity for desmins, smooth muscle actin, and vimentin; results of tests for S100, neuron-specific enolase, chromogranins, synaptophysin, leukocyte common antigen, and CD57 were negative. Myoglobin stain was noncontributory.

No evidence of metastatic disease was noted on computed tomography of the chest, abdomen, and pelvis; bone scan; and bone marrow examination. The patient was started on a chemotherapy regimen consisting of actinomycin D and vincristine.

Comment

Although controversy exists regarding the precise risk of malignant degeneration in GCMN, it presents a major concern. Often, extensive surgical procedures are undertaken to eliminate or manage the risk of malignancy, primarily to minimize the risk of melanoma, the most commonly associated malignancy.5

Rhabdomyosarcoma is the most common soft tissue sarcoma and the third most common extracranial solid tumor of childhood. It is responsible for up to 25% of malignant cutaneous neoplasms in the pediatric population.6 Most tumors occur in the head and neck region, as well as the genitourinary tract; other areas include the extremities and trunk. Rhabdomyosarcoma occurring in the skin de novo may present as an asymptomatic, firm red nodule or as a lobulated mass with a shiny erythematous surface and telangiectatic vessels.6,7 The differential diagnosis includes hemangioma, lymphangioma, hygroma, lymphoma, leukemia cutis, amelanotic melanoma, and angiofibroma.7

The 4 most common histologic subtypes of rhabdomyosarcoma include the following: embryonal, embryonal-botryoid, alveolar, and pleomorphic. The embryonal and embryonal-butryoid subtypes account for 50% to 60% of childhood rhabdomyosarcomas. The alveolar pattern is seen more commonly in older children, and the pleomorphic pattern is seen more in adults.7

Immunohistochemical stains used to identify rhabdomyosarcoma include the intermediate filaments vimentin and desmins. Vimentin highlights undifferentiated cells of mesenchymal origin, whereas desmins become positive as a cell becomes committed to rhabdomyoblastic differentiation. Because myoglobin is also found in skeletal muscle, myoglobin stains less consistently in rhabdomyosarcomas. This is most likely a result of its expression later in the development of skeletal muscle.7,8 Other muscle-specific proteins used in identification are Myo-D, myogenin, muscle- specific actin, and Z-band protein.9

Staging of rhabdomyosarcoma by the Intergroup Rhabdomyosarcoma Study (IRS) initially was based on a clinical grouping that sorted patients according to the extent of disease after surgical resection: group I, complete resection; group II, microscopic residual disease after gross resection, with or without nodal involvement; group III, gross residual disease after surgery; and group IV, metastatic disease at diagnosis. Now, the IRS is incorporating a more prognostically significant TNM staging. The TNM Staging System, in addition to clinical grouping, includes favorable versus unfavorable sites, along with increasing the stage number for bulky disease measuring greater than 5 cm in diameter or for nodal involvement. Favorable sites include the orbit, eyelid, head and neck, nonparameningeal, and genitourinary areas not including bladder or prostate. Unfavorable areas include extremities, bladder, prostate, parameningeal, retroperitoneum, and, as in our patient, the trunk.8,9 According to the latest IRS staging, our patient falls into the clinical group I, TNM stage II category, which places her in the low-risk rhabdomyosarcoma group.

The treatment of rhabdomyosarcoma in a GCMN consists of surgical resection and combination chemotherapy with or without radiation therapy, depending on the clinical grouping of the patient. According to the IRS definition of low-risk patients, the chemotherapy regimen consists of actinomycin D and vincristine with or without cyclophosphamide, depending on stage and location. Radiation therapy is added for patients with groups II through IV disease and for some unfavorable locations with a high risk of recurrence.9,10

Rhabdomyosarcoma arising in a GCMN has been reported rarely, with only 4 cases to date in the literature (Table).4,5,11,12 Three of the 4 cases occurred in infants, with a fatal outcome reported in one of the infants. In 3 of 4 cases, the trunk was indicated as the site of the rhabdomyosarcoma, with only one case associated with leptomeningeal involvement. In all cases, the rhabdomyosarcoma was excised, with subsequent chemotherapy in 2 of the 4 previously reported cases.

The occurrence of rhabdomyosarcoma arising in a GCMN could be explained by the pluripotential nature of undifferentiated neural crest cells. These cells likely maintain the ability for rhabdomyoblastic differentiation. This mesenchymal derivative originates from the cranial or cephalic portion of the neural crest. The term ectomesenchyme applies to the potential of the ectoderm to give rise to mesenchymal tissue and indeed may be the pathway by which a rhabdomyosarcoma arises.5

Conclusion

We report a fifth case of rhabdomyosarcoma arising in a GCMN. Our patient underwent surgical resection of the rhabdyomyosarcoma at age 2 months, with subsequent chemotherapy consisting of actinomycin D and vincristine. She has tolerated outpatient chemotherapy well, with no gross evidence of local recurrence, and will complete 12 months of therapy for her low-risk rhabdomyosarcoma. 

We report the case of a 6-week-old girl who presented with a pedunculated embryonal rhabdomyosarcoma arising in a giant congenital melanocytic nevus (GCMN) on her lower back. There was no associated leptomeningeal involvement. The patient underwent surgical resection of the rhabdomyosarcoma at age 2 months, with subsequent chemotherapy consisting of actinomycin D and vincristine. No recurrences of metastases of tumor have been noted at 5 months of age.

Giant congenital melanocytic nevus (GCMN), defined as measuring or predicted to measure greater than 20 cm in diameter by adulthood, uncommonly occurs in newborns.1 Concerns arise regarding malignant degeneration, with melanoma developing in 4.5% to 8.5% of cases.2,3 Other malignancies rarely have been reported in a GCMN, including rhabdomyosarcoma, melanosarcoma, undifferentiated spindle cell tumor, neuroblastoma, melanoblastoma, myoblastic sarcoma, liposarcoma, and malignant peripheral nerve sheath tumor.1,4 We report a case of rhabdomyosarcoma arising in a GCMN. 

CASE REPORT

A 6-week-old infant girl presented with an 18x13-cm pigmented hairy nevus extending from the lower back onto the abdomen. A rapidly enlarging, soft pink pedunculated polyp measuring 3 cm in diameter had been present centrally at birth (Figure 1). An ultrasound of the spine revealed no abnormalities.

The polyp was surgically resected, along with a portion of the GCMN. Results of the histologic examination disclosed a rhabdomyosarcoma, embryonal type, located superficially within the dermis (Figure 2). The deep and lateral margins showed no evidence of tumor. Immunohistochemistry results of the neoplastic cells showed marked positivity for desmins, smooth muscle actin, and vimentin; results of tests for S100, neuron-specific enolase, chromogranins, synaptophysin, leukocyte common antigen, and CD57 were negative. Myoglobin stain was noncontributory.

No evidence of metastatic disease was noted on computed tomography of the chest, abdomen, and pelvis; bone scan; and bone marrow examination. The patient was started on a chemotherapy regimen consisting of actinomycin D and vincristine.

Comment

Although controversy exists regarding the precise risk of malignant degeneration in GCMN, it presents a major concern. Often, extensive surgical procedures are undertaken to eliminate or manage the risk of malignancy, primarily to minimize the risk of melanoma, the most commonly associated malignancy.5

Rhabdomyosarcoma is the most common soft tissue sarcoma and the third most common extracranial solid tumor of childhood. It is responsible for up to 25% of malignant cutaneous neoplasms in the pediatric population.6 Most tumors occur in the head and neck region, as well as the genitourinary tract; other areas include the extremities and trunk. Rhabdomyosarcoma occurring in the skin de novo may present as an asymptomatic, firm red nodule or as a lobulated mass with a shiny erythematous surface and telangiectatic vessels.6,7 The differential diagnosis includes hemangioma, lymphangioma, hygroma, lymphoma, leukemia cutis, amelanotic melanoma, and angiofibroma.7

The 4 most common histologic subtypes of rhabdomyosarcoma include the following: embryonal, embryonal-botryoid, alveolar, and pleomorphic. The embryonal and embryonal-butryoid subtypes account for 50% to 60% of childhood rhabdomyosarcomas. The alveolar pattern is seen more commonly in older children, and the pleomorphic pattern is seen more in adults.7

Immunohistochemical stains used to identify rhabdomyosarcoma include the intermediate filaments vimentin and desmins. Vimentin highlights undifferentiated cells of mesenchymal origin, whereas desmins become positive as a cell becomes committed to rhabdomyoblastic differentiation. Because myoglobin is also found in skeletal muscle, myoglobin stains less consistently in rhabdomyosarcomas. This is most likely a result of its expression later in the development of skeletal muscle.7,8 Other muscle-specific proteins used in identification are Myo-D, myogenin, muscle- specific actin, and Z-band protein.9

Staging of rhabdomyosarcoma by the Intergroup Rhabdomyosarcoma Study (IRS) initially was based on a clinical grouping that sorted patients according to the extent of disease after surgical resection: group I, complete resection; group II, microscopic residual disease after gross resection, with or without nodal involvement; group III, gross residual disease after surgery; and group IV, metastatic disease at diagnosis. Now, the IRS is incorporating a more prognostically significant TNM staging. The TNM Staging System, in addition to clinical grouping, includes favorable versus unfavorable sites, along with increasing the stage number for bulky disease measuring greater than 5 cm in diameter or for nodal involvement. Favorable sites include the orbit, eyelid, head and neck, nonparameningeal, and genitourinary areas not including bladder or prostate. Unfavorable areas include extremities, bladder, prostate, parameningeal, retroperitoneum, and, as in our patient, the trunk.8,9 According to the latest IRS staging, our patient falls into the clinical group I, TNM stage II category, which places her in the low-risk rhabdomyosarcoma group.

The treatment of rhabdomyosarcoma in a GCMN consists of surgical resection and combination chemotherapy with or without radiation therapy, depending on the clinical grouping of the patient. According to the IRS definition of low-risk patients, the chemotherapy regimen consists of actinomycin D and vincristine with or without cyclophosphamide, depending on stage and location. Radiation therapy is added for patients with groups II through IV disease and for some unfavorable locations with a high risk of recurrence.9,10

Rhabdomyosarcoma arising in a GCMN has been reported rarely, with only 4 cases to date in the literature (Table).4,5,11,12 Three of the 4 cases occurred in infants, with a fatal outcome reported in one of the infants. In 3 of 4 cases, the trunk was indicated as the site of the rhabdomyosarcoma, with only one case associated with leptomeningeal involvement. In all cases, the rhabdomyosarcoma was excised, with subsequent chemotherapy in 2 of the 4 previously reported cases.

The occurrence of rhabdomyosarcoma arising in a GCMN could be explained by the pluripotential nature of undifferentiated neural crest cells. These cells likely maintain the ability for rhabdomyoblastic differentiation. This mesenchymal derivative originates from the cranial or cephalic portion of the neural crest. The term ectomesenchyme applies to the potential of the ectoderm to give rise to mesenchymal tissue and indeed may be the pathway by which a rhabdomyosarcoma arises.5

Conclusion

We report a fifth case of rhabdomyosarcoma arising in a GCMN. Our patient underwent surgical resection of the rhabdyomyosarcoma at age 2 months, with subsequent chemotherapy consisting of actinomycin D and vincristine. She has tolerated outpatient chemotherapy well, with no gross evidence of local recurrence, and will complete 12 months of therapy for her low-risk rhabdomyosarcoma. 

We report the case of a 6-week-old girl who presented with a pedunculated embryonal rhabdomyosarcoma arising in a giant congenital melanocytic nevus (GCMN) on her lower back. There was no associated leptomeningeal involvement. The patient underwent surgical resection of the rhabdomyosarcoma at age 2 months, with subsequent chemotherapy consisting of actinomycin D and vincristine. No recurrences of metastases of tumor have been noted at 5 months of age.

Giant congenital melanocytic nevus (GCMN), defined as measuring or predicted to measure greater than 20 cm in diameter by adulthood, uncommonly occurs in newborns.1 Concerns arise regarding malignant degeneration, with melanoma developing in 4.5% to 8.5% of cases.2,3 Other malignancies rarely have been reported in a GCMN, including rhabdomyosarcoma, melanosarcoma, undifferentiated spindle cell tumor, neuroblastoma, melanoblastoma, myoblastic sarcoma, liposarcoma, and malignant peripheral nerve sheath tumor.1,4 We report a case of rhabdomyosarcoma arising in a GCMN. 

CASE REPORT

A 6-week-old infant girl presented with an 18x13-cm pigmented hairy nevus extending from the lower back onto the abdomen. A rapidly enlarging, soft pink pedunculated polyp measuring 3 cm in diameter had been present centrally at birth (Figure 1). An ultrasound of the spine revealed no abnormalities.

The polyp was surgically resected, along with a portion of the GCMN. Results of the histologic examination disclosed a rhabdomyosarcoma, embryonal type, located superficially within the dermis (Figure 2). The deep and lateral margins showed no evidence of tumor. Immunohistochemistry results of the neoplastic cells showed marked positivity for desmins, smooth muscle actin, and vimentin; results of tests for S100, neuron-specific enolase, chromogranins, synaptophysin, leukocyte common antigen, and CD57 were negative. Myoglobin stain was noncontributory.

No evidence of metastatic disease was noted on computed tomography of the chest, abdomen, and pelvis; bone scan; and bone marrow examination. The patient was started on a chemotherapy regimen consisting of actinomycin D and vincristine.

Comment

Although controversy exists regarding the precise risk of malignant degeneration in GCMN, it presents a major concern. Often, extensive surgical procedures are undertaken to eliminate or manage the risk of malignancy, primarily to minimize the risk of melanoma, the most commonly associated malignancy.5

Rhabdomyosarcoma is the most common soft tissue sarcoma and the third most common extracranial solid tumor of childhood. It is responsible for up to 25% of malignant cutaneous neoplasms in the pediatric population.6 Most tumors occur in the head and neck region, as well as the genitourinary tract; other areas include the extremities and trunk. Rhabdomyosarcoma occurring in the skin de novo may present as an asymptomatic, firm red nodule or as a lobulated mass with a shiny erythematous surface and telangiectatic vessels.6,7 The differential diagnosis includes hemangioma, lymphangioma, hygroma, lymphoma, leukemia cutis, amelanotic melanoma, and angiofibroma.7

The 4 most common histologic subtypes of rhabdomyosarcoma include the following: embryonal, embryonal-botryoid, alveolar, and pleomorphic. The embryonal and embryonal-butryoid subtypes account for 50% to 60% of childhood rhabdomyosarcomas. The alveolar pattern is seen more commonly in older children, and the pleomorphic pattern is seen more in adults.7

Immunohistochemical stains used to identify rhabdomyosarcoma include the intermediate filaments vimentin and desmins. Vimentin highlights undifferentiated cells of mesenchymal origin, whereas desmins become positive as a cell becomes committed to rhabdomyoblastic differentiation. Because myoglobin is also found in skeletal muscle, myoglobin stains less consistently in rhabdomyosarcomas. This is most likely a result of its expression later in the development of skeletal muscle.7,8 Other muscle-specific proteins used in identification are Myo-D, myogenin, muscle- specific actin, and Z-band protein.9

Staging of rhabdomyosarcoma by the Intergroup Rhabdomyosarcoma Study (IRS) initially was based on a clinical grouping that sorted patients according to the extent of disease after surgical resection: group I, complete resection; group II, microscopic residual disease after gross resection, with or without nodal involvement; group III, gross residual disease after surgery; and group IV, metastatic disease at diagnosis. Now, the IRS is incorporating a more prognostically significant TNM staging. The TNM Staging System, in addition to clinical grouping, includes favorable versus unfavorable sites, along with increasing the stage number for bulky disease measuring greater than 5 cm in diameter or for nodal involvement. Favorable sites include the orbit, eyelid, head and neck, nonparameningeal, and genitourinary areas not including bladder or prostate. Unfavorable areas include extremities, bladder, prostate, parameningeal, retroperitoneum, and, as in our patient, the trunk.8,9 According to the latest IRS staging, our patient falls into the clinical group I, TNM stage II category, which places her in the low-risk rhabdomyosarcoma group.

The treatment of rhabdomyosarcoma in a GCMN consists of surgical resection and combination chemotherapy with or without radiation therapy, depending on the clinical grouping of the patient. According to the IRS definition of low-risk patients, the chemotherapy regimen consists of actinomycin D and vincristine with or without cyclophosphamide, depending on stage and location. Radiation therapy is added for patients with groups II through IV disease and for some unfavorable locations with a high risk of recurrence.9,10

Rhabdomyosarcoma arising in a GCMN has been reported rarely, with only 4 cases to date in the literature (Table).4,5,11,12 Three of the 4 cases occurred in infants, with a fatal outcome reported in one of the infants. In 3 of 4 cases, the trunk was indicated as the site of the rhabdomyosarcoma, with only one case associated with leptomeningeal involvement. In all cases, the rhabdomyosarcoma was excised, with subsequent chemotherapy in 2 of the 4 previously reported cases.

The occurrence of rhabdomyosarcoma arising in a GCMN could be explained by the pluripotential nature of undifferentiated neural crest cells. These cells likely maintain the ability for rhabdomyoblastic differentiation. This mesenchymal derivative originates from the cranial or cephalic portion of the neural crest. The term ectomesenchyme applies to the potential of the ectoderm to give rise to mesenchymal tissue and indeed may be the pathway by which a rhabdomyosarcoma arises.5

Conclusion

We report a fifth case of rhabdomyosarcoma arising in a GCMN. Our patient underwent surgical resection of the rhabdyomyosarcoma at age 2 months, with subsequent chemotherapy consisting of actinomycin D and vincristine. She has tolerated outpatient chemotherapy well, with no gross evidence of local recurrence, and will complete 12 months of therapy for her low-risk rhabdomyosarcoma. 

Granuloma faciale (GF) is an uncommon inflammatory condition characterized by reddish brown papules and plaques that usually involve the facial area. Extrafacial lesions are rare. Histologically, the lesions are marked by leukocytoclastic vasculitis and extensive fibrin deposition. There are a variety of treatment options available for GF.

Granuloma faciale (GF) is an uncommon disease of unknown etiology presenting with asymptomatic cutaneous papules, nodules, and plaques of the face. However, there has been some confusion and evolution of the term granuloma faciale. In 1937, the term eosinophilic granuloma of the skin was used to describe ulcerated lesions of the mouth and anus that were associated with tuberculosis.1,2 Cobane et al3 used the term facial granuloma with eosinophilia. Confusion continued until Lever and Leeper4 subdivided eosinophilic granuloma of the skin into 3 groups. The first group consisted of cases with cutaneous lesions associated with and histologically identical to eosinophilic granuloma of the bone (Langerhans cell histiocytosis). The second group included cases with cutaneous lesions consisting of torpid, asymptomatic purplish patches on the face. The last group was cases with a preponderance of eosinophils in a granulomatous infiltrate that were associated with a variety of diseases.1,4 A case described by Wigley5 in 1945 as Sarcoid of Boeck may, in fact, be the first reported case of GF.6 It was Pinkus,7 however, who in 1952 finally suggested the term granuloma faciale.

GF is characterized by papules, nodules, and plaques that are usually solitary, though multiple or disseminated lesions can be seen.8 The lesions usually are soft, elevated, well-circumscribed nodules ranging in size from millimeters to centimeters.3 The lesions can be shades of red, brown, or purple and may darken with sun exposure. Lesions usually have a smooth surface with follicular accentuation but may have telangiectasias. Ulceration or crusting rarely occurs. These lesions usually develop very slowly and remain unchanged, though occasionally they will involute.6 Tenderness, burning, and pruritus also have been reported.9,10

Although extracutaneous involvement is rare, there are reports of oral mucosa/upper airway involvement. GF can occur in patients of any age, sex, or race but is usually found in middle-aged Caucasian men.1,6,11-13 

Materials and Methods

The clinical presentation and treatment of 38 patients with GF was reviewed. Patient information was obtained from a database covering the past 10 years of patient activity at a large dermatopathology laboratory in Michigan. GF was diagnosed by clinical and histologic criteria including an infiltrate composed of lymphocytes, neutrophils, histiocytes, and eosinophils in the superficial and deep dermis and fibrin deposition within dermal blood vessels confirming the presence of vascular damage. The patients were reviewed according to demographics, location, treatment, and prognosis. Follow-up was obtained through a questionnaire sent to each referring physician. To our knowledge, this review represents the largest series of patients with GF ever described. 

Results

The clinical features of the patients are summarized in the Table. Their ages ranged from 28 to 85 years, with a mean age of 51.9 years for men and 55.4 years for women. The study consisted of 24 men and 14 women, which is in concordance with an early study showing a predominance of GF in men.1 One man and one woman (patients 1 and 7) had multiple lesions. Interestingly, five men (patients 19, 22, 25, 29, and 38) had extrafacial lesions; there are very few reported cases of extrafacial GF.

Comment

GF is characterized by solitary nodules and plaques.1 Most lesions are asymptomatic red, brown, or purple nodules that are soft, elevated, well-circumscribed, and slow to develop (Figure 1).

Lesions usually are seen on the face but may occur elsewhere.14 Particularly, lesions may appear on light-exposed areas, and some lesions are photoexacerbated.10 Sites of predilection are the sides (30%) and tip (7%) of the nose, preauricular area (22%), cheeks (22%), forehead (15%), and helix of the ear (4%).10,15 In a clinical and histopathologic review, Pedace and Perry1 described 21 cases of GF seen at the Mayo Clinic from 1945 to 1965. They noted a predominance of the lesions on the face (nose, forehead, malar, preauricular and postauricular areas, and chin) and less frequently on the forearms and elsewhere.

A review of the literature reveals 14 reported cases of extrafacial involvement.14-18 The clinical aspects of facial and extrafacial lesions are similar.8 Extrafacial lesions usually are found on the trunk and proximal extremities.19 Extrafacial lesions have been reported as isolated findings and in conjunction with facial lesions.17,18 The infrequent reports of extrafacial lesions may reflect either the inconspicuous nature of extrafacial lesions or a failure to examine patients specifically for the lesions.8

Extrafacial GF may be difficult to differentiate from erythema elevatum diutinum (EED). In fact, some authors believe EED and GF represent different parts of the spectrum of the same disease.20 Both are rare chronic forms of cutaneous small vessel vasculitis and may share some pathogenic mechanisms, but there are several clinical and histologic differences. EED is characterized by multiple lesions localized on the extensor surfaces of extremities in an acral, bilateral, and symmetrical distribution. Bulla formation and hemorrhagic crusting may be seen. The trunk is usually spared, and facial lesions are rare. Histopathologic features of EED include a dense superficial and deep polymorphous dermal infiltrate where neutrophils are prominent and eosinophils are scanty or absent. A grenz zone of normal collagen beneath the epidermis rarely exists and the epidermis is not always spared. EED may be associated with systemic conditions, primarily gammopathies. EED shows an excellent response to dapsone.15,21,22

There is a relatively large clinical differential diagnosis for GF including lupus erythematosus, polymorphous light eruption, fixed drug eruption, benign and malignant lymphoid proliferations, sarcoidosis, granuloma annulare, foreign body reaction, tinea faciei, insect bite reaction, juvenile xanthogranuloma, mastocytoma, Spitz nevus, EED, mycosis fungoides, basal cell carcinoma, histiocytosis X, and rosacea.1,6,23-26

There is one case report of Trichophyton rubrum causing histologic changes similar to GF.26 There also has been a case of GF mimicking rhinophyma.27

Histologic findings of GF show a normal epidermis that may be thinned and flattened by underlying infiltrate (Figure 2). There is a narrow grenz zone between the epidermis and the dermal inflammatory infiltrate consisting of lymphocytes, eosinophils, and neutrophils with leukocytoclasis (Figure 3). The infiltrate usually is distributed diffusely in the upper two thirds of the dermis. Fibrin deposition around blood vessels is evidence of vasculitis (Figure 4). In the later fibrotic stage, perivascular fibrin deposition predominates, and the number of inflammatory cells is greatly reduced.6

Microscopically, the primary differential diagnosis is EED, insect bite reaction, cutaneous lymphoma, or leukocytoclastic vasculitis. The exact pathogenesis is unclear, but some consider it a variant of leukocytoclastic vasculitis. Immunoglobulins, fibrin, and complement can be found at the dermal-epidermal junction and around blood vessels on direct immunofluorescence.28-30

GF usually lacks systemic symptoms or laboratory findings other than rare peripheral eosinophilia.31 Immunohistochemical analysis revealed the majority of lymphocytes to be helper T-cell lymphocytes. The cells stained strongly with antibodies against IL-2 receptor and with antibodies to lymphocyte functional antigen-1 α. Overlying keratinocytes did not stain with intracellular adhesion molecule-1 or HLA-DR, which may account for the presence of the grenz zone in GF. These findings suggest that a γ–interferon-mediated process may play some role in the pathogenesis of this disorder.32

GF is known to be resistant to therapy. Numerous physical modalities and medical therapeutics have been tried. Laser therapy, including the CO2,33 argon,34 pulsed dye, and long-pulsed tunable dye lasers,35-38 all have been attempted with varying success. A study showed that lesions treated with a CO2 laser and dermabrasion had a more even texture compared with lesions treated with electrosurgery alone. Healing times were similar between lesions treated with electrosurgery and CO2 laser; however, lesions treated with dermabrasion healed more quickly.39 Studies of patients treated with an argon laser resulted in total resolution of plaques of GF but had a remaining white collagenous scar.34

A case report by Elston37 showed complete resolution of 3 lesions of GF when treated with a pulsed dye laser after the patient failed topical corticosteroids and oral dapsone. A case report by Ammirati et al35 of a patient treated with the 585-nm pulsed dye laser showed clinical eradication of the lesion at 6-year follow-up. Another report by Welsh et al36 showed good results when GF was treated with the pulsed dye laser. Recently, the long-pulsed tunable dye laser was used successfully with no scarring.38 Other modalities that have been used include surgical excision,7,10 dermabrasion, superficial ionizing radiation,6,10 topical psoralen plus UV light,40 cryosurgery,41 intralesional corticosteroids,42 combined cryosurgery and intralesional steroid injection,43 and electrodesiccation.10,39

Medical treatment has included intralesional gold, colchicine, isoniazid, corticosteroids, potassium arsenite, testosterone, antimalarials, dapsone, and clofazimine.9,10,25,27,34,39,44-46 Most medical therapies have shown varying success. No controlled trials are available because of the rarity of the condition.

In our review, most patients were treated with topical and intralesional steroids with varying results that ranged from mild improvement to complete resolution. Because there is a lack of scarring with steroid therapy, we recommend this as a good first-line therapy. Although none of the patients were treated with pulsed dye laser therapy, review of the literature demonstrates favorable results with this treatment modality. Pulsed dye laser should be considered as an alternative therapy.

Granuloma faciale (GF) is an uncommon inflammatory condition characterized by reddish brown papules and plaques that usually involve the facial area. Extrafacial lesions are rare. Histologically, the lesions are marked by leukocytoclastic vasculitis and extensive fibrin deposition. There are a variety of treatment options available for GF.

Granuloma faciale (GF) is an uncommon disease of unknown etiology presenting with asymptomatic cutaneous papules, nodules, and plaques of the face. However, there has been some confusion and evolution of the term granuloma faciale. In 1937, the term eosinophilic granuloma of the skin was used to describe ulcerated lesions of the mouth and anus that were associated with tuberculosis.1,2 Cobane et al3 used the term facial granuloma with eosinophilia. Confusion continued until Lever and Leeper4 subdivided eosinophilic granuloma of the skin into 3 groups. The first group consisted of cases with cutaneous lesions associated with and histologically identical to eosinophilic granuloma of the bone (Langerhans cell histiocytosis). The second group included cases with cutaneous lesions consisting of torpid, asymptomatic purplish patches on the face. The last group was cases with a preponderance of eosinophils in a granulomatous infiltrate that were associated with a variety of diseases.1,4 A case described by Wigley5 in 1945 as Sarcoid of Boeck may, in fact, be the first reported case of GF.6 It was Pinkus,7 however, who in 1952 finally suggested the term granuloma faciale.

GF is characterized by papules, nodules, and plaques that are usually solitary, though multiple or disseminated lesions can be seen.8 The lesions usually are soft, elevated, well-circumscribed nodules ranging in size from millimeters to centimeters.3 The lesions can be shades of red, brown, or purple and may darken with sun exposure. Lesions usually have a smooth surface with follicular accentuation but may have telangiectasias. Ulceration or crusting rarely occurs. These lesions usually develop very slowly and remain unchanged, though occasionally they will involute.6 Tenderness, burning, and pruritus also have been reported.9,10

Although extracutaneous involvement is rare, there are reports of oral mucosa/upper airway involvement. GF can occur in patients of any age, sex, or race but is usually found in middle-aged Caucasian men.1,6,11-13 

Materials and Methods

The clinical presentation and treatment of 38 patients with GF was reviewed. Patient information was obtained from a database covering the past 10 years of patient activity at a large dermatopathology laboratory in Michigan. GF was diagnosed by clinical and histologic criteria including an infiltrate composed of lymphocytes, neutrophils, histiocytes, and eosinophils in the superficial and deep dermis and fibrin deposition within dermal blood vessels confirming the presence of vascular damage. The patients were reviewed according to demographics, location, treatment, and prognosis. Follow-up was obtained through a questionnaire sent to each referring physician. To our knowledge, this review represents the largest series of patients with GF ever described. 

Results

The clinical features of the patients are summarized in the Table. Their ages ranged from 28 to 85 years, with a mean age of 51.9 years for men and 55.4 years for women. The study consisted of 24 men and 14 women, which is in concordance with an early study showing a predominance of GF in men.1 One man and one woman (patients 1 and 7) had multiple lesions. Interestingly, five men (patients 19, 22, 25, 29, and 38) had extrafacial lesions; there are very few reported cases of extrafacial GF.

Comment

GF is characterized by solitary nodules and plaques.1 Most lesions are asymptomatic red, brown, or purple nodules that are soft, elevated, well-circumscribed, and slow to develop (Figure 1).

Lesions usually are seen on the face but may occur elsewhere.14 Particularly, lesions may appear on light-exposed areas, and some lesions are photoexacerbated.10 Sites of predilection are the sides (30%) and tip (7%) of the nose, preauricular area (22%), cheeks (22%), forehead (15%), and helix of the ear (4%).10,15 In a clinical and histopathologic review, Pedace and Perry1 described 21 cases of GF seen at the Mayo Clinic from 1945 to 1965. They noted a predominance of the lesions on the face (nose, forehead, malar, preauricular and postauricular areas, and chin) and less frequently on the forearms and elsewhere.

A review of the literature reveals 14 reported cases of extrafacial involvement.14-18 The clinical aspects of facial and extrafacial lesions are similar.8 Extrafacial lesions usually are found on the trunk and proximal extremities.19 Extrafacial lesions have been reported as isolated findings and in conjunction with facial lesions.17,18 The infrequent reports of extrafacial lesions may reflect either the inconspicuous nature of extrafacial lesions or a failure to examine patients specifically for the lesions.8

Extrafacial GF may be difficult to differentiate from erythema elevatum diutinum (EED). In fact, some authors believe EED and GF represent different parts of the spectrum of the same disease.20 Both are rare chronic forms of cutaneous small vessel vasculitis and may share some pathogenic mechanisms, but there are several clinical and histologic differences. EED is characterized by multiple lesions localized on the extensor surfaces of extremities in an acral, bilateral, and symmetrical distribution. Bulla formation and hemorrhagic crusting may be seen. The trunk is usually spared, and facial lesions are rare. Histopathologic features of EED include a dense superficial and deep polymorphous dermal infiltrate where neutrophils are prominent and eosinophils are scanty or absent. A grenz zone of normal collagen beneath the epidermis rarely exists and the epidermis is not always spared. EED may be associated with systemic conditions, primarily gammopathies. EED shows an excellent response to dapsone.15,21,22

There is a relatively large clinical differential diagnosis for GF including lupus erythematosus, polymorphous light eruption, fixed drug eruption, benign and malignant lymphoid proliferations, sarcoidosis, granuloma annulare, foreign body reaction, tinea faciei, insect bite reaction, juvenile xanthogranuloma, mastocytoma, Spitz nevus, EED, mycosis fungoides, basal cell carcinoma, histiocytosis X, and rosacea.1,6,23-26

There is one case report of Trichophyton rubrum causing histologic changes similar to GF.26 There also has been a case of GF mimicking rhinophyma.27

Histologic findings of GF show a normal epidermis that may be thinned and flattened by underlying infiltrate (Figure 2). There is a narrow grenz zone between the epidermis and the dermal inflammatory infiltrate consisting of lymphocytes, eosinophils, and neutrophils with leukocytoclasis (Figure 3). The infiltrate usually is distributed diffusely in the upper two thirds of the dermis. Fibrin deposition around blood vessels is evidence of vasculitis (Figure 4). In the later fibrotic stage, perivascular fibrin deposition predominates, and the number of inflammatory cells is greatly reduced.6

Microscopically, the primary differential diagnosis is EED, insect bite reaction, cutaneous lymphoma, or leukocytoclastic vasculitis. The exact pathogenesis is unclear, but some consider it a variant of leukocytoclastic vasculitis. Immunoglobulins, fibrin, and complement can be found at the dermal-epidermal junction and around blood vessels on direct immunofluorescence.28-30

GF usually lacks systemic symptoms or laboratory findings other than rare peripheral eosinophilia.31 Immunohistochemical analysis revealed the majority of lymphocytes to be helper T-cell lymphocytes. The cells stained strongly with antibodies against IL-2 receptor and with antibodies to lymphocyte functional antigen-1 α. Overlying keratinocytes did not stain with intracellular adhesion molecule-1 or HLA-DR, which may account for the presence of the grenz zone in GF. These findings suggest that a γ–interferon-mediated process may play some role in the pathogenesis of this disorder.32

GF is known to be resistant to therapy. Numerous physical modalities and medical therapeutics have been tried. Laser therapy, including the CO2,33 argon,34 pulsed dye, and long-pulsed tunable dye lasers,35-38 all have been attempted with varying success. A study showed that lesions treated with a CO2 laser and dermabrasion had a more even texture compared with lesions treated with electrosurgery alone. Healing times were similar between lesions treated with electrosurgery and CO2 laser; however, lesions treated with dermabrasion healed more quickly.39 Studies of patients treated with an argon laser resulted in total resolution of plaques of GF but had a remaining white collagenous scar.34

A case report by Elston37 showed complete resolution of 3 lesions of GF when treated with a pulsed dye laser after the patient failed topical corticosteroids and oral dapsone. A case report by Ammirati et al35 of a patient treated with the 585-nm pulsed dye laser showed clinical eradication of the lesion at 6-year follow-up. Another report by Welsh et al36 showed good results when GF was treated with the pulsed dye laser. Recently, the long-pulsed tunable dye laser was used successfully with no scarring.38 Other modalities that have been used include surgical excision,7,10 dermabrasion, superficial ionizing radiation,6,10 topical psoralen plus UV light,40 cryosurgery,41 intralesional corticosteroids,42 combined cryosurgery and intralesional steroid injection,43 and electrodesiccation.10,39

Medical treatment has included intralesional gold, colchicine, isoniazid, corticosteroids, potassium arsenite, testosterone, antimalarials, dapsone, and clofazimine.9,10,25,27,34,39,44-46 Most medical therapies have shown varying success. No controlled trials are available because of the rarity of the condition.

In our review, most patients were treated with topical and intralesional steroids with varying results that ranged from mild improvement to complete resolution. Because there is a lack of scarring with steroid therapy, we recommend this as a good first-line therapy. Although none of the patients were treated with pulsed dye laser therapy, review of the literature demonstrates favorable results with this treatment modality. Pulsed dye laser should be considered as an alternative therapy.

Granuloma faciale (GF) is an uncommon inflammatory condition characterized by reddish brown papules and plaques that usually involve the facial area. Extrafacial lesions are rare. Histologically, the lesions are marked by leukocytoclastic vasculitis and extensive fibrin deposition. There are a variety of treatment options available for GF.

Granuloma faciale (GF) is an uncommon disease of unknown etiology presenting with asymptomatic cutaneous papules, nodules, and plaques of the face. However, there has been some confusion and evolution of the term granuloma faciale. In 1937, the term eosinophilic granuloma of the skin was used to describe ulcerated lesions of the mouth and anus that were associated with tuberculosis.1,2 Cobane et al3 used the term facial granuloma with eosinophilia. Confusion continued until Lever and Leeper4 subdivided eosinophilic granuloma of the skin into 3 groups. The first group consisted of cases with cutaneous lesions associated with and histologically identical to eosinophilic granuloma of the bone (Langerhans cell histiocytosis). The second group included cases with cutaneous lesions consisting of torpid, asymptomatic purplish patches on the face. The last group was cases with a preponderance of eosinophils in a granulomatous infiltrate that were associated with a variety of diseases.1,4 A case described by Wigley5 in 1945 as Sarcoid of Boeck may, in fact, be the first reported case of GF.6 It was Pinkus,7 however, who in 1952 finally suggested the term granuloma faciale.

GF is characterized by papules, nodules, and plaques that are usually solitary, though multiple or disseminated lesions can be seen.8 The lesions usually are soft, elevated, well-circumscribed nodules ranging in size from millimeters to centimeters.3 The lesions can be shades of red, brown, or purple and may darken with sun exposure. Lesions usually have a smooth surface with follicular accentuation but may have telangiectasias. Ulceration or crusting rarely occurs. These lesions usually develop very slowly and remain unchanged, though occasionally they will involute.6 Tenderness, burning, and pruritus also have been reported.9,10

Although extracutaneous involvement is rare, there are reports of oral mucosa/upper airway involvement. GF can occur in patients of any age, sex, or race but is usually found in middle-aged Caucasian men.1,6,11-13 

Materials and Methods

The clinical presentation and treatment of 38 patients with GF was reviewed. Patient information was obtained from a database covering the past 10 years of patient activity at a large dermatopathology laboratory in Michigan. GF was diagnosed by clinical and histologic criteria including an infiltrate composed of lymphocytes, neutrophils, histiocytes, and eosinophils in the superficial and deep dermis and fibrin deposition within dermal blood vessels confirming the presence of vascular damage. The patients were reviewed according to demographics, location, treatment, and prognosis. Follow-up was obtained through a questionnaire sent to each referring physician. To our knowledge, this review represents the largest series of patients with GF ever described. 

Results

The clinical features of the patients are summarized in the Table. Their ages ranged from 28 to 85 years, with a mean age of 51.9 years for men and 55.4 years for women. The study consisted of 24 men and 14 women, which is in concordance with an early study showing a predominance of GF in men.1 One man and one woman (patients 1 and 7) had multiple lesions. Interestingly, five men (patients 19, 22, 25, 29, and 38) had extrafacial lesions; there are very few reported cases of extrafacial GF.

Comment

GF is characterized by solitary nodules and plaques.1 Most lesions are asymptomatic red, brown, or purple nodules that are soft, elevated, well-circumscribed, and slow to develop (Figure 1).

Lesions usually are seen on the face but may occur elsewhere.14 Particularly, lesions may appear on light-exposed areas, and some lesions are photoexacerbated.10 Sites of predilection are the sides (30%) and tip (7%) of the nose, preauricular area (22%), cheeks (22%), forehead (15%), and helix of the ear (4%).10,15 In a clinical and histopathologic review, Pedace and Perry1 described 21 cases of GF seen at the Mayo Clinic from 1945 to 1965. They noted a predominance of the lesions on the face (nose, forehead, malar, preauricular and postauricular areas, and chin) and less frequently on the forearms and elsewhere.

A review of the literature reveals 14 reported cases of extrafacial involvement.14-18 The clinical aspects of facial and extrafacial lesions are similar.8 Extrafacial lesions usually are found on the trunk and proximal extremities.19 Extrafacial lesions have been reported as isolated findings and in conjunction with facial lesions.17,18 The infrequent reports of extrafacial lesions may reflect either the inconspicuous nature of extrafacial lesions or a failure to examine patients specifically for the lesions.8

Extrafacial GF may be difficult to differentiate from erythema elevatum diutinum (EED). In fact, some authors believe EED and GF represent different parts of the spectrum of the same disease.20 Both are rare chronic forms of cutaneous small vessel vasculitis and may share some pathogenic mechanisms, but there are several clinical and histologic differences. EED is characterized by multiple lesions localized on the extensor surfaces of extremities in an acral, bilateral, and symmetrical distribution. Bulla formation and hemorrhagic crusting may be seen. The trunk is usually spared, and facial lesions are rare. Histopathologic features of EED include a dense superficial and deep polymorphous dermal infiltrate where neutrophils are prominent and eosinophils are scanty or absent. A grenz zone of normal collagen beneath the epidermis rarely exists and the epidermis is not always spared. EED may be associated with systemic conditions, primarily gammopathies. EED shows an excellent response to dapsone.15,21,22

There is a relatively large clinical differential diagnosis for GF including lupus erythematosus, polymorphous light eruption, fixed drug eruption, benign and malignant lymphoid proliferations, sarcoidosis, granuloma annulare, foreign body reaction, tinea faciei, insect bite reaction, juvenile xanthogranuloma, mastocytoma, Spitz nevus, EED, mycosis fungoides, basal cell carcinoma, histiocytosis X, and rosacea.1,6,23-26

There is one case report of Trichophyton rubrum causing histologic changes similar to GF.26 There also has been a case of GF mimicking rhinophyma.27

Histologic findings of GF show a normal epidermis that may be thinned and flattened by underlying infiltrate (Figure 2). There is a narrow grenz zone between the epidermis and the dermal inflammatory infiltrate consisting of lymphocytes, eosinophils, and neutrophils with leukocytoclasis (Figure 3). The infiltrate usually is distributed diffusely in the upper two thirds of the dermis. Fibrin deposition around blood vessels is evidence of vasculitis (Figure 4). In the later fibrotic stage, perivascular fibrin deposition predominates, and the number of inflammatory cells is greatly reduced.6

Microscopically, the primary differential diagnosis is EED, insect bite reaction, cutaneous lymphoma, or leukocytoclastic vasculitis. The exact pathogenesis is unclear, but some consider it a variant of leukocytoclastic vasculitis. Immunoglobulins, fibrin, and complement can be found at the dermal-epidermal junction and around blood vessels on direct immunofluorescence.28-30

GF usually lacks systemic symptoms or laboratory findings other than rare peripheral eosinophilia.31 Immunohistochemical analysis revealed the majority of lymphocytes to be helper T-cell lymphocytes. The cells stained strongly with antibodies against IL-2 receptor and with antibodies to lymphocyte functional antigen-1 α. Overlying keratinocytes did not stain with intracellular adhesion molecule-1 or HLA-DR, which may account for the presence of the grenz zone in GF. These findings suggest that a γ–interferon-mediated process may play some role in the pathogenesis of this disorder.32

GF is known to be resistant to therapy. Numerous physical modalities and medical therapeutics have been tried. Laser therapy, including the CO2,33 argon,34 pulsed dye, and long-pulsed tunable dye lasers,35-38 all have been attempted with varying success. A study showed that lesions treated with a CO2 laser and dermabrasion had a more even texture compared with lesions treated with electrosurgery alone. Healing times were similar between lesions treated with electrosurgery and CO2 laser; however, lesions treated with dermabrasion healed more quickly.39 Studies of patients treated with an argon laser resulted in total resolution of plaques of GF but had a remaining white collagenous scar.34

A case report by Elston37 showed complete resolution of 3 lesions of GF when treated with a pulsed dye laser after the patient failed topical corticosteroids and oral dapsone. A case report by Ammirati et al35 of a patient treated with the 585-nm pulsed dye laser showed clinical eradication of the lesion at 6-year follow-up. Another report by Welsh et al36 showed good results when GF was treated with the pulsed dye laser. Recently, the long-pulsed tunable dye laser was used successfully with no scarring.38 Other modalities that have been used include surgical excision,7,10 dermabrasion, superficial ionizing radiation,6,10 topical psoralen plus UV light,40 cryosurgery,41 intralesional corticosteroids,42 combined cryosurgery and intralesional steroid injection,43 and electrodesiccation.10,39

Medical treatment has included intralesional gold, colchicine, isoniazid, corticosteroids, potassium arsenite, testosterone, antimalarials, dapsone, and clofazimine.9,10,25,27,34,39,44-46 Most medical therapies have shown varying success. No controlled trials are available because of the rarity of the condition.

In our review, most patients were treated with topical and intralesional steroids with varying results that ranged from mild improvement to complete resolution. Because there is a lack of scarring with steroid therapy, we recommend this as a good first-line therapy. Although none of the patients were treated with pulsed dye laser therapy, review of the literature demonstrates favorable results with this treatment modality. Pulsed dye laser should be considered as an alternative therapy.