Nonmelanoma Skin Cancer

The Diagnosis: Myeloid Leukemia Cutis

Leukemia cutis represents the infiltration of leukemic cells into the skin. It has been described in the setting of both myeloid and lymphoid leukemia. In the setting of acute myeloid leukemia, it has been reported to occur in 2% to 13% of patients overall,^1,2 but it may occur in 31% of patients with the acute myelomonocytic or acute monocytic leukemia subtypes.³ Leukemia cutis is less common, with chronic myeloid leukemia occurring in 2.7% of patients in one study.⁴ In another study, 65% of patients with myeloid leukemia cutis had an acute myeloid leukemia.⁵

Myeloid leukemia cutis has been reported in patients aged 22 days to 90 years, with a median age of 62 years. There is a male predominance (1.4:1 ratio).^5,6 The diagnosis of leukemia cutis is made concurrently with the diagnosis of leukemia in approximately 30% of cases, subsequent to the diagnosis of leukemia in approximately 60% of cases, and prior to the diagnosis of leukemia in approximately 10% of cases.⁵

Clinically, myeloid leukemia cutis presents as an asymptomatic solitary lesion in 23% of cases or as multiple lesions in 77% of cases. Lesions consist of pink to red to violaceous papules, nodules, and macules that are occasionally purpuric and involve any cutaneous surface.⁵

Histologically, the epidermis is unremarkable. Beneath a grenz zone within the dermis and usually extending into the subcutis there is a diffuse or nodular proliferation of neoplastic cells, often with perivascular and periadnexal accentuation and sometimes single filing of cells between collagen bundles (Figure 1). The cells are immature myeloid cells with irregular nuclear contours that may be indented or reniform (Figure 2). Nuclei contain finely dispersed chromatin with variably prominent nucleoli.^5,6 Immunohistochemically, CD68 is positive in approximately 97% of cases, myeloperoxidase in 62%, and lysozyme in 85%. CD168, CD14, CD4, CD33, CD117, CD34, CD56, CD123, and CD303 are variably positive. CD3 and CD20, markers of lymphoid leukemia, are negative.^5-8

Leukemia cutis in the setting of a myeloid leukemia portends a grave prognosis. In a series of 18 patients, 16 had additional extramedullary leukemia, including meningeal leukemia in 6 patients.² Most patients with myeloid leukemia cutis die within an average of 1 to 8 months of diagnosis.⁹

The Diagnosis: Myeloid Leukemia Cutis

Leukemia cutis represents the infiltration of leukemic cells into the skin. It has been described in the setting of both myeloid and lymphoid leukemia. In the setting of acute myeloid leukemia, it has been reported to occur in 2% to 13% of patients overall,^1,2 but it may occur in 31% of patients with the acute myelomonocytic or acute monocytic leukemia subtypes.³ Leukemia cutis is less common, with chronic myeloid leukemia occurring in 2.7% of patients in one study.⁴ In another study, 65% of patients with myeloid leukemia cutis had an acute myeloid leukemia.⁵

Myeloid leukemia cutis has been reported in patients aged 22 days to 90 years, with a median age of 62 years. There is a male predominance (1.4:1 ratio).^5,6 The diagnosis of leukemia cutis is made concurrently with the diagnosis of leukemia in approximately 30% of cases, subsequent to the diagnosis of leukemia in approximately 60% of cases, and prior to the diagnosis of leukemia in approximately 10% of cases.⁵

Clinically, myeloid leukemia cutis presents as an asymptomatic solitary lesion in 23% of cases or as multiple lesions in 77% of cases. Lesions consist of pink to red to violaceous papules, nodules, and macules that are occasionally purpuric and involve any cutaneous surface.⁵

Histologically, the epidermis is unremarkable. Beneath a grenz zone within the dermis and usually extending into the subcutis there is a diffuse or nodular proliferation of neoplastic cells, often with perivascular and periadnexal accentuation and sometimes single filing of cells between collagen bundles (Figure 1). The cells are immature myeloid cells with irregular nuclear contours that may be indented or reniform (Figure 2). Nuclei contain finely dispersed chromatin with variably prominent nucleoli.^5,6 Immunohistochemically, CD68 is positive in approximately 97% of cases, myeloperoxidase in 62%, and lysozyme in 85%. CD168, CD14, CD4, CD33, CD117, CD34, CD56, CD123, and CD303 are variably positive. CD3 and CD20, markers of lymphoid leukemia, are negative.^5-8

Leukemia cutis in the setting of a myeloid leukemia portends a grave prognosis. In a series of 18 patients, 16 had additional extramedullary leukemia, including meningeal leukemia in 6 patients.² Most patients with myeloid leukemia cutis die within an average of 1 to 8 months of diagnosis.⁹

The Diagnosis: Myeloid Leukemia Cutis

Leukemia cutis represents the infiltration of leukemic cells into the skin. It has been described in the setting of both myeloid and lymphoid leukemia. In the setting of acute myeloid leukemia, it has been reported to occur in 2% to 13% of patients overall,^1,2 but it may occur in 31% of patients with the acute myelomonocytic or acute monocytic leukemia subtypes.³ Leukemia cutis is less common, with chronic myeloid leukemia occurring in 2.7% of patients in one study.⁴ In another study, 65% of patients with myeloid leukemia cutis had an acute myeloid leukemia.⁵

Myeloid leukemia cutis has been reported in patients aged 22 days to 90 years, with a median age of 62 years. There is a male predominance (1.4:1 ratio).^5,6 The diagnosis of leukemia cutis is made concurrently with the diagnosis of leukemia in approximately 30% of cases, subsequent to the diagnosis of leukemia in approximately 60% of cases, and prior to the diagnosis of leukemia in approximately 10% of cases.⁵

Clinically, myeloid leukemia cutis presents as an asymptomatic solitary lesion in 23% of cases or as multiple lesions in 77% of cases. Lesions consist of pink to red to violaceous papules, nodules, and macules that are occasionally purpuric and involve any cutaneous surface.⁵

Histologically, the epidermis is unremarkable. Beneath a grenz zone within the dermis and usually extending into the subcutis there is a diffuse or nodular proliferation of neoplastic cells, often with perivascular and periadnexal accentuation and sometimes single filing of cells between collagen bundles (Figure 1). The cells are immature myeloid cells with irregular nuclear contours that may be indented or reniform (Figure 2). Nuclei contain finely dispersed chromatin with variably prominent nucleoli.^5,6 Immunohistochemically, CD68 is positive in approximately 97% of cases, myeloperoxidase in 62%, and lysozyme in 85%. CD168, CD14, CD4, CD33, CD117, CD34, CD56, CD123, and CD303 are variably positive. CD3 and CD20, markers of lymphoid leukemia, are negative.^5-8

Leukemia cutis in the setting of a myeloid leukemia portends a grave prognosis. In a series of 18 patients, 16 had additional extramedullary leukemia, including meningeal leukemia in 6 patients.² Most patients with myeloid leukemia cutis die within an average of 1 to 8 months of diagnosis.⁹

The Diagnosis: Merkel Cell Carcinoma

Histopathology showed small round cells (Figure 1) that stained positive for cytokeratin 20 in a paranuclear dotlike pattern (Figure 2). The tumor stained negative for lymphoma (CD45) marker. Fluorodeoxyglucose positron emission tomography showed focally increased activity at cutaneous sites corresponding to the nodules, but lymph nodes and visceral sites did not show areas of increased metabolic activity. She underwent an above-knee amputation. She was started on a chemotherapy regimen of etoposide and carboplatin given that the pathology of the excised limb demonstrated vascular and lymphatic invasion by the tumor cells in the proximal skin margin. After 4 months she presented with gangrenous changes of the amputated limb and evidence of metastasis to the region of the skin flap. Similar tumors presented on the ipsilateral hip. Given her general poor condition and aggressive nature of the tumor, the patient decided to pursue hospice care 6 months after her diagnosis of Merkel cell carcinoma (MCC).

Figure 1. The tumor was composed of sheets of cells with a high nuclear-cytoplasmic ratio and fine chromatin without nucleoli (H&E, original magnification ×40).

Figure 2. Immunohistochemical staining for cytokera-tin 20 showed positivity in a paranuclear dotlike pattern (original magnification ×40).

Merkel cell carcinoma usually presents as firm, red to purple papules on sun-exposed skin in older patients with light skin. Factors strongly associated with the development of MCC are age (>65 years), lighter skin types, history of extensive sun exposure, and chronic immune suppression (eg, kidney or heart transplantation, human immunodeficiency virus).¹ The rate of MCC has increased 3-fold between 1986 and 2001; the rate of MCC was 0.15 cases per 100,000 individuals in 1986, climbing up to 0.44 cases per 100,000 individuals in 2001.² Our patient had been on immunosuppressants—prednisone, cyclosporine, and sirolimus—for nearly a decade following kidney transplants, which had been discontinued 2 years prior to presentation.

Heath et al³ defined an acronym AEIOU (asymptomatic/lack of tenderness, expanding rapidly, immune suppression, older than 50 years, UV-exposed site on a person with fair skin) for MCC features derived from 195 patients. They advised that a biopsy is warranted if the patient presents with more than 3 of these features.³

The 1991 MCC staging system was revised in 1999 and 2005 based on experience at Memorial Sloan Kettering Cancer Center (New York, New York).⁴ In 2010 the American Joint Committee on Cancer staging was introduced for MCC, which follows other skin malignancies.⁵ Using this TNM staging system for primary tumors, regional lymph nodes, and distant metastasis, our patient at the time of presentation was stage IIB (T3N0M0), with tumor size greater than 5 cm, nodes negative by clinical examination, and no distant metastasis. In a span of 3 months, she had metastasis to the skin, subcutaneous tissue, and distant lymph nodes, which resulted in classification as stage IV, proving the aggressive nature of the tumor.

The newly discovered Merkel cell polyomavirus (MCPyV) is found integrating into the Merkel cell genome. Merkel cell polyomavirus is present in 80% of cancers and is expressed in a clonal pattern, while 90% of MCC patients are seropositive for the same. Unlike antibodies to MCPyV VP1 protein, antibodies to the T antigen for MCPyV track disease burden and may be a useful biomarker for MCC in the future.⁶

A study of 251 patients in 1970-2002 showed that pathologic nodal staging identifies a group of patients with excellent long-term survival.¹ Our patient preferred to undergo positron emission tomography rather than a sentinel lymph node biopsy prior to surgery. Also, after margin-negative excision and pathologic nodal staging, local and nodal recurrence rates were low. Adjuvant chemotherapy for stage III patients showed a trend (P=.08) to decreased survival compared with stage II patients who did not receive chemotherapy.⁷ A multidisciplinary approach to treatment including surgery, radiation,⁸ and chemotherapy needs to be created for each individual patient. Merkel cell carcinoma is the cause of death in 35% of patients within 3 years of diagnosis.⁹

Merkel cell carcinoma is a rare orphan tumor with rapidly increasing incidence in an era of immunosuppression. It has a grave prognosis, as demonstrated in our case, if not detected early. People at increased risk for MCC must have regular skin checks. Unfortunately, our patient was a nursing home resident and had not had a skin check for 2 years prior to presentation.

The Diagnosis: Merkel Cell Carcinoma

Histopathology showed small round cells (Figure 1) that stained positive for cytokeratin 20 in a paranuclear dotlike pattern (Figure 2). The tumor stained negative for lymphoma (CD45) marker. Fluorodeoxyglucose positron emission tomography showed focally increased activity at cutaneous sites corresponding to the nodules, but lymph nodes and visceral sites did not show areas of increased metabolic activity. She underwent an above-knee amputation. She was started on a chemotherapy regimen of etoposide and carboplatin given that the pathology of the excised limb demonstrated vascular and lymphatic invasion by the tumor cells in the proximal skin margin. After 4 months she presented with gangrenous changes of the amputated limb and evidence of metastasis to the region of the skin flap. Similar tumors presented on the ipsilateral hip. Given her general poor condition and aggressive nature of the tumor, the patient decided to pursue hospice care 6 months after her diagnosis of Merkel cell carcinoma (MCC).

Figure 1. The tumor was composed of sheets of cells with a high nuclear-cytoplasmic ratio and fine chromatin without nucleoli (H&E, original magnification ×40).

Figure 2. Immunohistochemical staining for cytokera-tin 20 showed positivity in a paranuclear dotlike pattern (original magnification ×40).

Merkel cell carcinoma usually presents as firm, red to purple papules on sun-exposed skin in older patients with light skin. Factors strongly associated with the development of MCC are age (>65 years), lighter skin types, history of extensive sun exposure, and chronic immune suppression (eg, kidney or heart transplantation, human immunodeficiency virus).¹ The rate of MCC has increased 3-fold between 1986 and 2001; the rate of MCC was 0.15 cases per 100,000 individuals in 1986, climbing up to 0.44 cases per 100,000 individuals in 2001.² Our patient had been on immunosuppressants—prednisone, cyclosporine, and sirolimus—for nearly a decade following kidney transplants, which had been discontinued 2 years prior to presentation.

Heath et al³ defined an acronym AEIOU (asymptomatic/lack of tenderness, expanding rapidly, immune suppression, older than 50 years, UV-exposed site on a person with fair skin) for MCC features derived from 195 patients. They advised that a biopsy is warranted if the patient presents with more than 3 of these features.³

The 1991 MCC staging system was revised in 1999 and 2005 based on experience at Memorial Sloan Kettering Cancer Center (New York, New York).⁴ In 2010 the American Joint Committee on Cancer staging was introduced for MCC, which follows other skin malignancies.⁵ Using this TNM staging system for primary tumors, regional lymph nodes, and distant metastasis, our patient at the time of presentation was stage IIB (T3N0M0), with tumor size greater than 5 cm, nodes negative by clinical examination, and no distant metastasis. In a span of 3 months, she had metastasis to the skin, subcutaneous tissue, and distant lymph nodes, which resulted in classification as stage IV, proving the aggressive nature of the tumor.

The newly discovered Merkel cell polyomavirus (MCPyV) is found integrating into the Merkel cell genome. Merkel cell polyomavirus is present in 80% of cancers and is expressed in a clonal pattern, while 90% of MCC patients are seropositive for the same. Unlike antibodies to MCPyV VP1 protein, antibodies to the T antigen for MCPyV track disease burden and may be a useful biomarker for MCC in the future.⁶

A study of 251 patients in 1970-2002 showed that pathologic nodal staging identifies a group of patients with excellent long-term survival.¹ Our patient preferred to undergo positron emission tomography rather than a sentinel lymph node biopsy prior to surgery. Also, after margin-negative excision and pathologic nodal staging, local and nodal recurrence rates were low. Adjuvant chemotherapy for stage III patients showed a trend (P=.08) to decreased survival compared with stage II patients who did not receive chemotherapy.⁷ A multidisciplinary approach to treatment including surgery, radiation,⁸ and chemotherapy needs to be created for each individual patient. Merkel cell carcinoma is the cause of death in 35% of patients within 3 years of diagnosis.⁹

Merkel cell carcinoma is a rare orphan tumor with rapidly increasing incidence in an era of immunosuppression. It has a grave prognosis, as demonstrated in our case, if not detected early. People at increased risk for MCC must have regular skin checks. Unfortunately, our patient was a nursing home resident and had not had a skin check for 2 years prior to presentation.

The Diagnosis: Merkel Cell Carcinoma

Histopathology showed small round cells (Figure 1) that stained positive for cytokeratin 20 in a paranuclear dotlike pattern (Figure 2). The tumor stained negative for lymphoma (CD45) marker. Fluorodeoxyglucose positron emission tomography showed focally increased activity at cutaneous sites corresponding to the nodules, but lymph nodes and visceral sites did not show areas of increased metabolic activity. She underwent an above-knee amputation. She was started on a chemotherapy regimen of etoposide and carboplatin given that the pathology of the excised limb demonstrated vascular and lymphatic invasion by the tumor cells in the proximal skin margin. After 4 months she presented with gangrenous changes of the amputated limb and evidence of metastasis to the region of the skin flap. Similar tumors presented on the ipsilateral hip. Given her general poor condition and aggressive nature of the tumor, the patient decided to pursue hospice care 6 months after her diagnosis of Merkel cell carcinoma (MCC).

Figure 1. The tumor was composed of sheets of cells with a high nuclear-cytoplasmic ratio and fine chromatin without nucleoli (H&E, original magnification ×40).

Figure 2. Immunohistochemical staining for cytokera-tin 20 showed positivity in a paranuclear dotlike pattern (original magnification ×40).

Merkel cell carcinoma usually presents as firm, red to purple papules on sun-exposed skin in older patients with light skin. Factors strongly associated with the development of MCC are age (>65 years), lighter skin types, history of extensive sun exposure, and chronic immune suppression (eg, kidney or heart transplantation, human immunodeficiency virus).¹ The rate of MCC has increased 3-fold between 1986 and 2001; the rate of MCC was 0.15 cases per 100,000 individuals in 1986, climbing up to 0.44 cases per 100,000 individuals in 2001.² Our patient had been on immunosuppressants—prednisone, cyclosporine, and sirolimus—for nearly a decade following kidney transplants, which had been discontinued 2 years prior to presentation.

Heath et al³ defined an acronym AEIOU (asymptomatic/lack of tenderness, expanding rapidly, immune suppression, older than 50 years, UV-exposed site on a person with fair skin) for MCC features derived from 195 patients. They advised that a biopsy is warranted if the patient presents with more than 3 of these features.³

The 1991 MCC staging system was revised in 1999 and 2005 based on experience at Memorial Sloan Kettering Cancer Center (New York, New York).⁴ In 2010 the American Joint Committee on Cancer staging was introduced for MCC, which follows other skin malignancies.⁵ Using this TNM staging system for primary tumors, regional lymph nodes, and distant metastasis, our patient at the time of presentation was stage IIB (T3N0M0), with tumor size greater than 5 cm, nodes negative by clinical examination, and no distant metastasis. In a span of 3 months, she had metastasis to the skin, subcutaneous tissue, and distant lymph nodes, which resulted in classification as stage IV, proving the aggressive nature of the tumor.

The newly discovered Merkel cell polyomavirus (MCPyV) is found integrating into the Merkel cell genome. Merkel cell polyomavirus is present in 80% of cancers and is expressed in a clonal pattern, while 90% of MCC patients are seropositive for the same. Unlike antibodies to MCPyV VP1 protein, antibodies to the T antigen for MCPyV track disease burden and may be a useful biomarker for MCC in the future.⁶

A study of 251 patients in 1970-2002 showed that pathologic nodal staging identifies a group of patients with excellent long-term survival.¹ Our patient preferred to undergo positron emission tomography rather than a sentinel lymph node biopsy prior to surgery. Also, after margin-negative excision and pathologic nodal staging, local and nodal recurrence rates were low. Adjuvant chemotherapy for stage III patients showed a trend (P=.08) to decreased survival compared with stage II patients who did not receive chemotherapy.⁷ A multidisciplinary approach to treatment including surgery, radiation,⁸ and chemotherapy needs to be created for each individual patient. Merkel cell carcinoma is the cause of death in 35% of patients within 3 years of diagnosis.⁹

Merkel cell carcinoma is a rare orphan tumor with rapidly increasing incidence in an era of immunosuppression. It has a grave prognosis, as demonstrated in our case, if not detected early. People at increased risk for MCC must have regular skin checks. Unfortunately, our patient was a nursing home resident and had not had a skin check for 2 years prior to presentation.

A 70-year-old woman presented to our dermatology clinic with an enlarging lesion on the left anterior aspect of the scalp of 4 years’ duration. She had a history of breast carcinoma in the left breast with positive lymph nodes 2 years prior. Physical examination revealed a 2.5-cm pink, pearly, exophytic plaque on the left anterior aspect of the scalp. The lesion was removed with clear margins by excisional surgery.

The Diagnosis: Clear Cell Hidradenoma

Clear cell hidradenoma (CCH) is a variant of nodular hidradenoma that may contain varying quantities of solid and cystic components and comprises approximately one-third of hidradenomas.¹ Clear cell hidradenomas are slow-growing and fairly uncommon adnexal neoplasms derived from either eccrine sweat glands or apocrine glands. Some researchers have regarded hidradenomas as apocrine tumors due to evidence of apocrine decapitation secretion, whereas others note the lack of apocrine and ultrastructural features of immature eccrine glands.² Clear cell hidradenomas typically develop between the fourth and eighth decades of life, usually peaking during the sixth decade.³ Clear cell hidradenomas usually range in size from 5 to 30 mm and frequently present on the scalp, head, chest, and abdomen; rarely, CCHs present on the joint spaces of the shoulders and knees.^3-5 This neoplasm is more common in women than men³ and generally has a flesh-colored, erythematous, red-brown or blue appearance with a tendency to ulcerate and exude a serous discharge (Figure 1).⁵ The clinical differential diagnosis includes metastatic cancer (eg, renal cell carcinoma, keratoacanthoma, trichoblastoma, trichilemmoma) or other benign adnexal neoplasms.

Figure 1. A 2.5-cm pink plaque on the scalp.

Histopathologic examination of a CCH generally reveals an unencapsulated and circumscribed neoplasm in the mid or upper dermis with occasional extensions into the subcutaneous fat (Figure 2). The tumor typically presents with 2 types of cells: (1) round, fusiform, or polygonal cells with vesicular nuclei and eosinophilic cytoplasm, and (2) cells with clear cytoplasm and basophilic, often eccentrically located nuclei.⁶ Ducts are scattered within the neoplasm and are lined by a layer of cuboidal cells that can be highlighted on carcinoembryonic antigen and epithelial membrane antigen immunostaining.⁶ The tumor cells themselves are highlighted on cytokeratin AE1/AE3 staining.

Figure 2. Histopathologic examination revealed an endophytic/exophytic circumscribed neoplasm extending from the epidermis to the mid reticular dermis with several lobules composed of round cells with clear cytoplasm with several scattered ducts (H&E, original magnification ×4).

Malignant transformation rarely is associated with CCH, with de novo clear cell hidradenocarcinoma being more common. Only approximately 6.7% of CCHs have been shown to be malignant, and the malignant tumors feature nuclear atypia, abnormal mitotic figures, necrosis, and infiltration.^1,7 Although CCH is a benign adnexal neoplasm, it has a high recurrence rate (approximately 10%) following excision.⁷ The treatment of choice is complete surgical excision, though Mohs micrographic surgery is advocated, as it promotes thorough examination of the tumor margin to ensure complete tumor removal.8 Our case illustrates the importance of a broad differential diagnosis when treating patients with CCH as well as keeping in mind nonmalignant lesions are far more common than malignant lesions.  

A 70-year-old woman presented to our dermatology clinic with an enlarging lesion on the left anterior aspect of the scalp of 4 years’ duration. She had a history of breast carcinoma in the left breast with positive lymph nodes 2 years prior. Physical examination revealed a 2.5-cm pink, pearly, exophytic plaque on the left anterior aspect of the scalp. The lesion was removed with clear margins by excisional surgery.

The Diagnosis: Clear Cell Hidradenoma

Clear cell hidradenoma (CCH) is a variant of nodular hidradenoma that may contain varying quantities of solid and cystic components and comprises approximately one-third of hidradenomas.¹ Clear cell hidradenomas are slow-growing and fairly uncommon adnexal neoplasms derived from either eccrine sweat glands or apocrine glands. Some researchers have regarded hidradenomas as apocrine tumors due to evidence of apocrine decapitation secretion, whereas others note the lack of apocrine and ultrastructural features of immature eccrine glands.² Clear cell hidradenomas typically develop between the fourth and eighth decades of life, usually peaking during the sixth decade.³ Clear cell hidradenomas usually range in size from 5 to 30 mm and frequently present on the scalp, head, chest, and abdomen; rarely, CCHs present on the joint spaces of the shoulders and knees.^3-5 This neoplasm is more common in women than men³ and generally has a flesh-colored, erythematous, red-brown or blue appearance with a tendency to ulcerate and exude a serous discharge (Figure 1).⁵ The clinical differential diagnosis includes metastatic cancer (eg, renal cell carcinoma, keratoacanthoma, trichoblastoma, trichilemmoma) or other benign adnexal neoplasms.

Figure 1. A 2.5-cm pink plaque on the scalp.

Histopathologic examination of a CCH generally reveals an unencapsulated and circumscribed neoplasm in the mid or upper dermis with occasional extensions into the subcutaneous fat (Figure 2). The tumor typically presents with 2 types of cells: (1) round, fusiform, or polygonal cells with vesicular nuclei and eosinophilic cytoplasm, and (2) cells with clear cytoplasm and basophilic, often eccentrically located nuclei.⁶ Ducts are scattered within the neoplasm and are lined by a layer of cuboidal cells that can be highlighted on carcinoembryonic antigen and epithelial membrane antigen immunostaining.⁶ The tumor cells themselves are highlighted on cytokeratin AE1/AE3 staining.

Figure 2. Histopathologic examination revealed an endophytic/exophytic circumscribed neoplasm extending from the epidermis to the mid reticular dermis with several lobules composed of round cells with clear cytoplasm with several scattered ducts (H&E, original magnification ×4).

Malignant transformation rarely is associated with CCH, with de novo clear cell hidradenocarcinoma being more common. Only approximately 6.7% of CCHs have been shown to be malignant, and the malignant tumors feature nuclear atypia, abnormal mitotic figures, necrosis, and infiltration.^1,7 Although CCH is a benign adnexal neoplasm, it has a high recurrence rate (approximately 10%) following excision.⁷ The treatment of choice is complete surgical excision, though Mohs micrographic surgery is advocated, as it promotes thorough examination of the tumor margin to ensure complete tumor removal.8 Our case illustrates the importance of a broad differential diagnosis when treating patients with CCH as well as keeping in mind nonmalignant lesions are far more common than malignant lesions.  

A 70-year-old woman presented to our dermatology clinic with an enlarging lesion on the left anterior aspect of the scalp of 4 years’ duration. She had a history of breast carcinoma in the left breast with positive lymph nodes 2 years prior. Physical examination revealed a 2.5-cm pink, pearly, exophytic plaque on the left anterior aspect of the scalp. The lesion was removed with clear margins by excisional surgery.

The Diagnosis: Clear Cell Hidradenoma

Clear cell hidradenoma (CCH) is a variant of nodular hidradenoma that may contain varying quantities of solid and cystic components and comprises approximately one-third of hidradenomas.¹ Clear cell hidradenomas are slow-growing and fairly uncommon adnexal neoplasms derived from either eccrine sweat glands or apocrine glands. Some researchers have regarded hidradenomas as apocrine tumors due to evidence of apocrine decapitation secretion, whereas others note the lack of apocrine and ultrastructural features of immature eccrine glands.² Clear cell hidradenomas typically develop between the fourth and eighth decades of life, usually peaking during the sixth decade.³ Clear cell hidradenomas usually range in size from 5 to 30 mm and frequently present on the scalp, head, chest, and abdomen; rarely, CCHs present on the joint spaces of the shoulders and knees.^3-5 This neoplasm is more common in women than men³ and generally has a flesh-colored, erythematous, red-brown or blue appearance with a tendency to ulcerate and exude a serous discharge (Figure 1).⁵ The clinical differential diagnosis includes metastatic cancer (eg, renal cell carcinoma, keratoacanthoma, trichoblastoma, trichilemmoma) or other benign adnexal neoplasms.

Figure 1. A 2.5-cm pink plaque on the scalp.

Histopathologic examination of a CCH generally reveals an unencapsulated and circumscribed neoplasm in the mid or upper dermis with occasional extensions into the subcutaneous fat (Figure 2). The tumor typically presents with 2 types of cells: (1) round, fusiform, or polygonal cells with vesicular nuclei and eosinophilic cytoplasm, and (2) cells with clear cytoplasm and basophilic, often eccentrically located nuclei.⁶ Ducts are scattered within the neoplasm and are lined by a layer of cuboidal cells that can be highlighted on carcinoembryonic antigen and epithelial membrane antigen immunostaining.⁶ The tumor cells themselves are highlighted on cytokeratin AE1/AE3 staining.

Figure 2. Histopathologic examination revealed an endophytic/exophytic circumscribed neoplasm extending from the epidermis to the mid reticular dermis with several lobules composed of round cells with clear cytoplasm with several scattered ducts (H&E, original magnification ×4).

Malignant transformation rarely is associated with CCH, with de novo clear cell hidradenocarcinoma being more common. Only approximately 6.7% of CCHs have been shown to be malignant, and the malignant tumors feature nuclear atypia, abnormal mitotic figures, necrosis, and infiltration.^1,7 Although CCH is a benign adnexal neoplasm, it has a high recurrence rate (approximately 10%) following excision.⁷ The treatment of choice is complete surgical excision, though Mohs micrographic surgery is advocated, as it promotes thorough examination of the tumor margin to ensure complete tumor removal.8 Our case illustrates the importance of a broad differential diagnosis when treating patients with CCH as well as keeping in mind nonmalignant lesions are far more common than malignant lesions.  

Tumor of the follicular infundibulum (TFI) was first described by Mehregan and Butler¹ in a patient with multiple papules. It typically presents as a solitary lesion that mainly affects the face, neck, and upper trunk, and it generally occurs in elderly patients with a female predilection and occasional vulvar involvement. Sometimes TFI may coexist with an unusual trichilemmal tumor or basal cell carcinoma (BCC) with sebaceous or sweat duct differentiation. Other features of TFI include an eosinophilic cuticle, ductal differentiation, coronoid lamellae, and desmoplasia. Interestingly, approximately one-fourth of reported TFIs were found to be associated with other cutaneous lesions, including BCC, actinic keratosis, desmoplastic malignant melanoma, junctional melanocytic nevus, trichilemmoma, and epidermal inclusion cyst.² Eruptive forms of TFI are rare, presenting as macules, smooth or slightly keratotic papules, or depressed lesions with a flesh-colored erythematous or hypopigmented appearance. We report the case of a 49-year-old woman with multiple TFIs and some new features.

Case Report

A 49-year-old woman presented with multiple lesions on the arms, shoulders, trunk, buttocks, and legs of more than 3 years’ duration. According to the patient, multiple small, reddish papules gradually appeared on the arms and legs approximately 3 years prior to presentation and were accompanied by considerable pruritus. She sought medical assistance several times at local clinics. A diagnosis of eczema and prurigo was made and oral antihistamines and topical glucocorticoids were administered for more than 2 years. The pruritus was controlled to some degree but recurred after discontinuation of treatment. Five months later, the lesions flared up suddenly and rapidly to the back and buttocks, just around the skin areas treated with cupping glass, a traditional Chinese therapy, for heat syncope. She reported constant itching that kept her awake at night.

Physical examination revealed hundreds of erythematous maculopapules scattered over the arms, shoulders, trunk, buttocks, and legs. The individual lesions were minimally elevated, irregularly shaped, and slightly scaly, and they were distributed in a relatively symmetrical manner. Some of the lesions coalesced to form small plaques measuring approximately 0.5 to 3 cm in diameter (Figure 1). Interestingly, several annulated lesions with a hypopigmented center and hyperpigmented periphery could be observed at areas treated with cupping glass, showing a typical presentation of the Köbner phenomenon (Figure 2). No obvious association with sun exposure or hair loss was detected. The patient’s medical history was unremarkable and there was no known family history of similar skin lesions.

Figure 1. Erythematous maculopapules scattered over the upper back. Lesions were minimally elevated, irregularly shaped, and slightly scaly, and they were distributed in a relatively symmetrical pattern. Some of the lesions coalesced to form small plaques measuring approximately 0.5 to 3 cm in diameter. Figure 2. Several annulated lesions with a hypopigmented center and hyperpigmented periphery could be observed on the back at areas treated with cupping glass, a typical presentation of the Köbner phenomenon.

The differential diagnosis included lichen planus, prurigo, and adnexal tumors. Histopathologic examination of biopsies from lesions on the back and around the cupping glass areas revealed a benign platelike proliferation of pale-staining epithelial cells in the papillary dermis connected to the overlying epidermis with a moderate lymphatic cell infiltration (Figure 3A). Weigert staining revealed a network of elastic fibers surrounding the base of the tumor (Figure 3B). The pale epithelial cells were positive on periodic acid–Schiff staining (Figure 3C). Immunohistochemical staining revealed that the proliferation was positive for keratin 17 (Figure 3D).

These striking clinical and histological findings suggested the lesions were multiple TFIs. Treatment with tretinoin ointment 0.1% twice daily for 2 months was ineffective. The patient refused treatment with either oral acitretin or dapsone or invasive techniques such as lasers and cryotherapy. She has been on careful follow-up for the last 2 years with new lesions appearing intermittently.

Comment

The etiology of TFI still is unknown but may be related to environmental factors or genetic changes. Tumors of the follicular infundibulum generally are classified as solitary, eruptive, associated with other lesions of Cowden disease, associated with a single tumor, or TFI-like epidermal changes.³ The eruptive form has seldom been reported to date. Eruptive TFIs are nonspecific, ranging in number from several to more than 100. Clinical characteristics and distribution of the lesions can vary from patient to patient, but the lesions tend to be quite monomorphous, even in cases with more than 100 lesions.⁴ Histopathologic features usually are typical and distinctive, allowing its definite diagnosis. To confirm the diagnosis, the immunohistochemical profile may be useful to characterize its follicular origin, which is positive for keratin 17. Tumors of the follicular infundibulum usually are benign; however, in one patient with more than 100 lesions, there was documented transformation into BCC.⁵ Due to the potential for malignant transformation as well as its occurrence within the spectrum of lesions associated with Cowden disease,^6,7 long-term supervision of TFI is strongly recommended, as was the case with our patient.

A remarkable feature in our case was the patient’s severe pruritus, as most reported cases have been asymptomatic. The increased association with other cutaneous lesions,² the Köbner phenomenon, and the underlying inflammatory cell infiltration of the tumors in our case strongly suggested that eruptive TFI may represent a kind of cutaneous reaction.

Figure 3. Histopathologically, a benign platelike proliferation of pale-staining keratinocytes and follicular structures could be observed in the papillary dermis connected to the overlying epidermis with a moderate lymphatic cell infiltration (A)(H&E, original magnification ×40). Weigert staining showed a network of black-blue elastic fi-bers at the base of the tumor (B) (original magnification ×200). The pale kerat- inocytes were positive on periodic acid–Schiff staining (C)(original magnification ×100). Immunohis-tochemically, the proliferation of keratinocytes was positive for keratin 17 (D)(diaminobenzidine, original magnification ×100).

Conclusion

The clinical findings of severe pruritus and the Köbner phenomenon in our patient further expand the constellation of the clinical presentation of the eruptive variant of TFI.

Tumor of the follicular infundibulum (TFI) was first described by Mehregan and Butler¹ in a patient with multiple papules. It typically presents as a solitary lesion that mainly affects the face, neck, and upper trunk, and it generally occurs in elderly patients with a female predilection and occasional vulvar involvement. Sometimes TFI may coexist with an unusual trichilemmal tumor or basal cell carcinoma (BCC) with sebaceous or sweat duct differentiation. Other features of TFI include an eosinophilic cuticle, ductal differentiation, coronoid lamellae, and desmoplasia. Interestingly, approximately one-fourth of reported TFIs were found to be associated with other cutaneous lesions, including BCC, actinic keratosis, desmoplastic malignant melanoma, junctional melanocytic nevus, trichilemmoma, and epidermal inclusion cyst.² Eruptive forms of TFI are rare, presenting as macules, smooth or slightly keratotic papules, or depressed lesions with a flesh-colored erythematous or hypopigmented appearance. We report the case of a 49-year-old woman with multiple TFIs and some new features.

Case Report

A 49-year-old woman presented with multiple lesions on the arms, shoulders, trunk, buttocks, and legs of more than 3 years’ duration. According to the patient, multiple small, reddish papules gradually appeared on the arms and legs approximately 3 years prior to presentation and were accompanied by considerable pruritus. She sought medical assistance several times at local clinics. A diagnosis of eczema and prurigo was made and oral antihistamines and topical glucocorticoids were administered for more than 2 years. The pruritus was controlled to some degree but recurred after discontinuation of treatment. Five months later, the lesions flared up suddenly and rapidly to the back and buttocks, just around the skin areas treated with cupping glass, a traditional Chinese therapy, for heat syncope. She reported constant itching that kept her awake at night.

Physical examination revealed hundreds of erythematous maculopapules scattered over the arms, shoulders, trunk, buttocks, and legs. The individual lesions were minimally elevated, irregularly shaped, and slightly scaly, and they were distributed in a relatively symmetrical manner. Some of the lesions coalesced to form small plaques measuring approximately 0.5 to 3 cm in diameter (Figure 1). Interestingly, several annulated lesions with a hypopigmented center and hyperpigmented periphery could be observed at areas treated with cupping glass, showing a typical presentation of the Köbner phenomenon (Figure 2). No obvious association with sun exposure or hair loss was detected. The patient’s medical history was unremarkable and there was no known family history of similar skin lesions.

Figure 1. Erythematous maculopapules scattered over the upper back. Lesions were minimally elevated, irregularly shaped, and slightly scaly, and they were distributed in a relatively symmetrical pattern. Some of the lesions coalesced to form small plaques measuring approximately 0.5 to 3 cm in diameter. Figure 2. Several annulated lesions with a hypopigmented center and hyperpigmented periphery could be observed on the back at areas treated with cupping glass, a typical presentation of the Köbner phenomenon.

The differential diagnosis included lichen planus, prurigo, and adnexal tumors. Histopathologic examination of biopsies from lesions on the back and around the cupping glass areas revealed a benign platelike proliferation of pale-staining epithelial cells in the papillary dermis connected to the overlying epidermis with a moderate lymphatic cell infiltration (Figure 3A). Weigert staining revealed a network of elastic fibers surrounding the base of the tumor (Figure 3B). The pale epithelial cells were positive on periodic acid–Schiff staining (Figure 3C). Immunohistochemical staining revealed that the proliferation was positive for keratin 17 (Figure 3D).

These striking clinical and histological findings suggested the lesions were multiple TFIs. Treatment with tretinoin ointment 0.1% twice daily for 2 months was ineffective. The patient refused treatment with either oral acitretin or dapsone or invasive techniques such as lasers and cryotherapy. She has been on careful follow-up for the last 2 years with new lesions appearing intermittently.

Comment

The etiology of TFI still is unknown but may be related to environmental factors or genetic changes. Tumors of the follicular infundibulum generally are classified as solitary, eruptive, associated with other lesions of Cowden disease, associated with a single tumor, or TFI-like epidermal changes.³ The eruptive form has seldom been reported to date. Eruptive TFIs are nonspecific, ranging in number from several to more than 100. Clinical characteristics and distribution of the lesions can vary from patient to patient, but the lesions tend to be quite monomorphous, even in cases with more than 100 lesions.⁴ Histopathologic features usually are typical and distinctive, allowing its definite diagnosis. To confirm the diagnosis, the immunohistochemical profile may be useful to characterize its follicular origin, which is positive for keratin 17. Tumors of the follicular infundibulum usually are benign; however, in one patient with more than 100 lesions, there was documented transformation into BCC.⁵ Due to the potential for malignant transformation as well as its occurrence within the spectrum of lesions associated with Cowden disease,^6,7 long-term supervision of TFI is strongly recommended, as was the case with our patient.

A remarkable feature in our case was the patient’s severe pruritus, as most reported cases have been asymptomatic. The increased association with other cutaneous lesions,² the Köbner phenomenon, and the underlying inflammatory cell infiltration of the tumors in our case strongly suggested that eruptive TFI may represent a kind of cutaneous reaction.

Figure 3. Histopathologically, a benign platelike proliferation of pale-staining keratinocytes and follicular structures could be observed in the papillary dermis connected to the overlying epidermis with a moderate lymphatic cell infiltration (A)(H&E, original magnification ×40). Weigert staining showed a network of black-blue elastic fi-bers at the base of the tumor (B) (original magnification ×200). The pale kerat- inocytes were positive on periodic acid–Schiff staining (C)(original magnification ×100). Immunohis-tochemically, the proliferation of keratinocytes was positive for keratin 17 (D)(diaminobenzidine, original magnification ×100).

Conclusion

The clinical findings of severe pruritus and the Köbner phenomenon in our patient further expand the constellation of the clinical presentation of the eruptive variant of TFI.

Tumor of the follicular infundibulum (TFI) was first described by Mehregan and Butler¹ in a patient with multiple papules. It typically presents as a solitary lesion that mainly affects the face, neck, and upper trunk, and it generally occurs in elderly patients with a female predilection and occasional vulvar involvement. Sometimes TFI may coexist with an unusual trichilemmal tumor or basal cell carcinoma (BCC) with sebaceous or sweat duct differentiation. Other features of TFI include an eosinophilic cuticle, ductal differentiation, coronoid lamellae, and desmoplasia. Interestingly, approximately one-fourth of reported TFIs were found to be associated with other cutaneous lesions, including BCC, actinic keratosis, desmoplastic malignant melanoma, junctional melanocytic nevus, trichilemmoma, and epidermal inclusion cyst.² Eruptive forms of TFI are rare, presenting as macules, smooth or slightly keratotic papules, or depressed lesions with a flesh-colored erythematous or hypopigmented appearance. We report the case of a 49-year-old woman with multiple TFIs and some new features.

Case Report

A 49-year-old woman presented with multiple lesions on the arms, shoulders, trunk, buttocks, and legs of more than 3 years’ duration. According to the patient, multiple small, reddish papules gradually appeared on the arms and legs approximately 3 years prior to presentation and were accompanied by considerable pruritus. She sought medical assistance several times at local clinics. A diagnosis of eczema and prurigo was made and oral antihistamines and topical glucocorticoids were administered for more than 2 years. The pruritus was controlled to some degree but recurred after discontinuation of treatment. Five months later, the lesions flared up suddenly and rapidly to the back and buttocks, just around the skin areas treated with cupping glass, a traditional Chinese therapy, for heat syncope. She reported constant itching that kept her awake at night.

Physical examination revealed hundreds of erythematous maculopapules scattered over the arms, shoulders, trunk, buttocks, and legs. The individual lesions were minimally elevated, irregularly shaped, and slightly scaly, and they were distributed in a relatively symmetrical manner. Some of the lesions coalesced to form small plaques measuring approximately 0.5 to 3 cm in diameter (Figure 1). Interestingly, several annulated lesions with a hypopigmented center and hyperpigmented periphery could be observed at areas treated with cupping glass, showing a typical presentation of the Köbner phenomenon (Figure 2). No obvious association with sun exposure or hair loss was detected. The patient’s medical history was unremarkable and there was no known family history of similar skin lesions.

Figure 1. Erythematous maculopapules scattered over the upper back. Lesions were minimally elevated, irregularly shaped, and slightly scaly, and they were distributed in a relatively symmetrical pattern. Some of the lesions coalesced to form small plaques measuring approximately 0.5 to 3 cm in diameter. Figure 2. Several annulated lesions with a hypopigmented center and hyperpigmented periphery could be observed on the back at areas treated with cupping glass, a typical presentation of the Köbner phenomenon.

The differential diagnosis included lichen planus, prurigo, and adnexal tumors. Histopathologic examination of biopsies from lesions on the back and around the cupping glass areas revealed a benign platelike proliferation of pale-staining epithelial cells in the papillary dermis connected to the overlying epidermis with a moderate lymphatic cell infiltration (Figure 3A). Weigert staining revealed a network of elastic fibers surrounding the base of the tumor (Figure 3B). The pale epithelial cells were positive on periodic acid–Schiff staining (Figure 3C). Immunohistochemical staining revealed that the proliferation was positive for keratin 17 (Figure 3D).

These striking clinical and histological findings suggested the lesions were multiple TFIs. Treatment with tretinoin ointment 0.1% twice daily for 2 months was ineffective. The patient refused treatment with either oral acitretin or dapsone or invasive techniques such as lasers and cryotherapy. She has been on careful follow-up for the last 2 years with new lesions appearing intermittently.

Comment

The etiology of TFI still is unknown but may be related to environmental factors or genetic changes. Tumors of the follicular infundibulum generally are classified as solitary, eruptive, associated with other lesions of Cowden disease, associated with a single tumor, or TFI-like epidermal changes.³ The eruptive form has seldom been reported to date. Eruptive TFIs are nonspecific, ranging in number from several to more than 100. Clinical characteristics and distribution of the lesions can vary from patient to patient, but the lesions tend to be quite monomorphous, even in cases with more than 100 lesions.⁴ Histopathologic features usually are typical and distinctive, allowing its definite diagnosis. To confirm the diagnosis, the immunohistochemical profile may be useful to characterize its follicular origin, which is positive for keratin 17. Tumors of the follicular infundibulum usually are benign; however, in one patient with more than 100 lesions, there was documented transformation into BCC.⁵ Due to the potential for malignant transformation as well as its occurrence within the spectrum of lesions associated with Cowden disease,^6,7 long-term supervision of TFI is strongly recommended, as was the case with our patient.

A remarkable feature in our case was the patient’s severe pruritus, as most reported cases have been asymptomatic. The increased association with other cutaneous lesions,² the Köbner phenomenon, and the underlying inflammatory cell infiltration of the tumors in our case strongly suggested that eruptive TFI may represent a kind of cutaneous reaction.

Figure 3. Histopathologically, a benign platelike proliferation of pale-staining keratinocytes and follicular structures could be observed in the papillary dermis connected to the overlying epidermis with a moderate lymphatic cell infiltration (A)(H&E, original magnification ×40). Weigert staining showed a network of black-blue elastic fi-bers at the base of the tumor (B) (original magnification ×200). The pale kerat- inocytes were positive on periodic acid–Schiff staining (C)(original magnification ×100). Immunohis-tochemically, the proliferation of keratinocytes was positive for keratin 17 (D)(diaminobenzidine, original magnification ×100).

Conclusion

The clinical findings of severe pruritus and the Köbner phenomenon in our patient further expand the constellation of the clinical presentation of the eruptive variant of TFI.

SAN DIEGO – Histology of basal cell carcinomas removed by Mohs micrographic surgery showed that presurgical biopsies had not revealed all tumor subtypes in 64% of cases, and had underestimated the aggressiveness of the tumors 24% of the time, according to data from a large, multicenter, retrospective study.

“Unfortunately, while cheap and cost-effective, biopsies are a subsample of the full malignancy,” said Dr. Murad Alam, professor of dermatology, otolaryngology, and surgery at Northwestern University in Chicago. “Skin biopsy of basal cell carcinoma [BCC] may fail to detect all BCC subtypes, and as such may underestimate the aggressiveness of an individual BCC tumor.”

©Kelly Nelson/National Cancer Institute

Basal cell carcinoma is the most common skin cancer worldwide, and can broadly be grouped into aggressive and indolent types, Dr. Alam said at the annual meeting of the American Society for Dermatologic Surgery. But tumors often show mixed histology, and cancer treatment needs to target the most aggressive subtype present in the tumor, he added. Results of past studies suggested that biopsies of BCCs could miss tumor subtypes, but the current research is the first large, multicenter study to confirm these findings, he and his associates said.

For the study, the investigators compared biopsy reports and microscopic slides of Mohs micrographic surgery (MMS) specimens from 871 consecutive cases of BCC treated at three hospitals in Illinois from 2013 to 2014. Patients first underwent biopsies, followed by complete excision of their tumors during MMS. Almost 59% of patients were male, and tumors were most commonly removed from the nose or cheek. In all, 78% of biopsies were obtained by the shave technique, but punch and excisional biopsies also were performed, the researchers noted.

Using standard definitions of BCC subtypes, the investigators compared levels of concordance between biopsy and MMS histology findings, Dr. Alam said. They also grouped tumor specimens as high risk (that is, infiltrative, morpheic, micronodular, basosquamous) or low risk (superficial or nodular), and determined whether tumor biopsy and MMS histology yielded the same or discordant risk assessments, he added.

Biopsies identified only 18% of tumors as being of mixed histology, compared with 57% of MMS specimens, said Dr. Alam. Biopsy results matched MMS histologies in only 31% of cases, while in 64% of cases, the MMS specimen yielded more tumor subtypes than the biopsy specimen. The researchers noted that biopsy yielded more subtypes than did MMS in 4% of cases, and that MMS and biopsy subtypes were fully discordant in only four cases.

Dr. Alam and his associates declared no external funding sources or conflicts of interest.

SAN DIEGO – Histology of basal cell carcinomas removed by Mohs micrographic surgery showed that presurgical biopsies had not revealed all tumor subtypes in 64% of cases, and had underestimated the aggressiveness of the tumors 24% of the time, according to data from a large, multicenter, retrospective study.

“Unfortunately, while cheap and cost-effective, biopsies are a subsample of the full malignancy,” said Dr. Murad Alam, professor of dermatology, otolaryngology, and surgery at Northwestern University in Chicago. “Skin biopsy of basal cell carcinoma [BCC] may fail to detect all BCC subtypes, and as such may underestimate the aggressiveness of an individual BCC tumor.”

©Kelly Nelson/National Cancer Institute

Basal cell carcinoma is the most common skin cancer worldwide, and can broadly be grouped into aggressive and indolent types, Dr. Alam said at the annual meeting of the American Society for Dermatologic Surgery. But tumors often show mixed histology, and cancer treatment needs to target the most aggressive subtype present in the tumor, he added. Results of past studies suggested that biopsies of BCCs could miss tumor subtypes, but the current research is the first large, multicenter study to confirm these findings, he and his associates said.

For the study, the investigators compared biopsy reports and microscopic slides of Mohs micrographic surgery (MMS) specimens from 871 consecutive cases of BCC treated at three hospitals in Illinois from 2013 to 2014. Patients first underwent biopsies, followed by complete excision of their tumors during MMS. Almost 59% of patients were male, and tumors were most commonly removed from the nose or cheek. In all, 78% of biopsies were obtained by the shave technique, but punch and excisional biopsies also were performed, the researchers noted.

Using standard definitions of BCC subtypes, the investigators compared levels of concordance between biopsy and MMS histology findings, Dr. Alam said. They also grouped tumor specimens as high risk (that is, infiltrative, morpheic, micronodular, basosquamous) or low risk (superficial or nodular), and determined whether tumor biopsy and MMS histology yielded the same or discordant risk assessments, he added.

Biopsies identified only 18% of tumors as being of mixed histology, compared with 57% of MMS specimens, said Dr. Alam. Biopsy results matched MMS histologies in only 31% of cases, while in 64% of cases, the MMS specimen yielded more tumor subtypes than the biopsy specimen. The researchers noted that biopsy yielded more subtypes than did MMS in 4% of cases, and that MMS and biopsy subtypes were fully discordant in only four cases.

Dr. Alam and his associates declared no external funding sources or conflicts of interest.

SAN DIEGO – Histology of basal cell carcinomas removed by Mohs micrographic surgery showed that presurgical biopsies had not revealed all tumor subtypes in 64% of cases, and had underestimated the aggressiveness of the tumors 24% of the time, according to data from a large, multicenter, retrospective study.

“Unfortunately, while cheap and cost-effective, biopsies are a subsample of the full malignancy,” said Dr. Murad Alam, professor of dermatology, otolaryngology, and surgery at Northwestern University in Chicago. “Skin biopsy of basal cell carcinoma [BCC] may fail to detect all BCC subtypes, and as such may underestimate the aggressiveness of an individual BCC tumor.”

©Kelly Nelson/National Cancer Institute

Basal cell carcinoma is the most common skin cancer worldwide, and can broadly be grouped into aggressive and indolent types, Dr. Alam said at the annual meeting of the American Society for Dermatologic Surgery. But tumors often show mixed histology, and cancer treatment needs to target the most aggressive subtype present in the tumor, he added. Results of past studies suggested that biopsies of BCCs could miss tumor subtypes, but the current research is the first large, multicenter study to confirm these findings, he and his associates said.

For the study, the investigators compared biopsy reports and microscopic slides of Mohs micrographic surgery (MMS) specimens from 871 consecutive cases of BCC treated at three hospitals in Illinois from 2013 to 2014. Patients first underwent biopsies, followed by complete excision of their tumors during MMS. Almost 59% of patients were male, and tumors were most commonly removed from the nose or cheek. In all, 78% of biopsies were obtained by the shave technique, but punch and excisional biopsies also were performed, the researchers noted.

Using standard definitions of BCC subtypes, the investigators compared levels of concordance between biopsy and MMS histology findings, Dr. Alam said. They also grouped tumor specimens as high risk (that is, infiltrative, morpheic, micronodular, basosquamous) or low risk (superficial or nodular), and determined whether tumor biopsy and MMS histology yielded the same or discordant risk assessments, he added.

Biopsies identified only 18% of tumors as being of mixed histology, compared with 57% of MMS specimens, said Dr. Alam. Biopsy results matched MMS histologies in only 31% of cases, while in 64% of cases, the MMS specimen yielded more tumor subtypes than the biopsy specimen. The researchers noted that biopsy yielded more subtypes than did MMS in 4% of cases, and that MMS and biopsy subtypes were fully discordant in only four cases.

Dr. Alam and his associates declared no external funding sources or conflicts of interest.

SAN DIEGO – Patients treated with vismodegib for locally advanced or metastatic basal cell carcinoma went a median of 15 months before their disease progressed or they stopped treatment because of side effects, according to a 30-month update of the pivotal ERIVANCE basal cell carcinoma study.

Median progression-free survival on the first-in-class oral hedgehog-pathway inhibitor was 9 months, reported Dr. Seaver Soon at the annual meeting of the American Society for Dermatologic Surgery.

Data from two other trials of vismodegib resemble results from ERIVANCE, added Dr. Soon, a dermatologist in private practice in La Jolla, Calif. An expanded access study (J. Am. Acad. Dermatol 2014;70:60-9) of 119 patients with advanced basal cell carcinoma (BCC) reported comparable objective response rates (46.4% for patients with locally advanced BCC and 30.8% for patients with metastatic disease), and an interim analysis of data from the STEVIE trial had findings that were “very similar” to ERIVANCE, he said.

Thus far, vismodegib “offers a hope in treating otherwise difficult to manage, unresectable basal cell carcinoma tumors,” said Dr. Iren Kossintseva, a dermatologist in Vancouver, B.C. But the drug “may not be as tissue sparing as promised, she added. In a patient with chronic lymphocytic leukemia who had a large BCC on his lower eyelid and cheek, 7.5 months of vismodegib reduced the exophyticity and erosiveness of the tumor, but “likely did not substantially reduce the overall extent of necessary reconstruction,” she reported.

Vismodegib can cause potentially severe side effects. All seven patients who Dr. Kossintseva treated with 150 mg vismodegib per day during 2013-2014 developed “notable” adverse effects – including polycyclic rash, sensory and motor problems within the tumor area, bilateral edema of the lower limbs, congestive heart failure, and renal failure that has been slow to improve after stopping vismodegib, she said. “These are unique patients, and it’s often an uphill battle with these patients,” she added.

Tumors also can exhibit primary and secondary resistance to vismodegib, Dr. Soon noted. Studies have shown primary resistance characterized by tumor progression after as little as 2 months of treatment (Mol. Oncol. 2014; S1574-7891:00216-6) while secondary (or acquired) resistance occurs after an initial response to treatment and is linked to a mutation that interferes with drug binding, he said. Acquired resistance typically occurs when patients have been on vismodegib for about a year, Dr. Soon added. “Concurrent treatment with an alternative smoothened inhibitor, such as itraconazole, and downstream target inhibitors may overcome resistance,” he said. Dr. Kossintseva declared no conflicts of interest. Dr. Soon reported receiving honoraria and research grants from Genentech, the maker of vismodegib.

SAN DIEGO – Patients treated with vismodegib for locally advanced or metastatic basal cell carcinoma went a median of 15 months before their disease progressed or they stopped treatment because of side effects, according to a 30-month update of the pivotal ERIVANCE basal cell carcinoma study.

Median progression-free survival on the first-in-class oral hedgehog-pathway inhibitor was 9 months, reported Dr. Seaver Soon at the annual meeting of the American Society for Dermatologic Surgery.

Data from two other trials of vismodegib resemble results from ERIVANCE, added Dr. Soon, a dermatologist in private practice in La Jolla, Calif. An expanded access study (J. Am. Acad. Dermatol 2014;70:60-9) of 119 patients with advanced basal cell carcinoma (BCC) reported comparable objective response rates (46.4% for patients with locally advanced BCC and 30.8% for patients with metastatic disease), and an interim analysis of data from the STEVIE trial had findings that were “very similar” to ERIVANCE, he said.

Thus far, vismodegib “offers a hope in treating otherwise difficult to manage, unresectable basal cell carcinoma tumors,” said Dr. Iren Kossintseva, a dermatologist in Vancouver, B.C. But the drug “may not be as tissue sparing as promised, she added. In a patient with chronic lymphocytic leukemia who had a large BCC on his lower eyelid and cheek, 7.5 months of vismodegib reduced the exophyticity and erosiveness of the tumor, but “likely did not substantially reduce the overall extent of necessary reconstruction,” she reported.

Vismodegib can cause potentially severe side effects. All seven patients who Dr. Kossintseva treated with 150 mg vismodegib per day during 2013-2014 developed “notable” adverse effects – including polycyclic rash, sensory and motor problems within the tumor area, bilateral edema of the lower limbs, congestive heart failure, and renal failure that has been slow to improve after stopping vismodegib, she said. “These are unique patients, and it’s often an uphill battle with these patients,” she added.

Tumors also can exhibit primary and secondary resistance to vismodegib, Dr. Soon noted. Studies have shown primary resistance characterized by tumor progression after as little as 2 months of treatment (Mol. Oncol. 2014; S1574-7891:00216-6) while secondary (or acquired) resistance occurs after an initial response to treatment and is linked to a mutation that interferes with drug binding, he said. Acquired resistance typically occurs when patients have been on vismodegib for about a year, Dr. Soon added. “Concurrent treatment with an alternative smoothened inhibitor, such as itraconazole, and downstream target inhibitors may overcome resistance,” he said. Dr. Kossintseva declared no conflicts of interest. Dr. Soon reported receiving honoraria and research grants from Genentech, the maker of vismodegib.

SAN DIEGO – Patients treated with vismodegib for locally advanced or metastatic basal cell carcinoma went a median of 15 months before their disease progressed or they stopped treatment because of side effects, according to a 30-month update of the pivotal ERIVANCE basal cell carcinoma study.

Median progression-free survival on the first-in-class oral hedgehog-pathway inhibitor was 9 months, reported Dr. Seaver Soon at the annual meeting of the American Society for Dermatologic Surgery.

Data from two other trials of vismodegib resemble results from ERIVANCE, added Dr. Soon, a dermatologist in private practice in La Jolla, Calif. An expanded access study (J. Am. Acad. Dermatol 2014;70:60-9) of 119 patients with advanced basal cell carcinoma (BCC) reported comparable objective response rates (46.4% for patients with locally advanced BCC and 30.8% for patients with metastatic disease), and an interim analysis of data from the STEVIE trial had findings that were “very similar” to ERIVANCE, he said.

Thus far, vismodegib “offers a hope in treating otherwise difficult to manage, unresectable basal cell carcinoma tumors,” said Dr. Iren Kossintseva, a dermatologist in Vancouver, B.C. But the drug “may not be as tissue sparing as promised, she added. In a patient with chronic lymphocytic leukemia who had a large BCC on his lower eyelid and cheek, 7.5 months of vismodegib reduced the exophyticity and erosiveness of the tumor, but “likely did not substantially reduce the overall extent of necessary reconstruction,” she reported.

Vismodegib can cause potentially severe side effects. All seven patients who Dr. Kossintseva treated with 150 mg vismodegib per day during 2013-2014 developed “notable” adverse effects – including polycyclic rash, sensory and motor problems within the tumor area, bilateral edema of the lower limbs, congestive heart failure, and renal failure that has been slow to improve after stopping vismodegib, she said. “These are unique patients, and it’s often an uphill battle with these patients,” she added.

Tumors also can exhibit primary and secondary resistance to vismodegib, Dr. Soon noted. Studies have shown primary resistance characterized by tumor progression after as little as 2 months of treatment (Mol. Oncol. 2014; S1574-7891:00216-6) while secondary (or acquired) resistance occurs after an initial response to treatment and is linked to a mutation that interferes with drug binding, he said. Acquired resistance typically occurs when patients have been on vismodegib for about a year, Dr. Soon added. “Concurrent treatment with an alternative smoothened inhibitor, such as itraconazole, and downstream target inhibitors may overcome resistance,” he said. Dr. Kossintseva declared no conflicts of interest. Dr. Soon reported receiving honoraria and research grants from Genentech, the maker of vismodegib.

In a June 29 article published online in Molecular Carcinogenesis, Fenton et al demonstrated that topical dasatinib treatment of UVB-exposed SKH1 hairless mice reduced the total tumor burden (ie, benign tumors, atypical benign tumors, squamous cell carcinomas) per mouse.

Dasatinib is a tyrosine kinase inhibitor currently used to treat imatinib-resistant chronic myeloid leukemia and Philadelphia chromosome positive acute lymphoblastic leukemia. Its mechanism of action is to block the activity of tyrosine kinases by attaching to their adenosine triphosphate–binding site. It can inhibit the activity of the following tyrosine kinases: Src family kinases (SFK), break point cluster region-Abelson (Bcr-Abl), Ephrin type-A receptor 2 (EphA2), platelet-derived growth factor receptor, and mast/stem cell factor receptor (also called CD117 or c-Kit).

Src family kinases are associated with transformation of cells and progression of cancer. Elevated Src family kinases activity is present in the majority of human carcinomas.

Fyn, a nonreceptor tyrosine kinase, is a member of the Src family kinases. Cell growth, cell migration, and protein kinase B (Akt)–mediated inhibition of apoptosis are influenced by Fyn activity. In addition, Fyn activity is overexpressed in cutaneous squamous cell carcinoma.

In conclusion, dasatinib—an Src family kinases inhibitor—was able to inhibit Fyn activity and thereby reduce UV-induced skin carcinogenesis.

What’s the issue?

In 1962, Falkson and Schulz (Br J Dermatol. 1962;74:229-236) noted not only inflammation and subsequent resolution of actinic keratoses after exposure to sunlight in a woman with colon cancer being treated with systemic 5-fluorouracil but also several other patients whose keratoses were seen to disappear during therapy without preceding erythema. Omura and Torre (JAMA. 1969;208:150-151) confirmed these observations in a woman with breast cancer whose actinic keratoses became inflamed after receiving intravenous 5-fluorouracil and subsequently faded. The route of drug administration was modified and 5-fluorouracil was applied topically. Today topical 5-fluorouracil is still used for the treatment of actinic keratoses.

Topical application of nitrogen mustard is used in the treatment of cutaneous T-cell lymphoma. In addition, intralesional administration of systemic antineoplastic agents has been used to treat cutaneous neoplasms: methotrexate for keratoacanthomas and rituximab for primary cutaneous B-cell lymphomas.

The Fenton et al study suggests that topical dasatinib may be a potential therapeutic intervention for the treatment of cutaneous squamous cell carcinoma. The investigators not only demonstrate laboratory data from mouse studies but also provide a potential molecular mechanism for drug-associated tumor suppression. Indeed, dasatinib solution, dasatinib cream, or both may be the next innovative therapy for the suppression of cutaneous squamous cell carcinoma in organ transplant and immunocompromised patients and for the potential management of this skin cancer in immunocompetent individuals. What do you think?

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In a June 29 article published online in Molecular Carcinogenesis, Fenton et al demonstrated that topical dasatinib treatment of UVB-exposed SKH1 hairless mice reduced the total tumor burden (ie, benign tumors, atypical benign tumors, squamous cell carcinomas) per mouse.

Dasatinib is a tyrosine kinase inhibitor currently used to treat imatinib-resistant chronic myeloid leukemia and Philadelphia chromosome positive acute lymphoblastic leukemia. Its mechanism of action is to block the activity of tyrosine kinases by attaching to their adenosine triphosphate–binding site. It can inhibit the activity of the following tyrosine kinases: Src family kinases (SFK), break point cluster region-Abelson (Bcr-Abl), Ephrin type-A receptor 2 (EphA2), platelet-derived growth factor receptor, and mast/stem cell factor receptor (also called CD117 or c-Kit).

Src family kinases are associated with transformation of cells and progression of cancer. Elevated Src family kinases activity is present in the majority of human carcinomas.

Fyn, a nonreceptor tyrosine kinase, is a member of the Src family kinases. Cell growth, cell migration, and protein kinase B (Akt)–mediated inhibition of apoptosis are influenced by Fyn activity. In addition, Fyn activity is overexpressed in cutaneous squamous cell carcinoma.

In conclusion, dasatinib—an Src family kinases inhibitor—was able to inhibit Fyn activity and thereby reduce UV-induced skin carcinogenesis.

What’s the issue?

In 1962, Falkson and Schulz (Br J Dermatol. 1962;74:229-236) noted not only inflammation and subsequent resolution of actinic keratoses after exposure to sunlight in a woman with colon cancer being treated with systemic 5-fluorouracil but also several other patients whose keratoses were seen to disappear during therapy without preceding erythema. Omura and Torre (JAMA. 1969;208:150-151) confirmed these observations in a woman with breast cancer whose actinic keratoses became inflamed after receiving intravenous 5-fluorouracil and subsequently faded. The route of drug administration was modified and 5-fluorouracil was applied topically. Today topical 5-fluorouracil is still used for the treatment of actinic keratoses.

Topical application of nitrogen mustard is used in the treatment of cutaneous T-cell lymphoma. In addition, intralesional administration of systemic antineoplastic agents has been used to treat cutaneous neoplasms: methotrexate for keratoacanthomas and rituximab for primary cutaneous B-cell lymphomas.

The Fenton et al study suggests that topical dasatinib may be a potential therapeutic intervention for the treatment of cutaneous squamous cell carcinoma. The investigators not only demonstrate laboratory data from mouse studies but also provide a potential molecular mechanism for drug-associated tumor suppression. Indeed, dasatinib solution, dasatinib cream, or both may be the next innovative therapy for the suppression of cutaneous squamous cell carcinoma in organ transplant and immunocompromised patients and for the potential management of this skin cancer in immunocompetent individuals. What do you think?

We want to know your views! Tell us what you think.

In a June 29 article published online in Molecular Carcinogenesis, Fenton et al demonstrated that topical dasatinib treatment of UVB-exposed SKH1 hairless mice reduced the total tumor burden (ie, benign tumors, atypical benign tumors, squamous cell carcinomas) per mouse.

Dasatinib is a tyrosine kinase inhibitor currently used to treat imatinib-resistant chronic myeloid leukemia and Philadelphia chromosome positive acute lymphoblastic leukemia. Its mechanism of action is to block the activity of tyrosine kinases by attaching to their adenosine triphosphate–binding site. It can inhibit the activity of the following tyrosine kinases: Src family kinases (SFK), break point cluster region-Abelson (Bcr-Abl), Ephrin type-A receptor 2 (EphA2), platelet-derived growth factor receptor, and mast/stem cell factor receptor (also called CD117 or c-Kit).

Src family kinases are associated with transformation of cells and progression of cancer. Elevated Src family kinases activity is present in the majority of human carcinomas.

Fyn, a nonreceptor tyrosine kinase, is a member of the Src family kinases. Cell growth, cell migration, and protein kinase B (Akt)–mediated inhibition of apoptosis are influenced by Fyn activity. In addition, Fyn activity is overexpressed in cutaneous squamous cell carcinoma.

In conclusion, dasatinib—an Src family kinases inhibitor—was able to inhibit Fyn activity and thereby reduce UV-induced skin carcinogenesis.

What’s the issue?

In 1962, Falkson and Schulz (Br J Dermatol. 1962;74:229-236) noted not only inflammation and subsequent resolution of actinic keratoses after exposure to sunlight in a woman with colon cancer being treated with systemic 5-fluorouracil but also several other patients whose keratoses were seen to disappear during therapy without preceding erythema. Omura and Torre (JAMA. 1969;208:150-151) confirmed these observations in a woman with breast cancer whose actinic keratoses became inflamed after receiving intravenous 5-fluorouracil and subsequently faded. The route of drug administration was modified and 5-fluorouracil was applied topically. Today topical 5-fluorouracil is still used for the treatment of actinic keratoses.

Topical application of nitrogen mustard is used in the treatment of cutaneous T-cell lymphoma. In addition, intralesional administration of systemic antineoplastic agents has been used to treat cutaneous neoplasms: methotrexate for keratoacanthomas and rituximab for primary cutaneous B-cell lymphomas.

The Fenton et al study suggests that topical dasatinib may be a potential therapeutic intervention for the treatment of cutaneous squamous cell carcinoma. The investigators not only demonstrate laboratory data from mouse studies but also provide a potential molecular mechanism for drug-associated tumor suppression. Indeed, dasatinib solution, dasatinib cream, or both may be the next innovative therapy for the suppression of cutaneous squamous cell carcinoma in organ transplant and immunocompromised patients and for the potential management of this skin cancer in immunocompetent individuals. What do you think?

We want to know your views! Tell us what you think.

A 59-year-old white man presented with 2 large erythematous lesions on the right side of the chest wall that had gradually progressed over the last 1.5 years. The patient denied any fever, night sweats, fatigue, unintentional weight loss, or loss of appetite. Physical examination revealed 2 large, well-circumscribed, nearly contiguous, firm, erythematous tumors. One tumor measured 7.5×4.5 cm and the other measured 4×3.5 cm.

The Diagnosis: Cutaneous B-cell Lymphoma

Biopsies from the right side of the chest wall (Figure 1) revealed an atypical dense and diffuse lymphocytic infiltrate throughout the dermis. There was extensive crush artifact throughout the specimen. However, the findings were consistent with cutaneous B-cell lymphoma (CBCL), and the diffuse large B-cell type was favored (Figure 2). Atypical lymphocytes stained positively for antibodies against CD20 (Figure 3), CD79a, and BCL-6, and stained negatively for antibodies against MUM-1 and BCL-2. Although flow cytometry revealed no definitive immunophenotypic lymphoma population, polymerase chain reaction analysis revealed a monoclonal immunoglobulin heavy chain gene rearrangement. Computed tomography (CT) scans of the chest, abdomen, and pelvis were unremarkable. A preliminary diagnosis of primary CBCL (PCBCL) was formulated. Diffuse large B-cell lymphoma (DLBCL) and follicle center lymphoma subtypes were each considered, which triggered further workup to rule out systemic involvement.

Figure 1. Erythematous firm tumors of the right side of the chest wall (A and B).

Figure 2. Atypical lymphocytic infiltrate with background crush artifact (A and B)(both H&E, original magnifications ×20 and ×40).

Figure 3. Atypical lymphocytes stained positively for antibodies against CD20 (original magnification ×40).

Figure 4. A focus of increased radiotracer deposition is seen in the left proximal humerus on positron emission tomography–computed tomography scanning.

A bone marrow biopsy from the posterior iliac crest revealed normocellular bone marrow with normal trilineage hematopoiesis. However, whole-body staging with positron emission tomography (PET)–CT scanning revealed osseous disease in the left proximal humerus (Figure 4) as well as a slightly hypermetabolic right axillary lymph node. Magnetic resonance imaging of the brain showed no evidence of intracranial disease. Because of the apparent systemic involvement, stage IV non-Hodgkin lymphoma (DLBCL) became the new suspected diagnosis. The patient was started on the first of 6 cycles of chemotherapy with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP), and the skin lesions quickly dissipated and flattened. A faint pink discoloration remained over a slightly indented area. A repeat PET-CT scan following 4 cycles of R-CHOP chemotherapy also confirmed a complete response to therapy.

In general, CBCL tends to affect adults and presents as relatively firm and plum-colored papules, nodules, tumors, or plaques, which can be either fast or slow growing. Cutaneous B-cell lymphoma may be primary or secondary to systemic involvement. Primary CBCL refers to a group of non-Hodgkin lymphomas that initially present in the skin with no evidence of extracutaneous involvement at the time of diagnosis.^1,2 Secondary CBCL (SCBCL) refers to cutaneous disease that occurs secondary to systemic B-cell lymphoma. Detecting systemic involvement and distinguishing between PCBCL and SCBCL is valuable in determining prognosis and therapeutic options, as subtypes of PCBCL often have an improved prognosis and may be treated with local irradiation.

The initial staging techniques that are preferred for cutaneous lymphomas have been debated.^3-5 For cutaneous lymphomas, except mycosis fungoides and Sézary syndrome, the International Society for Cutaneous Lymphomas and the Cutaneous Lymphoma Task Force of the European Organization of Research and Treatment of Cancer recommends obtaining a complete blood cell count with differential; complete metabolic studies including lactate dehydrogenase; and imaging studies of the chest, abdomen, and pelvis. Bone marrow biopsies and imaging studies of the neck or whole-body PET-CT scanning also may be useful depending on the clinical scenario.³ Although a more limited workup may be sufficient for PCBCLs such as primary cutaneous marginal zone lymphoma,⁵ a bone marrow biopsy is recommended for cases of primary cutaneous DLBCL (leg type).³ Senff et al⁵ supported the use of a bone marrow biopsy in the evaluation of follicle center lymphomas first presenting in the skin, though this method is controversial. In our patient, the laboratory results; bone marrow biopsy; and CT scan of the chest, abdomen, and pelvis failed to suggest extracutaneous disease, while the PET-CT scan revealed systemic involvement.

The differential diagnosis of CBCL includes cutaneous lymphoid hyperplasia (pseudolymphoma), which may be the result of insults such as arthropod bites, stings, vaccinations, or trauma. The clinical presentation, histology, and results of molecular studies and immunohistochemistry are essential in differentiating benign versus malignant processes.⁶ Lymphomas are expected to be larger and more persistent than benign processes, demonstrating an atypical lymphocytic infiltrate and monoclonality; immunohistochemistry will aid in the distinction between B-cell and T-cell processes and can delineate the type of B-cell lymphoma. Histology for CBCL typically reveals an atypical lymphocytic infiltrate showing a CD20⁺ and CD79a⁺ immunophenotype. Staining for antibodies against BCL-2, BCL-6, CD10, and MUM-1 also plays an important role in the diagnosis of cutaneous lymphoma and determining where the lesion(s) falls within the classification schemes. For example, to differentiate between primary cutaneous lymphoma subtypes, BCL-2 negativity and BCL-6 positivity in the context of a CD20⁺ and CD79a⁺ immunophenotype supports a follicle center lymphoma or a DLBCL (non–leg type). By contrast, CD20, CD79a, BCL-2, and MUM-1 positivity would favor a DLBCL (leg type).⁷

The natural history and therapeutic options differ greatly between subtypes of CBCL. For example, the prognosis of primary cutaneous follicle center lymphoma is generally favorable with a 5-year disease-specific survival rate of roughly 95%, and radiation therapy is recommended as a first-line therapy for localized disease.^2,8 Conversely, primary cutaneous DLBCL (leg type) frequently spreads to extracutaneous sites⁸ and carries a much lower estimated 5-year disease-specific survival rate of 55%.² Chemotherapy with R-CHOP is typically included in initial therapy for primary cutaneous DLBCL (leg type).⁸ The prognosis of systemic B-cell lymphomas also is highly variable and may depend on the type of B-cell lymphoma, the stage of disease at diagnosis, histologic and immunologic characteristics, and the therapy received. Wright et al⁹ reported that patients with systemic germinal center B cell–like DLBCL had a 5-year survival rate of 62%, whereas patients with activated B cell–like variants of DLBCL had a 5-year survival rate of 26%. Expression of CD40 may be a favorable prognostic factor following treatment with systemic chemotherapy in patients with DLBCL,¹⁰ whereas FOXP1 protein overexpression is correlated with poor disease-specific survival in certain DLBCL phenotypes.¹¹

Although it is uncertain whether the cutaneous lesions preceded systemic disease in our patient, the cutaneous lesions could be arbitrarily classified as secondary because extracutaneous disease was discovered within 6 months of the initial diagnosis.¹ However, classifying the CBCL as primary or secondary did not alter the course of treatment in our patient, as the presumed systemic disease necessitated treatment with systemic chemotherapy; both PCBCLs that develop systemic involvement and SCBCLs (primary extracutaneous disease) usually are treated with systemic chemotherapy. Our case highlights the importance of whole-body staging, as PET-CT scanning changed the course of care by detecting osseous involvement, necessitating systemic therapy as opposed to local radiation therapy alone. A multidisciplinary team with a focus on the diagnosis and management of cutaneous lymphomas helped streamline our patient’s laboratory testing and imaging studies, diagnostic and therapeutic decision making, and treatment implementation. Open channels and frequent opportunities for communication among dermatologists, dermatopathologists, medical oncologists, hematopathologists, radiologists, and radiation oncologists are needed to optimize and coordinate care for patients with cutaneous lymphoma who require transdisciplinary care.

Acknowledgement—The authors would like to thank Henry Koon, MD (hematology/oncology), for his input and expertise.

A 59-year-old white man presented with 2 large erythematous lesions on the right side of the chest wall that had gradually progressed over the last 1.5 years. The patient denied any fever, night sweats, fatigue, unintentional weight loss, or loss of appetite. Physical examination revealed 2 large, well-circumscribed, nearly contiguous, firm, erythematous tumors. One tumor measured 7.5×4.5 cm and the other measured 4×3.5 cm.

The Diagnosis: Cutaneous B-cell Lymphoma

Biopsies from the right side of the chest wall (Figure 1) revealed an atypical dense and diffuse lymphocytic infiltrate throughout the dermis. There was extensive crush artifact throughout the specimen. However, the findings were consistent with cutaneous B-cell lymphoma (CBCL), and the diffuse large B-cell type was favored (Figure 2). Atypical lymphocytes stained positively for antibodies against CD20 (Figure 3), CD79a, and BCL-6, and stained negatively for antibodies against MUM-1 and BCL-2. Although flow cytometry revealed no definitive immunophenotypic lymphoma population, polymerase chain reaction analysis revealed a monoclonal immunoglobulin heavy chain gene rearrangement. Computed tomography (CT) scans of the chest, abdomen, and pelvis were unremarkable. A preliminary diagnosis of primary CBCL (PCBCL) was formulated. Diffuse large B-cell lymphoma (DLBCL) and follicle center lymphoma subtypes were each considered, which triggered further workup to rule out systemic involvement.

Figure 1. Erythematous firm tumors of the right side of the chest wall (A and B).

Figure 2. Atypical lymphocytic infiltrate with background crush artifact (A and B)(both H&E, original magnifications ×20 and ×40).

Figure 3. Atypical lymphocytes stained positively for antibodies against CD20 (original magnification ×40).

Figure 4. A focus of increased radiotracer deposition is seen in the left proximal humerus on positron emission tomography–computed tomography scanning.

A bone marrow biopsy from the posterior iliac crest revealed normocellular bone marrow with normal trilineage hematopoiesis. However, whole-body staging with positron emission tomography (PET)–CT scanning revealed osseous disease in the left proximal humerus (Figure 4) as well as a slightly hypermetabolic right axillary lymph node. Magnetic resonance imaging of the brain showed no evidence of intracranial disease. Because of the apparent systemic involvement, stage IV non-Hodgkin lymphoma (DLBCL) became the new suspected diagnosis. The patient was started on the first of 6 cycles of chemotherapy with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP), and the skin lesions quickly dissipated and flattened. A faint pink discoloration remained over a slightly indented area. A repeat PET-CT scan following 4 cycles of R-CHOP chemotherapy also confirmed a complete response to therapy.

In general, CBCL tends to affect adults and presents as relatively firm and plum-colored papules, nodules, tumors, or plaques, which can be either fast or slow growing. Cutaneous B-cell lymphoma may be primary or secondary to systemic involvement. Primary CBCL refers to a group of non-Hodgkin lymphomas that initially present in the skin with no evidence of extracutaneous involvement at the time of diagnosis.^1,2 Secondary CBCL (SCBCL) refers to cutaneous disease that occurs secondary to systemic B-cell lymphoma. Detecting systemic involvement and distinguishing between PCBCL and SCBCL is valuable in determining prognosis and therapeutic options, as subtypes of PCBCL often have an improved prognosis and may be treated with local irradiation.

The initial staging techniques that are preferred for cutaneous lymphomas have been debated.^3-5 For cutaneous lymphomas, except mycosis fungoides and Sézary syndrome, the International Society for Cutaneous Lymphomas and the Cutaneous Lymphoma Task Force of the European Organization of Research and Treatment of Cancer recommends obtaining a complete blood cell count with differential; complete metabolic studies including lactate dehydrogenase; and imaging studies of the chest, abdomen, and pelvis. Bone marrow biopsies and imaging studies of the neck or whole-body PET-CT scanning also may be useful depending on the clinical scenario.³ Although a more limited workup may be sufficient for PCBCLs such as primary cutaneous marginal zone lymphoma,⁵ a bone marrow biopsy is recommended for cases of primary cutaneous DLBCL (leg type).³ Senff et al⁵ supported the use of a bone marrow biopsy in the evaluation of follicle center lymphomas first presenting in the skin, though this method is controversial. In our patient, the laboratory results; bone marrow biopsy; and CT scan of the chest, abdomen, and pelvis failed to suggest extracutaneous disease, while the PET-CT scan revealed systemic involvement.

The differential diagnosis of CBCL includes cutaneous lymphoid hyperplasia (pseudolymphoma), which may be the result of insults such as arthropod bites, stings, vaccinations, or trauma. The clinical presentation, histology, and results of molecular studies and immunohistochemistry are essential in differentiating benign versus malignant processes.⁶ Lymphomas are expected to be larger and more persistent than benign processes, demonstrating an atypical lymphocytic infiltrate and monoclonality; immunohistochemistry will aid in the distinction between B-cell and T-cell processes and can delineate the type of B-cell lymphoma. Histology for CBCL typically reveals an atypical lymphocytic infiltrate showing a CD20⁺ and CD79a⁺ immunophenotype. Staining for antibodies against BCL-2, BCL-6, CD10, and MUM-1 also plays an important role in the diagnosis of cutaneous lymphoma and determining where the lesion(s) falls within the classification schemes. For example, to differentiate between primary cutaneous lymphoma subtypes, BCL-2 negativity and BCL-6 positivity in the context of a CD20⁺ and CD79a⁺ immunophenotype supports a follicle center lymphoma or a DLBCL (non–leg type). By contrast, CD20, CD79a, BCL-2, and MUM-1 positivity would favor a DLBCL (leg type).⁷

The natural history and therapeutic options differ greatly between subtypes of CBCL. For example, the prognosis of primary cutaneous follicle center lymphoma is generally favorable with a 5-year disease-specific survival rate of roughly 95%, and radiation therapy is recommended as a first-line therapy for localized disease.^2,8 Conversely, primary cutaneous DLBCL (leg type) frequently spreads to extracutaneous sites⁸ and carries a much lower estimated 5-year disease-specific survival rate of 55%.² Chemotherapy with R-CHOP is typically included in initial therapy for primary cutaneous DLBCL (leg type).⁸ The prognosis of systemic B-cell lymphomas also is highly variable and may depend on the type of B-cell lymphoma, the stage of disease at diagnosis, histologic and immunologic characteristics, and the therapy received. Wright et al⁹ reported that patients with systemic germinal center B cell–like DLBCL had a 5-year survival rate of 62%, whereas patients with activated B cell–like variants of DLBCL had a 5-year survival rate of 26%. Expression of CD40 may be a favorable prognostic factor following treatment with systemic chemotherapy in patients with DLBCL,¹⁰ whereas FOXP1 protein overexpression is correlated with poor disease-specific survival in certain DLBCL phenotypes.¹¹

Although it is uncertain whether the cutaneous lesions preceded systemic disease in our patient, the cutaneous lesions could be arbitrarily classified as secondary because extracutaneous disease was discovered within 6 months of the initial diagnosis.¹ However, classifying the CBCL as primary or secondary did not alter the course of treatment in our patient, as the presumed systemic disease necessitated treatment with systemic chemotherapy; both PCBCLs that develop systemic involvement and SCBCLs (primary extracutaneous disease) usually are treated with systemic chemotherapy. Our case highlights the importance of whole-body staging, as PET-CT scanning changed the course of care by detecting osseous involvement, necessitating systemic therapy as opposed to local radiation therapy alone. A multidisciplinary team with a focus on the diagnosis and management of cutaneous lymphomas helped streamline our patient’s laboratory testing and imaging studies, diagnostic and therapeutic decision making, and treatment implementation. Open channels and frequent opportunities for communication among dermatologists, dermatopathologists, medical oncologists, hematopathologists, radiologists, and radiation oncologists are needed to optimize and coordinate care for patients with cutaneous lymphoma who require transdisciplinary care.

Acknowledgement—The authors would like to thank Henry Koon, MD (hematology/oncology), for his input and expertise.

A 59-year-old white man presented with 2 large erythematous lesions on the right side of the chest wall that had gradually progressed over the last 1.5 years. The patient denied any fever, night sweats, fatigue, unintentional weight loss, or loss of appetite. Physical examination revealed 2 large, well-circumscribed, nearly contiguous, firm, erythematous tumors. One tumor measured 7.5×4.5 cm and the other measured 4×3.5 cm.

The Diagnosis: Cutaneous B-cell Lymphoma

Biopsies from the right side of the chest wall (Figure 1) revealed an atypical dense and diffuse lymphocytic infiltrate throughout the dermis. There was extensive crush artifact throughout the specimen. However, the findings were consistent with cutaneous B-cell lymphoma (CBCL), and the diffuse large B-cell type was favored (Figure 2). Atypical lymphocytes stained positively for antibodies against CD20 (Figure 3), CD79a, and BCL-6, and stained negatively for antibodies against MUM-1 and BCL-2. Although flow cytometry revealed no definitive immunophenotypic lymphoma population, polymerase chain reaction analysis revealed a monoclonal immunoglobulin heavy chain gene rearrangement. Computed tomography (CT) scans of the chest, abdomen, and pelvis were unremarkable. A preliminary diagnosis of primary CBCL (PCBCL) was formulated. Diffuse large B-cell lymphoma (DLBCL) and follicle center lymphoma subtypes were each considered, which triggered further workup to rule out systemic involvement.

Figure 1. Erythematous firm tumors of the right side of the chest wall (A and B).

Figure 2. Atypical lymphocytic infiltrate with background crush artifact (A and B)(both H&E, original magnifications ×20 and ×40).

Figure 3. Atypical lymphocytes stained positively for antibodies against CD20 (original magnification ×40).

Figure 4. A focus of increased radiotracer deposition is seen in the left proximal humerus on positron emission tomography–computed tomography scanning.

A bone marrow biopsy from the posterior iliac crest revealed normocellular bone marrow with normal trilineage hematopoiesis. However, whole-body staging with positron emission tomography (PET)–CT scanning revealed osseous disease in the left proximal humerus (Figure 4) as well as a slightly hypermetabolic right axillary lymph node. Magnetic resonance imaging of the brain showed no evidence of intracranial disease. Because of the apparent systemic involvement, stage IV non-Hodgkin lymphoma (DLBCL) became the new suspected diagnosis. The patient was started on the first of 6 cycles of chemotherapy with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP), and the skin lesions quickly dissipated and flattened. A faint pink discoloration remained over a slightly indented area. A repeat PET-CT scan following 4 cycles of R-CHOP chemotherapy also confirmed a complete response to therapy.

In general, CBCL tends to affect adults and presents as relatively firm and plum-colored papules, nodules, tumors, or plaques, which can be either fast or slow growing. Cutaneous B-cell lymphoma may be primary or secondary to systemic involvement. Primary CBCL refers to a group of non-Hodgkin lymphomas that initially present in the skin with no evidence of extracutaneous involvement at the time of diagnosis.^1,2 Secondary CBCL (SCBCL) refers to cutaneous disease that occurs secondary to systemic B-cell lymphoma. Detecting systemic involvement and distinguishing between PCBCL and SCBCL is valuable in determining prognosis and therapeutic options, as subtypes of PCBCL often have an improved prognosis and may be treated with local irradiation.

The initial staging techniques that are preferred for cutaneous lymphomas have been debated.^3-5 For cutaneous lymphomas, except mycosis fungoides and Sézary syndrome, the International Society for Cutaneous Lymphomas and the Cutaneous Lymphoma Task Force of the European Organization of Research and Treatment of Cancer recommends obtaining a complete blood cell count with differential; complete metabolic studies including lactate dehydrogenase; and imaging studies of the chest, abdomen, and pelvis. Bone marrow biopsies and imaging studies of the neck or whole-body PET-CT scanning also may be useful depending on the clinical scenario.³ Although a more limited workup may be sufficient for PCBCLs such as primary cutaneous marginal zone lymphoma,⁵ a bone marrow biopsy is recommended for cases of primary cutaneous DLBCL (leg type).³ Senff et al⁵ supported the use of a bone marrow biopsy in the evaluation of follicle center lymphomas first presenting in the skin, though this method is controversial. In our patient, the laboratory results; bone marrow biopsy; and CT scan of the chest, abdomen, and pelvis failed to suggest extracutaneous disease, while the PET-CT scan revealed systemic involvement.

The differential diagnosis of CBCL includes cutaneous lymphoid hyperplasia (pseudolymphoma), which may be the result of insults such as arthropod bites, stings, vaccinations, or trauma. The clinical presentation, histology, and results of molecular studies and immunohistochemistry are essential in differentiating benign versus malignant processes.⁶ Lymphomas are expected to be larger and more persistent than benign processes, demonstrating an atypical lymphocytic infiltrate and monoclonality; immunohistochemistry will aid in the distinction between B-cell and T-cell processes and can delineate the type of B-cell lymphoma. Histology for CBCL typically reveals an atypical lymphocytic infiltrate showing a CD20⁺ and CD79a⁺ immunophenotype. Staining for antibodies against BCL-2, BCL-6, CD10, and MUM-1 also plays an important role in the diagnosis of cutaneous lymphoma and determining where the lesion(s) falls within the classification schemes. For example, to differentiate between primary cutaneous lymphoma subtypes, BCL-2 negativity and BCL-6 positivity in the context of a CD20⁺ and CD79a⁺ immunophenotype supports a follicle center lymphoma or a DLBCL (non–leg type). By contrast, CD20, CD79a, BCL-2, and MUM-1 positivity would favor a DLBCL (leg type).⁷

The natural history and therapeutic options differ greatly between subtypes of CBCL. For example, the prognosis of primary cutaneous follicle center lymphoma is generally favorable with a 5-year disease-specific survival rate of roughly 95%, and radiation therapy is recommended as a first-line therapy for localized disease.^2,8 Conversely, primary cutaneous DLBCL (leg type) frequently spreads to extracutaneous sites⁸ and carries a much lower estimated 5-year disease-specific survival rate of 55%.² Chemotherapy with R-CHOP is typically included in initial therapy for primary cutaneous DLBCL (leg type).⁸ The prognosis of systemic B-cell lymphomas also is highly variable and may depend on the type of B-cell lymphoma, the stage of disease at diagnosis, histologic and immunologic characteristics, and the therapy received. Wright et al⁹ reported that patients with systemic germinal center B cell–like DLBCL had a 5-year survival rate of 62%, whereas patients with activated B cell–like variants of DLBCL had a 5-year survival rate of 26%. Expression of CD40 may be a favorable prognostic factor following treatment with systemic chemotherapy in patients with DLBCL,¹⁰ whereas FOXP1 protein overexpression is correlated with poor disease-specific survival in certain DLBCL phenotypes.¹¹

Although it is uncertain whether the cutaneous lesions preceded systemic disease in our patient, the cutaneous lesions could be arbitrarily classified as secondary because extracutaneous disease was discovered within 6 months of the initial diagnosis.¹ However, classifying the CBCL as primary or secondary did not alter the course of treatment in our patient, as the presumed systemic disease necessitated treatment with systemic chemotherapy; both PCBCLs that develop systemic involvement and SCBCLs (primary extracutaneous disease) usually are treated with systemic chemotherapy. Our case highlights the importance of whole-body staging, as PET-CT scanning changed the course of care by detecting osseous involvement, necessitating systemic therapy as opposed to local radiation therapy alone. A multidisciplinary team with a focus on the diagnosis and management of cutaneous lymphomas helped streamline our patient’s laboratory testing and imaging studies, diagnostic and therapeutic decision making, and treatment implementation. Open channels and frequent opportunities for communication among dermatologists, dermatopathologists, medical oncologists, hematopathologists, radiologists, and radiation oncologists are needed to optimize and coordinate care for patients with cutaneous lymphoma who require transdisciplinary care.

Acknowledgement—The authors would like to thank Henry Koon, MD (hematology/oncology), for his input and expertise.