Nonmelanoma Skin Cancer

Case Report

A 27-year-old black man was admitted to the hospital with chills; night sweats; unintentional 25-lb weight loss; and multiple widespread, painful, progressively enlarging skin nodules of 3 months’ duration. The lesions had first developed on the back and later appeared on the face, trunk, arms, thighs, and genital region. He denied dysuria or urethral discharge. He had a remote history of adequately treated chlamydia infection but no other remarkable personal or family history.

		Figure 1. Firm subcutaneous nodules on the back with no epidermal change.
		Figure 2. Firm dermal papule on the anterior aspect of the left shoulder with violaceous hyperpigmentation (dermatofibromalike).

Physical examination revealed a thin man with more than 20 lesions on the face, trunk, arms, thighs, and genital region ranging in size from 1 to 4 cm. Lesion morphologies varied greatly and included subcutaneous firm nodules with no epidermal change (Figure 1); dermatofibromalike nodules with overlying erythema and hyperpigmentation (Figure 2); condylomalike, verrucous, pink papulonodules (Figure 3); ulcerated angular plaques with rolled borders and palpable tumor extension deep (1–2 cm) to the subcutis (Figure 4); and a vegetative, eroded, exophytic tumor with palpable deep extension (Figure 4). A diffuse, erythematous, macular eruption also was noted on the trunk and bilateral arms and legs including the soles of both feet along with nontender cervical, axillary, and inguinal lymphadenopathy. The ocular, oral, and nasal mucosae were not affected.

The differential diagnosis for each lesion differed based on morphology. Infectious, inflammatory, and neoplastic processes were considered, including syphilis, dermatofibroma, dermatofibrosarcoma protuberans, metastatic disease, leukemia cutis, sarcoidosis, panniculitis, condyloma acuminatum, and vegetative herpes simplex virus infection (inguinal lesion).

Laboratory data revealed a reactive rapid plasma reagin with treponemal IgG titers of 1:64. Urine chlamydia RNA probe and lymphogranuloma venereum (LGV) serum antibodies also were positive. Human immunodeficiency virus screening was negative. Positron emission tomography–computerized tomography revealed enlarged and hypermetabolic lymphadenopathy above and below the diaphragm.

After therapy with intravenous penicillin G and oral doxycycline for concurrent secondary syphilis and LGV, the patient’s macular eruption and constitutional symptoms resolved within weeks of the initial presentation. His lymphadenopathy improved, his rapid plasma reagin titer decreased, and his chlamydia RNA became undetectable. However, the skin lesions remained unchanged.

Incisional biopsies of 4 clinically distinct skin lesions revealed well-delineated dermal proliferations of cells with eosinophilic granular cytoplasm and indistinct cell borders (Figure 5). Two specimens displayed marked epidermal hyperplasia (Figure 6).
No atypical mitotic figures were identified. Immunohistochemistry for S-100 protein was diffusely positive in the neoplastic cells. Immunohistochemistry for Treponema pallidum was negative.
No mycobacterial or fungal organisms were identified in acid-fast bacillus, periodic acid–Schiff, or Gomori methenamine-silver–stained sections. All 4 lesions had histopathologic findings characteristic of granular cell tumors (GCTs). A lesion in the left inguinal region (Figure 4 [medial lesion]), which initially was thought to be condyloma latum or a squamous cell carcinoma (SCC), also was later confirmed to be a GCT.

Repeat positron emission tomography–computerized tomography several weeks later confirmed resolution of the previously noted lymphadenopathy. Although 2 GCTs have not recurred after biopsy, the other 2, which the patient refused to have completely excised, continued to grow. Follow-up 2.5 years after hospitalization revealed persistence of the lesions with no remarkable morphological changes.

Figure 3. Verrucous pink papule on the right side of the neck.		Figure 4. Ulcerated angular plaque in the left inguinal/genital area with rolled borders and tumor extension deep to the subcutis adjacent to a vegetative, eroded, exophytic tumor with palpable deep extension.
Figure 5. Large polygonal cells with eosinophilic granular cytoplasm, prominent bland nuclei, and indistinct cell borders (H&E, original magnification ×40).		Figure 6. Marked pseudoepitheliomatous hyperplasia (H&E, original magnification ×10).

Comment

First described in 1854, GCTs are uncommon neoplasms of probable Schwann cell origin that can arise in almost any location of the body but most often appear on the skin and in the subcutaneous tissues and oral cavity.^1,2 The commonly regarded rule of thirds describes its most favored locations: one-third on the tongue, one-third on the skin, and one-third in internal organs.^3,4 Granular cell tumors occur with greater frequency in adults, females, and black individuals.^1-5

Cutaneous GCTs usually present as solitary asymptomatic masses; however, multiple tumors have been noted in up to 25% of reported cases.^4,6 In children, multiple cutaneous GCTs have been reported in the setting of neurofibromatosis type I as well as with other disorders.^2,5,7-9

Cutaneous GCTs have been reported to range from sessile, pedunculated, or verrucous nodules to subcutaneous papules and nodules with no epidermal change. Our case not only illustrated the diverse clinical appearance of cutaneous GCTs but also demonstrated multiple morphologically distinct cutaneous GCTs occurring in a single patient. Of particular interest is our patient’s coexisting secondary syphilis and LGV infections, which can pose a diagnostic dilemma to the unsuspecting clinician. The manifold appearances of this patient’s GCTs resulted in a broad differential diagnosis. Syphilis (condyloma latum), condyloma acuminatum, LGV, metastatic disease, Kaposi sarcoma, lymphoma, dermatofibrosarcoma protuberans, leiomyoma, SCC, and deep fungal and atypical mycobacterial infection were all considerations. In 1981, Apisarnthanarax¹ reviewed 88 cases of GCTs seen over a 15-year period and discovered that the preoperative clinical diagnoses were incorrect in all cases. Skin biopsy is necessary to diagnose GCT, and our patient’s case underscores the need for a thorough history, physical examination, and laboratory evaluation to rule out coexisting diseases.

Histopathology of cutaneous GCTs shows an unencapsulated dermal proliferation of large monotonous polygonal cells with blurred cell borders and fine, granular, eosinophilic cytoplasm arranged in irregular sheets and nests. Nuclei are small, uniform, round, centrally located, and rarely contain mitoses.³ The presence of mitotic activity on histopathology does not necessarily portend malignant biological behavior.⁵ Overlying pseudoepitheliomatous hyperplasia has been reported in as many as 85% of GCTs and may mimic SCC.¹⁰ The neoplastic cells stain positively with S-100 protein, neuron-specific enolase, and peripheral nerve myelin proteins.^3,4 The cytoplasmic granules are positive on periodic acid–Schiff staining and diastase resistant and will sometimes stain for CD68.¹ Electron microscopy shows degraded myelinated axons intracellularly.⁴

Malignancy is rare and reportedly occurs in 1% to 3% of cases.^4,5 Consideration of both clinical behavior and histopathology is important in distinguishing benign from malignant lesions. According to published reports, in GCTs that were regarded as malignant, size tended to be greater than 4 cm, growth was rapid, and metastases to regional lymph nodes were observed.^4,5 Histologically, nuclear pleomorphism and atypia, cell spindling, vesicular nuclei with prominent nucleoli, necrosis, and high mitotic activity favor malignancy.^1,3

Treatment is complete surgical excision. Observation is acceptable if tumors are asymptomatic and do not impede function. Regression of some GCTs has been induced with use of intralesional corticosteroids.⁵ Spontaneous regression is rare. Prior reports have emphasized the importance of long-term follow-up in patients with multiple GCTs to monitor for development of systemic lesions.⁴

Case Report

A 27-year-old black man was admitted to the hospital with chills; night sweats; unintentional 25-lb weight loss; and multiple widespread, painful, progressively enlarging skin nodules of 3 months’ duration. The lesions had first developed on the back and later appeared on the face, trunk, arms, thighs, and genital region. He denied dysuria or urethral discharge. He had a remote history of adequately treated chlamydia infection but no other remarkable personal or family history.

		Figure 1. Firm subcutaneous nodules on the back with no epidermal change.
		Figure 2. Firm dermal papule on the anterior aspect of the left shoulder with violaceous hyperpigmentation (dermatofibromalike).

Physical examination revealed a thin man with more than 20 lesions on the face, trunk, arms, thighs, and genital region ranging in size from 1 to 4 cm. Lesion morphologies varied greatly and included subcutaneous firm nodules with no epidermal change (Figure 1); dermatofibromalike nodules with overlying erythema and hyperpigmentation (Figure 2); condylomalike, verrucous, pink papulonodules (Figure 3); ulcerated angular plaques with rolled borders and palpable tumor extension deep (1–2 cm) to the subcutis (Figure 4); and a vegetative, eroded, exophytic tumor with palpable deep extension (Figure 4). A diffuse, erythematous, macular eruption also was noted on the trunk and bilateral arms and legs including the soles of both feet along with nontender cervical, axillary, and inguinal lymphadenopathy. The ocular, oral, and nasal mucosae were not affected.

The differential diagnosis for each lesion differed based on morphology. Infectious, inflammatory, and neoplastic processes were considered, including syphilis, dermatofibroma, dermatofibrosarcoma protuberans, metastatic disease, leukemia cutis, sarcoidosis, panniculitis, condyloma acuminatum, and vegetative herpes simplex virus infection (inguinal lesion).

Laboratory data revealed a reactive rapid plasma reagin with treponemal IgG titers of 1:64. Urine chlamydia RNA probe and lymphogranuloma venereum (LGV) serum antibodies also were positive. Human immunodeficiency virus screening was negative. Positron emission tomography–computerized tomography revealed enlarged and hypermetabolic lymphadenopathy above and below the diaphragm.

After therapy with intravenous penicillin G and oral doxycycline for concurrent secondary syphilis and LGV, the patient’s macular eruption and constitutional symptoms resolved within weeks of the initial presentation. His lymphadenopathy improved, his rapid plasma reagin titer decreased, and his chlamydia RNA became undetectable. However, the skin lesions remained unchanged.

Incisional biopsies of 4 clinically distinct skin lesions revealed well-delineated dermal proliferations of cells with eosinophilic granular cytoplasm and indistinct cell borders (Figure 5). Two specimens displayed marked epidermal hyperplasia (Figure 6).
No atypical mitotic figures were identified. Immunohistochemistry for S-100 protein was diffusely positive in the neoplastic cells. Immunohistochemistry for Treponema pallidum was negative.
No mycobacterial or fungal organisms were identified in acid-fast bacillus, periodic acid–Schiff, or Gomori methenamine-silver–stained sections. All 4 lesions had histopathologic findings characteristic of granular cell tumors (GCTs). A lesion in the left inguinal region (Figure 4 [medial lesion]), which initially was thought to be condyloma latum or a squamous cell carcinoma (SCC), also was later confirmed to be a GCT.

Repeat positron emission tomography–computerized tomography several weeks later confirmed resolution of the previously noted lymphadenopathy. Although 2 GCTs have not recurred after biopsy, the other 2, which the patient refused to have completely excised, continued to grow. Follow-up 2.5 years after hospitalization revealed persistence of the lesions with no remarkable morphological changes.

Figure 3. Verrucous pink papule on the right side of the neck.		Figure 4. Ulcerated angular plaque in the left inguinal/genital area with rolled borders and tumor extension deep to the subcutis adjacent to a vegetative, eroded, exophytic tumor with palpable deep extension.
Figure 5. Large polygonal cells with eosinophilic granular cytoplasm, prominent bland nuclei, and indistinct cell borders (H&E, original magnification ×40).		Figure 6. Marked pseudoepitheliomatous hyperplasia (H&E, original magnification ×10).

Comment

First described in 1854, GCTs are uncommon neoplasms of probable Schwann cell origin that can arise in almost any location of the body but most often appear on the skin and in the subcutaneous tissues and oral cavity.^1,2 The commonly regarded rule of thirds describes its most favored locations: one-third on the tongue, one-third on the skin, and one-third in internal organs.^3,4 Granular cell tumors occur with greater frequency in adults, females, and black individuals.^1-5

Cutaneous GCTs usually present as solitary asymptomatic masses; however, multiple tumors have been noted in up to 25% of reported cases.^4,6 In children, multiple cutaneous GCTs have been reported in the setting of neurofibromatosis type I as well as with other disorders.^2,5,7-9

Cutaneous GCTs have been reported to range from sessile, pedunculated, or verrucous nodules to subcutaneous papules and nodules with no epidermal change. Our case not only illustrated the diverse clinical appearance of cutaneous GCTs but also demonstrated multiple morphologically distinct cutaneous GCTs occurring in a single patient. Of particular interest is our patient’s coexisting secondary syphilis and LGV infections, which can pose a diagnostic dilemma to the unsuspecting clinician. The manifold appearances of this patient’s GCTs resulted in a broad differential diagnosis. Syphilis (condyloma latum), condyloma acuminatum, LGV, metastatic disease, Kaposi sarcoma, lymphoma, dermatofibrosarcoma protuberans, leiomyoma, SCC, and deep fungal and atypical mycobacterial infection were all considerations. In 1981, Apisarnthanarax¹ reviewed 88 cases of GCTs seen over a 15-year period and discovered that the preoperative clinical diagnoses were incorrect in all cases. Skin biopsy is necessary to diagnose GCT, and our patient’s case underscores the need for a thorough history, physical examination, and laboratory evaluation to rule out coexisting diseases.

Histopathology of cutaneous GCTs shows an unencapsulated dermal proliferation of large monotonous polygonal cells with blurred cell borders and fine, granular, eosinophilic cytoplasm arranged in irregular sheets and nests. Nuclei are small, uniform, round, centrally located, and rarely contain mitoses.³ The presence of mitotic activity on histopathology does not necessarily portend malignant biological behavior.⁵ Overlying pseudoepitheliomatous hyperplasia has been reported in as many as 85% of GCTs and may mimic SCC.¹⁰ The neoplastic cells stain positively with S-100 protein, neuron-specific enolase, and peripheral nerve myelin proteins.^3,4 The cytoplasmic granules are positive on periodic acid–Schiff staining and diastase resistant and will sometimes stain for CD68.¹ Electron microscopy shows degraded myelinated axons intracellularly.⁴

Malignancy is rare and reportedly occurs in 1% to 3% of cases.^4,5 Consideration of both clinical behavior and histopathology is important in distinguishing benign from malignant lesions. According to published reports, in GCTs that were regarded as malignant, size tended to be greater than 4 cm, growth was rapid, and metastases to regional lymph nodes were observed.^4,5 Histologically, nuclear pleomorphism and atypia, cell spindling, vesicular nuclei with prominent nucleoli, necrosis, and high mitotic activity favor malignancy.^1,3

Treatment is complete surgical excision. Observation is acceptable if tumors are asymptomatic and do not impede function. Regression of some GCTs has been induced with use of intralesional corticosteroids.⁵ Spontaneous regression is rare. Prior reports have emphasized the importance of long-term follow-up in patients with multiple GCTs to monitor for development of systemic lesions.⁴

Case Report

A 27-year-old black man was admitted to the hospital with chills; night sweats; unintentional 25-lb weight loss; and multiple widespread, painful, progressively enlarging skin nodules of 3 months’ duration. The lesions had first developed on the back and later appeared on the face, trunk, arms, thighs, and genital region. He denied dysuria or urethral discharge. He had a remote history of adequately treated chlamydia infection but no other remarkable personal or family history.

		Figure 1. Firm subcutaneous nodules on the back with no epidermal change.
		Figure 2. Firm dermal papule on the anterior aspect of the left shoulder with violaceous hyperpigmentation (dermatofibromalike).

Physical examination revealed a thin man with more than 20 lesions on the face, trunk, arms, thighs, and genital region ranging in size from 1 to 4 cm. Lesion morphologies varied greatly and included subcutaneous firm nodules with no epidermal change (Figure 1); dermatofibromalike nodules with overlying erythema and hyperpigmentation (Figure 2); condylomalike, verrucous, pink papulonodules (Figure 3); ulcerated angular plaques with rolled borders and palpable tumor extension deep (1–2 cm) to the subcutis (Figure 4); and a vegetative, eroded, exophytic tumor with palpable deep extension (Figure 4). A diffuse, erythematous, macular eruption also was noted on the trunk and bilateral arms and legs including the soles of both feet along with nontender cervical, axillary, and inguinal lymphadenopathy. The ocular, oral, and nasal mucosae were not affected.

The differential diagnosis for each lesion differed based on morphology. Infectious, inflammatory, and neoplastic processes were considered, including syphilis, dermatofibroma, dermatofibrosarcoma protuberans, metastatic disease, leukemia cutis, sarcoidosis, panniculitis, condyloma acuminatum, and vegetative herpes simplex virus infection (inguinal lesion).

Laboratory data revealed a reactive rapid plasma reagin with treponemal IgG titers of 1:64. Urine chlamydia RNA probe and lymphogranuloma venereum (LGV) serum antibodies also were positive. Human immunodeficiency virus screening was negative. Positron emission tomography–computerized tomography revealed enlarged and hypermetabolic lymphadenopathy above and below the diaphragm.

After therapy with intravenous penicillin G and oral doxycycline for concurrent secondary syphilis and LGV, the patient’s macular eruption and constitutional symptoms resolved within weeks of the initial presentation. His lymphadenopathy improved, his rapid plasma reagin titer decreased, and his chlamydia RNA became undetectable. However, the skin lesions remained unchanged.

Incisional biopsies of 4 clinically distinct skin lesions revealed well-delineated dermal proliferations of cells with eosinophilic granular cytoplasm and indistinct cell borders (Figure 5). Two specimens displayed marked epidermal hyperplasia (Figure 6).
No atypical mitotic figures were identified. Immunohistochemistry for S-100 protein was diffusely positive in the neoplastic cells. Immunohistochemistry for Treponema pallidum was negative.
No mycobacterial or fungal organisms were identified in acid-fast bacillus, periodic acid–Schiff, or Gomori methenamine-silver–stained sections. All 4 lesions had histopathologic findings characteristic of granular cell tumors (GCTs). A lesion in the left inguinal region (Figure 4 [medial lesion]), which initially was thought to be condyloma latum or a squamous cell carcinoma (SCC), also was later confirmed to be a GCT.

Repeat positron emission tomography–computerized tomography several weeks later confirmed resolution of the previously noted lymphadenopathy. Although 2 GCTs have not recurred after biopsy, the other 2, which the patient refused to have completely excised, continued to grow. Follow-up 2.5 years after hospitalization revealed persistence of the lesions with no remarkable morphological changes.

Figure 3. Verrucous pink papule on the right side of the neck.		Figure 4. Ulcerated angular plaque in the left inguinal/genital area with rolled borders and tumor extension deep to the subcutis adjacent to a vegetative, eroded, exophytic tumor with palpable deep extension.
Figure 5. Large polygonal cells with eosinophilic granular cytoplasm, prominent bland nuclei, and indistinct cell borders (H&E, original magnification ×40).		Figure 6. Marked pseudoepitheliomatous hyperplasia (H&E, original magnification ×10).

Comment

First described in 1854, GCTs are uncommon neoplasms of probable Schwann cell origin that can arise in almost any location of the body but most often appear on the skin and in the subcutaneous tissues and oral cavity.^1,2 The commonly regarded rule of thirds describes its most favored locations: one-third on the tongue, one-third on the skin, and one-third in internal organs.^3,4 Granular cell tumors occur with greater frequency in adults, females, and black individuals.^1-5

Cutaneous GCTs usually present as solitary asymptomatic masses; however, multiple tumors have been noted in up to 25% of reported cases.^4,6 In children, multiple cutaneous GCTs have been reported in the setting of neurofibromatosis type I as well as with other disorders.^2,5,7-9

Cutaneous GCTs have been reported to range from sessile, pedunculated, or verrucous nodules to subcutaneous papules and nodules with no epidermal change. Our case not only illustrated the diverse clinical appearance of cutaneous GCTs but also demonstrated multiple morphologically distinct cutaneous GCTs occurring in a single patient. Of particular interest is our patient’s coexisting secondary syphilis and LGV infections, which can pose a diagnostic dilemma to the unsuspecting clinician. The manifold appearances of this patient’s GCTs resulted in a broad differential diagnosis. Syphilis (condyloma latum), condyloma acuminatum, LGV, metastatic disease, Kaposi sarcoma, lymphoma, dermatofibrosarcoma protuberans, leiomyoma, SCC, and deep fungal and atypical mycobacterial infection were all considerations. In 1981, Apisarnthanarax¹ reviewed 88 cases of GCTs seen over a 15-year period and discovered that the preoperative clinical diagnoses were incorrect in all cases. Skin biopsy is necessary to diagnose GCT, and our patient’s case underscores the need for a thorough history, physical examination, and laboratory evaluation to rule out coexisting diseases.

Histopathology of cutaneous GCTs shows an unencapsulated dermal proliferation of large monotonous polygonal cells with blurred cell borders and fine, granular, eosinophilic cytoplasm arranged in irregular sheets and nests. Nuclei are small, uniform, round, centrally located, and rarely contain mitoses.³ The presence of mitotic activity on histopathology does not necessarily portend malignant biological behavior.⁵ Overlying pseudoepitheliomatous hyperplasia has been reported in as many as 85% of GCTs and may mimic SCC.¹⁰ The neoplastic cells stain positively with S-100 protein, neuron-specific enolase, and peripheral nerve myelin proteins.^3,4 The cytoplasmic granules are positive on periodic acid–Schiff staining and diastase resistant and will sometimes stain for CD68.¹ Electron microscopy shows degraded myelinated axons intracellularly.⁴

Malignancy is rare and reportedly occurs in 1% to 3% of cases.^4,5 Consideration of both clinical behavior and histopathology is important in distinguishing benign from malignant lesions. According to published reports, in GCTs that were regarded as malignant, size tended to be greater than 4 cm, growth was rapid, and metastases to regional lymph nodes were observed.^4,5 Histologically, nuclear pleomorphism and atypia, cell spindling, vesicular nuclei with prominent nucleoli, necrosis, and high mitotic activity favor malignancy.^1,3

Treatment is complete surgical excision. Observation is acceptable if tumors are asymptomatic and do not impede function. Regression of some GCTs has been induced with use of intralesional corticosteroids.⁵ Spontaneous regression is rare. Prior reports have emphasized the importance of long-term follow-up in patients with multiple GCTs to monitor for development of systemic lesions.⁴

The Diagnosis: Primary Cutaneous Carcinosarcoma

A generous shave biopsy and debulking performed on the initial visit revealed an infiltrating tumor consisting of malignant epithelial and stromal components (Figure). The basaloid and squamoid epithelial cells were keratin positive. The stromal cells demonstrated positivity for CD10 but were keratin negative. The epithelial portion of the tumor was composed mostly of basaloid islands of cells with nuclear pleomorphism, scattered mitoses, and focal sebaceous differentiation. The mesenchymal portion of the tumor displayed florid pleomorphism and polymorphism, with many large atypical cells and proliferation. A diagnosis of primary cutaneous carcinosarcoma (PCC) was rendered. Head and neck computed tomography showed tumor penetration of less than 1 cm into scalp soft tissues with no involvement of the underlying bone. There was some evidence of swelling of the supragaleal soft tissues without indication of perineural spread. An 11-mm hyperlucent lower cervical lymph node on the left side that likely represented an incidental finding was noted. Surgical excision with margin evaluation was recommended, but the patient declined. He instead received radiation therapy to the left side of the posterior scalp with a total dose of 30 Gy at 6 Gy per fraction and 1 fraction daily. The patient was found to have a well-healed scar with no evidence of recurrence at 4-week follow-up and again at 5 months after radiation therapy.

A generous shave biopsy and debulking performed on the initial visit revealed an inflitrating tumor consisting on malignant epithelial and stromal components (A-C)(H&E; original magnifications ×10, ×20, and ×40, respectively).

Primary cutaneous carcinosarcoma is a rare biphasic neoplasm of unknown etiology that is characterized by the presence of both malignant epithelial and mesenchymal components.¹ Carcinosarcomas have been reported in both the male and female reproductive tracts, urinary tract, gastrointestinal tract, lungs, breasts, larynx, thymus, and thyroid but is uncommon as a primary neoplasm of the skin.² Epidermal PCC occurs with greater frequency in males than in females and typically presents in the eighth or ninth decades of life.³ These tumors tend to arise in sun-exposed regions, most commonly on the face and scalp.²

Morphologically, PCCs typically are exophytic growths that often feature surface ulceration and may or may not bleed upon palpation.⁴ Primary cutaneous carcinosarcomas may present as long-standing lesions that have undergone rapid transformation in the weeks preceding presentation.⁴ It is not uncommon for PCC lesions to carry the clinical diagnosis of squamous cell carcinoma, which suggests notable morphologic overlap between these entities. Histopathologically, PCC shows a basal cell carcinoma and/or a squamous cell carcinoma epithelial component intimately admixed with a sarcomatous component.⁵ The mesenchymal component of PCC typically resembles a superficial malignant fibrous histiocytoma characterized by pleomorphic nuclei and cytoplasm, necrosis, and an increased number of mitotic figures.² Immunohistochemistry can be beneficial in the diagnosis of PCC. A combination of p63 and AE1/AE3 stains can be used to confirm cells of epithelial origin. Staining with vimentin, CD10, or caldesmon can help to delineate the mesenchymal component of PCC.

Epidermal PCC most commonly affects elderly individuals with a history of extensive sun exposure. It has been suggested that p53 mutations due to UV damage are key in tumor formation for both epithelial and mesenchymal elements.⁵ Literature supports a monoclonal origin for the epithelial and mesenchymal components of this tumor; however, there is insufficient evidence.⁶ Surgical excision is the primary treatment modality for epidermal PCC, but adjuvant or substitutive radiotherapy has been used in some cases.⁴ The prognosis of PCC is notably better than its visceral counterpart due to early diagnosis and treatment of easily visible lesions. Epidermal PCC has a 70% 5-year disease-free survival rate, while adnexal PCC tends to occur in younger patients and has a 25% 5-year disease-free survival rate.³ Due to the rarity of reported cases and limited follow-up, the long-term prognosis for PCC remains unclear.

We report an unusual case of PCC on the scalp that was successfully treated with radiation therapy alone. This modality should be considered in patients with large tumors who refuse surgery or are not good surgical candidates.

The Diagnosis: Primary Cutaneous Carcinosarcoma

A generous shave biopsy and debulking performed on the initial visit revealed an infiltrating tumor consisting of malignant epithelial and stromal components (Figure). The basaloid and squamoid epithelial cells were keratin positive. The stromal cells demonstrated positivity for CD10 but were keratin negative. The epithelial portion of the tumor was composed mostly of basaloid islands of cells with nuclear pleomorphism, scattered mitoses, and focal sebaceous differentiation. The mesenchymal portion of the tumor displayed florid pleomorphism and polymorphism, with many large atypical cells and proliferation. A diagnosis of primary cutaneous carcinosarcoma (PCC) was rendered. Head and neck computed tomography showed tumor penetration of less than 1 cm into scalp soft tissues with no involvement of the underlying bone. There was some evidence of swelling of the supragaleal soft tissues without indication of perineural spread. An 11-mm hyperlucent lower cervical lymph node on the left side that likely represented an incidental finding was noted. Surgical excision with margin evaluation was recommended, but the patient declined. He instead received radiation therapy to the left side of the posterior scalp with a total dose of 30 Gy at 6 Gy per fraction and 1 fraction daily. The patient was found to have a well-healed scar with no evidence of recurrence at 4-week follow-up and again at 5 months after radiation therapy.

A generous shave biopsy and debulking performed on the initial visit revealed an inflitrating tumor consisting on malignant epithelial and stromal components (A-C)(H&E; original magnifications ×10, ×20, and ×40, respectively).

Primary cutaneous carcinosarcoma is a rare biphasic neoplasm of unknown etiology that is characterized by the presence of both malignant epithelial and mesenchymal components.¹ Carcinosarcomas have been reported in both the male and female reproductive tracts, urinary tract, gastrointestinal tract, lungs, breasts, larynx, thymus, and thyroid but is uncommon as a primary neoplasm of the skin.² Epidermal PCC occurs with greater frequency in males than in females and typically presents in the eighth or ninth decades of life.³ These tumors tend to arise in sun-exposed regions, most commonly on the face and scalp.²

Morphologically, PCCs typically are exophytic growths that often feature surface ulceration and may or may not bleed upon palpation.⁴ Primary cutaneous carcinosarcomas may present as long-standing lesions that have undergone rapid transformation in the weeks preceding presentation.⁴ It is not uncommon for PCC lesions to carry the clinical diagnosis of squamous cell carcinoma, which suggests notable morphologic overlap between these entities. Histopathologically, PCC shows a basal cell carcinoma and/or a squamous cell carcinoma epithelial component intimately admixed with a sarcomatous component.⁵ The mesenchymal component of PCC typically resembles a superficial malignant fibrous histiocytoma characterized by pleomorphic nuclei and cytoplasm, necrosis, and an increased number of mitotic figures.² Immunohistochemistry can be beneficial in the diagnosis of PCC. A combination of p63 and AE1/AE3 stains can be used to confirm cells of epithelial origin. Staining with vimentin, CD10, or caldesmon can help to delineate the mesenchymal component of PCC.

Epidermal PCC most commonly affects elderly individuals with a history of extensive sun exposure. It has been suggested that p53 mutations due to UV damage are key in tumor formation for both epithelial and mesenchymal elements.⁵ Literature supports a monoclonal origin for the epithelial and mesenchymal components of this tumor; however, there is insufficient evidence.⁶ Surgical excision is the primary treatment modality for epidermal PCC, but adjuvant or substitutive radiotherapy has been used in some cases.⁴ The prognosis of PCC is notably better than its visceral counterpart due to early diagnosis and treatment of easily visible lesions. Epidermal PCC has a 70% 5-year disease-free survival rate, while adnexal PCC tends to occur in younger patients and has a 25% 5-year disease-free survival rate.³ Due to the rarity of reported cases and limited follow-up, the long-term prognosis for PCC remains unclear.

We report an unusual case of PCC on the scalp that was successfully treated with radiation therapy alone. This modality should be considered in patients with large tumors who refuse surgery or are not good surgical candidates.

The Diagnosis: Primary Cutaneous Carcinosarcoma

A generous shave biopsy and debulking performed on the initial visit revealed an infiltrating tumor consisting of malignant epithelial and stromal components (Figure). The basaloid and squamoid epithelial cells were keratin positive. The stromal cells demonstrated positivity for CD10 but were keratin negative. The epithelial portion of the tumor was composed mostly of basaloid islands of cells with nuclear pleomorphism, scattered mitoses, and focal sebaceous differentiation. The mesenchymal portion of the tumor displayed florid pleomorphism and polymorphism, with many large atypical cells and proliferation. A diagnosis of primary cutaneous carcinosarcoma (PCC) was rendered. Head and neck computed tomography showed tumor penetration of less than 1 cm into scalp soft tissues with no involvement of the underlying bone. There was some evidence of swelling of the supragaleal soft tissues without indication of perineural spread. An 11-mm hyperlucent lower cervical lymph node on the left side that likely represented an incidental finding was noted. Surgical excision with margin evaluation was recommended, but the patient declined. He instead received radiation therapy to the left side of the posterior scalp with a total dose of 30 Gy at 6 Gy per fraction and 1 fraction daily. The patient was found to have a well-healed scar with no evidence of recurrence at 4-week follow-up and again at 5 months after radiation therapy.

A generous shave biopsy and debulking performed on the initial visit revealed an inflitrating tumor consisting on malignant epithelial and stromal components (A-C)(H&E; original magnifications ×10, ×20, and ×40, respectively).

Primary cutaneous carcinosarcoma is a rare biphasic neoplasm of unknown etiology that is characterized by the presence of both malignant epithelial and mesenchymal components.¹ Carcinosarcomas have been reported in both the male and female reproductive tracts, urinary tract, gastrointestinal tract, lungs, breasts, larynx, thymus, and thyroid but is uncommon as a primary neoplasm of the skin.² Epidermal PCC occurs with greater frequency in males than in females and typically presents in the eighth or ninth decades of life.³ These tumors tend to arise in sun-exposed regions, most commonly on the face and scalp.²

Morphologically, PCCs typically are exophytic growths that often feature surface ulceration and may or may not bleed upon palpation.⁴ Primary cutaneous carcinosarcomas may present as long-standing lesions that have undergone rapid transformation in the weeks preceding presentation.⁴ It is not uncommon for PCC lesions to carry the clinical diagnosis of squamous cell carcinoma, which suggests notable morphologic overlap between these entities. Histopathologically, PCC shows a basal cell carcinoma and/or a squamous cell carcinoma epithelial component intimately admixed with a sarcomatous component.⁵ The mesenchymal component of PCC typically resembles a superficial malignant fibrous histiocytoma characterized by pleomorphic nuclei and cytoplasm, necrosis, and an increased number of mitotic figures.² Immunohistochemistry can be beneficial in the diagnosis of PCC. A combination of p63 and AE1/AE3 stains can be used to confirm cells of epithelial origin. Staining with vimentin, CD10, or caldesmon can help to delineate the mesenchymal component of PCC.

Epidermal PCC most commonly affects elderly individuals with a history of extensive sun exposure. It has been suggested that p53 mutations due to UV damage are key in tumor formation for both epithelial and mesenchymal elements.⁵ Literature supports a monoclonal origin for the epithelial and mesenchymal components of this tumor; however, there is insufficient evidence.⁶ Surgical excision is the primary treatment modality for epidermal PCC, but adjuvant or substitutive radiotherapy has been used in some cases.⁴ The prognosis of PCC is notably better than its visceral counterpart due to early diagnosis and treatment of easily visible lesions. Epidermal PCC has a 70% 5-year disease-free survival rate, while adnexal PCC tends to occur in younger patients and has a 25% 5-year disease-free survival rate.³ Due to the rarity of reported cases and limited follow-up, the long-term prognosis for PCC remains unclear.

We report an unusual case of PCC on the scalp that was successfully treated with radiation therapy alone. This modality should be considered in patients with large tumors who refuse surgery or are not good surgical candidates.

Merkel cells originally were described by German histopathologist Friedrich Sigmund Merkel in 1875. These unique tactile cells were described as epidermal, nondendritic, and nonkeratinizing. Merkel cells are thought to arise from the neural crest and are believed to be primary neural cells found within the basal layer of the epidermis.^1,2 They likely function primarily as slowly adapting type I mechanoreceptors. Origin from the neural crest is controversial, as other investigators have suggested derivation from epidermal keratinocytes.^1,2 Tumor cells have been linked to the amine precursor uptake and decarboxylation system.³ In 1972, Toker⁴ described several cases of trabecular or sweat gland carcinomas of the skin. Upon further investigation, the cells that comprised these tumors were found to have dense core granules on electron microscopy, typical of Merkel cells.^1,2 Other terms such as neuroendocrine carcinoma of the skin, small cell carcinoma of the skin, and anaplastic carcinoma of the skin have been used to describe Merkel cell carcinoma (MCC),¹ which was suggested by De Wolf-Peeters et al⁵ in 1980.

Despite being a rare malignancy, MCC follows an aggressive clinical course. Upon presentation, approximately 66% of patients have local disease, 27% have nodal involvement, and 7% have distant metastasis.¹ Future treatments will likely center around the novel Merkel cell polyomavirus (MCPyV) and modification of immune responses toward tumor cells. Standardization continues to be lacking in both staging and treatment of this aggressive tumor.

Epidemiology of MCC

Figure 1. A 2.3×1.5×1.2-cm, hemorrhagic, crusted, exophytic tumor on the left cheek.

Figure 2. Merkel cells are small- to medium-sized cells with round nuclei and scant cytoplasm. Granular or stippled chromatin can be seen (A)(H&E, original magnification ×40). Merkel cell carcinoma with trabecular pattern (B) (H&E, original magnification ×10).

Between 1986 and 2006, the incidence of MCC grew substantially.^1,2 Figures have been reported at 0.15 cases per 100,000 individuals to 0.6 cases per 100,000 individuals worldwide. In the United States, the age-adjusted incidence of MCC is estimated at 0.24 per 100,000 person-years, which is higher than the estimated 0.13 per 100,000 person-years found in Europe.³ The highest incidence worldwide has been noted in Western Australia, likely due to high levels of UV exposure.¹ The incidence of MCC in psoriasis patients who are treated with oral methoxsalen (psoralen) and UVA photochemotherapy is 100 times greater than in the general population, further supporting the role of UV light in the development of MCC.¹ White individuals have the highest incidence of MCC worldwide, with men being affected more frequently than women.^1,3 The majority of patients with MCC are diagnosed at 70 years or older.¹ Approximately 5% of reported MCC patients are diagnosed before 50 years of age.² Immunosuppression and immunodeficiency likely play a role in the pathogenesis of MCC, and the incidence is increased in solid organ transplant recipients, most commonly renal transplant recipients,¹ as well as individuals with chronic lymphocytic leukemia, human immunodeficiency virus infection, and AIDS.^1,3 Patients with autoimmune diseases such as rheumatoid arthritis also are at increased risk for MCC.³ Individuals who are diagnosed with MCC are at an increased risk for development of other malignancies including nonmelanoma skin cancers, chronic lymphocytic leukemia, Hodgkin lymphoma, and non-Hodgkin lymphoma.³

Clinical Presentation of MCC

The clinical presentation of MCC can be variable. Most tumors present as firm, red to purple, nontender papules or nodules (Figure 1).¹ Tumor size may range from 2 to 200 mm but is most commonly less than 20 mm.² Growth can be rapid, and tumors are most commonly located on sun-exposed skin. The head and neck areas account for 48% of all MCC cases,¹ with the eyelids being frequently involved.² Merkel cell carcinoma also has been reported on the arms, legs, trunk, back, and buttocks.¹ Non–sun-exposed areas are less commonly affected. Mucosal sites (eg, larynx, nasal cavity, pharynx, mouth) account for 5% of primary MCCs.¹ Merkel cell carcinoma also has been reported to affect the vulva and penis. Subcutaneous primary MCC has presented without overlying epidermal changes.¹ In a case series by Heath et al,⁶ 14% (27/195) of MCC patients presented with nodal disease without any identifiable primary tumor, with the inguinal nodal chain being the most common for this presentation. It currently is not known whether these nodal tumors are primary tumors or metastatic disease with a regression of the primary tumor.¹

Histopathology of MCC

Figure 3. Positive chromogranin staining (A)(original magnification ×40). Cytokeratin 20 staining in the characteristic paranuclear dot–like pattern (B)(original magnification ×40). Negative thyroid transcription factor 1 staining (C)(original magnification ×40).

Merkel cells are small- to medium-sized basophilic cells with round nuclei and scant cytoplasm. Granular or stippled chromatin can be seen on histopathology (Figure 2A).¹ Some tumor cells have more vesicular chromatin, multiple small nucleoli, irregular contours, and more abundant cytoplasm. In some reports, irregular contours and abundant cytoplasm were associated with no detectible MCPyV infection.^1,3 Merkel cell carcinomas have a primarily nodular architecture, and classification is based on growth pattern and cell size. Three histopathologic growth patterns have been described: nodular, infiltrative, and trabecular. The trabecular pattern is composed of interconnecting strands ofcells (Figure 2B). Tumors with solely intraepidermal involvement (MCC in situ) have been described but are exceedingly rare.¹ Cell types are classified according to size, with the intermediate cell type being the most common. The small cell variant may be mistaken for a lymphocytic infiltrate due to the similar size and appearance of both types of cells.^1,3

Merkel cell carcinomas can have histopathological overlap with lymphomas, small cell lung cancers, carcinoid tumors, primitive neuroectodermal tumors, neuroblastomas, small cell osteosarcomas, rhabdomyosarcomas, or Ewing sarcomas.^1,3 Specifically, differentiation from small cell carcinoma of the lung is of utmost importance. Merkel cell carcinoma stains positively for cytokeratins 8, 18, 19, and 20. The neuroendocrine markers chromogranin (Figure 3A), synaptophysin, and neuron-specific enolase also may show positive staining. Cytokeratin 20, low-molecular-weight cytokeratins (CAM 5.2), and neurofilament immunostains have a high sensitivity for MCC and are the most frequently used.¹ Cytokeratin 20 stains in the characteristic paranuclear dot–like pattern, which is a hallmark of MCC (Figure 3B). Cytokeratin 20 positivity in conjunction with negative staining for thyroid transcription factor 1 (Figure 3C) and cytokeratin 7 can aid in differentiation from small cell carcinoma of the lung.^1,3

Pathogenesis of MCC

In 2008, Feng et al⁷ discovered a novel polyomavirus associated with the development of MCC. This novel polyomavirus, MCPyV, is found in approximately 80% of all cases of MCC. Seventeen members of the polyomavirus family have been identified, 9 of which have been found to infect humans, including BK virus, JC virus, WU, MCPyV, human polyomavirus 6, human polyomavirus 7, trichodysplasia spinulosa–associated polyomavirus, human polyomavirus 9, and Simian virus 40.¹ Merkel cell polyomavirus infection is found in approximately 60% of the general population and exposure likely occurs early in life. The virus likely is transmitted through skin shedding and nasal secretions, though it also has been found in urine specimens.³ Currently, there is no evidence to suggest vertical viral transmission from mother to fetus.

Merkel cell polyomavirus is composed of early and late gene regions. The early gene region contains both large T antigen (LT) and small T antigen reading frames, which are necessary for viral replication.⁸ The late region is responsible for encoding viral proteins necessary for viral capsid assembly. Mutations found in viral protein 1 prevent formation of viral particles.⁹ Large T antigen is substantially overexpressed in MCC and is responsible for tumor suppression through retinoblastoma tumor suppressor protein. It also serves as a binding domain for both heat shock proteins and helicases.^8,10 These domains allow the polyomaviruses to use host-cell machinery for viral genome replication while targeting tumor suppressor proteins.⁸ Upon viral integration into host DNA, viral replication ceases while oncogenic function persists.

The exact mechanism by which the MCPyV contributes to the development of MCC still has yet to be identified. Hypotheses suggest a combination of viral infection with external mutagens (eg, UV radiation). Experimental observations suggest viral contribution is likely due to the large percentage of MCCs that are positive for MCPyV, the identification of LT antigen expression and the role it plays in preserving cell cycle progression, and the role persistent LT antigen expression plays in continued growth of MCC cell lines in vitro.⁸ Two important cell line preservation mechanisms ensure continued tumor growth, including prevention of apoptosis triggered by DNA damage response mechanisms following UV damage and interaction with the retinoblastoma tumor suppressor protein allowing continued growth.^8,11 Other important factors in tumor growth and survival may be the inhibition of apoptosis through the BCL2 (B-cell chronic lymphocytic leukemia/lymphoma 2) proto-oncogene and survivin (baculoviral inhibitor of apoptosis repeat-containing 5 [BIRC5]).¹² Survivin has been found to play an important role in MCPyV-positive MCCs.^12,13 It has been suggested that lymphangiogenesis in MCC likely is driven by vascular endothelial growth factor-C⁺CD68⁺CD163⁺ M2 macrophages.¹⁴ Another survival mechanism specific to polyomaviruses is their ability to interfere with the p53 tumor suppressor pathway.⁸ Loss of p53 expression by tumor cell nuclei has been associated with poor prognosis.¹⁵

Immune Response

Immune response as a role in tumor progression can be primarily centered on the concept of persistent antigen expression as a means of immune downregulation. Dunn et al¹⁶ suggested that cancer cells must interact through 3 consecutive phases with the host immune system (immunoediting hypothesis). In the elimination phase, the host immune system is able to recognize and destroy newly transformed cells through both the innate and adaptive immune systems. The second equilibrium phase allows the tumor to remain dormant and growth remains stagnant. Lastly, the tumor is allowed to evade the immune system through the escape phase.⁸

Host immune responses play an important role in both the progression and prognosis of MCC. High anti-MCPyV capsid antibody titers have been associated with better progression-free survival in some patients.⁸ Patients with high antibody titers (>10,000) likely have better progression-free survival than those with low antibody titers (<10,000).¹⁷ Antibody titers to the LT antigen may serve as a biomarker of MCC disease burden in the future. Rising LT antigen titers have been shown to correlate with disease progression and falling titers correlate with successful treatment.⁸ Tumoral infiltration of CD8⁺ T lymphocytes has been shown to be a predictor of survival compared to no intratumoral infiltration.⁶ Sihto et al¹⁸ suggested that this better prognosis from high intratumoral infiltration is not specific to MCPyV-positive MCC; however, it does highlight an important aspect of tumor evasion through the downregulation of cell surface expression of class I major histocompatibility complex antigens, which allows presentation of tumor intracellular peptides to CD8⁺ T lymphocytes.⁸ Upregulation of this specific immune response may play a role in the future treatment of MCC.

Staging and Prognosis

Due to the extremely aggressive nature of MCC, patients with local disease and tumors 2 cm or smaller in diameter have a 66% survival at 5 years.^1,3 The 5-year survival rate for patients with local metastasis to regional lymph nodes ranges from 26% to 42%. Patients with distant metastasis have an 18% survival rate at 5 years.^1,3 Data suggest that sentinel lymph node biopsy should be performed on all patients with MCC regardless of tumor size.¹ There are no consensus guidelines to date regarding imaging for the staging of MCC patients. It is suggested that (18F)fluorodeoxyglucose positron emission tomography alone or in combination with computed tomography (CT) may be of value as a single whole-body diagnostic tool for accurate staging.¹⁰ It also has been suggested that (18F)fluorodeoxyglucose positron emission tomography and CT may offer more accurate staging than other screening modalities such as CT alone or magnetic resonance imaging.^14,19

Treatment of MCC

Surgery remains the mainstay of treatment of MCC. Current National Comprehensive Cancer Network guidelines²⁰ recommend 1- to 2-cm margins for wide local excision or treatment with Mohs micrographic surgery. Sentinel lymph node biopsy should be performed intraoperatively in patients undergoing wide local excision and preoperatively for patients undergoing Mohs micrographic surgery due to potential alterations in lymphatic drainage that may affect lymphoscintigraphy.¹

Radiation may be used as primary or adjuvant therapy in patients with MCC. Radiation as primary therapy generally is reserved for patients who are not surgical candidates. It has been suggested that there was no difference in outcome in a small group of patients treated with radiation alone compared to patients who underwent surgery and radiation to the tumor bed.¹ Current guidelines suggest a small group of patients may not require adjuvant therapy following adequate resection of some small tumors, and clinical observation may be appropriate.^1,3 Chemotherapy may play a palliative role in patients with metastatic MCC. Merkel cell carcinoma has been shown to be chemosensitive but with a high recurrence rate.¹ Because the immune system plays an important role in disease prognosis, having an intact immune system likely is paramount in the prevention of further disease progression.

Future Treatments of MCC

Future treatment of MCC may be focused on the viral etiology of most tumors and upregulation of the immune response, which may lead to the possibility of specifically interfering with virus-specific oncoproteins and stimulation of immune responses to virally infected tumor cells.⁸ The MCPyV large T antigen has been found to be overexpressed in some tumors and may serve as a specific target of therapy.^10,21 Survivin, a key cell cycle protein encoded by LT antigen, may be an interesting target given its implication in other cancers.¹³ Other potential nonviral molecular target antigens include the oncoprotein H1P1 that interacts with c-KIT.⁸ Specific immunostimulatory cytokines that may be used to upregulate the immune response to tumoral cells may include IL-2, IL-12, IL-15, or IL-21. Therapeutic agents that may be studied in the future to target the immune exhaustion phenomenon associated with tumorigenesis include ipilimumab (cytotoxic T lymphocyte antigen 4 receptor-blocking agent) as well as programmed cell death 1 and programmed cell death 1 ligand 1 (PD-1/PD-L1).⁸ Neuroendocrine tumors including MCC tend to be highly vascular and express vascular endothelial growth factors and platelet-derived growth factors, which may be other potential therapeutic targets. It has been reported that approximately 95% of MCC patients have CD56⁺ tumors, and current clinical trials suggest a promising therapeutic response with the immunogen anti-CD56 monoclonal antibody.³

Conclusion

Merkel cell carcinoma is a rare aggressive neuroendocrine tumor that has been associated with a novel polyomavirus. Merkel cell carcinoma tends to affect elderly and immunocompromised patients as well as white individuals. Tumors are most often found in areas of high UV exposure and clinically on sun-exposed skin. Merkel cell polyomavirus is associated with approximately 80% of tumors, and tumorigenesis likely is caused by a number of sequential steps from viral integration into host DNA, mutagenic events, and specific immune responses. Currently there are no consensus guidelines for using imaging for staging of MCCs, but sentinel lymph node biopsy is recommended for all cases due to the aggressive nature of even smaller tumors. Surgery remains the mainstay of treatment, and radiation therapy may be used as a primary or adjuvant treatment. Chemotherapy usually is reserved for patients with metastatic disease purely for palliation. Future treatments of MCC likely will center on the viral etiology of MCC and upregulation of immune responses to virally infected tumor cells.

Merkel cells originally were described by German histopathologist Friedrich Sigmund Merkel in 1875. These unique tactile cells were described as epidermal, nondendritic, and nonkeratinizing. Merkel cells are thought to arise from the neural crest and are believed to be primary neural cells found within the basal layer of the epidermis.^1,2 They likely function primarily as slowly adapting type I mechanoreceptors. Origin from the neural crest is controversial, as other investigators have suggested derivation from epidermal keratinocytes.^1,2 Tumor cells have been linked to the amine precursor uptake and decarboxylation system.³ In 1972, Toker⁴ described several cases of trabecular or sweat gland carcinomas of the skin. Upon further investigation, the cells that comprised these tumors were found to have dense core granules on electron microscopy, typical of Merkel cells.^1,2 Other terms such as neuroendocrine carcinoma of the skin, small cell carcinoma of the skin, and anaplastic carcinoma of the skin have been used to describe Merkel cell carcinoma (MCC),¹ which was suggested by De Wolf-Peeters et al⁵ in 1980.

Despite being a rare malignancy, MCC follows an aggressive clinical course. Upon presentation, approximately 66% of patients have local disease, 27% have nodal involvement, and 7% have distant metastasis.¹ Future treatments will likely center around the novel Merkel cell polyomavirus (MCPyV) and modification of immune responses toward tumor cells. Standardization continues to be lacking in both staging and treatment of this aggressive tumor.

Epidemiology of MCC

Figure 1. A 2.3×1.5×1.2-cm, hemorrhagic, crusted, exophytic tumor on the left cheek.

Figure 2. Merkel cells are small- to medium-sized cells with round nuclei and scant cytoplasm. Granular or stippled chromatin can be seen (A)(H&E, original magnification ×40). Merkel cell carcinoma with trabecular pattern (B) (H&E, original magnification ×10).

Between 1986 and 2006, the incidence of MCC grew substantially.^1,2 Figures have been reported at 0.15 cases per 100,000 individuals to 0.6 cases per 100,000 individuals worldwide. In the United States, the age-adjusted incidence of MCC is estimated at 0.24 per 100,000 person-years, which is higher than the estimated 0.13 per 100,000 person-years found in Europe.³ The highest incidence worldwide has been noted in Western Australia, likely due to high levels of UV exposure.¹ The incidence of MCC in psoriasis patients who are treated with oral methoxsalen (psoralen) and UVA photochemotherapy is 100 times greater than in the general population, further supporting the role of UV light in the development of MCC.¹ White individuals have the highest incidence of MCC worldwide, with men being affected more frequently than women.^1,3 The majority of patients with MCC are diagnosed at 70 years or older.¹ Approximately 5% of reported MCC patients are diagnosed before 50 years of age.² Immunosuppression and immunodeficiency likely play a role in the pathogenesis of MCC, and the incidence is increased in solid organ transplant recipients, most commonly renal transplant recipients,¹ as well as individuals with chronic lymphocytic leukemia, human immunodeficiency virus infection, and AIDS.^1,3 Patients with autoimmune diseases such as rheumatoid arthritis also are at increased risk for MCC.³ Individuals who are diagnosed with MCC are at an increased risk for development of other malignancies including nonmelanoma skin cancers, chronic lymphocytic leukemia, Hodgkin lymphoma, and non-Hodgkin lymphoma.³

Clinical Presentation of MCC

The clinical presentation of MCC can be variable. Most tumors present as firm, red to purple, nontender papules or nodules (Figure 1).¹ Tumor size may range from 2 to 200 mm but is most commonly less than 20 mm.² Growth can be rapid, and tumors are most commonly located on sun-exposed skin. The head and neck areas account for 48% of all MCC cases,¹ with the eyelids being frequently involved.² Merkel cell carcinoma also has been reported on the arms, legs, trunk, back, and buttocks.¹ Non–sun-exposed areas are less commonly affected. Mucosal sites (eg, larynx, nasal cavity, pharynx, mouth) account for 5% of primary MCCs.¹ Merkel cell carcinoma also has been reported to affect the vulva and penis. Subcutaneous primary MCC has presented without overlying epidermal changes.¹ In a case series by Heath et al,⁶ 14% (27/195) of MCC patients presented with nodal disease without any identifiable primary tumor, with the inguinal nodal chain being the most common for this presentation. It currently is not known whether these nodal tumors are primary tumors or metastatic disease with a regression of the primary tumor.¹

Histopathology of MCC

Figure 3. Positive chromogranin staining (A)(original magnification ×40). Cytokeratin 20 staining in the characteristic paranuclear dot–like pattern (B)(original magnification ×40). Negative thyroid transcription factor 1 staining (C)(original magnification ×40).

Merkel cells are small- to medium-sized basophilic cells with round nuclei and scant cytoplasm. Granular or stippled chromatin can be seen on histopathology (Figure 2A).¹ Some tumor cells have more vesicular chromatin, multiple small nucleoli, irregular contours, and more abundant cytoplasm. In some reports, irregular contours and abundant cytoplasm were associated with no detectible MCPyV infection.^1,3 Merkel cell carcinomas have a primarily nodular architecture, and classification is based on growth pattern and cell size. Three histopathologic growth patterns have been described: nodular, infiltrative, and trabecular. The trabecular pattern is composed of interconnecting strands ofcells (Figure 2B). Tumors with solely intraepidermal involvement (MCC in situ) have been described but are exceedingly rare.¹ Cell types are classified according to size, with the intermediate cell type being the most common. The small cell variant may be mistaken for a lymphocytic infiltrate due to the similar size and appearance of both types of cells.^1,3

Merkel cell carcinomas can have histopathological overlap with lymphomas, small cell lung cancers, carcinoid tumors, primitive neuroectodermal tumors, neuroblastomas, small cell osteosarcomas, rhabdomyosarcomas, or Ewing sarcomas.^1,3 Specifically, differentiation from small cell carcinoma of the lung is of utmost importance. Merkel cell carcinoma stains positively for cytokeratins 8, 18, 19, and 20. The neuroendocrine markers chromogranin (Figure 3A), synaptophysin, and neuron-specific enolase also may show positive staining. Cytokeratin 20, low-molecular-weight cytokeratins (CAM 5.2), and neurofilament immunostains have a high sensitivity for MCC and are the most frequently used.¹ Cytokeratin 20 stains in the characteristic paranuclear dot–like pattern, which is a hallmark of MCC (Figure 3B). Cytokeratin 20 positivity in conjunction with negative staining for thyroid transcription factor 1 (Figure 3C) and cytokeratin 7 can aid in differentiation from small cell carcinoma of the lung.^1,3

Pathogenesis of MCC

In 2008, Feng et al⁷ discovered a novel polyomavirus associated with the development of MCC. This novel polyomavirus, MCPyV, is found in approximately 80% of all cases of MCC. Seventeen members of the polyomavirus family have been identified, 9 of which have been found to infect humans, including BK virus, JC virus, WU, MCPyV, human polyomavirus 6, human polyomavirus 7, trichodysplasia spinulosa–associated polyomavirus, human polyomavirus 9, and Simian virus 40.¹ Merkel cell polyomavirus infection is found in approximately 60% of the general population and exposure likely occurs early in life. The virus likely is transmitted through skin shedding and nasal secretions, though it also has been found in urine specimens.³ Currently, there is no evidence to suggest vertical viral transmission from mother to fetus.

Merkel cell polyomavirus is composed of early and late gene regions. The early gene region contains both large T antigen (LT) and small T antigen reading frames, which are necessary for viral replication.⁸ The late region is responsible for encoding viral proteins necessary for viral capsid assembly. Mutations found in viral protein 1 prevent formation of viral particles.⁹ Large T antigen is substantially overexpressed in MCC and is responsible for tumor suppression through retinoblastoma tumor suppressor protein. It also serves as a binding domain for both heat shock proteins and helicases.^8,10 These domains allow the polyomaviruses to use host-cell machinery for viral genome replication while targeting tumor suppressor proteins.⁸ Upon viral integration into host DNA, viral replication ceases while oncogenic function persists.

The exact mechanism by which the MCPyV contributes to the development of MCC still has yet to be identified. Hypotheses suggest a combination of viral infection with external mutagens (eg, UV radiation). Experimental observations suggest viral contribution is likely due to the large percentage of MCCs that are positive for MCPyV, the identification of LT antigen expression and the role it plays in preserving cell cycle progression, and the role persistent LT antigen expression plays in continued growth of MCC cell lines in vitro.⁸ Two important cell line preservation mechanisms ensure continued tumor growth, including prevention of apoptosis triggered by DNA damage response mechanisms following UV damage and interaction with the retinoblastoma tumor suppressor protein allowing continued growth.^8,11 Other important factors in tumor growth and survival may be the inhibition of apoptosis through the BCL2 (B-cell chronic lymphocytic leukemia/lymphoma 2) proto-oncogene and survivin (baculoviral inhibitor of apoptosis repeat-containing 5 [BIRC5]).¹² Survivin has been found to play an important role in MCPyV-positive MCCs.^12,13 It has been suggested that lymphangiogenesis in MCC likely is driven by vascular endothelial growth factor-C⁺CD68⁺CD163⁺ M2 macrophages.¹⁴ Another survival mechanism specific to polyomaviruses is their ability to interfere with the p53 tumor suppressor pathway.⁸ Loss of p53 expression by tumor cell nuclei has been associated with poor prognosis.¹⁵

Immune Response

Immune response as a role in tumor progression can be primarily centered on the concept of persistent antigen expression as a means of immune downregulation. Dunn et al¹⁶ suggested that cancer cells must interact through 3 consecutive phases with the host immune system (immunoediting hypothesis). In the elimination phase, the host immune system is able to recognize and destroy newly transformed cells through both the innate and adaptive immune systems. The second equilibrium phase allows the tumor to remain dormant and growth remains stagnant. Lastly, the tumor is allowed to evade the immune system through the escape phase.⁸

Host immune responses play an important role in both the progression and prognosis of MCC. High anti-MCPyV capsid antibody titers have been associated with better progression-free survival in some patients.⁸ Patients with high antibody titers (>10,000) likely have better progression-free survival than those with low antibody titers (<10,000).¹⁷ Antibody titers to the LT antigen may serve as a biomarker of MCC disease burden in the future. Rising LT antigen titers have been shown to correlate with disease progression and falling titers correlate with successful treatment.⁸ Tumoral infiltration of CD8⁺ T lymphocytes has been shown to be a predictor of survival compared to no intratumoral infiltration.⁶ Sihto et al¹⁸ suggested that this better prognosis from high intratumoral infiltration is not specific to MCPyV-positive MCC; however, it does highlight an important aspect of tumor evasion through the downregulation of cell surface expression of class I major histocompatibility complex antigens, which allows presentation of tumor intracellular peptides to CD8⁺ T lymphocytes.⁸ Upregulation of this specific immune response may play a role in the future treatment of MCC.

Staging and Prognosis

Due to the extremely aggressive nature of MCC, patients with local disease and tumors 2 cm or smaller in diameter have a 66% survival at 5 years.^1,3 The 5-year survival rate for patients with local metastasis to regional lymph nodes ranges from 26% to 42%. Patients with distant metastasis have an 18% survival rate at 5 years.^1,3 Data suggest that sentinel lymph node biopsy should be performed on all patients with MCC regardless of tumor size.¹ There are no consensus guidelines to date regarding imaging for the staging of MCC patients. It is suggested that (18F)fluorodeoxyglucose positron emission tomography alone or in combination with computed tomography (CT) may be of value as a single whole-body diagnostic tool for accurate staging.¹⁰ It also has been suggested that (18F)fluorodeoxyglucose positron emission tomography and CT may offer more accurate staging than other screening modalities such as CT alone or magnetic resonance imaging.^14,19

Treatment of MCC

Surgery remains the mainstay of treatment of MCC. Current National Comprehensive Cancer Network guidelines²⁰ recommend 1- to 2-cm margins for wide local excision or treatment with Mohs micrographic surgery. Sentinel lymph node biopsy should be performed intraoperatively in patients undergoing wide local excision and preoperatively for patients undergoing Mohs micrographic surgery due to potential alterations in lymphatic drainage that may affect lymphoscintigraphy.¹

Radiation may be used as primary or adjuvant therapy in patients with MCC. Radiation as primary therapy generally is reserved for patients who are not surgical candidates. It has been suggested that there was no difference in outcome in a small group of patients treated with radiation alone compared to patients who underwent surgery and radiation to the tumor bed.¹ Current guidelines suggest a small group of patients may not require adjuvant therapy following adequate resection of some small tumors, and clinical observation may be appropriate.^1,3 Chemotherapy may play a palliative role in patients with metastatic MCC. Merkel cell carcinoma has been shown to be chemosensitive but with a high recurrence rate.¹ Because the immune system plays an important role in disease prognosis, having an intact immune system likely is paramount in the prevention of further disease progression.

Future Treatments of MCC

Future treatment of MCC may be focused on the viral etiology of most tumors and upregulation of the immune response, which may lead to the possibility of specifically interfering with virus-specific oncoproteins and stimulation of immune responses to virally infected tumor cells.⁸ The MCPyV large T antigen has been found to be overexpressed in some tumors and may serve as a specific target of therapy.^10,21 Survivin, a key cell cycle protein encoded by LT antigen, may be an interesting target given its implication in other cancers.¹³ Other potential nonviral molecular target antigens include the oncoprotein H1P1 that interacts with c-KIT.⁸ Specific immunostimulatory cytokines that may be used to upregulate the immune response to tumoral cells may include IL-2, IL-12, IL-15, or IL-21. Therapeutic agents that may be studied in the future to target the immune exhaustion phenomenon associated with tumorigenesis include ipilimumab (cytotoxic T lymphocyte antigen 4 receptor-blocking agent) as well as programmed cell death 1 and programmed cell death 1 ligand 1 (PD-1/PD-L1).⁸ Neuroendocrine tumors including MCC tend to be highly vascular and express vascular endothelial growth factors and platelet-derived growth factors, which may be other potential therapeutic targets. It has been reported that approximately 95% of MCC patients have CD56⁺ tumors, and current clinical trials suggest a promising therapeutic response with the immunogen anti-CD56 monoclonal antibody.³

Conclusion

Merkel cell carcinoma is a rare aggressive neuroendocrine tumor that has been associated with a novel polyomavirus. Merkel cell carcinoma tends to affect elderly and immunocompromised patients as well as white individuals. Tumors are most often found in areas of high UV exposure and clinically on sun-exposed skin. Merkel cell polyomavirus is associated with approximately 80% of tumors, and tumorigenesis likely is caused by a number of sequential steps from viral integration into host DNA, mutagenic events, and specific immune responses. Currently there are no consensus guidelines for using imaging for staging of MCCs, but sentinel lymph node biopsy is recommended for all cases due to the aggressive nature of even smaller tumors. Surgery remains the mainstay of treatment, and radiation therapy may be used as a primary or adjuvant treatment. Chemotherapy usually is reserved for patients with metastatic disease purely for palliation. Future treatments of MCC likely will center on the viral etiology of MCC and upregulation of immune responses to virally infected tumor cells.

Merkel cells originally were described by German histopathologist Friedrich Sigmund Merkel in 1875. These unique tactile cells were described as epidermal, nondendritic, and nonkeratinizing. Merkel cells are thought to arise from the neural crest and are believed to be primary neural cells found within the basal layer of the epidermis.^1,2 They likely function primarily as slowly adapting type I mechanoreceptors. Origin from the neural crest is controversial, as other investigators have suggested derivation from epidermal keratinocytes.^1,2 Tumor cells have been linked to the amine precursor uptake and decarboxylation system.³ In 1972, Toker⁴ described several cases of trabecular or sweat gland carcinomas of the skin. Upon further investigation, the cells that comprised these tumors were found to have dense core granules on electron microscopy, typical of Merkel cells.^1,2 Other terms such as neuroendocrine carcinoma of the skin, small cell carcinoma of the skin, and anaplastic carcinoma of the skin have been used to describe Merkel cell carcinoma (MCC),¹ which was suggested by De Wolf-Peeters et al⁵ in 1980.

Despite being a rare malignancy, MCC follows an aggressive clinical course. Upon presentation, approximately 66% of patients have local disease, 27% have nodal involvement, and 7% have distant metastasis.¹ Future treatments will likely center around the novel Merkel cell polyomavirus (MCPyV) and modification of immune responses toward tumor cells. Standardization continues to be lacking in both staging and treatment of this aggressive tumor.

Epidemiology of MCC

Figure 1. A 2.3×1.5×1.2-cm, hemorrhagic, crusted, exophytic tumor on the left cheek.

Figure 2. Merkel cells are small- to medium-sized cells with round nuclei and scant cytoplasm. Granular or stippled chromatin can be seen (A)(H&E, original magnification ×40). Merkel cell carcinoma with trabecular pattern (B) (H&E, original magnification ×10).

Between 1986 and 2006, the incidence of MCC grew substantially.^1,2 Figures have been reported at 0.15 cases per 100,000 individuals to 0.6 cases per 100,000 individuals worldwide. In the United States, the age-adjusted incidence of MCC is estimated at 0.24 per 100,000 person-years, which is higher than the estimated 0.13 per 100,000 person-years found in Europe.³ The highest incidence worldwide has been noted in Western Australia, likely due to high levels of UV exposure.¹ The incidence of MCC in psoriasis patients who are treated with oral methoxsalen (psoralen) and UVA photochemotherapy is 100 times greater than in the general population, further supporting the role of UV light in the development of MCC.¹ White individuals have the highest incidence of MCC worldwide, with men being affected more frequently than women.^1,3 The majority of patients with MCC are diagnosed at 70 years or older.¹ Approximately 5% of reported MCC patients are diagnosed before 50 years of age.² Immunosuppression and immunodeficiency likely play a role in the pathogenesis of MCC, and the incidence is increased in solid organ transplant recipients, most commonly renal transplant recipients,¹ as well as individuals with chronic lymphocytic leukemia, human immunodeficiency virus infection, and AIDS.^1,3 Patients with autoimmune diseases such as rheumatoid arthritis also are at increased risk for MCC.³ Individuals who are diagnosed with MCC are at an increased risk for development of other malignancies including nonmelanoma skin cancers, chronic lymphocytic leukemia, Hodgkin lymphoma, and non-Hodgkin lymphoma.³

Clinical Presentation of MCC

The clinical presentation of MCC can be variable. Most tumors present as firm, red to purple, nontender papules or nodules (Figure 1).¹ Tumor size may range from 2 to 200 mm but is most commonly less than 20 mm.² Growth can be rapid, and tumors are most commonly located on sun-exposed skin. The head and neck areas account for 48% of all MCC cases,¹ with the eyelids being frequently involved.² Merkel cell carcinoma also has been reported on the arms, legs, trunk, back, and buttocks.¹ Non–sun-exposed areas are less commonly affected. Mucosal sites (eg, larynx, nasal cavity, pharynx, mouth) account for 5% of primary MCCs.¹ Merkel cell carcinoma also has been reported to affect the vulva and penis. Subcutaneous primary MCC has presented without overlying epidermal changes.¹ In a case series by Heath et al,⁶ 14% (27/195) of MCC patients presented with nodal disease without any identifiable primary tumor, with the inguinal nodal chain being the most common for this presentation. It currently is not known whether these nodal tumors are primary tumors or metastatic disease with a regression of the primary tumor.¹

Histopathology of MCC

Figure 3. Positive chromogranin staining (A)(original magnification ×40). Cytokeratin 20 staining in the characteristic paranuclear dot–like pattern (B)(original magnification ×40). Negative thyroid transcription factor 1 staining (C)(original magnification ×40).

Merkel cells are small- to medium-sized basophilic cells with round nuclei and scant cytoplasm. Granular or stippled chromatin can be seen on histopathology (Figure 2A).¹ Some tumor cells have more vesicular chromatin, multiple small nucleoli, irregular contours, and more abundant cytoplasm. In some reports, irregular contours and abundant cytoplasm were associated with no detectible MCPyV infection.^1,3 Merkel cell carcinomas have a primarily nodular architecture, and classification is based on growth pattern and cell size. Three histopathologic growth patterns have been described: nodular, infiltrative, and trabecular. The trabecular pattern is composed of interconnecting strands ofcells (Figure 2B). Tumors with solely intraepidermal involvement (MCC in situ) have been described but are exceedingly rare.¹ Cell types are classified according to size, with the intermediate cell type being the most common. The small cell variant may be mistaken for a lymphocytic infiltrate due to the similar size and appearance of both types of cells.^1,3

Merkel cell carcinomas can have histopathological overlap with lymphomas, small cell lung cancers, carcinoid tumors, primitive neuroectodermal tumors, neuroblastomas, small cell osteosarcomas, rhabdomyosarcomas, or Ewing sarcomas.^1,3 Specifically, differentiation from small cell carcinoma of the lung is of utmost importance. Merkel cell carcinoma stains positively for cytokeratins 8, 18, 19, and 20. The neuroendocrine markers chromogranin (Figure 3A), synaptophysin, and neuron-specific enolase also may show positive staining. Cytokeratin 20, low-molecular-weight cytokeratins (CAM 5.2), and neurofilament immunostains have a high sensitivity for MCC and are the most frequently used.¹ Cytokeratin 20 stains in the characteristic paranuclear dot–like pattern, which is a hallmark of MCC (Figure 3B). Cytokeratin 20 positivity in conjunction with negative staining for thyroid transcription factor 1 (Figure 3C) and cytokeratin 7 can aid in differentiation from small cell carcinoma of the lung.^1,3

Pathogenesis of MCC

In 2008, Feng et al⁷ discovered a novel polyomavirus associated with the development of MCC. This novel polyomavirus, MCPyV, is found in approximately 80% of all cases of MCC. Seventeen members of the polyomavirus family have been identified, 9 of which have been found to infect humans, including BK virus, JC virus, WU, MCPyV, human polyomavirus 6, human polyomavirus 7, trichodysplasia spinulosa–associated polyomavirus, human polyomavirus 9, and Simian virus 40.¹ Merkel cell polyomavirus infection is found in approximately 60% of the general population and exposure likely occurs early in life. The virus likely is transmitted through skin shedding and nasal secretions, though it also has been found in urine specimens.³ Currently, there is no evidence to suggest vertical viral transmission from mother to fetus.

Merkel cell polyomavirus is composed of early and late gene regions. The early gene region contains both large T antigen (LT) and small T antigen reading frames, which are necessary for viral replication.⁸ The late region is responsible for encoding viral proteins necessary for viral capsid assembly. Mutations found in viral protein 1 prevent formation of viral particles.⁹ Large T antigen is substantially overexpressed in MCC and is responsible for tumor suppression through retinoblastoma tumor suppressor protein. It also serves as a binding domain for both heat shock proteins and helicases.^8,10 These domains allow the polyomaviruses to use host-cell machinery for viral genome replication while targeting tumor suppressor proteins.⁸ Upon viral integration into host DNA, viral replication ceases while oncogenic function persists.

The exact mechanism by which the MCPyV contributes to the development of MCC still has yet to be identified. Hypotheses suggest a combination of viral infection with external mutagens (eg, UV radiation). Experimental observations suggest viral contribution is likely due to the large percentage of MCCs that are positive for MCPyV, the identification of LT antigen expression and the role it plays in preserving cell cycle progression, and the role persistent LT antigen expression plays in continued growth of MCC cell lines in vitro.⁸ Two important cell line preservation mechanisms ensure continued tumor growth, including prevention of apoptosis triggered by DNA damage response mechanisms following UV damage and interaction with the retinoblastoma tumor suppressor protein allowing continued growth.^8,11 Other important factors in tumor growth and survival may be the inhibition of apoptosis through the BCL2 (B-cell chronic lymphocytic leukemia/lymphoma 2) proto-oncogene and survivin (baculoviral inhibitor of apoptosis repeat-containing 5 [BIRC5]).¹² Survivin has been found to play an important role in MCPyV-positive MCCs.^12,13 It has been suggested that lymphangiogenesis in MCC likely is driven by vascular endothelial growth factor-C⁺CD68⁺CD163⁺ M2 macrophages.¹⁴ Another survival mechanism specific to polyomaviruses is their ability to interfere with the p53 tumor suppressor pathway.⁸ Loss of p53 expression by tumor cell nuclei has been associated with poor prognosis.¹⁵

Immune Response

Immune response as a role in tumor progression can be primarily centered on the concept of persistent antigen expression as a means of immune downregulation. Dunn et al¹⁶ suggested that cancer cells must interact through 3 consecutive phases with the host immune system (immunoediting hypothesis). In the elimination phase, the host immune system is able to recognize and destroy newly transformed cells through both the innate and adaptive immune systems. The second equilibrium phase allows the tumor to remain dormant and growth remains stagnant. Lastly, the tumor is allowed to evade the immune system through the escape phase.⁸

Host immune responses play an important role in both the progression and prognosis of MCC. High anti-MCPyV capsid antibody titers have been associated with better progression-free survival in some patients.⁸ Patients with high antibody titers (>10,000) likely have better progression-free survival than those with low antibody titers (<10,000).¹⁷ Antibody titers to the LT antigen may serve as a biomarker of MCC disease burden in the future. Rising LT antigen titers have been shown to correlate with disease progression and falling titers correlate with successful treatment.⁸ Tumoral infiltration of CD8⁺ T lymphocytes has been shown to be a predictor of survival compared to no intratumoral infiltration.⁶ Sihto et al¹⁸ suggested that this better prognosis from high intratumoral infiltration is not specific to MCPyV-positive MCC; however, it does highlight an important aspect of tumor evasion through the downregulation of cell surface expression of class I major histocompatibility complex antigens, which allows presentation of tumor intracellular peptides to CD8⁺ T lymphocytes.⁸ Upregulation of this specific immune response may play a role in the future treatment of MCC.

Staging and Prognosis

Due to the extremely aggressive nature of MCC, patients with local disease and tumors 2 cm or smaller in diameter have a 66% survival at 5 years.^1,3 The 5-year survival rate for patients with local metastasis to regional lymph nodes ranges from 26% to 42%. Patients with distant metastasis have an 18% survival rate at 5 years.^1,3 Data suggest that sentinel lymph node biopsy should be performed on all patients with MCC regardless of tumor size.¹ There are no consensus guidelines to date regarding imaging for the staging of MCC patients. It is suggested that (18F)fluorodeoxyglucose positron emission tomography alone or in combination with computed tomography (CT) may be of value as a single whole-body diagnostic tool for accurate staging.¹⁰ It also has been suggested that (18F)fluorodeoxyglucose positron emission tomography and CT may offer more accurate staging than other screening modalities such as CT alone or magnetic resonance imaging.^14,19

Treatment of MCC

Surgery remains the mainstay of treatment of MCC. Current National Comprehensive Cancer Network guidelines²⁰ recommend 1- to 2-cm margins for wide local excision or treatment with Mohs micrographic surgery. Sentinel lymph node biopsy should be performed intraoperatively in patients undergoing wide local excision and preoperatively for patients undergoing Mohs micrographic surgery due to potential alterations in lymphatic drainage that may affect lymphoscintigraphy.¹

Radiation may be used as primary or adjuvant therapy in patients with MCC. Radiation as primary therapy generally is reserved for patients who are not surgical candidates. It has been suggested that there was no difference in outcome in a small group of patients treated with radiation alone compared to patients who underwent surgery and radiation to the tumor bed.¹ Current guidelines suggest a small group of patients may not require adjuvant therapy following adequate resection of some small tumors, and clinical observation may be appropriate.^1,3 Chemotherapy may play a palliative role in patients with metastatic MCC. Merkel cell carcinoma has been shown to be chemosensitive but with a high recurrence rate.¹ Because the immune system plays an important role in disease prognosis, having an intact immune system likely is paramount in the prevention of further disease progression.

Future Treatments of MCC

Future treatment of MCC may be focused on the viral etiology of most tumors and upregulation of the immune response, which may lead to the possibility of specifically interfering with virus-specific oncoproteins and stimulation of immune responses to virally infected tumor cells.⁸ The MCPyV large T antigen has been found to be overexpressed in some tumors and may serve as a specific target of therapy.^10,21 Survivin, a key cell cycle protein encoded by LT antigen, may be an interesting target given its implication in other cancers.¹³ Other potential nonviral molecular target antigens include the oncoprotein H1P1 that interacts with c-KIT.⁸ Specific immunostimulatory cytokines that may be used to upregulate the immune response to tumoral cells may include IL-2, IL-12, IL-15, or IL-21. Therapeutic agents that may be studied in the future to target the immune exhaustion phenomenon associated with tumorigenesis include ipilimumab (cytotoxic T lymphocyte antigen 4 receptor-blocking agent) as well as programmed cell death 1 and programmed cell death 1 ligand 1 (PD-1/PD-L1).⁸ Neuroendocrine tumors including MCC tend to be highly vascular and express vascular endothelial growth factors and platelet-derived growth factors, which may be other potential therapeutic targets. It has been reported that approximately 95% of MCC patients have CD56⁺ tumors, and current clinical trials suggest a promising therapeutic response with the immunogen anti-CD56 monoclonal antibody.³

Conclusion

Merkel cell carcinoma is a rare aggressive neuroendocrine tumor that has been associated with a novel polyomavirus. Merkel cell carcinoma tends to affect elderly and immunocompromised patients as well as white individuals. Tumors are most often found in areas of high UV exposure and clinically on sun-exposed skin. Merkel cell polyomavirus is associated with approximately 80% of tumors, and tumorigenesis likely is caused by a number of sequential steps from viral integration into host DNA, mutagenic events, and specific immune responses. Currently there are no consensus guidelines for using imaging for staging of MCCs, but sentinel lymph node biopsy is recommended for all cases due to the aggressive nature of even smaller tumors. Surgery remains the mainstay of treatment, and radiation therapy may be used as a primary or adjuvant treatment. Chemotherapy usually is reserved for patients with metastatic disease purely for palliation. Future treatments of MCC likely will center on the viral etiology of MCC and upregulation of immune responses to virally infected tumor cells.

The US Food and Drug Administration (FDA) has proposed 2 new rules to protect consumers from health risks associated with indoor tanning by banning use of indoor tanning devices by minors and imposing safety measures.

The first proposed rule restricts the use of indoor tanning devices to adults 18 years and older. It also requires indoor tanning facilities to inform adult users about the health risks of indoor tanning and obtain a signed risk acknowledgement from consumers before their first tanning session and every 6 months thereafter.

“Exposure to UV radiation from indoor tanning is a preventable cause of skin cancer,” explained Markham C. Luke, MD, PhD, deputy office director for the Office of Device Evaluation at the FDA’s Center for Devices and Radiological Health. “The FDA is committed to protecting public health by informing consumers of the risks of indoor tanning.”

The second proposed rule addresses performance standards, requiring manufacturers and indoor tanning facilities to take measures to improve the overall safety of tanning devices. Key changes would include:

• Make consumer warnings more prominent and easier to read on tanning devices.

• Require an easily accessible emergency shutoff switch (or panic button) on all tanning devices.

• Add requirements to limit the amount of light allowed through protective eyewear to protect the eyes.

• Improve labeling on replacement bulbs to ensure tanning facility operators use the proper bulbs to reduce risk for accidental burns.

• Prohibit tanning facilities from making dangerous device modifications (eg, installing stronger bulbs) without recertifying and reidentifying the device with the FDA.

The FDA reports that more than 1 million minors use indoor tanning facilities each year. According to the American Academy of Dermatology, consumers younger than 35 years who use indoor tanning facilities are 59% more likely to develop melanoma than those who have never tanned indoors. Because the effects of UV exposure are cumulative and add up over the course of one’s lifetime, minors who use indoor tanning devices are at an increased risk for developing melanoma and nonmelanoma skin cancers later in life.

In 2014 the FDA began requiring tanning devices to be labeled with a visible warning stating that individuals younger than 18 years should not use them. Additionally, several states have already passed laws prohibiting minors from indoor tanning; in Connecticut, New Jersey, New York, and Pennsylvania, tanning devices are banned in individuals younger than 17 years.

Dermatologists are in the position to discuss the health risks of indoor tanning with all patients regardless of age. Patients should be reminded that failure to wear appropriate protective eyewear can lead to short-term and long-term eye injury and that long exposures can lead to burning that may not be recognized until it is too late. It also is important to warn patients that tanning while using certain medications or cosmetics may cause increased sensitivity to UV radiation. Patients can be referred to the FDA website for more consumer updates about indoor tanning and the proposed rules.

The US Food and Drug Administration (FDA) has proposed 2 new rules to protect consumers from health risks associated with indoor tanning by banning use of indoor tanning devices by minors and imposing safety measures.

The first proposed rule restricts the use of indoor tanning devices to adults 18 years and older. It also requires indoor tanning facilities to inform adult users about the health risks of indoor tanning and obtain a signed risk acknowledgement from consumers before their first tanning session and every 6 months thereafter.

“Exposure to UV radiation from indoor tanning is a preventable cause of skin cancer,” explained Markham C. Luke, MD, PhD, deputy office director for the Office of Device Evaluation at the FDA’s Center for Devices and Radiological Health. “The FDA is committed to protecting public health by informing consumers of the risks of indoor tanning.”

The second proposed rule addresses performance standards, requiring manufacturers and indoor tanning facilities to take measures to improve the overall safety of tanning devices. Key changes would include:

• Make consumer warnings more prominent and easier to read on tanning devices.

• Require an easily accessible emergency shutoff switch (or panic button) on all tanning devices.

• Add requirements to limit the amount of light allowed through protective eyewear to protect the eyes.

• Improve labeling on replacement bulbs to ensure tanning facility operators use the proper bulbs to reduce risk for accidental burns.

• Prohibit tanning facilities from making dangerous device modifications (eg, installing stronger bulbs) without recertifying and reidentifying the device with the FDA.

The FDA reports that more than 1 million minors use indoor tanning facilities each year. According to the American Academy of Dermatology, consumers younger than 35 years who use indoor tanning facilities are 59% more likely to develop melanoma than those who have never tanned indoors. Because the effects of UV exposure are cumulative and add up over the course of one’s lifetime, minors who use indoor tanning devices are at an increased risk for developing melanoma and nonmelanoma skin cancers later in life.

In 2014 the FDA began requiring tanning devices to be labeled with a visible warning stating that individuals younger than 18 years should not use them. Additionally, several states have already passed laws prohibiting minors from indoor tanning; in Connecticut, New Jersey, New York, and Pennsylvania, tanning devices are banned in individuals younger than 17 years.

Dermatologists are in the position to discuss the health risks of indoor tanning with all patients regardless of age. Patients should be reminded that failure to wear appropriate protective eyewear can lead to short-term and long-term eye injury and that long exposures can lead to burning that may not be recognized until it is too late. It also is important to warn patients that tanning while using certain medications or cosmetics may cause increased sensitivity to UV radiation. Patients can be referred to the FDA website for more consumer updates about indoor tanning and the proposed rules.

The US Food and Drug Administration (FDA) has proposed 2 new rules to protect consumers from health risks associated with indoor tanning by banning use of indoor tanning devices by minors and imposing safety measures.

The first proposed rule restricts the use of indoor tanning devices to adults 18 years and older. It also requires indoor tanning facilities to inform adult users about the health risks of indoor tanning and obtain a signed risk acknowledgement from consumers before their first tanning session and every 6 months thereafter.

“Exposure to UV radiation from indoor tanning is a preventable cause of skin cancer,” explained Markham C. Luke, MD, PhD, deputy office director for the Office of Device Evaluation at the FDA’s Center for Devices and Radiological Health. “The FDA is committed to protecting public health by informing consumers of the risks of indoor tanning.”

The second proposed rule addresses performance standards, requiring manufacturers and indoor tanning facilities to take measures to improve the overall safety of tanning devices. Key changes would include:

• Make consumer warnings more prominent and easier to read on tanning devices.

• Require an easily accessible emergency shutoff switch (or panic button) on all tanning devices.

• Add requirements to limit the amount of light allowed through protective eyewear to protect the eyes.

• Improve labeling on replacement bulbs to ensure tanning facility operators use the proper bulbs to reduce risk for accidental burns.

• Prohibit tanning facilities from making dangerous device modifications (eg, installing stronger bulbs) without recertifying and reidentifying the device with the FDA.

The FDA reports that more than 1 million minors use indoor tanning facilities each year. According to the American Academy of Dermatology, consumers younger than 35 years who use indoor tanning facilities are 59% more likely to develop melanoma than those who have never tanned indoors. Because the effects of UV exposure are cumulative and add up over the course of one’s lifetime, minors who use indoor tanning devices are at an increased risk for developing melanoma and nonmelanoma skin cancers later in life.

In 2014 the FDA began requiring tanning devices to be labeled with a visible warning stating that individuals younger than 18 years should not use them. Additionally, several states have already passed laws prohibiting minors from indoor tanning; in Connecticut, New Jersey, New York, and Pennsylvania, tanning devices are banned in individuals younger than 17 years.

Dermatologists are in the position to discuss the health risks of indoor tanning with all patients regardless of age. Patients should be reminded that failure to wear appropriate protective eyewear can lead to short-term and long-term eye injury and that long exposures can lead to burning that may not be recognized until it is too late. It also is important to warn patients that tanning while using certain medications or cosmetics may cause increased sensitivity to UV radiation. Patients can be referred to the FDA website for more consumer updates about indoor tanning and the proposed rules.

To the Editor:
Lichen sclerosus (LS) is a chronic inflammatory disorder of unknown etiology that most commonly affects the anogenital region. Progressive sclerosis results in scarring with distortion of the normal epithelial architecture.^1,2 The lifetime risk for developing squamous cell carcinoma (SCC) as a complication of long-standing LS has been estimated as 4% to 6%.^3,4 However, there is no general agreement concerning the exact relationship between anogenital LS and SCC.¹ The coexistence of histologic findings of LS, vulvar intraepithelial neoplasia (VIN), and SCC in the same tissue is rare. We report a case of VIN and SCC developing in a region of preexisting LS.

A 76-year-old woman presented with a 7-mm nodule on the clitoris that was surrounded by a pearly white, smooth, glistening area (Figure 1). The patient reported pain and tenderness associated with the nodule. No regional lymphadenopathy was evident. We performed an excisional biopsy of the entire nodule and a small part of the whitish patch (Figure 2A). On histologic examination, the presence of hyperkeratosis, epidermal atrophy, a swollen dermal collagen bundle, and prominent edema was consistent with LS (Figure 2B). The presence of dysplastic changes with mild disturbance of the epithelial architecture as well as acanthosis and dyskeratosis in the same tissue confirmed VIN (Figure 2C). Dermal invasion and transition to SCC were seen in the part of the tissue verified as VIN. The presence of dermal tumor nests and an irregular border between the epidermis and dermis pointed to the existence of fully developed SCC (Figure 2D). To prevent the recurrence of SCC, the patient returned for follow-up periodically. There was no recurrence within 6 months after excision.

Figure 2. An excisional biopsy showed epidermal thinning on the left side and invasion of the dermis by a tumor nest on the right side (A)(H&E, original magnification ×10). Left, center, and right boxes indicate areas shown in Figures 2B, 2C and 2D, respectively. Hyperkeratosis, epidermal atrophy, a swollen dermal collagen bundle, and prominent edema was evident (B)(H&E, original magnification ×200). Dysplactic changes with mild disturbance of the epithelial architecture accompanied by acanthosis and nuclear atypia were seen (C)(H&E, original magnification ×200). Irregular masses of atypical squamous cells spread downward into the dermis representing squamous cell carcinoma of a well-differentiated type (D)(H&E, original magnification ×200).

Although LS is considered a premalignant condition, only a small portion of patients with LS ultimately develop vulvar SCC.⁵ There are a number of reasons for linking LS with the development of vulvar SCC. First, in the majority of cases of vulvar SCC, LS, squamous cell hyperplasia, or VIN is present in the adjacent epithelium. Lichen sclerosus is found in adjacent regions in up to 62% of vulvar SCC cases.⁶ Second, patients with LS may develop vulvar SCC, as frequently reported. Third, in a series of LS patients who underwent long-term follow-up, 4% to 6% were reported to have developed vulvar SCC.^3,4,7

Lichen sclerosus is an inflammatory dermatosis characterized by clinicopathologic persistence and hypocellular fibrosis.² Changes in the local environment of the keratinocyte, including chronic inflammation and sclerosis, may be responsible for the promotion of carcinogenesis.⁸ However, no molecular markers have been proven to identify the LS lesions that are at risk for developing into vulvar SCC.^9,10 It has been suggested that VIN is the direct precursor of vulvar SCC.^11,12

Histologic diagnosis of VIN is difficult. Its identification is hindered by a high degree of cellular differentiation combined with the absence of widespread architectural disorder, nuclear pleomorphism, and diffuse nuclear atypia.¹³ The atypia in VIN lesions is strictly confined to the basal and parabasal layers of the epithelium.¹¹ Vulvar intraepithelial neoplasia has seldom been diagnosed as a solitary lesion because it appears to have a short intraepithelial lifetime.

Vulvar SCC can be divided into 2 patterns. The first is found in older women, which is unrelated to human papillomavirus (HPV). This type occurs in a background of LS and/or differentiated VIN. The second is predominantly found in younger women, which is related to high-risk HPV. This type of vulvar SCC frequently is associated with the histologic subtypes of warty and basaloid differentiations and is referred to as undifferentiated VIN. There is no association with LS in these cases.^2,14,15

It has been suggested that LS and HPV may not be mutually exclusive but may act as cofactors in SCC pathogenesis.¹⁶ Infection with HPV is an early event in the multistep process of vulvar carcinogenesis, and HPV integration into host cell genome seems to be related to the progression of vulvar dysplasia.¹⁷ Viral integration generally disrupts the E2 region, resulting in enhanced expression of E6 and E7. E6 and E7 have the ability to bind and inactivate the protein p53 and retinoblastoma protein, which promotes rapid progression through the cell cycle without p53-mediated control of DNA integrity.¹⁸ However, the exact influence of HPV in vulvar SCC is uncertain, as divergent prevalence rates have been published.

In our case, histologic examination revealed the characteristic findings of LS, VIN, and SCC in succession. This sequence is evidence of progressive transition from LS to VIN and then to SCC. Consequently, this case suggests that vulvar LS may act as both an initiator and a promoter of carcinogenesis and that VIN may be the direct precursor of vulvar SCC. In conclusion, LS has a considerable risk for malignant transformation and requires continuous follow-up in all patients. Early histological detection of invasive lesions is crucial to reduce the risk for vulvar cancer.

To the Editor:
Lichen sclerosus (LS) is a chronic inflammatory disorder of unknown etiology that most commonly affects the anogenital region. Progressive sclerosis results in scarring with distortion of the normal epithelial architecture.^1,2 The lifetime risk for developing squamous cell carcinoma (SCC) as a complication of long-standing LS has been estimated as 4% to 6%.^3,4 However, there is no general agreement concerning the exact relationship between anogenital LS and SCC.¹ The coexistence of histologic findings of LS, vulvar intraepithelial neoplasia (VIN), and SCC in the same tissue is rare. We report a case of VIN and SCC developing in a region of preexisting LS.

A 76-year-old woman presented with a 7-mm nodule on the clitoris that was surrounded by a pearly white, smooth, glistening area (Figure 1). The patient reported pain and tenderness associated with the nodule. No regional lymphadenopathy was evident. We performed an excisional biopsy of the entire nodule and a small part of the whitish patch (Figure 2A). On histologic examination, the presence of hyperkeratosis, epidermal atrophy, a swollen dermal collagen bundle, and prominent edema was consistent with LS (Figure 2B). The presence of dysplastic changes with mild disturbance of the epithelial architecture as well as acanthosis and dyskeratosis in the same tissue confirmed VIN (Figure 2C). Dermal invasion and transition to SCC were seen in the part of the tissue verified as VIN. The presence of dermal tumor nests and an irregular border between the epidermis and dermis pointed to the existence of fully developed SCC (Figure 2D). To prevent the recurrence of SCC, the patient returned for follow-up periodically. There was no recurrence within 6 months after excision.

Figure 2. An excisional biopsy showed epidermal thinning on the left side and invasion of the dermis by a tumor nest on the right side (A)(H&E, original magnification ×10). Left, center, and right boxes indicate areas shown in Figures 2B, 2C and 2D, respectively. Hyperkeratosis, epidermal atrophy, a swollen dermal collagen bundle, and prominent edema was evident (B)(H&E, original magnification ×200). Dysplactic changes with mild disturbance of the epithelial architecture accompanied by acanthosis and nuclear atypia were seen (C)(H&E, original magnification ×200). Irregular masses of atypical squamous cells spread downward into the dermis representing squamous cell carcinoma of a well-differentiated type (D)(H&E, original magnification ×200).

Although LS is considered a premalignant condition, only a small portion of patients with LS ultimately develop vulvar SCC.⁵ There are a number of reasons for linking LS with the development of vulvar SCC. First, in the majority of cases of vulvar SCC, LS, squamous cell hyperplasia, or VIN is present in the adjacent epithelium. Lichen sclerosus is found in adjacent regions in up to 62% of vulvar SCC cases.⁶ Second, patients with LS may develop vulvar SCC, as frequently reported. Third, in a series of LS patients who underwent long-term follow-up, 4% to 6% were reported to have developed vulvar SCC.^3,4,7

Lichen sclerosus is an inflammatory dermatosis characterized by clinicopathologic persistence and hypocellular fibrosis.² Changes in the local environment of the keratinocyte, including chronic inflammation and sclerosis, may be responsible for the promotion of carcinogenesis.⁸ However, no molecular markers have been proven to identify the LS lesions that are at risk for developing into vulvar SCC.^9,10 It has been suggested that VIN is the direct precursor of vulvar SCC.^11,12

Histologic diagnosis of VIN is difficult. Its identification is hindered by a high degree of cellular differentiation combined with the absence of widespread architectural disorder, nuclear pleomorphism, and diffuse nuclear atypia.¹³ The atypia in VIN lesions is strictly confined to the basal and parabasal layers of the epithelium.¹¹ Vulvar intraepithelial neoplasia has seldom been diagnosed as a solitary lesion because it appears to have a short intraepithelial lifetime.

Vulvar SCC can be divided into 2 patterns. The first is found in older women, which is unrelated to human papillomavirus (HPV). This type occurs in a background of LS and/or differentiated VIN. The second is predominantly found in younger women, which is related to high-risk HPV. This type of vulvar SCC frequently is associated with the histologic subtypes of warty and basaloid differentiations and is referred to as undifferentiated VIN. There is no association with LS in these cases.^2,14,15

It has been suggested that LS and HPV may not be mutually exclusive but may act as cofactors in SCC pathogenesis.¹⁶ Infection with HPV is an early event in the multistep process of vulvar carcinogenesis, and HPV integration into host cell genome seems to be related to the progression of vulvar dysplasia.¹⁷ Viral integration generally disrupts the E2 region, resulting in enhanced expression of E6 and E7. E6 and E7 have the ability to bind and inactivate the protein p53 and retinoblastoma protein, which promotes rapid progression through the cell cycle without p53-mediated control of DNA integrity.¹⁸ However, the exact influence of HPV in vulvar SCC is uncertain, as divergent prevalence rates have been published.

In our case, histologic examination revealed the characteristic findings of LS, VIN, and SCC in succession. This sequence is evidence of progressive transition from LS to VIN and then to SCC. Consequently, this case suggests that vulvar LS may act as both an initiator and a promoter of carcinogenesis and that VIN may be the direct precursor of vulvar SCC. In conclusion, LS has a considerable risk for malignant transformation and requires continuous follow-up in all patients. Early histological detection of invasive lesions is crucial to reduce the risk for vulvar cancer.

To the Editor:
Lichen sclerosus (LS) is a chronic inflammatory disorder of unknown etiology that most commonly affects the anogenital region. Progressive sclerosis results in scarring with distortion of the normal epithelial architecture.^1,2 The lifetime risk for developing squamous cell carcinoma (SCC) as a complication of long-standing LS has been estimated as 4% to 6%.^3,4 However, there is no general agreement concerning the exact relationship between anogenital LS and SCC.¹ The coexistence of histologic findings of LS, vulvar intraepithelial neoplasia (VIN), and SCC in the same tissue is rare. We report a case of VIN and SCC developing in a region of preexisting LS.

A 76-year-old woman presented with a 7-mm nodule on the clitoris that was surrounded by a pearly white, smooth, glistening area (Figure 1). The patient reported pain and tenderness associated with the nodule. No regional lymphadenopathy was evident. We performed an excisional biopsy of the entire nodule and a small part of the whitish patch (Figure 2A). On histologic examination, the presence of hyperkeratosis, epidermal atrophy, a swollen dermal collagen bundle, and prominent edema was consistent with LS (Figure 2B). The presence of dysplastic changes with mild disturbance of the epithelial architecture as well as acanthosis and dyskeratosis in the same tissue confirmed VIN (Figure 2C). Dermal invasion and transition to SCC were seen in the part of the tissue verified as VIN. The presence of dermal tumor nests and an irregular border between the epidermis and dermis pointed to the existence of fully developed SCC (Figure 2D). To prevent the recurrence of SCC, the patient returned for follow-up periodically. There was no recurrence within 6 months after excision.

Figure 2. An excisional biopsy showed epidermal thinning on the left side and invasion of the dermis by a tumor nest on the right side (A)(H&E, original magnification ×10). Left, center, and right boxes indicate areas shown in Figures 2B, 2C and 2D, respectively. Hyperkeratosis, epidermal atrophy, a swollen dermal collagen bundle, and prominent edema was evident (B)(H&E, original magnification ×200). Dysplactic changes with mild disturbance of the epithelial architecture accompanied by acanthosis and nuclear atypia were seen (C)(H&E, original magnification ×200). Irregular masses of atypical squamous cells spread downward into the dermis representing squamous cell carcinoma of a well-differentiated type (D)(H&E, original magnification ×200).

Although LS is considered a premalignant condition, only a small portion of patients with LS ultimately develop vulvar SCC.⁵ There are a number of reasons for linking LS with the development of vulvar SCC. First, in the majority of cases of vulvar SCC, LS, squamous cell hyperplasia, or VIN is present in the adjacent epithelium. Lichen sclerosus is found in adjacent regions in up to 62% of vulvar SCC cases.⁶ Second, patients with LS may develop vulvar SCC, as frequently reported. Third, in a series of LS patients who underwent long-term follow-up, 4% to 6% were reported to have developed vulvar SCC.^3,4,7

Lichen sclerosus is an inflammatory dermatosis characterized by clinicopathologic persistence and hypocellular fibrosis.² Changes in the local environment of the keratinocyte, including chronic inflammation and sclerosis, may be responsible for the promotion of carcinogenesis.⁸ However, no molecular markers have been proven to identify the LS lesions that are at risk for developing into vulvar SCC.^9,10 It has been suggested that VIN is the direct precursor of vulvar SCC.^11,12

Histologic diagnosis of VIN is difficult. Its identification is hindered by a high degree of cellular differentiation combined with the absence of widespread architectural disorder, nuclear pleomorphism, and diffuse nuclear atypia.¹³ The atypia in VIN lesions is strictly confined to the basal and parabasal layers of the epithelium.¹¹ Vulvar intraepithelial neoplasia has seldom been diagnosed as a solitary lesion because it appears to have a short intraepithelial lifetime.

Vulvar SCC can be divided into 2 patterns. The first is found in older women, which is unrelated to human papillomavirus (HPV). This type occurs in a background of LS and/or differentiated VIN. The second is predominantly found in younger women, which is related to high-risk HPV. This type of vulvar SCC frequently is associated with the histologic subtypes of warty and basaloid differentiations and is referred to as undifferentiated VIN. There is no association with LS in these cases.^2,14,15

It has been suggested that LS and HPV may not be mutually exclusive but may act as cofactors in SCC pathogenesis.¹⁶ Infection with HPV is an early event in the multistep process of vulvar carcinogenesis, and HPV integration into host cell genome seems to be related to the progression of vulvar dysplasia.¹⁷ Viral integration generally disrupts the E2 region, resulting in enhanced expression of E6 and E7. E6 and E7 have the ability to bind and inactivate the protein p53 and retinoblastoma protein, which promotes rapid progression through the cell cycle without p53-mediated control of DNA integrity.¹⁸ However, the exact influence of HPV in vulvar SCC is uncertain, as divergent prevalence rates have been published.

In our case, histologic examination revealed the characteristic findings of LS, VIN, and SCC in succession. This sequence is evidence of progressive transition from LS to VIN and then to SCC. Consequently, this case suggests that vulvar LS may act as both an initiator and a promoter of carcinogenesis and that VIN may be the direct precursor of vulvar SCC. In conclusion, LS has a considerable risk for malignant transformation and requires continuous follow-up in all patients. Early histological detection of invasive lesions is crucial to reduce the risk for vulvar cancer.

WAIKOLOA, HAWAII – Intralesional injection of interferon alfa-2b is an excellent option for the treatment of large problematic basal cell carcinomas in patients who aren’t interested in the higher-morbidity options, Dr. David L. Swanson said at the Hawaii Dermatology Seminar provided by Global Academy for Medical Education/Skin Disease Education Foundation.

“This is a really effective way to treat basal cell carcinomas. These things just melt away before your eyes. It’s really quite amazing,” observed Dr. Swanson of Mayo Clinic Scottsdale (Ariz.).

He finds this therapy particularly useful in frail elderly patients who have a large BCC on the head or neck. A good example would be an 89-year-old with multiple comorbid conditions who has a 2-cm BCC on the tip of the nose and doesn’t want anything done about it. The patient declines the options of Mohs micrographic surgery or radiotherapy.

“This is the patient who just wants to be left alone. That’s fine if they’re going to be dead within a year, but if they’re going to be around for several years, that basal cell carcinoma could become a major issue for them,” the dermatologist continued.

He and his colleagues at the Mayo Clinic follow a treatment regimen similar to one laid out by Turkish investigators more than a decade ago in one of the few long-term outcome studies of intralesional interferon for treatment of BCCs.

Although interferon alfa-2b is approved for the intralesional treatment of genital warts and subcutaneously for Kaposi’s sarcoma and malignant melanoma, among other conditions, it’s off-label therapy for BCCs. The treatment entails thrice-weekly intralesional injections for 3 weeks. The dosing is 1.5 million units per injection for BCCs smaller than 2 cm and 3 million units per injection for BCCs that are 2 cm or larger. The injections are given without anesthesia, but premedication with 500-1,000 mg of acetaminophen is advisable to minimize aches and fever.

Interferon alfa-2b (Intron A) comes in a vial containing 10 million units with 1 mL of diluent. It’s important to reconstitute it carefully, similar to onabotulinumtoxin. Don’t shake it, Dr. Swanson advised.

The Turkish report included 20 patients with histopathologically proven BCCs on the head or neck. At clinical and dermatopathologic follow-up 8 weeks after the last interferon injection, 11 BCCs showed complete clinical and histopathologic cure, six showed partial remission, two showed no response, and one actually increased in size during treatment.

The 11 patients with an initial complete cure were followed for 7 years. During that period, only one of the 11 skin cancers recurred, at the fifth year (Clin Drug Investig. 2005;25[10]:661-7).

Dr. Swanson reported having no financial conflicts regarding his presentation. SDEF and this news organization are owned by the same parent company.

bjancin@frontlinemedcom.com

WAIKOLOA, HAWAII – Intralesional injection of interferon alfa-2b is an excellent option for the treatment of large problematic basal cell carcinomas in patients who aren’t interested in the higher-morbidity options, Dr. David L. Swanson said at the Hawaii Dermatology Seminar provided by Global Academy for Medical Education/Skin Disease Education Foundation.

“This is a really effective way to treat basal cell carcinomas. These things just melt away before your eyes. It’s really quite amazing,” observed Dr. Swanson of Mayo Clinic Scottsdale (Ariz.).

He finds this therapy particularly useful in frail elderly patients who have a large BCC on the head or neck. A good example would be an 89-year-old with multiple comorbid conditions who has a 2-cm BCC on the tip of the nose and doesn’t want anything done about it. The patient declines the options of Mohs micrographic surgery or radiotherapy.

“This is the patient who just wants to be left alone. That’s fine if they’re going to be dead within a year, but if they’re going to be around for several years, that basal cell carcinoma could become a major issue for them,” the dermatologist continued.

He and his colleagues at the Mayo Clinic follow a treatment regimen similar to one laid out by Turkish investigators more than a decade ago in one of the few long-term outcome studies of intralesional interferon for treatment of BCCs.

Although interferon alfa-2b is approved for the intralesional treatment of genital warts and subcutaneously for Kaposi’s sarcoma and malignant melanoma, among other conditions, it’s off-label therapy for BCCs. The treatment entails thrice-weekly intralesional injections for 3 weeks. The dosing is 1.5 million units per injection for BCCs smaller than 2 cm and 3 million units per injection for BCCs that are 2 cm or larger. The injections are given without anesthesia, but premedication with 500-1,000 mg of acetaminophen is advisable to minimize aches and fever.

Interferon alfa-2b (Intron A) comes in a vial containing 10 million units with 1 mL of diluent. It’s important to reconstitute it carefully, similar to onabotulinumtoxin. Don’t shake it, Dr. Swanson advised.

The Turkish report included 20 patients with histopathologically proven BCCs on the head or neck. At clinical and dermatopathologic follow-up 8 weeks after the last interferon injection, 11 BCCs showed complete clinical and histopathologic cure, six showed partial remission, two showed no response, and one actually increased in size during treatment.

The 11 patients with an initial complete cure were followed for 7 years. During that period, only one of the 11 skin cancers recurred, at the fifth year (Clin Drug Investig. 2005;25[10]:661-7).

Dr. Swanson reported having no financial conflicts regarding his presentation. SDEF and this news organization are owned by the same parent company.

bjancin@frontlinemedcom.com

WAIKOLOA, HAWAII – Intralesional injection of interferon alfa-2b is an excellent option for the treatment of large problematic basal cell carcinomas in patients who aren’t interested in the higher-morbidity options, Dr. David L. Swanson said at the Hawaii Dermatology Seminar provided by Global Academy for Medical Education/Skin Disease Education Foundation.

“This is a really effective way to treat basal cell carcinomas. These things just melt away before your eyes. It’s really quite amazing,” observed Dr. Swanson of Mayo Clinic Scottsdale (Ariz.).

He finds this therapy particularly useful in frail elderly patients who have a large BCC on the head or neck. A good example would be an 89-year-old with multiple comorbid conditions who has a 2-cm BCC on the tip of the nose and doesn’t want anything done about it. The patient declines the options of Mohs micrographic surgery or radiotherapy.

“This is the patient who just wants to be left alone. That’s fine if they’re going to be dead within a year, but if they’re going to be around for several years, that basal cell carcinoma could become a major issue for them,” the dermatologist continued.

He and his colleagues at the Mayo Clinic follow a treatment regimen similar to one laid out by Turkish investigators more than a decade ago in one of the few long-term outcome studies of intralesional interferon for treatment of BCCs.

Although interferon alfa-2b is approved for the intralesional treatment of genital warts and subcutaneously for Kaposi’s sarcoma and malignant melanoma, among other conditions, it’s off-label therapy for BCCs. The treatment entails thrice-weekly intralesional injections for 3 weeks. The dosing is 1.5 million units per injection for BCCs smaller than 2 cm and 3 million units per injection for BCCs that are 2 cm or larger. The injections are given without anesthesia, but premedication with 500-1,000 mg of acetaminophen is advisable to minimize aches and fever.

Interferon alfa-2b (Intron A) comes in a vial containing 10 million units with 1 mL of diluent. It’s important to reconstitute it carefully, similar to onabotulinumtoxin. Don’t shake it, Dr. Swanson advised.

The Turkish report included 20 patients with histopathologically proven BCCs on the head or neck. At clinical and dermatopathologic follow-up 8 weeks after the last interferon injection, 11 BCCs showed complete clinical and histopathologic cure, six showed partial remission, two showed no response, and one actually increased in size during treatment.

The 11 patients with an initial complete cure were followed for 7 years. During that period, only one of the 11 skin cancers recurred, at the fifth year (Clin Drug Investig. 2005;25[10]:661-7).

Dr. Swanson reported having no financial conflicts regarding his presentation. SDEF and this news organization are owned by the same parent company.

bjancin@frontlinemedcom.com

At the 74th Annual Meeting of the American Academy of Dermatology, Dr. Orit Markowitz discussed noninvasive imaging tools that can help dermatologists diagnose skin cancers earlier. She provides highlights from this session, including the use of dermoscopy and optical coherence technology to detect features of early melanoma and nonmelanoma skin cancers as well as monitor skin cancer management. A lesion that is pink clinically but shows pigment dermoscopically should be biopsied, Dr. Markowtiz advises, as it may be an early amelanotic melanoma. She also notes that noninvasive imaging tools can be used to detect residual tumor cells in treated skin that otherwise looks clinically normal.

At the 74th Annual Meeting of the American Academy of Dermatology, Dr. Orit Markowitz discussed noninvasive imaging tools that can help dermatologists diagnose skin cancers earlier. She provides highlights from this session, including the use of dermoscopy and optical coherence technology to detect features of early melanoma and nonmelanoma skin cancers as well as monitor skin cancer management. A lesion that is pink clinically but shows pigment dermoscopically should be biopsied, Dr. Markowtiz advises, as it may be an early amelanotic melanoma. She also notes that noninvasive imaging tools can be used to detect residual tumor cells in treated skin that otherwise looks clinically normal.

At the 74th Annual Meeting of the American Academy of Dermatology, Dr. Orit Markowitz discussed noninvasive imaging tools that can help dermatologists diagnose skin cancers earlier. She provides highlights from this session, including the use of dermoscopy and optical coherence technology to detect features of early melanoma and nonmelanoma skin cancers as well as monitor skin cancer management. A lesion that is pink clinically but shows pigment dermoscopically should be biopsied, Dr. Markowtiz advises, as it may be an early amelanotic melanoma. She also notes that noninvasive imaging tools can be used to detect residual tumor cells in treated skin that otherwise looks clinically normal.

Chen et al (N Engl J Med. 2015;373:1618-1626) performed a multicenter, phase 3, double-blind, randomized, placebo-controlled trial. Results demonstrated that nicotinamide effectively decreased the rates of new nonmelanoma skin cancers (NMSCs) and actinic keratoses (AKs) in high-risk patients who had at least 2 histologically confirmed NMSCs in the last 5 years. In comparison to participants who received placebo, individuals who received nicotinamide 500 mg twice daily during the 12-month study (branded with a predictive acronym ONTRAC [oral nicotinamide to reduce actinic cancer]) had reduced rates of AKs of up to 20%, basal cell carcinomas of 20%, squamous cell carcinomas of 30%, and NMSCs of 23%. However, the effect of nicotinamide on NMSCs was not maintained at evaluation 6 months after discontinuation; the number of basal cell carcinomas was similar, and the number of squamous cell carcinomas was greater in participants who received nicotinamide in comparison to individuals who received placebo.

What’s the issue?

The risk for skin cancer is increased by UV radiation that damages DNA, suppresses cutaneous immunity, and inhibits DNA repair by depleting cellular adenosine triphosphate. Nicotinamide, an amide form of vitamin B₃, has been demonstrated to not only reduce UV radiation–induced immunosuppression but also to prevent UV radiation–induced adenosine triphosphate depletion and glycolic blockade. Nicotinamide, which is classified as a food additive, also has neuroprotective and antioxidant functions and reduces pigmentation, wrinkles, and sebum production. Although oral nicotinamide has been demonstrated to reduce NMSCs and AKs, topical application has been shown to improve many skin conditions such as acne, atopic dermatitis, isoniazid-induced pellagra, and rosacea.

In contrast to nicotinic acid (niacin), nicotinamide is not associated with headaches, hypotension, flushing, itching, or vasodilatation. At high oral doses, side effects of nicotinamide that have been hypothesized or observed in animals, humans, or both have included the development of Parkinson disease, insulin sensitivity and diabetes mellitus, and liver toxicity. Although there are no reports in humans of growth retardation, teratogenicity, or oncogenicity, Rolfe (J Cosmet Dermatol. 2014;13:324-328) discussed that fetal blood levels of nicotinamide are greater than corresponding maternal blood levels because it is able to cross the placenta. However, according to Chen et al, no clinically significant between-group differences were found with respect to the number or types of adverse events that occurred in the placebo participants and the individuals who received 1000 mg daily of nicotinamide. Chen et al implied that there were additional benefits in the recipients of nicotinamide with regards to cognitive function and transepidermal water loss.

Perhaps all patients with a history of AKs, basal cell carcinomas, or squamous cell carcinomas should receive lifelong nicotinamide. Also, it might be reasonable to consider that all individuals older than 18 years who are not pregnant or breastfeeding with increased sun exposure but no history of AKs or NMSC add nicotinamide to their daily diets as a proactive measure for chemoprevention. Would you suggest nicotinamide to your patients?

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

Chen et al (N Engl J Med. 2015;373:1618-1626) performed a multicenter, phase 3, double-blind, randomized, placebo-controlled trial. Results demonstrated that nicotinamide effectively decreased the rates of new nonmelanoma skin cancers (NMSCs) and actinic keratoses (AKs) in high-risk patients who had at least 2 histologically confirmed NMSCs in the last 5 years. In comparison to participants who received placebo, individuals who received nicotinamide 500 mg twice daily during the 12-month study (branded with a predictive acronym ONTRAC [oral nicotinamide to reduce actinic cancer]) had reduced rates of AKs of up to 20%, basal cell carcinomas of 20%, squamous cell carcinomas of 30%, and NMSCs of 23%. However, the effect of nicotinamide on NMSCs was not maintained at evaluation 6 months after discontinuation; the number of basal cell carcinomas was similar, and the number of squamous cell carcinomas was greater in participants who received nicotinamide in comparison to individuals who received placebo.

What’s the issue?

The risk for skin cancer is increased by UV radiation that damages DNA, suppresses cutaneous immunity, and inhibits DNA repair by depleting cellular adenosine triphosphate. Nicotinamide, an amide form of vitamin B₃, has been demonstrated to not only reduce UV radiation–induced immunosuppression but also to prevent UV radiation–induced adenosine triphosphate depletion and glycolic blockade. Nicotinamide, which is classified as a food additive, also has neuroprotective and antioxidant functions and reduces pigmentation, wrinkles, and sebum production. Although oral nicotinamide has been demonstrated to reduce NMSCs and AKs, topical application has been shown to improve many skin conditions such as acne, atopic dermatitis, isoniazid-induced pellagra, and rosacea.

In contrast to nicotinic acid (niacin), nicotinamide is not associated with headaches, hypotension, flushing, itching, or vasodilatation. At high oral doses, side effects of nicotinamide that have been hypothesized or observed in animals, humans, or both have included the development of Parkinson disease, insulin sensitivity and diabetes mellitus, and liver toxicity. Although there are no reports in humans of growth retardation, teratogenicity, or oncogenicity, Rolfe (J Cosmet Dermatol. 2014;13:324-328) discussed that fetal blood levels of nicotinamide are greater than corresponding maternal blood levels because it is able to cross the placenta. However, according to Chen et al, no clinically significant between-group differences were found with respect to the number or types of adverse events that occurred in the placebo participants and the individuals who received 1000 mg daily of nicotinamide. Chen et al implied that there were additional benefits in the recipients of nicotinamide with regards to cognitive function and transepidermal water loss.

Perhaps all patients with a history of AKs, basal cell carcinomas, or squamous cell carcinomas should receive lifelong nicotinamide. Also, it might be reasonable to consider that all individuals older than 18 years who are not pregnant or breastfeeding with increased sun exposure but no history of AKs or NMSC add nicotinamide to their daily diets as a proactive measure for chemoprevention. Would you suggest nicotinamide to your patients?

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

Chen et al (N Engl J Med. 2015;373:1618-1626) performed a multicenter, phase 3, double-blind, randomized, placebo-controlled trial. Results demonstrated that nicotinamide effectively decreased the rates of new nonmelanoma skin cancers (NMSCs) and actinic keratoses (AKs) in high-risk patients who had at least 2 histologically confirmed NMSCs in the last 5 years. In comparison to participants who received placebo, individuals who received nicotinamide 500 mg twice daily during the 12-month study (branded with a predictive acronym ONTRAC [oral nicotinamide to reduce actinic cancer]) had reduced rates of AKs of up to 20%, basal cell carcinomas of 20%, squamous cell carcinomas of 30%, and NMSCs of 23%. However, the effect of nicotinamide on NMSCs was not maintained at evaluation 6 months after discontinuation; the number of basal cell carcinomas was similar, and the number of squamous cell carcinomas was greater in participants who received nicotinamide in comparison to individuals who received placebo.

What’s the issue?

The risk for skin cancer is increased by UV radiation that damages DNA, suppresses cutaneous immunity, and inhibits DNA repair by depleting cellular adenosine triphosphate. Nicotinamide, an amide form of vitamin B₃, has been demonstrated to not only reduce UV radiation–induced immunosuppression but also to prevent UV radiation–induced adenosine triphosphate depletion and glycolic blockade. Nicotinamide, which is classified as a food additive, also has neuroprotective and antioxidant functions and reduces pigmentation, wrinkles, and sebum production. Although oral nicotinamide has been demonstrated to reduce NMSCs and AKs, topical application has been shown to improve many skin conditions such as acne, atopic dermatitis, isoniazid-induced pellagra, and rosacea.

In contrast to nicotinic acid (niacin), nicotinamide is not associated with headaches, hypotension, flushing, itching, or vasodilatation. At high oral doses, side effects of nicotinamide that have been hypothesized or observed in animals, humans, or both have included the development of Parkinson disease, insulin sensitivity and diabetes mellitus, and liver toxicity. Although there are no reports in humans of growth retardation, teratogenicity, or oncogenicity, Rolfe (J Cosmet Dermatol. 2014;13:324-328) discussed that fetal blood levels of nicotinamide are greater than corresponding maternal blood levels because it is able to cross the placenta. However, according to Chen et al, no clinically significant between-group differences were found with respect to the number or types of adverse events that occurred in the placebo participants and the individuals who received 1000 mg daily of nicotinamide. Chen et al implied that there were additional benefits in the recipients of nicotinamide with regards to cognitive function and transepidermal water loss.

Perhaps all patients with a history of AKs, basal cell carcinomas, or squamous cell carcinomas should receive lifelong nicotinamide. Also, it might be reasonable to consider that all individuals older than 18 years who are not pregnant or breastfeeding with increased sun exposure but no history of AKs or NMSC add nicotinamide to their daily diets as a proactive measure for chemoprevention. Would you suggest nicotinamide to your patients?

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

The most common type of skin cancer in Hispanic patients is basal cell carcinoma, according to Maritza Perez, MD, Associate Clinical Professor of Dermatology at the Icahn School of Medicine at Mount Sinai, New York, New York. Dr. Perez reviewed skin cancer in Hispanics as part of the “Skin Issues in Latino Patients” forum at the 74th Annual Meeting of the American Academy of Dermatology (AAD)(March 4-8, 2016) in Washington, DC. The head and neck region is the most common location of BCC in Hispanics, and it is more common among Hispanic males. Squamous cell carcinomas are the second most common, and melanomas are third most common.

The mortality rate from squamous cell carcinoma is higher in Hispanic patients compared to white patients. Dr. Perez indicated that UV light exposure is a predisposing factor for these types of skin cancer, and poor sun protection practices in this population are to blame.

“Patients [in this population] do not perceive that they are prone to skin cancer,” said Dr. Perez. This erroneous perception has led to delayed diagnosis and treatment of patients in this group, which has caused increased mortality and decreased survival.

Marta Rendon, MD, director of the session at the AAD and Medical Director of The Rendon Center for Dermatology & Aesthetic Medicine, Boca Raton, Florida, noted that Latinos are the fastest growing minority population in the United States and it is estimated that they will be approximately 30% of the population by the year 2050. As a result, dermatologists must emphasize sun protection, avoidance of midday sun, and avoidance of UV radiation.

In his Cutis practical pearls, “Patient Compliance With Photoprotection,” Vincent A. DeLeo, MD, provided tips on sunscreen use. “Patients need a realistic approach to photoprotection based on their genetics, including Fitzpatrick skin type and family history . . . and lifestyle history, which should include location of residence as well as occupation and recreational pursuits,” he said. “These inquiries should lead to a frank discussion of the patient’s risk for developing photodamage and skin cancer.”

Encourage routine use of a sunscreen with a sun protection factor of 30 or higher that carries a “broad spectrum” label. “There is evidence that sunscreens prevent squamous cell carcinoma, actinic keratosis, and photoaging. Early evidence, less strong but positive, also suggests protection against basal cell carcinoma and melanoma,” Dr. DeLeo reported.

The most common type of skin cancer in Hispanic patients is basal cell carcinoma, according to Maritza Perez, MD, Associate Clinical Professor of Dermatology at the Icahn School of Medicine at Mount Sinai, New York, New York. Dr. Perez reviewed skin cancer in Hispanics as part of the “Skin Issues in Latino Patients” forum at the 74th Annual Meeting of the American Academy of Dermatology (AAD)(March 4-8, 2016) in Washington, DC. The head and neck region is the most common location of BCC in Hispanics, and it is more common among Hispanic males. Squamous cell carcinomas are the second most common, and melanomas are third most common.

The mortality rate from squamous cell carcinoma is higher in Hispanic patients compared to white patients. Dr. Perez indicated that UV light exposure is a predisposing factor for these types of skin cancer, and poor sun protection practices in this population are to blame.

“Patients [in this population] do not perceive that they are prone to skin cancer,” said Dr. Perez. This erroneous perception has led to delayed diagnosis and treatment of patients in this group, which has caused increased mortality and decreased survival.

Marta Rendon, MD, director of the session at the AAD and Medical Director of The Rendon Center for Dermatology & Aesthetic Medicine, Boca Raton, Florida, noted that Latinos are the fastest growing minority population in the United States and it is estimated that they will be approximately 30% of the population by the year 2050. As a result, dermatologists must emphasize sun protection, avoidance of midday sun, and avoidance of UV radiation.

In his Cutis practical pearls, “Patient Compliance With Photoprotection,” Vincent A. DeLeo, MD, provided tips on sunscreen use. “Patients need a realistic approach to photoprotection based on their genetics, including Fitzpatrick skin type and family history . . . and lifestyle history, which should include location of residence as well as occupation and recreational pursuits,” he said. “These inquiries should lead to a frank discussion of the patient’s risk for developing photodamage and skin cancer.”

Encourage routine use of a sunscreen with a sun protection factor of 30 or higher that carries a “broad spectrum” label. “There is evidence that sunscreens prevent squamous cell carcinoma, actinic keratosis, and photoaging. Early evidence, less strong but positive, also suggests protection against basal cell carcinoma and melanoma,” Dr. DeLeo reported.

The most common type of skin cancer in Hispanic patients is basal cell carcinoma, according to Maritza Perez, MD, Associate Clinical Professor of Dermatology at the Icahn School of Medicine at Mount Sinai, New York, New York. Dr. Perez reviewed skin cancer in Hispanics as part of the “Skin Issues in Latino Patients” forum at the 74th Annual Meeting of the American Academy of Dermatology (AAD)(March 4-8, 2016) in Washington, DC. The head and neck region is the most common location of BCC in Hispanics, and it is more common among Hispanic males. Squamous cell carcinomas are the second most common, and melanomas are third most common.

The mortality rate from squamous cell carcinoma is higher in Hispanic patients compared to white patients. Dr. Perez indicated that UV light exposure is a predisposing factor for these types of skin cancer, and poor sun protection practices in this population are to blame.

“Patients [in this population] do not perceive that they are prone to skin cancer,” said Dr. Perez. This erroneous perception has led to delayed diagnosis and treatment of patients in this group, which has caused increased mortality and decreased survival.

Marta Rendon, MD, director of the session at the AAD and Medical Director of The Rendon Center for Dermatology & Aesthetic Medicine, Boca Raton, Florida, noted that Latinos are the fastest growing minority population in the United States and it is estimated that they will be approximately 30% of the population by the year 2050. As a result, dermatologists must emphasize sun protection, avoidance of midday sun, and avoidance of UV radiation.

In his Cutis practical pearls, “Patient Compliance With Photoprotection,” Vincent A. DeLeo, MD, provided tips on sunscreen use. “Patients need a realistic approach to photoprotection based on their genetics, including Fitzpatrick skin type and family history . . . and lifestyle history, which should include location of residence as well as occupation and recreational pursuits,” he said. “These inquiries should lead to a frank discussion of the patient’s risk for developing photodamage and skin cancer.”

Encourage routine use of a sunscreen with a sun protection factor of 30 or higher that carries a “broad spectrum” label. “There is evidence that sunscreens prevent squamous cell carcinoma, actinic keratosis, and photoaging. Early evidence, less strong but positive, also suggests protection against basal cell carcinoma and melanoma,” Dr. DeLeo reported.

WAIKOLOA, HAWAII – The familiar oral triazole antifungal agent itraconazole (Sporanox) is under active investigation for an unexpected use: as adjunctive therapy in patients with locally advanced or metastatic basal cell carcinoma.

“The promise of this drug is that the use of itraconazole with vismodegib or sonidegib may actually enhance the effectiveness of those drugs and also reduce the frequency of grade 2 toxicities by perhaps allowing a lower dose of vismodegib or sonidegib,” Dr. David L. Swanson said at the Hawaii Dermatology Seminar provided by the Global Academy for Medical Education/Skin Disease Education Foundation.

“Be looking for this drug that we use to treat toenail fungus as a potential drug for locally advanced or metastatic basal cell carcinoma,” advised Dr. Swanson, a dermatologist at the Mayo Clinic in Scottsdale, Ariz.

Vismodegib (Erivedge) has been a game changer for patients with inoperable locally advanced or metastatic breast cancer. “The response to this drug was amazing,” Dr. Swanson said of the landmark study which led to its approval in 2012 (N Engl J Med. 2012; 366[23]:2171-9).

Sonidegib (Odomzo), which like vismodegib inhibits the essential Hedgehog signaling pathway component known as Smoothened, was approved by the Food and Drug Administration in 2015 as the second oral drug in this novel class.

While the clinical benefits of these two drugs in patients with the most horrific basal cell carcinomas are extremely impressive, vismodegib and sonidegib have two major drawbacks: The tumors eventually develop resistance and commence growing again, and onerous grade 2 side effects requiring dose reduction are extremely common. The most frequent of these limiting side effects are a disturbed sense of taste, muscle spasms, alopecia, and weight loss.

The hope is that itraconazole may be of help with both issues, according to Dr. Swanson. It turns out that the antifungal agent is also an inhibitor of the Hedgehog pathway, and via a different mechanism than that of vismodegib and sonidegib.

He pointed to an international open-label exploratory phase II study led by Dr. Jean Y. Tang of Stanford (Calif.) University. The investigators treated 19 patients with a total of 90 basal cell carcinomas with oral itraconazole at 200 mg twice a day for 1 month or 100 mg twice a day for an average of 2.3 months.

The treatment reduced Hedgehog signaling pathway activity by 65%, Ki67 tumor cell proliferation by 45%, and tumor area by 24% (J Clin Oncol. 2014 Mar 10;32[8]:745-51).

These results aren’t as dramatic as what’s achieved using vismodegib or sonidegib. As stand-alone therapy, itraconazole doesn’t compare with those agents. However, the hope is that when itraconazole is prescribed in conjunction with vismodegib or sonidegib it will permit the latter drugs to be used at lower doses with no drop-off in efficacy, which would mean less grade 2 toxicity. Moreover, since itraconazole inhibits Hedgehog signaling through a mechanism that is different from that of the more potent agents, combination therapy might delay onset of tumor resistance, Dr. Swanson explained.

He reported having no financial conflicts of interest regarding his presentation.

SDEF and this news organization are owned by the same parent company.

bjancin@frontlinemedcom.com

WAIKOLOA, HAWAII – The familiar oral triazole antifungal agent itraconazole (Sporanox) is under active investigation for an unexpected use: as adjunctive therapy in patients with locally advanced or metastatic basal cell carcinoma.

“The promise of this drug is that the use of itraconazole with vismodegib or sonidegib may actually enhance the effectiveness of those drugs and also reduce the frequency of grade 2 toxicities by perhaps allowing a lower dose of vismodegib or sonidegib,” Dr. David L. Swanson said at the Hawaii Dermatology Seminar provided by the Global Academy for Medical Education/Skin Disease Education Foundation.

“Be looking for this drug that we use to treat toenail fungus as a potential drug for locally advanced or metastatic basal cell carcinoma,” advised Dr. Swanson, a dermatologist at the Mayo Clinic in Scottsdale, Ariz.

Vismodegib (Erivedge) has been a game changer for patients with inoperable locally advanced or metastatic breast cancer. “The response to this drug was amazing,” Dr. Swanson said of the landmark study which led to its approval in 2012 (N Engl J Med. 2012; 366[23]:2171-9).

Sonidegib (Odomzo), which like vismodegib inhibits the essential Hedgehog signaling pathway component known as Smoothened, was approved by the Food and Drug Administration in 2015 as the second oral drug in this novel class.

While the clinical benefits of these two drugs in patients with the most horrific basal cell carcinomas are extremely impressive, vismodegib and sonidegib have two major drawbacks: The tumors eventually develop resistance and commence growing again, and onerous grade 2 side effects requiring dose reduction are extremely common. The most frequent of these limiting side effects are a disturbed sense of taste, muscle spasms, alopecia, and weight loss.

The hope is that itraconazole may be of help with both issues, according to Dr. Swanson. It turns out that the antifungal agent is also an inhibitor of the Hedgehog pathway, and via a different mechanism than that of vismodegib and sonidegib.

He pointed to an international open-label exploratory phase II study led by Dr. Jean Y. Tang of Stanford (Calif.) University. The investigators treated 19 patients with a total of 90 basal cell carcinomas with oral itraconazole at 200 mg twice a day for 1 month or 100 mg twice a day for an average of 2.3 months.

The treatment reduced Hedgehog signaling pathway activity by 65%, Ki67 tumor cell proliferation by 45%, and tumor area by 24% (J Clin Oncol. 2014 Mar 10;32[8]:745-51).

These results aren’t as dramatic as what’s achieved using vismodegib or sonidegib. As stand-alone therapy, itraconazole doesn’t compare with those agents. However, the hope is that when itraconazole is prescribed in conjunction with vismodegib or sonidegib it will permit the latter drugs to be used at lower doses with no drop-off in efficacy, which would mean less grade 2 toxicity. Moreover, since itraconazole inhibits Hedgehog signaling through a mechanism that is different from that of the more potent agents, combination therapy might delay onset of tumor resistance, Dr. Swanson explained.

He reported having no financial conflicts of interest regarding his presentation.

SDEF and this news organization are owned by the same parent company.

bjancin@frontlinemedcom.com

WAIKOLOA, HAWAII – The familiar oral triazole antifungal agent itraconazole (Sporanox) is under active investigation for an unexpected use: as adjunctive therapy in patients with locally advanced or metastatic basal cell carcinoma.

“The promise of this drug is that the use of itraconazole with vismodegib or sonidegib may actually enhance the effectiveness of those drugs and also reduce the frequency of grade 2 toxicities by perhaps allowing a lower dose of vismodegib or sonidegib,” Dr. David L. Swanson said at the Hawaii Dermatology Seminar provided by the Global Academy for Medical Education/Skin Disease Education Foundation.

“Be looking for this drug that we use to treat toenail fungus as a potential drug for locally advanced or metastatic basal cell carcinoma,” advised Dr. Swanson, a dermatologist at the Mayo Clinic in Scottsdale, Ariz.

Vismodegib (Erivedge) has been a game changer for patients with inoperable locally advanced or metastatic breast cancer. “The response to this drug was amazing,” Dr. Swanson said of the landmark study which led to its approval in 2012 (N Engl J Med. 2012; 366[23]:2171-9).

Sonidegib (Odomzo), which like vismodegib inhibits the essential Hedgehog signaling pathway component known as Smoothened, was approved by the Food and Drug Administration in 2015 as the second oral drug in this novel class.

While the clinical benefits of these two drugs in patients with the most horrific basal cell carcinomas are extremely impressive, vismodegib and sonidegib have two major drawbacks: The tumors eventually develop resistance and commence growing again, and onerous grade 2 side effects requiring dose reduction are extremely common. The most frequent of these limiting side effects are a disturbed sense of taste, muscle spasms, alopecia, and weight loss.

The hope is that itraconazole may be of help with both issues, according to Dr. Swanson. It turns out that the antifungal agent is also an inhibitor of the Hedgehog pathway, and via a different mechanism than that of vismodegib and sonidegib.

He pointed to an international open-label exploratory phase II study led by Dr. Jean Y. Tang of Stanford (Calif.) University. The investigators treated 19 patients with a total of 90 basal cell carcinomas with oral itraconazole at 200 mg twice a day for 1 month or 100 mg twice a day for an average of 2.3 months.

The treatment reduced Hedgehog signaling pathway activity by 65%, Ki67 tumor cell proliferation by 45%, and tumor area by 24% (J Clin Oncol. 2014 Mar 10;32[8]:745-51).

These results aren’t as dramatic as what’s achieved using vismodegib or sonidegib. As stand-alone therapy, itraconazole doesn’t compare with those agents. However, the hope is that when itraconazole is prescribed in conjunction with vismodegib or sonidegib it will permit the latter drugs to be used at lower doses with no drop-off in efficacy, which would mean less grade 2 toxicity. Moreover, since itraconazole inhibits Hedgehog signaling through a mechanism that is different from that of the more potent agents, combination therapy might delay onset of tumor resistance, Dr. Swanson explained.

He reported having no financial conflicts of interest regarding his presentation.

SDEF and this news organization are owned by the same parent company.

bjancin@frontlinemedcom.com