General
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• First described as an entity in 1972 as "trabecular carcinoma of skin" (Arch Dermatol 1972;105:107); renamed in 1980
• Patients with MCC are at higher risk to develop neoplasms of hepatobiliary tract, salivary glands, non-Hodgkin lymphoma
• Commonly coexists with chronic lymphocytic leukemia
• Merkel cell carcinoma (MCC) of vulva first reported in 1984 by Bottles et al (Obstet Gynecol 1984;63:61S), although extremely rare at this site
• Vulvar MCC is considered more aggressive than at other cutaneous sites; this may reflect delayed diagnosis and higher stage, but only limited case reports are available to confirm

Terminology
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• Synonym: primary cutaneous neuroendocrine carcinoma

Epidemiology
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• More common in elderly Caucasian population
• Frequently affects sun-exposed parts of body, especially head and neck (J Cutan Pathol 2010;37:20)
• Median age at diagnosis in immunocompetent patients: 70 years
• Median age at diagnosis in immunocompromised patients: 53 years
• Incidence is steadily increasing

Sites
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• Labia majus, labium minus, paraclitoral, posterior fourchette, Bartholin's gland
• May contiguously involve vaginal introitus

Etiopathogenesis
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• Merkel cell polyomavirus (MCPyV) DNA is detected in approximately 80% of MCC (Int J Biochem Cell Biol 2014;53:536, Hum Pathol 2013;44:1912)
• Immunocompromised patients are at a high risk for developing MCC
• UV-light exposure also seems to contribute to MCC development
• Retinoblastoma and p53 gene mutations are common in MCPyV negative MCC (Mod Pathol 2014;27:1073, Clin Cancer Res 2011;17:4806)

Clinical features
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• Rapidly growing reddish-purple subcutaneous nodule, otherwise usually asymptomatic
• Ulceration of overlying skin in some cases
• May present with lymph node metastases, without a vulvar mass
• Diagnosis requires histologic examination

Radiology
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• Essential for initial staging and follow up
• MCC usually presents as a radiologically heterogenous mass (European Journal of Radiology Extra 2010;75:e37)

Prognostic factors
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• Unpredictable prognosis, but poor outcome is seen with high stage at diagnosis (based on sentinel lymph node status, presence of in-transit or satellite lesions, distant metastasis) and in immunosuppressed patients (Cancer Treat Rev 2013;39:421, , J Am Acad Dermatol 2013;68:425)
• MCPyV negative MCCs may be more aggressive than MCPyV positive tumors

Case reports
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• 49 year old woman with MCC of Bartholin gland (Gynecol Oncol 2005;97:928)
• 63 year old women (Case Rep Med 2011;2011:546972, J Cancer Res Ther 2010;6:365)
• 79 year old woman (Pathol Res Pract 2000;196:503)
• Merkel cell carcinoma of vulva (Gynecol Oncol 1997;64:526)
• Primary neuroendocrine carcinoma of vulva mimicking Bartholin gland abscess (Ann Saudi Med 2005;25:161)
• Vulvar merkel cell tumor with glandular and squamous differentiation (Gynecol Oncol 1996;62:292)

Treatment
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• Surgical: wide local resection with 1-3 cm margins; partial, hemi- or radical vulvectomy with regional lymph node dissection (Semin Diagn Pathol 2013;30:234)
• Conventional chemotherapy: neoadjuvant and adjuvant
• Adjuvant radiotherapy
• Immunomodulators / immune stimulators: in clinical trial

Gross description
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• Cut sections reveal a variegated tan-yellow tumor with dark hemorrhage admixed with necrosis

Micro description
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• Usually centered in dermis; extensive deeper invasion is not uncommon
• Only rarely epidermal involvement (epidermotrophism or in-situ component)
• Growth patterns are solid, trabecular, nested, infiltrative
• Central necrosis is common in tumors with solid growth pattern
• MCC is a small round blue cell tumor, composed of monomorphous cells with scant, almost undiscernible cytoplasm and round to oval or polygonal hyperchromatic nuclei with dispersed chromatin and inconspicuous nucleoli
• The nuclei often appear to be arranged back to back and may show moulding
• Mitoses and apoptotic bodies are frequent
• Lymphovascular invasion is common
• Rarely associated with squamous cell carcinoma in situ and benign adnexal tumors
• Rarely squamous or glandular differentiation

Micro images
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Medium power

 

High power

Mitoses

Mitoses, apoptosis

   

Central necrosis

Solid and small infiltrative nests

Infiltrative pattern

Plasma cells

Hemorrhage

 

Lymphovascular invasion

 

Skin

Pancytokeratin

CK7

 

CK20

 

CK20

CD56

Synaptophysin

TTF1

SOX-10

p40

Positive stains
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• Cytokeratins: cocktail, AE1/AE3, CK20, CAM5.2, CK8/18, CK7
• EMA: paranuclear dot-like or diffuse cytoplasmic or crescent shaped staining pattern (corresponding to the small amount of eccentrically located cytoplasm)
• Neuroendocrine markers: neurofilament, synaptophysin, chromogranin A, CD56, NSE, calcitonin, VIP, somatostatin
• Staining for CK20 can be extremely focal or even absent on about 10% of all MCCs
• Newer markers include: ALK, OCT4 (cytoplasmic), PAX8, PAX5, CD99 (membranous or dot-like), TdT, BCL2, glypican
• Nuclear p63 staining is considered by some to be a negative prognostic indicator

Negative stains
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• TTF1, p40, vimentin, S100, CD45, CEA, HMB45, SOX-10, SMA, CD31, CD34

Electron microscopy description
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• Sparse, peripherally located dense neurosecretory or core granules, free ribosomes, perinuclear aggregate of intermediate filaments, ill-developed intercellular junctions and hemidesmosomes

Molecular / cytogenetics description
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• Loss of 1p, 3p, 4, 5q, 7, 10, 14 (Cancers (Basel) 2014;6:2116)
• Trisomy of 1, 3q, 5p, and 6
• Mutations in chromosome 4 (PDGFRα gene locus)
• Loss of RB1

Differential diagnosis
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• Bartholin gland abscess: clinically similar; an elderly or immunocompromised patient that does not respond to conventional antibiotic therapy should raise the possibility of MCC and be biopsied
• Basal cell carcinoma:, especially those with neuroendocrine features
• Metastatic small cell carcinoma of lung: ALK-, usually TTF1+
• Poorly differentiated squamous cell carcinoma
• Sebaceous carcinoma
• Other small round blue cell tumors

Additional references
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• Cancer Lett 2014;344:272, J Natl Compr Canc Netw 2014;12:434

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