Definition/General
Introduction:
Merkel cell carcinoma (MCC) is a rare aggressive neuroendocrine carcinoma of skin
It constitutes <1% of all skin cancers
It shows high metastatic potential with poor prognosis
It demonstrates neuroendocrine differentiation
It has strong association with Merkel cell polyomavirus (80% of cases).
Origin:
Origin remains controversial
Previously thought to arise from Merkel cells (mechanoreceptors)
Current evidence suggests origin from pluripotent stem cells
May arise from hair follicle or dermal stem cells
Shows neuroendocrine differentiation during carcinogenesis
Strong association with MCPyV infection.
Classification:
WHO classifies as neuroendocrine carcinoma of skin
Primary cutaneous (most common)
Metastatic (from unknown primary)
Combined MCC (with squamous cell carcinoma)
MCPyV-positive (80% of cases)
MCPyV-negative (20% of cases)
UV-signature positive (MCPyV-negative cases).
Epidemiology:
Peak incidence in 7th-8th decades
Male predominance (2:1 ratio)
Risk factors include advanced age
Fair skin
Chronic sun exposure
Immunosuppression
Rare in Indian population but increasing incidence worldwide.
Clinical Features
Presentation:
Rapidly growing dome-shaped nodule
Red to purple skin-colored lesion
Non-tender firm nodule
Often mistaken for benign lesion
Ulceration may be present
AEIOU criteria: Asymptomatic
Expanding rapidly
Immunosuppressed
Older than 50
UV-exposed site.
Symptoms:
Usually asymptomatic
Rapid growth over weeks to months (most characteristic)
Occasional tenderness
Ulceration in advanced cases
Regional lymphadenopathy (often present at diagnosis)
Patients may report recently appeared lump.
Risk Factors:
Age >50 years (90% of cases)
Male gender
Fair skin (Caucasian)
Chronic UV exposure
Immunosuppression (organ transplant, HIV, CLL)
History of skin cancer
MCPyV infection
Rare genetic syndromes.
Screening:
No specific screening guidelines
Clinical vigilance in high-risk patients
Rapid biopsy of suspicious lesions
Complete skin examination
Lymph node examination
Immunohistochemistry essential for diagnosis.
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Gross Description
Appearance:
Dome-shaped nodule with smooth surface
Red to purple or skin-colored
Firm consistency
Size typically 1-5 cm at diagnosis
May show surface ulceration
Cut surface appears fleshy and white.
Characteristics:
Well-circumscribed nodular lesion
Shiny surface with possible telangiectasia
Non-pigmented (unlike melanoma)
May be multinodular
Satellite lesions may be present
Cut surface shows homogeneous appearance.
Size Location:
Size ranges from 0.5-10 cm (median 2 cm)
Most common on head and neck (50%)
Extremities (35%)
Trunk (15%)
Preferentially affects sun-exposed areas
Eyelid is frequent site in head/neck region.
Multifocality:
Multifocal disease uncommon
Satellite metastases may occur
In-transit metastases possible
Regional lymph node involvement common (30-60%)
Distant metastases at presentation (5-10%).
Microscopic Description
Histological Features:
Sheets and nests of small blue cells
Uniform round nuclei with fine chromatin
Scant cytoplasm
High mitotic rate (>10/10 HPF)
Apoptotic bodies frequent
Crush artifact common in small biopsies.
Cellular Characteristics:
Small round cells with high N:C ratio
Uniform nuclei with finely dispersed chromatin
Inconspicuous nucleoli
Minimal cytoplasm
Molding of nuclei (neuroendocrine feature)
Salt-and-pepper chromatin pattern.
Architectural Patterns:
Sheets and nests of tumor cells
Trabecular pattern in some areas
Rosette formation (rare)
Crush artifact creating streaming pattern
Dermal involvement with possible subcutaneous extension
Connection to epidermis rare.
Grading Criteria:
High-grade neuroendocrine carcinoma (by definition)
Mitotic rate >10/10 HPF
Ki-67 proliferation index >60%
Necrosis often present
Nuclear pleomorphism minimal
Apoptotic rate high.
Immunohistochemistry
Positive Markers:
CK20 (95% positive, perinuclear dot-like)
Neurofilament (90-95%)
Synaptophysin (85-90%)
Chromogranin A (60-70%)
CD56 (NCAM) (80-85%)
Neuron-specific enolase (85-90%)
CM2B4 (novel MCC marker).
Negative Markers:
TTF-1 (negative, unlike lung small cell)
CK7 (usually negative)
CDX2 (negative)
LCA (CD45) (negative)
S-100 (negative)
Desmin (negative)
Vimentin (negative).
Diagnostic Utility:
CK20 most specific marker (perinuclear dot pattern)
TTF-1 negativity distinguishes from lung small cell carcinoma
Neuroendocrine markers confirm diagnosis
MCPyV immunostaining possible
Essential for differential diagnosis.
Molecular Subtypes:
MCPyV-positive (80% of cases)
MCPyV-negative (20% of cases)
UV-signature tumors (MCPyV-negative)
RB1 pathway alterations
TP53 mutations (MCPyV-negative)
PIK3CA mutations.
Molecular/Genetic
Genetic Mutations:
RB1 mutations/loss (80-90%)
TP53 mutations (MCPyV-negative cases)
PIK3CA mutations (10-15%)
MYC amplification (frequent)
NOTCH mutations (subset)
FBXW7 mutations
MCPyV integration (positive cases).
Molecular Markers:
MCPyV large T antigen (virus-positive cases)
RB protein loss
p53 accumulation (virus-negative)
MYC overexpression
Cyclin E overexpression
ATOH1 transcription factor
High mutation burden (UV-associated).
Prognostic Significance:
MCPyV status affects prognosis (positive better)
TP53 mutations associated with worse outcome
RB1 loss universal feature
UV signature in virus-negative cases
Tumor mutation burden predicts immunotherapy response.
Therapeutic Targets:
PD-1/PD-L1 inhibitors (pembrolizumab, nivolumab)
CTLA-4 inhibitors (ipilimumab)
Somatostatin analogues
mTOR inhibitors
PARP inhibitors (DNA repair defects)
Targeted therapy based on molecular profile.
Differential Diagnosis
Similar Entities:
Metastatic small cell carcinoma (lung primary)
Lymphoma (small cell type)
Metastatic neuroendocrine carcinoma (extrapulmonary)
Basal cell carcinoma (small cell variant)
Ewing sarcoma/PNET
Rhabdomyosarcoma (small cell).
Distinguishing Features:
MCC: CK20 positive (dot-like)
MCC: TTF-1 negative
Lung small cell: TTF-1 positive
Lymphoma: CD45 positive
Basal cell: Peripheral palisading
Ewing: CD99 positive
Rhabdomyosarcoma: Desmin positive.
Diagnostic Challenges:
Crush artifacts in small biopsies
Distinguishing from metastatic small cell carcinoma
Primary vs metastatic MCC
Combined tumors with SCC component
Lymph node involvement mimicking lymphoma
Immunohistochemistry essential.
Rare Variants:
Combined MCC (with squamous carcinoma)
Trabecular MCC (architectural variant)
Small cell MCC (classic type)
Intermediate cell MCC (larger cells)
Divergent differentiation (rare)
Primary nodal MCC (unknown primary).
Sample Pathology Report
Template Format
Sample Pathology Report
Complete Report: This is an example of how the final pathology report should be structured for this condition.
Specimen Information
Wide local excision from [site], measuring [X x Y x Z] cm
Diagnosis
Merkel Cell Carcinoma (Neuroendocrine Carcinoma of Skin)
Microscopic Features
Shows sheets of small blue cells with high mitotic rate and neuroendocrine features
Size and Depth
Tumor size: [X] cm; Depth of invasion: [X] mm
Mitotic Rate
Mitotic rate: [X] mitoses per 10 HPF
Margins
Margins: [involved/uninvolved], closest margin [X] mm
Lymphovascular Invasion
Lymphovascular invasion: [present/absent/not identified]
Immunohistochemistry
CK20: [positive dot-like/negative]; TTF-1: [positive/negative]; [other markers]: [results]
MCPyV Status
MCPyV immunostain: [positive/negative/not performed]
TNM Staging
pT[X]: [staging based on size and depth]
Final Diagnosis
Merkel Cell Carcinoma, [size] cm, pT[X]