Merkel Cell Carcinoma

Slide 1 · Merkel cell carcinoma

An aggressive cutaneous neuroendocrine carcinoma

Core mechanisms: polyomavirus-associated oncogenesis and ultraviolet DNA injury.

Clinical priority: recognize rapid growth, nodal risk, and the need for biopsy.

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning objectives

Distinguish the virus-associated and UV-driven molecular pathways.

Recognize the clinical and microscopic phenotype of MCC.

Select and interpret a discriminating immunohistochemical panel.

Relate primary tumor pathology to regional-node staging and reporting.

Explain why immune therapy has transformed advanced disease management.

Slide 3 · Definition and biological identity

A rare, high-grade neuroendocrine carcinoma arising in the skin

Epithelial and neuroendocrine features coexist.

Rapid growth and early regional spread distinguish it from many other cutaneous carcinomas.

Slide 4 · Where MCC sits among cutaneous tumors

Keratinocyte carcinomas

Basal cell carcinoma: Usually local invasion.

Squamous cell carcinoma: Invasive squamous differentiation.

UV exposure is an important shared context.

Merkel cell carcinoma

Cutaneous neuroendocrine carcinoma.

Morphology resembles a high-grade small-cell neoplasm.

Early nodal dissemination is a major clinical concern.

Slide 5 · Normal Merkel cells: Functional context

Epidermal basal region

Specialized tactile apparatus

Normal cell identity is not proof of the cancer cell of origin

Schematic — not a histologic specimen

Slide 6 · Cell of origin remains an active question

Merkel cells are specialized epithelial cells involved in light-touch sensation.

They also exhibit neuroendocrine characteristics.

The tumor is conventionally named for its phenotypic resemblance.

A definitive origin from mature Merkel cells is not established for every molecular subtype.

Slide 7 · Two pathways converge on one tumor phenotype

Merkel cell polyomavirus pathway

Loss of cell-cycle control

Cutaneous neuroendocrine carcinoma

An alternative UV-driven route creates many somatic DNA alterations rather than viral oncogene dependence.

Slide 8 · Risk contexts are clinically distinct

Chronic immunosuppression

Solid-organ transplantation.

HIV/AIDS and other impaired immune surveillance.

Virus-associated pathogenesis is especially relevant.

Chronic UV-exposure phenotype

Older patients.

Lightly pigmented, photodamaged skin.

Virus-negative tumors often carry a strong UV mutational signature.

Slide 9 · Immune surveillance is central to MCC biology

Common viral exposure

Virus-specific T-cell control

Rare malignant escape

Common infection does not imply that carcinoma is common; Host immune control is a key barrier.

Slide 10 · Why UV exposure matters

Ultraviolet light produces a characteristic DNA damage pattern.

Older, sun-exposed individuals form a major clinical risk group.

Virus-negative tumors typically exhibit a high somatic mutation burden.

UV exposure is a risk context—not a requirement for every patient.

Slide 11 · Merkel cell polyomavirus (MCPyV)

A member of the polyomavirus family.

Frequently encountered infection; MCC develops in only a small minority of exposed people.

Tumor-associated viral sequences may become integrated in the cancer genome.

The virus-associated tumor is biologically distinct from UV-driven MCC.

Slide 12 · Infection is not equivalent to transformation

Background infection

Host immune containment

Rare oncogenic events

Clonal tumor expansion

The presence of virus in normal skin is not sufficient to diagnose Merkel cell carcinoma.

Slide 13 · Clonal viral integration: The key observation

Viral DNA enters cell

Viral DNA integrates

Oncoprotein activity persists

Integrated viral DNA within the cancer genome supports a causal role in virus-associated tumors.

Slide 14 · Viral oncoproteins perturb host regulation

Viral T-antigen programs interfere with cellular tumor-suppressive controls.

Retinoblastoma pathway disruption is a central functional event.

The textbook also discusses altered p53, PP2A, and MYC-related functions.

These interactions are not identical to inactivating mutations in every named gene.

Slide 15 · Retinoblastoma gate: Normal function

Functioning RB protein

Restriction of G1–S entry

Controlled cell proliferation

RB pathway dysfunction weakens normal control over cell-cycle progression.

Slide 16 · Viral pathway: Functional RB suppression

MCPyV T antigen

RB pathway interference

Cell-cycle deregulation

This mechanism differs from genomic loss of RB1 in UV-driven tumors, even when the end effect overlaps.

Slide 17 · Additional host signaling interactions

Host regulator

Teaching relevance

RB

Central G1–S restriction checkpoint affected by viral oncoproteins.

P53

Tumor-suppressive stress-response network discussed in viral transformation.

PP2A

Phosphatase with tumor-suppressive activity; A reported interaction target.

MYC

Growth-related oncoprotein network discussed in the Robbins passage.

Slide 18 · Why widespread MCPyV is not widespread MCC

Exposure is common by adulthood account.

MCC requires additional tumor-promoting events and a permissive host setting.

MCPyV-specific T cells plausibly suppress virus-driven tumor emergence.

Immunosuppression can compromise this protective layer.

Slide 19 · The typical virus-positive genome

Integrated viral DNA with comparatively few acquired somatic mutations

Often near-diploid’ description.

Low mutation burden does not imply biologic indolence or absent metastatic risk.

Slide 20 · Virus-associated tumor as a dependency model

Integrated viral genome

Sustained viral oncoproteins

Tumor survival and growth

Conceptual model; Exact protein dependencies vary with experimental system and tumor biology.

Slide 21 · Virus-negative MCC: A separate oncogenic route

Ultraviolet mutagenesis can drive MCC without integrated oncogenic MCPyV

A high mutational burden and UV signature characterize this subtype.

Neuroendocrine appearance alone does not establish viral status.

Slide 22 · UV DNA injury accumulates with time

Chronic UV exposure

Somatic DNA alterations

Clonal selection

Aggressive tumor

Diagram illustrates an etiologic sequence, not a claim that every UV-damaged keratinocyte becomes MCC.

Slide 23 · RB1 and TP53 abnormalities in UV-driven MCC

RB1 loss of function is commonly acquired in virus-negative tumors.

TP53 loss of function is also frequent.

These are tumor-cell genetic lesions, unlike functional suppression by virus-encoded proteins.

The two processes converge on weakened proliferation and stress-response control.

Slide 24 · Copy-number complexity distinguishes the UV route

Virus-associated MCC

Generally low somatic mutational load.

Often relatively stable or diploid genome.

Integrated viral DNA and viral antigens.

UV-driven MCC

Abundant UV-signature substitutions.

Numerous copy-number gains and losses.

Common RB1 and TP53 inactivation.

Slide 25 · The pathways can converge morphologically

A shared high-grade neuroendocrine phenotype can arise from different molecular causes

Routine H&E alone does not reliably assign etiologic subtype.

Use clinical setting and validated ancillary assays; Do not infer viral status from morphology alone.

Slide 26 · Comparison: Molecular and clinical context

Feature

MCPyV-associated

UV-driven

Typical host context

Impaired immunity common

Older, sun-damaged skin

Driver

Viral oncogene program

Somatic UV mutagenesis

Mutation burden

Relatively low

Relatively high

RB pathway

Functional interference

Frequent RB1 alteration

TP53

Usually not heavily mutated

Frequently mutated

Genomic copy changes

Often fewer

Often numerous

Slide 27 · Interpret molecular subtype without overclaiming

Viral detection is helpful but technical methods and sensitivity differ.

Subtypes cannot be reliably assigned using patient age or location alone.

Mutation burden is not a direct substitute for a complete diagnostic work-up.

Molecular differences inform biology; Treatment choices require clinical staging and guidelines.

Slide 28 · The classic clinical presentation

A rapidly enlarging, usually painless cutaneous nodule

Erythematous to violaceous coloration may occur.

Clinical appearance is nonspecific; Tissue diagnosis is decisive.

Slide 29 · AEIOU: A clinical recognition aid

Letter

Clinical association

A

Asymptomatic lesion

E

Expanding rapidly

I

Immunosuppression

O

Older age

U

UV-exposed skin site

Mnemonic aids suspicion but is neither a diagnostic rule nor a substitute for biopsy.

Slide 30 · Distribution and examination

Often affects sun-exposed skin: Head and neck and extremities.

Examine the complete skin surface for a potential primary.

Inspect for local satellites or in-transit disease.

Palpate the draining nodal basin; Nodes may be occult.

Slide 31 · Why small appearance does not imply low risk

MCC can disseminate through regional lymphatics early.

The risk of microscopic nodal involvement is clinically relevant even without palpable nodes.

Size is informative for stage and risk but does not replace nodal assessment.

Slide 32 · From skin primary to regional disease

Primary skin tumor

Regional nodal basin

Potential distant spread

Lymphatic metastasis is a major practical consequence of aggressive MCC biology.

Slide 33 · What the clinician must communicate to pathology

Site, duration, recent growth rate, and lesion size.

Prior skin cancer or possible extracutaneous neuroendocrine malignancy.

History of transplantation, HIV, or other immune compromise.

Whether sampled tissue is the primary skin lesion or a regional node.

Slide 34 · MCC arises within the cutaneous compartment

Epidermal surface

Dermal-centered tumor (schematic)

Potential lymphatic access and spread

Schematic — not a histologic specimen

Slide 35 · High-grade neuroendocrine morphology

Microscopically resembles an aggressive neuroendocrine carcinoma.

Typical appearance is a dermal “small round blue cell” tumor.

Crowded cells, little cytoplasm, and brisk proliferation raise suspicion.

A tissue section and IHC are essential for lineage assignment.

Slide 36 · Nuclear features: What to look for

High nuclear-to-cytoplasmic ratio.

Round to oval nuclei with fine neuroendocrine-type chromatin.

Nuclear molding and numerous mitoses may be seen.

Necrosis and apoptosis underscore high-grade behavior.

Slide 37 · Histologic architecture is not pathognomonic

Diffuse sheets, nests, and trabecular arrangements are described.

An overlying epidermis may be relatively uninvolved.

Architecture overlaps other cutaneous or metastatic small-cell neoplasms.

Interpret the growth pattern together with immunophenotype.

Slide 38 · Proliferation and cell death: Aggressive phenotype

Histologic observations

Frequent mitotic figures.

Apoptotic fragments and necrosis.

Potential lymphovascular invasion.

Clinicopathologic implication

Rapidly enlarging lesion.

Propensity for early regional spread.

Risk stratification requires stage and other features.

Slide 39 · Small blue cell appearance is a starting point

A “small blue cell tumor” is a morphologic category—not a final diagnosis

Neuroendocrine carcinoma, lymphoma, melanoma and other entities may overlap.

Lineage-defining IHC resolves most common differentials.

Slide 40 · Diagnostic workflow: Morphology to classification

Clinical and biopsy context

Evaluate H&E phenotype

Lineage-directed IHC

Integrated diagnosis

No single immunostain should be interpreted in isolation.

Slide 41 · Why cytokeratins matter

Cytokeratin expression establishes epithelial differentiation.

CK20 is a particularly useful MCC-associated marker.

A classic perinuclear dot-like pattern is a key diagnostic clue.

A negative CK20 result does not exclude all MCC cases.

Slide 42 · CK20: Interpret the localization pattern

CK20 perinuclear dot

Neuroendocrine marker

TTF-1 usually absent

Schematic marker localization only — not a patient IHC image.

Slide 43 · Neuroendocrine markers support the phenotype

Synaptophysin and chromogranin support neuroendocrine differentiation.

CD56 and INSM1 may provide further supporting evidence.

The marker combination matters more than a single positive stain.

Other neuroendocrine carcinomas may share this expression profile.

Slide 44 · MCC versus metastatic pulmonary small-cell carcinoma

Favor cutaneous MCC

Characteristic CK20 dot positivity.

TTF-1 usually negative.

Compatible skin-centered clinical presentation.

Favor pulmonary origin

TTF-1 often positive.

CK20 usually negative.

Correlate with imaging and clinical history.

Exceptions exist: A full panel and clinical evaluation remain mandatory.

Slide 45 · Exclude melanoma and lymphoid malignancy

Melanoma lineage

SOX10 and other melanocytic markers support melanoma.

Usually lacks epithelial cytokeratin profile of MCC.

Can be amelanotic and mimic MCC.

Lymphoid lineage

CD45 and subtype markers support hematolymphoid origin.

Diffuse blue-cell infiltrates can be deceptive.

An epithelial/neuroendocrine signature redirects toward MCC.

Slide 46 · Practical immunohistochemistry comparison

Marker

MCC typical

Small-cell lung CA

Melanoma

Lymphoma

CK20

+; Dot-like

Usually −

−

−

TTF-1

Usually −

Often +

−

−

Synaptophysin

Often +

Often +

Usually −

Usually −

SOX10

Usually −

Usually −

Often +

Usually −

CD45

−

−

−

Often +

“Typical” patterns have exceptions; Use the clinical context and a panel, not an isolated stain.

Slide 47 · Interpreting CK20-negative suspected MCC

CK20 negativity is not sufficient to rule out MCC.

Revisit H&E and add broad cytokeratin and neuroendocrine markers.

Neurofilament and other supportive markers may be informative.

Exclude cutaneous metastasis of a visceral small-cell carcinoma.

Slide 48 · Viral large-T antigen testing

Large-T antigen IHC can provide evidence of MCPyV-associated tumor biology.

It is not a universal positive marker across all MCCs.

Virus-negative MCC retains the diagnosis when morphology and phenotype support it.

A molecular classification assay does not replace an adequate differential panel.

Slide 49 · MCC and basal cell carcinoma may overlap

Basal cell carcinoma

Basaloid nests, peripheral palisading.

Stromal clefting often present.

Characteristic Hedgehog pathway context.

Merkel cell carcinoma

High-grade neuroendocrine cytology.

CK20 dot and neuroendocrine IHC support diagnosis.

Aggressive lymph-node metastatic potential.

Slide 50 · Small biopsy pitfalls

Limited superficial samples may underrepresent tumor architecture.

Crush artifact can compromise nuclear evaluation.

Metastatic small-cell carcinoma may resemble a primary MCC.

A targeted but sufficiently broad IHC panel prevents premature closure.

Slide 51 · Primary MCC or metastasis to skin?

Identify small-cell phenotype

Confirm epithelial/neuroendocrine lineage

Correlate clinical sites

Exclude extracutaneous primary

TTF-1 and CK20 help orient the investigation but are not absolute site-of-origin tests.

Slide 52 · Why regional nodal staging changes interpretation

Occult lymph-node metastasis may be present despite clinically negative nodes.

Sentinel lymph node biopsy provides pathologic staging information.

Micrometastases may require keratin immunohistochemistry to identify.

Staging must combine primary-tumor, nodal, and distant-disease evidence.

Slide 53 · Staging assessment: The basic compartments

Primary tumor (T)

Regional nodes (N)

Distant metastasis (M)

Use the institutionally applicable current TNM system; Do not mix AJCC8 with UICC TNM9.

Slide 54 · Current staging references require edition control

ICCR’s January 2026 second-edition dataset incorporates UICC TNM9.

ESMO–EURACAN 2024 uses the eighth-edition UICC framework.

Stage boundaries and terminology should always be tied to the specific edition.

This lecture emphasizes T/N/M concepts rather than transplanting older tables into a newer framework.

Slide 55 · Imaging complements pathology

Assess the draining nodal basin and potential distant spread.

Guideline-directed CT or FDG-PET/CT may be indicated at initial staging.

Imaging does not replace histologic nodal staging when this is clinically appropriate.

A multidisciplinary pathway integrates examination, pathology, and imaging.

Slide 56 · MCC resection report: Essential questions

Reporting domain

Question to answer

Tumor identity

Is the sampled lesion primary cutaneous MCC?

Location and extent

Where is the tumor, and how far does it extend?

Size and dimensions

What are the measured tumor dimensions?

Margins

Is invasive tumor present at a resection margin?

Lymphovascular invasion

Is involvement observed?

Associated findings

Is there relevant morphologic diversity or other pathology?

Regional nodes

Are nodes submitted and what is their involvement?

Slide 57 · ICCR reporting has a defined specimen scope

The 2026 ICCR dataset is designed for primary cutaneous MCC excision specimens with tumor.

Partial superficial biopsies and cytology do not require the same complete synoptic elements.

A re-excision with no residual carcinoma should say so.

Prior diagnostic material may contribute when the final excision contains only part of the lesion.

Slide 58 · Pathologic risk assessment: What adds value

Extent of primary disease and nodal status dominate staging.

Tumor dimensions and invasion beyond the dermis can matter clinically.

Lymphovascular invasion and infiltrative pattern have been associated with outcomes in studies.

Do not convert retrospective prognostic associations into deterministic predictions.

Slide 59 · A structured sign-out logic

Diagnosis and site

Extent and dimensions

Margins / LVI / pattern

Nodal status + TNM edition

Example of report organization, not a fabricated patient report.

Slide 60 · Radiosensitivity does not guarantee cure

Tumor response

MCC is highly responsive to radiotherapy.

Chemotherapy can produce tumor regression.

Local control remains clinically important.

Why relapse occurs

Regional and distant spread may be present.

Systemic relapse can occur despite response.

Durability differs across treatment modalities.

Slide 61 · Immune checkpoint therapy: Biological rationale

Tumor antigens and immune evasion

Inhibitory T-cell signaling

Checkpoint blockade

Restored antitumor activity

The clinical response is variable; Blockade does not ensure immune eradication in every patient.

Slide 62 · Checkpoint inhibition changed advanced MCC care

Some patients with unresectable or metastatic disease achieve durable responses.

The clinical benefit can extend beyond conventional chemotherapy durability.

The textbook specifically highlights responses in UV-driven, mutation-rich disease.

Therapeutic sensitivity is not restricted to one molecular subtype.

Slide 63 · What PD-L1 does—and does not—tell us

PD-L1 expression reflects aspects of tumor–immune interaction.

It should not be treated as a universal binary gatekeeper for immune therapy.

Prognostic and predictive performance of candidate biomarkers remains imperfect.

Treatment decisions depend on disease stage and contemporary clinical guidance.

Slide 64 · Immunosuppression affects both risk and management

Impaired host immunity is a major susceptibility context.

Immune function also modulates antitumor responses.

Transplant and other immunosuppressed patients require individualized multidisciplinary decisions.

Oncologic benefit must be weighed against immune-mediated complications.

Slide 65 · Follow-up aims to detect early recurrence

Skin and regional nodal examination are central to surveillance.

Evaluate new rapidly growing lesions or nodal abnormalities promptly.

The schedule and imaging strategy should follow current risk-adapted clinical guidance.

A negative prior examination does not exclude subsequent dissemination.

Slide 66 · Case exercise: Immunosuppressed patient

A transplant recipient develops a quickly enlarging, painless dermal nodule. Biopsy shows a high-grade small-cell neuroendocrine carcinoma; MCPyV large-T antigen is detected.

Which oncogenic pathway is most directly supported?

Slide 67 · Case interpretation: Viral oncogenesis

Virus-associated MCC is strongly supported by viral large-T antigen detection.

Immune suppression is a relevant host context.

Expected biology includes viral oncogene activity and relatively low mutation burden.

Regional nodal assessment remains necessary regardless of viral status.

Slide 68 · Case exercise: An older sun-exposed patient

An older patient presents with a rapidly expanding forearm nodule. Histology shows cutaneous neuroendocrine carcinoma. Sequencing reveals a prominent UV mutational signature with RB1 and TP53 alterations.

Which pathogenetic route is favored, and why?

Slide 69 · Case interpretation: UV-driven oncogenesis

The UV signature and RB1/TP53 alterations favor virus-negative MCC.

The clinical context supports but does not independently prove the route.

Aggressive histology can overlap with virus-positive disease.

Immunophenotypic work-up and nodal staging remain essential.

Slide 70 · Case exercise: Small-cell carcinoma in a node

A regional lymph node contains small-cell carcinoma. CK20 has a dot-like pattern; Synaptophysin is positive, TTF-1 is negative, and no skin primary is immediately evident.

What is the most important next diagnostic interpretation?

Slide 71 · Case interpretation: A possible occult primary

The immunophenotype supports MCC in the appropriate setting.

Examine the entire skin and investigate alternative primary sites.

MCC may present with involved nodes and an occult or regressed skin primary.

Document the evidence and uncertainty; Do not invent a primary site.

Slide 72 · Synthesis: What determines diagnosis and risk?

Question

Evidence used

What tumor is present?

H&E morphology + epithelial/neuroendocrine IHC.

Is it primary cutaneous?

Skin examination, distribution and alternate-site assessment.

What pathway drove it?

Viral assay or validated molecular findings.

How far has it spread?

Primary features, nodal sampling and imaging.

How should it be reported?

Current ICCR dataset with specified TNM edition.

What informs treatment?

Stage, host immunity and multidisciplinary guidance.

Slide 73 · Final principles

MCC is uncommon but clinically aggressive: A rapidly growing nodule warrants biopsy.

Virus-associated and UV-driven routes converge on neuroendocrine carcinoma.

CK20 dot-like staining is a useful clue; Exceptions demand a panel.

Regional nodal disease drives much of clinical staging and risk assessment.

Pathology, current staging terminology, and systemic therapy decisions must remain integrated.

Slide 74 · Selected references

Robbins, Cotran & Kumar. Pathologic Basis of Disease. 11th ed. 2026; Ch 25.

NCI. Merkel Cell Carcinoma Treatment (PDQ), health professional version.

Lugowska et al. ESMO Open. 2024;9:102977. doi:10.1016/j.esmoop.2024.102977.

ICCR. Merkel Cell Carcinoma Histopathology Reporting Guide, 2nd ed (Jan 2026).

Merkel cell carcinoma pathology and molecular biology reviews: see lecturer notes and source manifest.