Merkel Cell Carcinoma (MCC)

 1. Definition

  • Merkel cell carcinoma (MCC) is a rare, aggressive primary neuroendocrine carcinoma of the skin.
  • It is characterized by:
    • Rapid growth
    • High propensity for regional lymph-node involvement
    • Early distant metastasis
    • Significant mortality
  • It usually arises in elderly patients on chronically sun-exposed skin.

 2. Epidemiology

  • Rare: approximately 0.1–0.7 cases per 100,000 persons/year, depending on population and surveillance.
  • Incidence has increased substantially over recent decades.
  • Predominantly affects older adults:
    • Median age at diagnosis: approximately 75 years.
    • Very uncommon in children and young adults.
  • Male predominance: approximately 2:1.
  • More common in fair-skinned/Caucasian populations.
  • Common anatomical sites:
    • Head and neck
    • Upper limbs
    • Lower limbs
    • Trunk
  • Important risk factors:
    • Advanced age
    • Chronic UV exposure
    • Fair skin
    • Immunosuppression
    • Solid-organ transplantation
    • HIV infection
    • Hematological malignancies, particularly CLL
    • Merkel cell polyomavirus (MCPyV) infection
  • Two major biological pathways:
    1. MCPyV-associated MCC
    2. UV-induced, virus-negative MCC

3. Etiology & Pathogenesis

  • Merkel cell polyomavirus
    • MCPyV is a major etiological factor in MCC.
    • Viral DNA is clonally integrated into the tumor genome in many MCPyV-associated tumors.
    • Viral large T antigen promotes:
      • Cell-cycle dysregulation
      • Inactivation of tumor-suppressor pathways
      •  Cellular proliferation
  • UV-associated pathway
    • Chronic ultraviolet exposure causes:
      • Extensive DNA damage
      • High tumor mutational burden
      • Mutations in tumor-suppressor pathways, particularly TP53
      • These tumors are generally MCPyV-negative.
  • Immunosuppression
    • Impaired immune surveillance facilitates:
      • Viral persistence
      • Tumor development
      • Tumor progression
4. Clinical Presentation
The classic clinical presentation is remembered by the AEIOU criteria.

A – Asymptomatic

  • Usually painless.
  • The lesion may produce no symptoms despite rapid growth.

E – Expanding rapidly

  • Rapid increase in size.
  • Often doubles in size within weeks rather than months.

I – Immune suppression

  • Patient may have:
    • Organ transplantation
    • HIV infection
    • Hematological malignancy
    • Immunosuppressive therapy

O – Older than 50 years

  • Typically occurs in elderly individuals.

U – UV-exposed fair skin

  • Usually occurs on sun-exposed skin.

Typical lesion

  • Firm, dome-shaped or nodular lesion
  • Smooth or shiny surface
  • Red, pink, violaceous or bluish coloration
  • Usually solitary
  • Usually non-tender
  • Rapidly enlarging

5. History

  • Lesion history
    • Date of onset
    • Rate of growth
    • Change in size
    • Change in color
    • Bleeding
    • Ulceration
    • Discharge
    • Pain or tenderness
    • Itching
    • Previous similar lesions
  • Risk-factor history
    • Chronic sunlight exposure
    • Occupational outdoor exposure
    • Previous skin cancers
    • Previous radiation therapy
    • Immunosuppressive medications
    • Organ transplantation
    • HIV infection
    • Hematological malignancy
    • Long-term steroid/immunosuppressive therapy
  • Cancer history
    • Ask about symptoms suggesting metastasis:
      • Enlarged lymph nodes
      • Weight loss
      • Anorexia
      • Persistent cough/dyspnea
      • Bone pain
      • Headache or neurological symptoms
      • Abdominal symptoms

6. Physical Examination

  • Local examination
    • Assess:
      • Site
      • Number of lesions
      • Size
      • Shape
      • Color
      • Surface
      • Consistency
      • Mobility
      • Tenderness
      • Ulceration
      • Bleeding
      • Fixation to underlying structures

Typical lesion: 

  • Rapidly growing, painless, firm, red/violaceous cutaneous nodule.

·         Regional lymph nodes

·         Examine systematically for:

·         Cervical nodes

·         Supraclavicular nodes

·         Axillary nodes

·         Inguinal nodes

Depending upon the anatomical site.

Complete skin examination

Look for:

  • Additional primary lesions
  • Satellite lesions
  • In-transit metastases
  • Previous skin cancers
  • Suspicious pigmented lesions
7. Differential Diagnosis

MCC can clinically resemble many other skin lesions.

Important differentials:

  • Basal cell carcinoma
  • Squamous cell carcinoma
  • Melanoma
  • Cutaneous lymphoma
  • Kaposi sarcoma
  • Sebaceous carcinoma
  • Angiosarcoma
  • Adnexal tumors
  • Metastatic small-cell carcinoma
  • Cutaneous metastasis from another neuroendocrine carcinoma

Histopathology and immunohistochemistry are therefore essential.

8. Investigations

A. Skin biopsy — most important investigation

  • Excisional biopsy is preferred when technically feasible.
  • Incisional or punch biopsy can be performed for large lesions or difficult anatomical sites.
  • Biopsy should include adequate depth.

Histopathology

Typical findings:

  • Dermal tumor
  • Sheets/nests of small round blue cells
  • High nuclear-to-cytoplasmic ratio
  • Round-to-oval nuclei
  • Finely granular ("salt-and-pepper") chromatin
  • Numerous mitoses
  • Apoptotic cells
  • Necrosis may be present
  • Tumor may extend into subcutaneous tissue

Characteristic feature

  • Nuclear molding may be present
  • Lymphovascular invasion is common.

9. Immunohistochemistry

MCC has a characteristic immunophenotype.

Usually positive

  • Cytokeratin 20 (CK20)
    • Typically shows perinuclear dot-like staining
    • Very useful diagnostic marker
  • Synaptophysin
  • Chromogranin
  • INSM1
  • Neurofilament may be positive
  • Pancytokeratin/AE1-AE3

Usually negative

  • TTF-1
  • CK7

This helps distinguish MCC from pulmonary small-cell carcinoma metastatic to skin.

Other useful markers

  • MCPyV large T antigen
  • SOX10
  • S100
  • NUT
  • CD45/LCA depending on the differential diagnosis.

 10. Diagnosis

Diagnosis is based on:

Clinical suspicion + Histopathology + Immunohistochemistry + Staging

A typical diagnostic profile:

Small round blue-cell cutaneous tumor + neuroendocrine differentiation + CK20 perinuclear dot-like positivity + TTF-1 negativity → strongly supports Merkel cell carcinoma.

11. Staging Investigations

Once MCC is confirmed, evaluate for regional and distant disease.

Regional lymph nodes

  • Clinical examination
  • Sentinel lymph-node biopsy (SLNB)

SLNB is particularly important because clinically normal lymph nodes can contain occult metastases.

Imaging

Depending on stage and clinical circumstances:

  • CT chest/abdomen/pelvis
  • PET-CT
  • MRI brain when clinically indicated
  • MRI for locally advanced tumors or involvement of critical structures

PET-CT

Useful for detecting:

  • Regional nodal disease
  • In-transit metastases
  • Distant metastases

12. Staging — Simplified

MCC is staged using the AJCC TNM system.

Stage I

  • Small primary tumor
  • No regional or distant metastasis

Stage II

  • Larger primary tumor
  • No nodal/distant metastasis

Stage III

  • Regional lymph-node or in-transit metastasis

Stage IV

  • Distant metastasis

Common metastatic sites include:

  • Lymph nodes
  • Skin/subcutaneous tissue
  • Lung
  • Liver
  • Bone
  • Brain

 13. Treatment

Treatment depends on:

  • Tumor size
  • Anatomical location
  • Regional nodal status
  • Distant metastasis
  • Patient's age/comorbidities
  • Immunosuppression

 A. Localized disease

1. Wide local excision

  • Wide local excision (WLE) is the principal treatment for localized MCC.
  • Aim is complete removal with histologically negative margins.

2. Sentinel lymph-node biopsy

  • Recommended for clinically node-negative patients who are suitable candidates.
  • Detects occult nodal metastasis.

3. Radiotherapy

MCC is highly radiosensitive.

Adjuvant radiotherapy may be considered particularly with:

  • Large tumor
  • Positive/close margins
  • Lymphovascular invasion
  • Immunosuppression
  • Recurrence
  • Head-and-neck tumors
  • Positive regional lymph nodes
  • High-risk pathological features

14. Regional Nodal Disease

If regional lymph nodes are involved:

  • Therapeutic lymph-node dissection may be considered in selected patients.
  • Nodal radiotherapy is frequently an important component of treatment.
  • Systemic immunotherapy may be used depending on disease extent.

15. Advanced / Metastatic MCC

Immunotherapy — major systemic treatment

MCC is particularly responsive to immune checkpoint inhibition.

PD-1/PD-L1 pathway inhibitors

Examples include:

  • Pembrolizumab
  • Nivolumab
  • Avelumab
  • Retifanlimab in appropriate settings

These agents can produce durable responses in advanced MCC.

Why immunotherapy works

MCC is an immunogenic tumor because of:

  • Viral antigens in MCPyV-positive tumors
  • High mutational burden in many UV-associated tumors

Therefore, immune checkpoint blockade has become central to treatment of advanced disease.

16. Chemotherapy

Historically used drugs include:

  • Platinum agents:
    • Cisplatin
    • Carboplatin
  • Etoposide
  • Topotecan
  • Other cytotoxic regimens

Important point

  • MCC is chemotherapy-sensitive, but responses are often short-lived.
  • Immunotherapy is generally preferred for advanced disease when appropriate.

 17. Prognostic Factors

Poor prognostic factors include:

  • Large primary tumor
  • Positive lymph nodes
  • Distant metastasis
  • Immunosuppression
  • Lymphovascular invasion
  • Positive surgical margins
  • Head-and-neck location in some settings
  • Rapid tumor progression

Most important prognostic factor

Stage at diagnosis is the major determinant of outcome.

 18. Recurrence

MCC has a high risk of recurrence, particularly during the first few years after diagnosis.

Recurrence can occur as:

  • Local recurrence
  • In-transit recurrence
  • Regional lymph-node recurrence
  • Distant metastasis

Therefore:

  • Regular skin examination
  • Regional lymph-node examination
  • Surveillance imaging when clinically indicated are important.

 

Comments

Post a Comment

Popular posts from this blog

Rhabdomyosarcoma (RMS) of the orbit

Rhabdomyosarcoma “A child with sudden, rapidly progressing unilateral proptosis with an orbital mass → think Rhabdomyosarcoma until proven otherwise.” Malignant tumour of mesenchymal origin showing skeletal muscle differentiation.  Most common primary orbital malignancy in children . Epidemiology Accounts for ~4% of all paediatric cancers . 10% of all RMS cases occur in the orbit . Age: usually 5–7 years (rare after adolescence). Sex: slight male predominance . Sites of Origin Orbit (most common intraocular adnexal site). Can arise from extraocular muscles, connective tissue, or blood vessel walls . Histological Subtypes Embryonal (60–70%) – most common in orbit; relatively better prognosis. Alveolar (20–25%) – more aggressive, seen in older children/adolescents. Pleomorphic (rare) – in adults, very aggressive. Botryoid variant – polypoid form under mucosal surfaces. Clinical Features R...
Read more

Iris Melanoma

Iris malignant melanoma is the most common primary neoplasm of the iris and can be most easily seen by the physician on clinical examination. It is usually a small, discrete lesion, although it may occasionally be diffuse and infiltrative; multiple; and result in heterochromia, glaucoma, chronic uveitis, or spontaneous hyphema. Many patients are often aware of a pigmented spot on the iris that has been present for many years and only recently has begun to grow. With a slit lamp, gonioscopy, and serial slit lamp photography, the ophthalmologist can document the size and growth of the tumor without biopsy. Fluorescein angiography may be helpful in demonstrating the vascularity of the lesion, but is not diagnostic. Ultrasonography is of little value in the evaluation of iris melanoma. Iris melanoma is relatively benign with a 5-year survival rate of approximately 95%. This is related to the fact that iris melanomas are predominantly of the spindle A-cell type and are usually smaller...
Read more

Adult Acute Lymphoblastic Leukemia in Remission

Current approaches to postremission therapy for adult acute lymphoblastic leukemia (ALL) include short-term, relatively intensive chemotherapy followed by longer-term therapy at lower doses (maintenance), high-dose marrow-ablative chemotherapy or chemoradiotherapy with allogeneic stem cell rescue (alloBMT), and high-dose therapy with autologous stem cell rescue (autoBMT). Several trials of aggressive postremission chemotherapy for adult ALL now confirm a long-term disease-free survival rate of approximately 40%. In the latter 2 series, especially good prognoses were found for patients with T-cell lineage ALL, with disease-free survival rates of 50% to 70% for patients receiving postremission therapy. These series represent a significant improvement in disease-free survival rates over previous, less intensive chemotherapeutic approaches. In contrast, poor cure rates were demonstrated in patients with Philadelphia chromosome-positive (Ph+) ALL, B-cell lineage ALL with an L3 phenotype (...
Read more