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Merkel cell tumour

Section: Skin and soft tissue Sub-section: Skin cancer Curriculum: Curriculum, page 52

Definition

  • Aggressive cutaneous malignancy
  • Arise from multipotent stem cells which undergo neuroendocrine transformation when they become malignant
    • The cell of origin is debated - it was traditionally believed that they arose from Merkel cells which are located in the basal layer of the epidermis - these are a/w with dermal papillae and skin mechanoreceptor
  • Also known as:
    • Cutaneous Neuroendocrine Carcinoma
    • Small Cell Tumour of the Skin
    • Primary undifferentiated carcinoma of the skin
    • Anaplastic carcinoma of the skin
    • Murky cell carcinoma

Incidence

  • Rare: 0.3 / 100,000
  • < 1% of skin malignancies
  • Older adult 60-80 years of age, whites, M≈F

  • 50% occur in the head and neck

Risk factors

  • Lighter skin colour
  • Increasing age
  • Male sex
  • Immunosuppression - especially organ transplant patients, HIV, and hematological malignancies.
  • Other malignancies increase risk - CLL, multiple myeloma, melanoma.
  • UV radiation exposure - more common in sun-exposed areas.
  • Merkel cell polyomarvirus infection
  • Germline nutations in BRCA1, BRCA2, TP53, ATM, are a/w Merkels

Merkel Cell polyomavirus

  • 60-80% of patients have detectable MCPyV in their specimens.
  • Merk Cell polyomavirus integrates two oncogenes into the host genome - which encode proteins large tumour antigen and small tumour antigen, which help with immune evasion.

Clinical Presentation

  • AEIOU
    • Asymptomatic
    • Expanding rapidly
    • Immunosuppressed
    • Older than 50yrs
    • UV exposed/fair skin
  • Firm, painless, shiny lump (raised intradermal nodule)
  • Can be red, pink, or blue (“violaceous”)
  • Overlying Epidermis intact
  • Ulceration rare; suggestive of rapid growth
  • Grows rapidly & often metastasizes → Lymphatics → Satellite Lesions → LNs
    • 70-80% present with localized disease
    • 1-4% present with metastatic disease

Differential diagnosis

Regional disease

  • Must examine nodal basins
  • High propensity for regional and distant mets
    • 15% <0.5, 25% <1cm, 40% <2cm
    • Spread via lymphatics
    • Mets to LN and liver > bone > brain > lung > skin
  • May completely regress (replaced by a lymphocytic infiltrate)

Pathology

  • Immunohistochemical
    • Stains are usually required to differentiate it from other poorly differentiated tumours.
    • Express AE1/AE3, CAM 5.2, and CK20
    • Also express various neuroendocrine markers on histochemistry including chromogranin, synaptophysin, calcitonin, VIP, and somatostatin
  • Microscopically
    • Dermal mass which extends into the subcutaneous tissue.
    • It rarely involves the epidermis.
    • Small round blue cells with neuroendocrine features
      • Nests of monotonous, round, blue cells, containing large basophilic nuclei and minimal cytoplasm.

Investigations

  • Excision biopsy
    • Narrow margins or incisional/punch biopsy
    • Immunohistochemistry (Cytokeratin 20 +ve)
      • Stain with K20, neuron specific enolase (neuroendocrine marker)
  • FNA any suspicious LN
  • Staging
    • All patients should undergo CT-PET
      •  In NZ, it is approved for patients prior to radical therapy for Merkel Cell Carcinoma
  • Others tests
    • Merkel Cell polyomarvirus serology - should be measured.
      • Patients who are seronegative have an increased risk of recurrence

Staging

T Staging

Clinical and pathological are the same

T categoryT criteria
TXPrimary tumor cannot be assessed (eg, curetted)
T0No evidence of primary tumor
TisIn situ primary tumor
T1Maximum clinical tumor diameter ≤2 cm
T2Maximum clinical tumor diameter >2 but ≤5 cm
T3Maximum clinical tumor diameter >5 cm
T4Primary tumor invades fascia, muscle, cartilage, or bone

N Staging

Clinical

N categoryN criteria
NXRegional lymph nodes cannot be clinically assessed (eg, previously removed for another reason, or because of body habitus)
N0No regional lymph node metastasis detected on clinical and/or radiologic examination
N1Metastasis in regional lymph node(s)
N2In-transit metastasis (discontinuous from primary tumor; located between primary tumor and draining regional nodal basin, or distal to the primary tumor) without lymph node metastasis
N3In-transit metastasis (discontinuous from primary tumor; located between primary tumor and draining regional nodal basin, or distal to the primary tumor) with lymph node metastasis
Pathological
N categorypN criteria
pNXRegional lymph nodes cannot be assessed (eg, previously removed for another reason or not removed for pathological evaluation)
pN0No regional lymph node metastasis detected on pathological evaluation
pN1Metastasis in regional lymph node(s)
pN1a(sn)Clinically occult regional lymph node metastasis identified only by sentinel lymph node biopsy
pN1aClinically occult regional lymph node metastasis following lymph node dissection
pN1bClinically and/or radiologically detected regional lymph node metastasis, microscopically confirmed
pN2In-transit metastasis (discontinuous from primary tumor; located between primary tumor and draining regional nodal basin, or distal to the primary tumor) without lymph node metastasis
pN3In-transit metastasis (discontinuous from primary tumor; located between primary tumor and draining regional nodal basin, or distal to the primary tumor) with lymph node metastasis

M stage

Clinical and pathological the same

Clinical

M categoryM criteria
M0No distant metastasis detected on clinical and/or radiologic examination
M1Distant metastasis detected on clinical and/or radiologic examination
M1aMetastasis to distant skin, distant subcutaneous tissue, or distant lymph node(s)
M1bMetastasis to lung
M1cMetastasis to all other visceral sites

Pathological

M categoryM criteria
M0No distant metastasis detected on clinical and/or radiologic examination
pM1Distant metastasis microscopically confirmed
pM1aMetastasis to distant skin, distant subcutaneous tissue, or distant lymph node(s), microscopically confirmed
pM1bMetastasis to lung, microscopically confirmed
pM1cMetastasis to all other distant sites, microscopically confirmed

TNM stage

  • Clinical
    • Stage 1
      • T1
    • Stage 2
      • A - T2-T3
      • B - T4
    • Stage 3
      • N1-N3
    • Stage 4
      • M1
  • Pathological
    • Stage 1
      • T1
    • Stage 2
      • A - T2-3
      • B - T4
    • Stage 3
      • A - N1a, N1a(sn)
      • B - N1b-3
    • Stage 4
      • M1

Break that down

  • Stage 1 - T1 <2cm
  • Stage 2 - T2-T4, >2cm +/- invasion
  • Stage 3 - positive lymph nodes
  • Stage 4 - distant mets

Management

Clinically negative regional lymph nodes

  • WLE of the primary tumour with SLNB
    • SLNB
      • Negative
        • Observe
      • Positive
        • Either completion lymph node dissection or RT to regional nodes.
          • If the completion lymph node dissection reveals multiple involved nodes or extracapsular extension - should consider adjuvant RT.
      • Note
        • Some centres = No SLNB if > 2cm - because the risk of LN positivity is so high the patient should be given RT regardless.
        • If a patient has a negative SLNB, they may still receive RT if they are perceived high risk

Clinically positive regional nodes

  • Should confirm diagnosis with FNA or excision biopsy
  • Patients should undergo therapeutic lymph node dissection or RT.
  • If there are multiple positive nodes OR extracapsular extension - should receive adjuvant RT

Management of the primary tumour

  • WLE with a margin of 1-3cm
  • Or
  • Primary RT
    • Peter Mac Lecture: Surgical excision rarely performed now and main treatment is primary radiotherapy + adjuvant PD-1 Inhibitor
  • Tumours with high risk features should also receive adjuvant RT

High risk features

  • Tumour >2cm
  • Microscopically positive or limited surgical margins.
  • LVI
  • Head and neck primary
  • Immunosuppression.

Unresectable disease

  • Definitive RT

Treatment of systemic disease

Outcomes

  • 5 year survival of 30-50%.

Graph View

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