Merkel Cell Carcinoma

A fit 80 year old woman presents with a Merkel cell carcinoma of the middle of the right cheek, 8mm in maximal transverse diameter. The lesion is excised but the surgical margins are involved.

a) How would you assess this patient and what investigations would you perform prior to further treatment?

  • History:
    • Development of lesion:
      • Merkel tends to grow rapidly over weeks to months and is commonest on sun-exposed skin
      • Satellite nodules are common
      • involvement of regional nodes is common about the time of presentation
    • Symptoms suggestive of disseminated disease
      • liver, lung, bone and brain are commonest
    • Other risk factors:
      • chemical carcinogens eg. Arsenic
      • pUVA treatment
      • immunosuppression eg. Post-transplant or HIV
      • Genetics:
        • Cowden’s syndrome
        • congenital ectodermal dysplasia.
      • Comorbidities:
        • esp those which may limit treatment options
        • previous radiotherapy for skin cancers.
  • Examination:
    • Assessment of primary:
      • Presents as red or violaceous nodule, with a shiny surface, often with overlying telangiectasia.
      • Most lesions are small and solitary
      • Examination for multiple satellite nodules, which may occur via dermal lymphatic spread (often not present initially)
      • Assessment of regional nodes:
        • Involved in 1/3 patients (including parotid and cervical nodes)
      • Assessment of distant disease:
        • Assess for lung mets, liver, bone and brain mets – all occurring in roughly 10% of patients.
  • Investigations: to stage patient
    • Staging: UICC staging:
      • Local disease: Stage I T1N0Mo (T<2cm) and Stage II T2N0M0 ( T>2 cm)
      • Regional disease : Stage III (any TN1M0)
      • Distant disease: Stage IV (anyT, any N, M1)
  • Biopsy/excision:
    • Only required for diagnosis
    • recurrence is very common after surgery even with adequate margins unless very small.
    • Gross morphology is fairly non-specific and may easily be mistaken for BCC, amelanotic melanoma, SCC and cutaneous lymphoma
    • Microscopy
      • small, blue round cell tumour (“small cell of skin”).
      • Usually located in dermis, but may extend into subcutaneous tissue, or epidermis.
      • Nuclei have finely dispersed chromatin and small nucleoli
      • Abundant mitoses
      • Apoptosis
      • Easily confused with other poorly differentiated small cell tumours ( Ewings, lymphoma, SCLC, neuroblastoma, melanoma and BCC)
    • Immunohistochemistry:
      • Epithelial markers ( cytokeratin 20 positive)
      • Neuroendocrine markers ( neurone-specific enolase, synaptophysin, chromogranin)
      • Negative for S100 and leukocyte common antigen ( seen in melanoma and lymphoma respectively).
  • Sentinel node biopsy/elective dissection:
    • USA doesn't see much, Townsville are experts!
    • Recommended by NCCN guidelines because several studies suggest that SLNB identifies patients at higher risk of relapse and changes practice. Patients with positive SLNB should be offered either elective lymph node dissection or elective nodal irradiation.
    • SLNB should be performed prior to definitive local excision and hence NOT appropriate in this patient.
    • Dana Farber:
      • Single institution case series of 61 patients, plus 92 patients from literature.
      • Positive SLNB in 39 patients (32%) who would otherwise be classified as node negative.
      • 3-year recurrence rate was 3 times higher in patients with positive SLNB vs. negative SLNB ( 60 vs.20%)
      • Adjuvant nodal treatment ( surgery or radiotherapy or chemotherapy) improved 3 year relapse-free survival ( 60 vs. 0%) only in patients with positive SLNB.
  • Non-significant trend towards improvement in SLNB negative disease (90 vs. 70%)
  • Imaging :
    • CT of draining nodes
    • CT of chest and liver, to exclude metastases and small cell lung cancer.

b) What are the indications and justification for radiotherapy in this scenario?

This patient is at high risk for developing local recurrence due to

  1. her positive margins.
  2. The histology of Merkel cell

In addition, the omission of sentinel lymph node biopsy means that the nodal status is unclear. As up to 30% of patients who are radiologically node negative are found to have positive sentinel nodes, and have significantly poorer 3 year relapse free survival (Dana Farber 2008), she is potentially at significantly higher risk of locoregional recurrence, which has a poor prognosis.

Data from case series and one meta-analysis suggest that adjuvant radiotherapy can reduce locoregional recurrence and prolong disease-free survival.Data also says that recurrence in the irradiated field is uncommon, unlike surgery and that nodal reucrrence is catastrophic for prognosis.

Hence, I would recommend adjuvant radiotherapy to the primary site, draining lymphatics in the skinup to the regional lymph node basins.

Prior to radiotherapy: Consider re-excision?
I would discuss in multi-disciplinary head and neck meeting to assess whether re-excision and clearance of surgical margins is possible with acceptable function and cosmesis but I would beat the surgeons off with a stick. More surgery is NOT REQUIRED as control rates after clear margins are <40% with surgery AND >95% after 60Gy RT. TROG has shown adequate control even with positive margins.The role of chemotherapy in the node negative patient is controversial and she is old, OLD, OLD.

c) Describe a suitable radiation technique and give your dose prescription to treat this woman. Include in your answer the expected outcome and toxicity.

Radiotherapy Technique Summary
For this case I would consider that 60Gy/30Fx is achievable and sufficient alone.

Radiotherapy technique:

  • immobilise with mask
  • Bolus to scar site, primary excision site and in-transit skin to ensure adequate dose to dermal lymphatics
  • CT simulation
    • volume primary site and regional nodes.
    • Set-up
      • neutral head position
    • CTVp
      • tumour bed + skin with a 3-5 cm margin(yes, 3-5cm, HWH skin coverage! “where do I have to stop?”)
    • CTVn
      • unilateral parotid, facial, submandibular, including the lower-risk deep cervical and supraclavicular nodes.
    • PTV
      • CTV +0.3 cm margin.

Treatment modalities:

  • IMRT
    • with all-in one treatment of primary, surrounding dermal lymphatics and draining nodes.
    • liberally apply bolus over affected skin
  • Field based photons
    • Primary and surrounding dermal lymphatics
      • treat with either electron specified with D90% at base of PTVprimary or 6 MV photons.
      • Bolus of 1cm
    • Lateral field to upper neck nodes, Direct anterior field to SCF, with junction below larynx.
  • Electron technique
    • not preferred because of potential cold spots on junctioning but OK if using Pb to collimated on surface. Use 2 fields with bolus fitting the skin closely
    • face field covering cheek with borders up to zygoma, under eye, onto nose, above lip and down lower nasolabial fold around to ear taking care to use shaped bolus with 16MeV e- (obliquity may be a problem)
    • neck field with patient's head turned to cover whole ipsilateral neck and posterior auricular nodes if possible

Treatment constraints:

  • Salivary glands
    • contralateral parotid and submandibular dose as low as achievable
    • literature says "mean dose<26Gy" but much less is possible
  • Spinal cord: <45 Gy

Outcome

  • I would expect a 3 year locoregional control rate of 95%, with a 3-year survival of 75%.

Toxicity

  • Acute toxicity
    • Radiotherapy related
      • Grade 3 skin toxicity (moist desquamation) in 60%.
  • Late toxicity
    • Grade 3-4 Skin and subcutaneous toxicity
    • telangiectasia, alopecia, pigmentation, fibrosis, ulceration developing in 15%.

Surgery can cure the very little lesions if clean, chemo cures no-one. Its the wide field RT that will save her, or nothing.

Any recurrence is an extremely grave prognosis if the proper initial treatment has been given (it means the disease has wider tentacles than you can cover).

Also WE (radiation oncologists) are the experts in this disease (think NPC!). Too many surgeons to make any of them an expert, chemoterrorists just have to have a finger in the pie without a lot of data. So at the MDT, our opinion is the one that counts.

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