Merkel cell carcinoma

Introduction

1. Merkel cell carcinoma (MCC) is a rare skin cancer, but is rising in incidence, and the Alliance sees approximately 3-5 cases per year. 

2. There are no NICE guidelines for management of MCC. These Alliance guidelines draw on guidelines from the European Dermatology Forum (which had input from EADO and the EORTC); the NCCN; literature review and regional practice experience.

3. Overall, significant controversies remain in the management of MCC, with discordant findings across clinical studies, at least partly due to aggregation of low-granularity data, and the fact that historical data predate the introduction of immunotherapy as a highly effective rescue measure for advanced disease. The Alliance aims formally to collate practice experience via SSMDT registration and discussion, learning from every case. All cases of MCC across the Alliance should be submitted for discussion at the SSMDT.

Initial management

Presentation

1. Merkel cell carcinoma typically presents as a painless flesh-coloured or erythematous nodule, often rapidly growing. The most common sites are the head and neck and the extremities, but the Alliance has seen cases in partially and fully sun-protected areas such as the abdomen, thighs and pelvic region.

2. Dermatoscopic features are non-specific, but polymorphous vessels and/ or a milky red colour raise the suspicion of malignancy and justify routine dermatoscopic evaluation prior to excision.

3. About 25% of cases present with lymph node metastasis at presentation and approximately 10% with distant metastases, most commonly adbominal viscera and distant lymph nodes.

4. A significant proportion of cases present with lymph node or metastatic disease with an occult primary, and spontaneous remissions also often occur.

5. Paraneoplastic syndromes such as Lambert Eaton syndrome can occur, may be underapprecaited, and should be considered for example in patients with significant fatigue.

Initial excision and histopathology

1. MCC is not typically clinically expected when it is initially sample or excised, so that initial excision will typically fall outside the scope of these guidelines. However it will be expected that depending on size and location, tissue samping will have been undertaken by punch, incisional or excisional biopsy.

2. Histologically, MCC shows typical neuroendocrine appearances with uniform small round blue cells and 'salt and pepper' chromatin.

3. Immunhistochemistry is mandatory to differentiate it from lymphoma, melanoma, other neuroendocrine tumours and sarcomas. MCC is charcterised by expression of cytokeratin markers (CK20, AE1/AE3, CAM5.2); neuroendocrine markers (NSE, synaptophysin, CD56, chromogranin A, the latter more specific for MCC); and absence of markers for other malignancies (TTF-1, S-100/ HMB45, CK7, CEA, lymphocyte markers). Occasional CK+ CK20- negative cases are described.

4. The histopathology report will indicate thickness and deep tissue invasion (fascian, muscle, cartilage, bone) to define the T stage, and also the presence or absence of an infiltrative growth pattern and lymphovascular invasion. 

Definitive management: principles and overview

Initial assessment

1. Patients should undergo a full skin examination and examination of all major lymph node basins.

2. If appropriate in the context of a patient's overall clinical condition, whole body 18FDG-PETCT (versus CT) should be performed. 

3. Ultrasound of the regional nodal basin is recommended, with fine-needle aspiration biopsy as indicated.

4. Routine brain imaging is not recommended in asymptomatic stage I-III patients.

Wide local excision

1. The surgical approach is informed by complementary adjuvant radiotherapy in two main respects. First, the operation should aim to allow adjuvant radiotherapy within a reasonable timeframe (ie avoidance of prolonged graft healing). Second, the need for extended margin surgery is obviated by the delivery of postoperative radiotherapy in most cases.

2. 1cm wide excision is recommended for majority of cases.

3. Mohs micrographic surgery may yield similar or better survival. However there this will require additional travel for the patient, and in practice Alliance experience is that Mohs surgery in general does not allow significant tissue sparing in comparison with standard wide local excision.

4. Wide local excision for Merkel cell carcinoma should be performed by a core member of the SSMDT. In the head and neck region, it may be performed by a core member of the head and neck MDT but only after discussion and management plan agreement at the SSMDT.

Definitive radiotherapy

1. MCC is a radiosensitive tumour (although there a range of radiation sensitivities, and the possibility of induced radioresistance during clonal evolution). Definitive radiotherapy is used variably across international centres as definitive treatment for some cases.

2. The Rational MCC trial was designed to compare the efficacy of surgery and radiotherapy for MCC, showing at least clinical equipoise between these options. Unfortunately this trial was terminated due to poor recruitment and this question is unlikely to be resolved with high quality comparative data.Definitive radiotherapy alone for macroscopic nodal disease is associated with at least as good regional control and recurrence free survival as CLND, with or without adjuvant radiotherapy.

3. Radiotherapy should be strongly considered as an alternative to surgery where surgery would cause significant functional or cosmetic detriment or require complex reconstruction. Conversely, radiotherapy should be avoided in areas of likely poor radiation tolerance.

4. The radiation dose used for definitive radiotherapy (gross disease in situ, margin positivity) is generally higher than that used in adjuvant radiotherapy. The Rational MCC trial directed the use of 60Gy in 30 fractions over six weeks, but this extended schedule anecdotally may have contributed to poor recruitment to this study. An alternative schedule of 45Gy in 15 fractions over three weeks may be considered case by case.

Sentinel lymph node biopsy: outside current ARSAC licence

1. The EFD and NCCN guidelines recomment sentinel lymph node biopsy (SLNB) for Merkel cell carcinoma.

2. Occult microscopic nodal involvement occurs in approximately a third of patients. Adjuvant regional radiotherapy after negative SLNB does not affect regional recurrence.

3. Regional ARSAC licences do not currently cite Merkel cell carcinoma, and out-of-licence SLNB cannot occur routinely. This should be addressed. In the meantime, the Alliance adopts working guidelines that are not predicated on information from SLNB. These will be revised when/ if SLNB becomes routine practice in the region.

Lymph node surgery

1. Lymph node surgery for Merkel cell carcinoma should be performed by a core member of the SSMDT. In the head and neck region, it may be performed by a core member of the head and neck MDT but only after discussion and management plan agreement at the SSMDT.

Principles of adjuvant radiotherapy: tumour bed

1. Adjuvant radiotherapy in MCC is an area of continued uncertainty, with discordant results across multiple studies. In the largest cohort study, adjuvant radiotherapy improved OS across all margin groups and in H&N and non-H&N sites. Patients with excision margins of 1cm or less who received adjuvant radiotherapy had comparable survival to ptients with margins of 1.1 - 2cm or larger than 2cm who did not receive adjuvant radiotherapy. However higher margin patients also had better survival than patiens who did not receive radiotherapy. 

2. In distinction, a study of 752 patients found that PORT was not associated with improved OS in node-negative patients and was associated with worse DSS.

3. Radiotherapy doses also remain controversial, and variable practices may also have contributed to uncertainty about the role of adjuvant radiotherapy in Merkel cell carcinoma. In a study of 2735 patients, overall survival was associated with radiotherapy doses of 50-57Gy, notably with increased hazard of death at doses both below and above this range. This study only included patients receiving approximately 2Gy per fraction.

4. Overall, a schedule of 40Gy in 15 fractions is supportable for the majority of patients. This is consistent with practice in small cell lung cancer with which Merkel cell carcinoma shares analogies. It reduces the burden of attendance for often older and more frail patients. In certain circumstances, a schedule of 50Gy in 25 fractions may be considered, most notably in the following circumstances:

   1. areas of poor vascularity and healing, such as the pretibial region;

   2. special attention needed to graft preservation;

   3. the eyelid and periorbital region.

5. Adjuvant radiotherapy should be initiated as soon as possible as all delays may risk interim progression, and definitely within eight weeks of surgery. 

Principles of adjuvant radiotherapy: regional nodes

1. Across stages, including after completion lymph node dissection, adjuvant radiotherapy to the regional nodes is associated with improved regional disease control but not increased survival.

2. The current absence of routine SLNB in our population increases uncertainty, and thereby might be considered as additional justification for regional radiotherapy. The Alliance position is that this is an insufficient argument, on its own, in the absence of a survival benefit from adjuvant nodal irradiation.

Staging

1. Merkel cell carcinoma is provisioned by the UICC 8 and AJCC 8 staging systems which appear to be fully congruent. 

2. NHSE provides a staging guidance sheet.

3. AJCC8-based survival outcomes may be underestimates. A recent study suggested 5Y OS of 72.6% for local disease and 62.7% for nodal disease. Nodal disease with an occult primary may have higher survival.

Stage I disease 

Surgery

1. The residual tumour or excision biopsy scar should be excised with a margin of 1cm.

2. If the patient is unlikely to be fit for adjuvant radiotherapy, a margin of 2cm should be considered.

3. Excision with a margin of less than 1cm should be considered where a larger margin may be excessively morbid, and where the smaller margin will expedite adjuvant radiotherapy.

Sentinel lymph node biopsy

1. When SLNB is formally enacted for MCC in the Alliance, it will be offered to all patients with MCC including stage I disease.

Adjuvant radiotherapy to the tumour bed

1. With regard to specific literature for stage I disease, a study of 147 patients with low risk MCC (including T1, negative margins, pathologically lymph node negative, no immunosuppression), postoperative radiotherapy significantly reduced local recurrence (<2cm of primary surgical bed) in patients with head and neck disease (0% v 21%), whereas no local recurrences were observed in patients with non-head and neck Merkel cell carcinoma managed with surgery alone. There were no differences in MCC-specific survival across the groups. A further study showed that in 46 H&N MCC T 1 patients with negative pathological margins, negative SLNB and no immunosuppression, adjuvant radiotherapy was associated with a local recurrence rate of 0% v 26% without radiotherapy. However all local failures were effectively salvaged. 

2. The Alliance recommendation is that adjuvant radiotherapy should be offered to the tumour bed to:

   1. all patients with T1 MCC in the head and neck region

   2. patients with T1 MCC elsewhere on the body where any of the following apply:

      1. the excision margin is clear but less than 1cm and further surgery would be excessively morbid;

      2. the patient is immunosuppressed due to medication or lymphoproliferative disease;

      3. it is a recurrent tumour;

      4. there is lymphovascular invasion;

      5. case by case, directed by SSMDT consensus recommendation.

Adjuvant radiotherapy to the regional lymph nodes

1. Specifically in stage I disease, a study of 83 patients found that adjuvant regional radiotherapy was associated with increased regional relapse-free survival (0% v 16.7%) but not overall survival.

2. The Alliance recommendation is that adjuvant radiotherapy to the regional lymph nodes should be offered to select patients with stage I disease case by case, via discussion at the SSMDT, taking the following factors into consideration:

   1. head and neck location;

   2. lymphvascular invasion;

   3. immunosuppression;

   4. ability of the patient to attend for radiotherapy and manage adverse effects;

   5. the desirability of de-intensified follow-up due to the near-elimination of regional relapse risk with radiotherapy, for example to finalise care in frail/ elderly patients.

Stage II disease

Surgery

1. The residual tumour or excision biopsy scar should be excised with a margin of 1cm.

2. If the patient is unlikely to be fit for adjuvant radiotherapy, a margin of 2cm should be considered.

3. Excision with a margin of less than 1cm should be considered where a larger margin may be excessively morbid, and where the smaller margin will expedite adjuvant radiotherapy.

Sentinel lymph node biopsy

1. When SLNB is formally enacted for MCC in the Alliance, it will be offered to all patients with stage II MCC.

Adjuvant radiotherapy to the tumour bed

1. With regard to specific results in stage II disease, adjuvant radiotherapy is associated with an improvement in medial survival from 21 to 50 months.

2. The Alliance recommendation is that adjuvant radiotherapy should be offered to all patients with stage II MCC.

Adjuvant radiotherapy to the regional nodes

1. Due to the homogeneity of the finding that adjuvant nodal irradiation improves regional control, but does not improve survival, across multiple MCC partitions, Alliance guidelines for stage II MCC are as for stage I MCC.

2. The Alliance recommendation is that adjuvant radiotherapy to the regional lymph nodes should be offered to patients with stage I disease case by case, via discussion at the SSMDT, taking the following factors into consideration:

   1. head and neck location;

   2. lymphvascular invasion;

   3. immunosuppression;

   4. ability of the patient to attend for radiotherapy and manage adverse effects;

   5. the desirability of de-intensified follow-up due to the near-elimination of regional relapse risk with radiotherapy.

Operable stage III disease

1. In the current absence of routine SLNB availability for patients in the Alliance, patients with microscopic stage III disease are not currently provisioned within these guidelines. When SLNB is enacted, guidelines will be finalised for this group, specifically concerning completion lymphadenectomy versus radiotherapy alone to the involved nodal basin.

2. For patients with macroscopic nodal disease, identified clinically or by imaging, completion lymph node dissection should normally be offered. However it should be noted that outcomes with definitive radiotherapy appear to be at least equivalent.

3. A study of 752 patients found that in patients with head and neck MCC and lymph node involvement, adjuvant radiotherapy was associated with improved overall survival (HR 0.55) and improved DSS (0.57).

4. The Alliance recommendation is that adjuvant radiotherapy should be offered routinely to patients with resected stage III MCC, especially in the following circumstances:

   1. head and neck site

   2. multiple node involvement

   3. extracapsular extension

5. The definition of the anatomic region for postoperative nodal irradiation should be discussed at the SSMDT but is ultimately determined by the Clinical Oncologist at radiation target volume definition.

Inoperable stage III and stage IV disease

Standard chemotherapy 

1. A systematic review has suggested response rates of approximately 50-60% with first-line chemotherapy in MCC. Alliance experience suggests a higher response rate than this, with rapid effects in most patients.

2. The standard schedule is carboplatin AUC5 d1 and etoposide 80mg/m2 IV on day 1 and PO on days 2-3 very three weeks for up to six cycles. Myelosuppression and other side effects are frequent.

3. Whilst supplanted by immunotherapy for most patients, chemotherapy should be considered at least in the following circumstances:

   1. where a rapid response is required due to major current or impending symptomatology or threat to life;

   2. where there are contraindications to immunotherapy, in particular a history of autoimmune disease;

   3. where commitment to prolonged two weekly immunotherapy (potentially for two years or more) is a disproportionate demand on patients and healthcare resources.

Single agent chemotherapy for higher risk patients

1. The Alliance has experience with oral etoposide as monotherapy at least one frail elderly patient with advanced Merkel cell carcinoma, consolidated by radotherapy. Significant and long-lasting, but not permanent, tumour control was achieved. 

2. This experience is mirrored in a case report, and a short case series. 

3. Based on local experience and the literature, treatment is tailored to the patient and may start at 50-100mg (absolute dose) daily for up to 10 days in a 28 day cycle, escalated as tolerated.

Consolidation radiotherapy after chemotherapy

1. Alliance experience suggests that induction chemotherapy folllowed by consolidation radiotherapy to involved sites can achieve durable remissions. In complete response, condolidation radiotherapy may be delivered as 40Gy in 15 fractions or 50Gy in 25 fractions; in incomplete response, a higher dose should be delivered such as 45Gy in 15 fractions or 60Gy in 30 fractions. 

Definitive radiotherapy

1. As described above, MCC is a radiosensitive disease and radiotherapy is an eminent option for advanced inoperable disease. 

2. Doses and schedules are individualised, but may include for example elective doses to involved nodal regions with boost to macroscopic in situ disease to 60Gy or equivalent.

3. Palliative radiotherapy may be delivered as an 8Gy single fraction or 20Gy in 5 fractions.

Avelumab 

1. Avelumab is approved by NICE for the treatment of metastatic MCC in patients who have previously received one or more lines of chemotherapy. This based on cohort A of the Javelin trial. Median survival was 12.6 months with a 5 year OS rate of 26%.

2. Avelumab is approved by NICE for the treatment-naive metastatic MCC, based on cohort B of the Javelin trial. The response rate was approximately 40%, median survival 20.3 but with a wide range. 

3. The dose is 800mg (fixed) IV every two weeks.

4. Treatment is continued by default until loss of clinical benefit or unacceptable toxicity. In practice most patients in complete remission stop treatment at around two years, although this will also permanently terminate funding for avelumab for the vast majority of patients.

5. The Alliance has extensive experience with avelumab in MCC, having participated in an early expanded access programme well before wider  NHS availablity. Our experience, as with chemotherapy, is of somewhat higher response rates, particularly when immunotherapy is combined with radiotherapy to non-responding or oligoprogressive sites of disease.

Immunosuppressed patients

1. For patients immunosuppressed due to solid organ transplantation, mycophenolate motefil may be a preferred immunosuppressant for patients with active MCC as it appears to have antitumour activity against MCC, albeit in an in vitro study. 

Follow up

1. There are no nationally-developed guidelines for follow-up of Merkel cell carcinoma after primary treatment. There is a significant risk of recurrence, especially in the first two years after diagnosis. In a study including 194 patients with stage I-III disease at presentation, 49% showed distant progression by one year, 80% by two years following initial diagnosis and 99% by five years. In order of frequency, distant metastases were found in distant lymph nodes (41%), skin/ body wall (25%), liver (23%), bone (21%), pancreas (8%) and lung (7%). LIver metastases were significantly more likely from a head/ neck primary than a lower limb primary (43% v 5%).

2. Alliance policy historically has been not to image the brain routinely in patients with Merkel cell carcinoma, but the above study reported 11 cases of brain metastasis, 5% of metastatic patients. The authors did not report how many of these cases had relapse in the brain as the only site of disease, versus synchrony with systemic progression. It would seem reasonable to continue with a policy of routine sytemic imaging surveillance, with brain imaging reserved for those with symptoms or on the development of systemic metastasis. 

3. Merkel cell carcinoma patients may have a 10-30x increased risk for basal cell carcinoma, squamous cell carcinoma and melanoma, representing additional justification for dermatological follow-up.

4. The reintroduction of routine SLNB for this patient population will prompt a revision to local follow up guidelines.

5. Follow-up is tailored to patients, and it is often the case that frail elderly patients will benefit from reduced intensity review, closer to home (for example with CT or ultrasound scans rather than at a centralised PETCT provider).

6. The following is a specimen follow-up schedule for patients who are fit to attend and potentially benefit from therapy at recurrence. Time zero is taken to be the end of first-line treatment, which may be wide excision or completion of radiotherapy.

7. Clinical review comprises (1) records and results review ('sweeper system') (2) history and examination of the primary site, locoregional skin and lymph nodes, principal lymph node stations and whole skin (3) instruction to patient and relatives/ caregivers regarding self-examination and interim self-reporting between scheduled visits.

8. Ultrasound assessment comprises US review of the at risk draining lymph node basin(s) (determined at SSMDT if necessary), +/- FNAC as indicated.

Stage I-II, low risk

Year 1: Clinical three monthly, ultrasound at months 3 and 9, PETCT at months 6 and 12

Year 2: Clinical three monthly, ultrasound at months 3 and 9, PETCT at months 6 and 12

Year 3: Clinical and ultrasound at months 6 and 12

Year 4: Clinical at month 12

Year 5: Clinical at month 12

Discharge

Stage I-II, high risk (immunosuppression, H&N site, LVI) and no radiotherapy to whole of at-risk regional nodal basin(s)

Year 1: Clinical and ultrasound three monthly, PETCT at months 6 and 12.

Year 2: Clinical and ultrasound three monthly, PETCT at months 6 and 12.

Year 3: Clinical three monthly, ultrasound at months 3 and 9, PETCT at months 6 and 12

Year 4: Clinical, ultrasound and PETCT at months 6 and 12

Year 5: Clinical, ultrasound and PETCT at months 6 and 12

Discharge

Stage I-II, high risk and received radiotherapy to whole of at-risk regional nodal basin(s)

Year 1: Clinical three monthly, PETCT at months 6 and 12

Year 2: Clinical three monthly, PETCT at months 6 and 12

Year 3: Clinical three monthly, PETCT at months 6 and 12

Year 4: Clinical and PETCT at months 6 and 12

Year 5: Clinical and PETCT at months 6 and 12

Discharge

Stage III, received either surgery or definitive radiotherapy to whole of at-risk regional nodal basin(s)

Year 1: Clinical three monthly, PETCT at months 6 and 12

Year 2: Clinical three monthly, PETCT at months 6 and 12

Year 3: Clinical three monthly, PETCT at months 6 and 12

Year 4: Clinical and PETCT at months 6 and 12

Year 5: Clinical and PETCT at months 6 and 12

Discharge

Stage IV and inoperable stage III

Individualised during and after treatment

Service improvement and horizon scanning

1. Sentinel lymph node biopsy should be brought within regional ARSAC licences for Merkel cell carcinoma as soon as possible. 

2. Testing for tumour and circulating Merkel cell polyomavirus and/ or antibodies may aid diagnosis, prognostication and follow-up, but is not yet considered standard of care.