Approach

Owing to the aggressive nature of MCC and the scarcity of evidence to guide management, optimal treatment is not well established. A multidisciplinary approach to care coordination is recommended and requires the expertise of pertinent specialties, including:[3][7][29][30][40]

  • Dermatologists/dermato-oncologists

  • Surgeons (dermatological surgeons, head and neck surgeons, surgical oncologists, and/or plastic surgeons)

  • Radiation oncologists

  • Medical oncologists

  • Pathologists.

As with all cancers, the US National Comprehensive Cancer Network (NCCN) encourages participation in available clinical trials.[3]

The most suitable treatment depends on staging according to the 8th Edition of the American Joint Committee on Cancer (AJCC8). Patients may present with localised disease (cN0), clinically detected regional disease (cN1, cN2, or cN3), or disseminated disease (M1).

Immunocompromised patients

For patients who are immunocompromised, it is important to reduce any immunosuppressive treatments as clinically feasible, in consultation with the relevant managing physician.[3][7] More frequent follow-up may be indicated for patients who are immunosuppressed.[3]

  • Immunosuppression in MCC is associated with an increased risk of recurrence and poorer outcomes.[18][27][71][72]​​

Localised disease

In patients who present with localised disease (AJCC8 clinical stage I or II: i.e., T-any cN0 M0) that is surgically resectable, the recommendation is for concomitant management of the primary tumour and staging of the lymph node basin with sentinel lymph node biopsy (SLNB).[3][19]​​[40][44]​​​

  • First-line treatment for the primary MCC tumour is surgical wide local excision to remove the lesion with histologically clear margins. Postoperative radiotherapy may be appropriate to manage a positive histological margin or narrow (<1 cm) surgical margin, or to decrease the risk of local recurrence, based upon the clinical size of the primary tumour (>1 cm) and/or other adverse risk factors.[3]

  • It is imperative to identify occult lymph node metastases in patients with early-stage localised disease. SLNB is recommended to be performed at the time of, or prior to, wide local excision of the primary tumour to stage the nodal basin.[1][3]​​[7][19]​​​[35][51]

  • Adjuvant systemic therapy is not recommended outside of a clinical trial for this patient group.[3]

  • After initial treatment, the patient should be monitored for disease recurrence with clinical surveillance and imaging studies as indicated.[3][7][29]​​​ If there are clear margins and no risk factors present, observation may be appropriate, with regular follow-up to monitor for recurrence.[3] See Monitoring below.

Note that in many Australian centres, radiotherapy is used as the primary modality after histopathological diagnosis.[38][73]

Surgical wide local excision of the primary tumour

There is a lack of consensus regarding the ideal surgical margin due to a paucity of evidence; therefore, multidisciplinary consultation and local guidelines should steer the approach.

In the US, the National Comprehensive Cancer Network (NCCN) recommends a 1-2 cm margin while noting that surgical margins should be balanced with the morbidity associated with surgery.[3]

  • For clear margins in a patient with no adverse risk factors, observation can be considered.

  • For microscopically positive margins, adjuvant radiotherapy is preferred over re-excision +/- adjuvant radiation.

  • For narrow clinical margin (<1 cm) and/or the presence of additional risk factors, excision should be followed by adjuvant radiotherapy. Relevant risk factors include: tumour size (primary tumour >1 cm); immunosuppressed state (chronic T-cell immunosuppression, HIV, chronic lymphocytic leukaemia (CLL), solid organ transplant); tumour location (head/neck primary site); presence of lymphovascular invasion (LVI).

  • If adjuvant radiotherapy is indicated, this should be initiated as soon as wound healing permits.[3] A delay > 8 weeks in starting radiotherapy has been associated with worse outcomes.[74]​​

European guidelines recommend a 1-2 cm margin. If this is difficult or not feasible (e.g., in cosmetically sensitive locations such as the face or in proximity to joints), a narrower margin of 0.5 to 1.0 cm with adjuvant radiotherapy may be acceptable.​[7][19]

  • Adjuvant radiotherapy to the tumour bed is recommended for tumours ≥1 cm and/or with negative prognostic features.

In selected patients (e.g., for sensitive areas such as the head and neck), a tissue-sparing approach such as Mohs or another form of peripheral and deep en face margin assessment (PDEMA) may be appropriate in place of wide local excision.[3]​​[7][19]

Sentinel lymph node biopsy (SLNB)

SLNB is an important staging tool, and every effort must be made to coordinate surgical management so that it can be performed before, or at the same time as, excision of the primary tumour.[3][19]

  • SLNB has been demonstrated to detect occult spread to the lymph node basin in up to one third of patients who have no clinical evidence of node disease and would therefore have otherwise been staged as node-negative.[52]

  • Patients found to have occult lymph node disease on SLNB are upstaged to stage IIIA.

Note that false-negative SLNBs may be seen in patients with profound immunosuppression, or in those who have anatomical compromise of the lymphatic system, such as those with aberrant lymph node drainage or multiple possible draining SLN basins (e.g., in MCC of the head, neck, or midline trunk).[19]

  • Because of this, the European Society for Medical Oncology (ESMO) guideline recommends consideration of adjuvant radiotherapy to the nodal basin for patients who are SLN-negative but who have one or more of these risk factors for a false-negative result. This decision should be made by specialists at a high-volume referral centre.

Unresectable primary tumour

In patients with locally advanced MCC for whom curative surgery and curative radiotherapy are not feasible, multidisciplinary consultation should inform management.[3][7][29]

  • In patients who are candidates for surgery, neoadjuvant therapy with a programmed cell death protein-1 (PD-1) inhibitor such as nivolumab may be considered prior to excision and SLNB.[3][19] If progression on nivolumab means that surgery is not feasible, radiotherapy may be considered.[3] Note that practice varies between countries, so check your local protocol. In the UK, the National Institute for Health and Care Excellence (NICE) has not recommended any checkpoint inhibitors for use in non-metastatic MCC. 

  • In non-surgical candidates (due to tumour characteristics or comorbidities), the tumour may be treated with radiotherapy.[3][19][29]

Regional disease

For those with regional disease, management differs depending on whether the lymph node disease is occult or clinically detectable. The precise choice and order of therapeutic interventions also varies somewhat in different countries, so check your local protocol.

Stage IIIA patients are those who present with occult lymph node metastasis, as confirmed by a positive SLNB during management of the primary tumour.

Stage IIIB covers patients who have clinically palpable/radiologically detected lymph node metastasis and/or in-transit disease but no distant metastatic disease. Lymph node metastasis is pathologically confirmed by fine-needle aspiration or core biopsy of the draining nodal basin with appropriate immunohistochemistry panel. In-transit metastasis is confirmed by skin biopsy.[3]

AJCC8 stage IIIA disease

For patients with SLNB-positive stage IIIA disease (i.e., with identified occult lymph node metastasis), treatment of the nodal basin is recommended along with baseline imaging studies to screen for distant metastases if not already performed. Multidisciplinary consultation should be sought.[3][7]

For treatment of the nodal basin, the NCCN in the US recommends:[3]

  • Radiotherapy to the nodal basin or

  • Lymph node dissection, which can be combined with adjuvant radiotherapy when indicated (e.g., for multiple involved nodes and/or in the presence of extranodal extension [ENE]).

ESMO recommends:[19]

  • Adjuvant radiotherapy alone as an option or complete lymph node dissection with adjuvant radiotherapy, with the decision made following multidisciplinary team discussion.

  • Consideration of entry into a clinical trial for neoadjuvant or adjuvant systemic therapy is also recommended, if available.

AJCC8 stage IIIB

Multidisciplinary consultation is recommended for any individual with stage IIIB disease.[3][7]​ Patients with stage IIIB disease have a primary tumour together with one of the following:[45]

  • Metastases to the draining lymph node basin (clinically/radiologically detected and pathologically confirmed), without in-transit disease (stage pN1b). In this group, the primary tumour is managed in the same way as for stages I/II.

  • In-transit metastasis without lymph node disease (stage pN2).

  • Both lymph node metastasis (clinically/radiologically detected and pathologically confirmed) and in-transit disease (stage pN3).

For management of the metastatic draining nodal basin in patients with stage IIIB MCC, the NCCN in the US recommends:[3]

  • Lymph node dissection with postoperative radiotherapy (preferred, although either dissection or radiotherapy alone may also be used).

  • Clinical trial enrolment, if available.

  • Consideration of neoadjuvant systemic immunotherapy prior to surgery, based upon multidisciplinary recommendations (e.g., nivolumab).

ESMO recommends a multidisciplinary team discussion to determine the best therapy options. Entry into a clinical trial is preferred. Surgical options include complete regional lymph node dissection with postoperative radiotherapy (or definitive radiotherapy in patients who are not surgical candidates).​[7][19]

  • The ESMO guideline also recommends consideration of entry into a clinical trial of adjuvant or neoadjuvant immunotherapy, if available, on the basis that neither adjuvant radiotherapy nor adjuvant chemotherapy has been found to have any statistically significant impact on overall survival.[19]

Stage III: in-transit disease

For management of in-transit disease (pN2/3), various factors will determine the most appropriate approach, including a decision on whether the disease is resectable. There is a lack of evidence to direct care in this scenario. The NCCN recommends multidisciplinary consultation for consideration of:[3]

  • Clinical trial enrolment, if available

  • Surgery and/or radiotherapy

  • Case-by-case consideration of systemic therapy, according to clinical judgement, if neither curative surgery nor radiotherapy is feasible. In practice, this scenario would generally be managed in the same way as stage IV disease.

The guideline from ESMO recommends surgery and/or radiotherapy or entry into a clinical trial for patients with in-transit disease, but recommends against adjuvant chemotherapy.[19]

Unknown primary MCC

Patients with MCC with unknown primary site present with a clinically identified, pathologically confirmed MCC metastasis to a lymph node without a primary MCC tumour.

  • In AJCC8, these patients were downstaged to IIIA (T0pN1bM0) as their prognosis aligns with the prognosis for patients with occult lymph node metastasis.[10]​​[35][45][46][47]​​​[70]

  • Multidisciplinary consultation will guide the preferred treatment approach in these patients, with modalities including node dissection with or without radiotherapy.[3][7]

Distant metastatic disease

Note that local protocols for metastatic MCC vary between countries and institutions, and the management plan for each individual is agreed on a case-by-case basis following discussion among the multidisciplinary team.

For disseminated metastatic MCC (AJCC8 stage IV), multidisciplinary consultation is recommended together with comprehensive imaging.[3][7][29]​​ Patients should receive treatment in centres that specialise in rare skin cancers and have access to clinical trials.[19]

The recommended approach to these patients (according to both US and European guidelines) is one of the following:[3]​​[7][19][29]

  • Enrolment in a clinical trial, if available (preferred) or

  • Any one of, or a combination of, the following therapies:

    • Systemic immunotherapy with a PD-1/programmed death-ligand 1 (PD-L1) inhibitor (preferred agents include avelumab, pembrolizumab, nivolumab, and retifanlimab).[3][29]​​ The ESMO guideline lists immunotherapy as a first-line option alongside enrolment in a clinical trial.[19] Note that in the UK, only avelumab is recommended for use in metastatic MCC by NICE.[75]

    • For patients who have contraindications to immune checkpoint inhibitors, systemic chemotherapy with cisplatin or carboplatin with or without etoposide, topotecan monotherapy, or cyclophosphamide plus doxorubicin (or epirubicin) plus vincristine (CAV) can be considered.[3]

    • Radiotherapy

    • Surgery.

      • Note that systemic therapy and radiotherapy are the primary options in most patients, with surgery reserved for selective circumstances (e.g., for resection of oligometastases or symptomatic lesions).[3]

  • Best supportive care

    • Depending on the extent of the disease and other individual patient circumstances, palliative care alone may be the most appropriate option for some patients, which may include radiation or systemic therapy.

Monitoring

Follow-up should aim to:[7]

  • Detect recurrence early

  • Detect second primary cancers at an early stage

  • Manage adverse effects of local or systemic treatment.

MCC will recur in up to half of patients.[3]​ Recurrence risk is highest within the first year, with most recurrences occurring within 3 years.[76][77]​​​

In the US, the NCCN recommends that follow-up visits should include:[3]

  • Physical examination including complete skin and complete lymph node exam every 3-6 months for 3 years and every 6-12 months thereafter. The precise frequency can be individualised according to risk of recurrence and stage of disease.

  • Imaging and other studies as clinically indicated, with routine imaging surveillance considered for those at high risk (e.g., immunosuppression, advancing age, stage II–IV disease, men, non-sentinel lymph node metastases, Merkel cell polyomavirus [MCPyV]-negative status).

The ESMO guideline recommends:[19]

  • Follow-up examinations for all radically treated patients every 3-6 months for the first 3 years, and then every 6 months up to year 5; thereafter a lifelong annual general physical examination, including a complete skin check-up.

  • Routine cross-sectional imaging may be appropriate in higher-risk patients.

Patients with MCC should be advised to perform self-examination of skin and lymph nodes every month.[29]

  • ESMO recommends patient education for self-examination of the whole skin because patients with a history of MCC have a higher risk of developing another skin cancer.[19]

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