How we treat Merkel cell carcinoma: within and beyond current guidelines

Abstract

Merkel cell carcinoma (MCC) is an aggressive skin cancer associated with a high risk of local recurrence and distant metastasis. Optimal care of this potentially life-threatening cancer is critical but challenging because: physicians are often unfamiliar with its management due to rarity, and MCC management remains controversial, in part because it is rapidly evolving across multiple specialties. While guidelines offer a broad overview of management, they are often not sufficient when making decisions for individual patients. Herein, we present a literature review as well as practical approaches adopted at our institutions for staging, surveillance and therapy of MCC. Each of these areas are discussed in light of how they can be appropriately customized for prevalent but challenging situations. We also provide representative examples of MCC patient scenarios and how they were managed by a multidisciplinary team to identify suitable evidence-based, individualized treatment plans.

Keywords: Merkel cell carcinoma; customized treatment; imaging; immunotherapy; multidisciplinary management; radiotherapy; surgery; surveillance.

Figure 1.. Merkel cell carcinoma: simplified evaluation and treatment.

(A) Consider baseline Merkel cell polyomavirus oncoprotein antibody test for prognostic significance and to track disease. (B) No pathologically enlarged nodes on physical examination and by imaging study. (C) Pathologically enlarged nodes on physical examination or by imaging study. (D) Select patients may not undergo SLNB (e.g., patients who cannot tolerate anesthesia for SLNB or who prefer no SLNB due to their medical condition). In those patients, treatment for draining lymph nodes can be considered based on the local recurrence risk. (E) Radiotherapy to the primary site is indicated in most patients; the exception is for low-risk disease (e.g., primary ≤1 cm, lesion on the extremities or trunk, no lymphovascular invasion, widely negative surgical margin and no chronic T-cell immunosuppression). (F) Consider radiation therapy to the nodal basin in high-risk patients or if SLNB dye did not migrate as expected. (G) Consider excisional biopsy primarily or after negative needle/core biopsy to exclude false-negative biopsy result. SLNB: Sentinel lymph node biopsy; PET: Positron emission tomography.

Figure 2.. Suggested algorithm to interpret Merkel cell polyomavirus oncoprotein antibody test (AMERK test).

(A) For seropositive patients, the AMERK titer decreases significantly within 3 months after successful treatment. A late baseline test that comes back negative (<74) may indicate that: the patient produced antibodies initially, but the antibody levels decreased to undetectable range after the tumor was removed, or the patient does not produce antibodies to MCPyV oncoprotein. In contrast, if the patient produces antibodies at any time after diagnosis, this test is positive and could be used for future surveillance. (B) AMERK titer between 74 and 150 is considered to be ‘borderline’. In our practice, this typically represents seropositivity, particularly if subsequent titer changes out of the borderline range. If titer still stays within borderline range in subsequent draws, AMERK titer for the patient is not reliable. (C) If the baseline test was done after more than 3 months from the initial diagnosis, or the size of MCC tumor at the time of the baseline test was extremely small (e.g., <5 mm), we consider repeating the AMERK test if the patient recurs in the future. (D) The AMERK test is most reliable for surveillance on patients who have not experienced a recurrence, or for detecting their first recurrence. After multiple recurrences and/or immunotherapy (systemic or local), the titer change of the AMERK testing is less reflective of disease burden. (E) Individual baseline titer could vary from less than 74 to more than 115,000. While this flowchart is designed to guide clinicians to interpret a test result at a single timepoint compared with the previous one, we find that consistent trends over time better correspond to disease status in the clinical setting. For instance, if the patient’s AMERK titer is slowly trending upward, we suggest interpreting the result as an ‘increase’ of titer and considering imaging studies. (F) In general, for the first 12 months following diagnosis, we recommend the patients have regular scans per the initial recurrence risk as determined by their disease stage and other factors (https://merkelcell.org/prognosis/recur/). In our practice, if the AMERK titer decreases by more than 70% from baseline, shows decreasing or stable trend for several consecutive draws, and the patient is more than 12 months out from their original diagnosis, we consider that AMERK can safely substitute for scans for surveillance. (G) Most patients that have two antibody tests with increased titers (e.g. ≥30% change) will eventually have MCC recurrence [9]. (H) Recurrence risk depends on stage at diagnosis and other patient characteristics. For most patients, it decreases dramatically by 2 years after diagnosis (https://merkelcell.org/prognosis/recur/). We generally recommend discontinuing or decreasing frequency of imaging and/or AMERK studies when a patient’s individual residual risk of recurrence is below 2%, or by 5–6 years after initial diagnosis. (I) To establish if either increasing or decreasing trend is outside of the margin of error. (J) PET/CT or CT with contrast could be considered. Some studies and our experience indicate that PET/CT has higher sensitivity. If imaging studies fail to locate disease repeatedly in the setting of rising antibodies, consider alternative scan modalities (e.g., MRI) or investigate other body parts (e.g., brain, extremities that were not included in the previous scan). (K) Concurrent imaging test may be indicated. If no clinically evident disease is detected in the setting of AMERK titer increase, we suggest considering more sensitive scan modalities (e.g., PET/CT) or evaluating anatomical site that has not been evaluated by imaging (e.g., extremities, brain). (L) The additive benefit of the AMERK test when patients are receiving routine scans is unknown. CT: Computed tomography; MCC: Merkel cell carcinoma; MCPyV: Merkel cell polyomavirus; PET: Positron emission tomography.

Figure 3.. Suggested local Merkel cell carcinoma treatment management.

Flowchart of local treatment of surgery and radiation that integrates risk factors that are associated with local recurrence. Certain risk factors are available at time of diagnosis (baseline), while others are only available after surgical excision (post re-excision). (A) Criteria for ‘local only MCC’ were clinically node-negative, no in-transit disease, and imaging negative for distant disease. (B) Sentinel lymph node biopsy typically performed at this time. (C) Narrow excision margins minimize morbidity and if aRT is performed microscopically positive margins are acceptable. (D) Goal should be primary tissue closure (i.e., without flap or graft) allowing aRT initiation within 3–4 weeks. (E) If sentinel lymph node biopsy positive, nodal aRT would typically be given, in addition to primary site aRT. (F) Decision on re-excision based on clinical setting (narrow path margins, e.g., <0.5 cm) and patient preference, re-excision versus aRT versus observation. aRT: Adjuvant radiation treatment; MCC: Merkel cell carcinoma. Adapted with permission from [27].