Dermatologic Manifestations of Merkel Cell Carcinoma

Background

Merkel cell carcinoma is a rare primary cutaneous neuroendocrine carcinoma with growing incidence and high metastatic potential. This skin cancer has been called by several other names, including primary small-cell carcinoma of the skin, APUDoma, primary undifferentiated carcinoma of the skin, and the Toker tumor.^[1] It was originally described by Cyril Toker in 1972 under the designation trabecular carcinoma of the skin.^[2] As neuroendocrine carcinomas were thought to be of neural crest origin, in 1978 Tang and Toker proposed that this carcinoma might be derived from Merkel cells. With the advent of improved immunohistochemical profiling, the tumor was reclassified as Merkel cell carcinoma because shared epithelial and neuroendocrine markers, along with ultrastructural features suggestive of neural crest origin, were observed in both the constituent tumor cell and the physiologic Merkel cell of the skin.^{[1, 3]}

Friedrich Sigmund Merkel discovered the Merkel cell in 1875. He observed tastzellen (touch cells) in the skin of the snouts of pigs and moles and deduced a mechanosensory function.^[4] These specialized sensory cells are normally found in the basal epidermis of skin and parts of mucosal surfaces derived from the ectoderm.^[1] They are present in high numbers in the lips, hard palate, palms, finger pads, proximal nail folds, and dorsa of the feet. Within skin, Merkel cells have also been shown to cluster in the basal layers of the interfollicular epidermis in specialized epithelial structures called touch domes, where they are juxtaposed with epidermal keratinocytes. Even as they secrete neuropeptides, Merkel cells additionally express intermediate filaments characteristic of primitive and simple epithelia such as cytokeratin (CK) 8, CK18, and CK20. They are densely innervated by slow-adapting type I mechanoreceptor nerve fibers and serve as critical transmitters for light touch and hair movement stimuli.^{[1, 4, 5, 6]}

Merkel cells were thought to be of neural crest origin because they are excitable cells that secrete neuropeptides and stain positively for neuroendocrine markers.^{[5, 6, 7]} However, lineage-tracing experiments have shown that in embryogenesis, Merkel cells differentiate from epidermal progenitors. Moreover, in adults, Merkel cells undergo slow turnover and are replaced by cells originating from epidermal stem cells, not through the proliferation of differentiated Merkel cells.^{[5, 6]} Furthermore, experiments have demonstrated that epidermal progenitors in the touch domes are capable of producing Merkel cell lines and that epithelial progenitor populations in adults have the capacity to give rise to both neuroendocrine and squamous lineages.^[6] As they are primarily postmitotic, Merkel cells putatively have low sensitivity to oncogenic stimuli, and they are found in the basal epidermis, whereas cutaneous neuroendocrine carcinomas arise in the dermis.^{[1, 7]}

Ultimately, it is unclear whether the eponymous Merkel cell is truly a histiogenic precursor of Merkel cell carcinoma. Other suggested cells of origin include the neural crest‒derived cell of amine precursor uptake and decarboxylation (APUD) system, dermal fibroblasts, pre or pro B cells, residual epidermal stem cells, and epithelial, non-Merkel cell progenitors.^{[7, 8]} Sunshine et al offer that perhaps there are multiple cell-line precursors of Merkel cell carcinoma.^[9] Since our understanding of the histogenesis is still evolving, some authors choose to refer to Merkel cell carcinoma as neuroendocrine carcinoma of the skin or cutaneous neuroendocrine carcinoma.^{[1, 10, 11]}

Also see Merkel Cell Tumors of the Head and Neck and Merkel Cell Carcinoma and Rare Appendageal Tumors.

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Pathophysiology

Even as the nature of the exact cell in which Merkel cell carcinoma oncogenesis occurs is controversial, there is strong support for the notion that Merkel cell carcinoma results from of one of two distinct pathways. Feng et al established in 2008 that approximately 80% of Merkel cell carcinomas in the Northern hemisphere occur after genomic integration by a ubiquitous skin commensal virus, Merkel cell polyoma virus (MCPyV).^{[7, 12, 13]} The remaining 20% of cases are precipitated by extensive ultraviolet radiation (UVR)‒mediated DNA damage and do not exhibit viral genomic integration.^{[12, 14]}

In the viral integration carcinogenesis pathway, viral oncoproteins called tumor-associated antigens—specifically the small T (sT) and large T (LT) antigens—are thought to be necessary for replication and survival of virus-positive tumor cells.^{[8, 15, 16]} Antibodies for the major MCPyV capsid protein (VP1) are associated with MCPyV infection, which is asymptomatic and the prevalence of which increases with age.^[8] VP1 antibodies are found in nearly all Merkel cell carcinoma patients, as well as in 42-77% of the general population, demonstrating that virally-induced carcinogenesis is a rare phenomenon. However, antibodies for T antigens are specific to Merkel cell carcinoma patients.^{[15, 17]} Serologic titers of T-antigen antibodies are used to detect MCPyV-positive Merkel cell carcinomas. The sT antigen antibodies appear to be slightly more specific for Merkel cell carcinoma.^[15]

In the setting of asymptomatic infection, MCPyV uses the host’s nuclear machinery for its own replication without genomic integration. Carcinogenesis occurs when the virus integrates its DNA into the host cell’s genome and expresses LT and sT oncoproteins. Merkel cell carcinoma cells produce a truncated LT mutant, which halts viral replication and possibly stabilizes further viral integration into the host genome. The LT protein’s truncating mutation also enables it to bind the retinoblastoma tumor suppressor gene (RB1) with increased affinity. This alters cell cycle progression and facilitates the unchecked cell proliferation required for tumorigenesis.^{[18, 19]} The other major oncoprotein, sT, also has strong oncogenic activity and, in Merkel cell carcinoma cells, acts on the F-box/WD (FBXW7) repeat-containing protein domain, a component of the cullin-RING ligase family of ubiquitin ligases.^{[3, 8, 19]} Yet, its exact molecular functions are not well understood.^[19] Based on murine models, it is thought that sT initiates tumorigenesis, while LT maintains it.^[3]

DNA sequencing studies corroborate the existence of two Merkel cell carcinoma subtypes.^{[20, 21, 22, 23, 24]} One group is characterized by numerous tumor mutations corresponding to UVR-mediated damage, and the other group contains integrated MCPyV DNA. MCPyV-positive tumors typically contain very few mutations, copy number variations, or evidence of UVR damage. In contrast, MCPyV-negative tumors have frequent UVR damage‒mediated DNA mutations such as are also seen in other skin cancers associated with sun exposure, specifically, melanoma, basal cell carcinoma, and cutaneous squamous cell carcinoma.^{[19, 20, 21, 22]} In MCPyV-negative tumors, UVR-induced mutations disrupt RB1, thereby inhibiting it from repressing the E2F family of transcription factors. The gene targets for these transcription factors participate in cell cycle signaling, checkpoint inhibition, DNA repair and replication, and apoptosis.^{[19, 25]}

Along with RB1 loss, MCPyV-negative tumors also feature inactivating mutations or deletions in TP53, while MCPyV-positive Merkel cell carcinomas contain the wild-type TP53. Therefore, RB1 and TP53 are both usually mutated in MCPyV-negative Merkel cell carcinomas and intact in the virally-induced counterpart. MCPyV-negative lesions frequently contain inactivating mutations in genes involved in several cell-signaling pathways, including the NOTCH1 and NOTCH2 DNA damage repair and chromatin-modifying pathways.^{[19, 20, 21, 22]} Remarkably, it seems that the MCPyV-positive Merkel cell carcinomas might functionally perturb the same pathways, albeit by means of the sT and LT oncoproteins. After all, RB1 is a target of both viral and nonviral subtypes.^[26] Both Merkel cell carcinoma subtypes also contain mutations that activate receptor tyrosine kinases and their PI3K, AKT, and mTOR growth-signaling pathways.^{[20, 21, 22]} Fortunately, both discrete and shared molecular oncogenic mechanisms of each Merkel cell carcinoma subtype exhibit immunogenicity, ostensibly enabling both subtypes to respond to molecularly targeted treatments and immunotherapies.

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Etiology

Viral integration by the Merkel cell polyoma virus (MCPyV), and ultraviolet radiation (UVR)‒mediated DNA damage due to sun exposure, have been distinguished as the triggers of Merkel cell carcinoma tumorigenesis. Despite the pervasiveness of asymptomatic MCPyV infections, viral integration into the host genome is thought to be infrequent since Merkel cell carcinoma has an inherently low incidence. The age, skin type, and immune competence of the host are significant risk factors. Merkel cell carcinoma is most often found in fair-skinned men, aged 70-79 years (median age 76 years), with reduced immune function.^[27] Immunosuppressed individuals represent approximately 10% of all Merkel cell carcinoma patients.^[27] Several forms of immune suppression are associated with increased incidence of Merkel cell carcinoma, including hematologic malignancies (most commonly chronic lymphocytic leukemia), HIV/AIDS, and immunosuppressive medications for autoimmune disease or transplantation.^{[28, 29, 30, 31, 32]} It has been shown that immunosuppressed people have both a significantly increased risk of developing the carcinoma and poorer disease-specific survival.^[30]

Chronic sun exposure is a well-established risk factor for Merkel cell carcinoma. People with fair skin types, who are more susceptible to UVR-mediated skin damage, have a greater risk of developing this skin cancer. Merkel cell carcinoma has a predilection for the head and neck, body sites with the most solar exposure.^{[27, 33]} The regional Merkel cell carcinoma incidence increases with increasing regional sun exposure, as measured by the UVB solar index. Patients from countries with relatively low sun exposure tend to have MCPyV-positive carcinomas, while the majority of cases in Australia, where there is more sun exposure, are MCPyV-negative and associated with UVR-mediated DNA damage.^[34] There is evidence that Merkel cell carcinomas occurring at non‒sun-exposed sites tend to be larger, have female predominance, and carry a higher risk of death from Merkel cell carcinoma.^[35] The idea that chronic exposure to solar UVR spurs carcinogenesis has been confirmed by studies that sequenced Merkel cell carcinoma lesions and found increased UVR-damage‒associated signatures in tumors that lacked viral integration.^{[20, 21, 22, 23]} UVR exposure could also play a part by causing local immunosuppression.^[19]

In summary, factors such as advanced age, immunosuppression, fair skin, and exposure to UVR are thought to influence the development of Merkel cell carcinoma through the viral-integration or UVR-mediated damage pathways. The risk factors for development are frequently interrelated. A Danish study implicated treatment with hydrochlorothiazide as a potential risk factor for Merkel cell carcinoma, but the study did not include information on sun exposure.^{[33, 36]} Another large population-based study found that patients with Merkel cell carcinoma had three times the risk of developing malignant melanoma, and these findings were statistically significant.^[37]

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Epidemiology

Merkel cell carcinoma occurs almost twice as commonly in men (62.1%) as in women (37.9%).^[27] It primarily affects older patients: 33.1% of patients are between age 70 and 79 years, and 30% are between age 80 and 89 years.^[27] Most commonly, Merkel cell carcinoma arises in the head and neck (42.6%), followed by the upper limbs and shoulders (23.6%). The majority of patients (96.4%) are White, reflecting the carcinoma’s well-established proclivity for pale skin. It is rare among Black Americans (1.2%) and those of Asian ancestry (0.8%).^{[27, 28]} Immunosuppressed patients, such as those with hematological malignancies, are affected more often than the general population.^[30]

The incidence of Merkel cell carcinoma has been steadily increasing since it was first described in 1972. The increases were initially thought to represent a correction for years of prior underdiagnosis or misdiagnosis, with presumed stabilization by the 1990s, when the (CK20) antibody immunohistochemical stain became an accessible diagnostic tool. However, worldwide incidences have continued to rise, as evidenced by reports from France,^[38] Sweden,^[39] Germany,^[40] Australia,^[41] China,^[42] Denmark,^{[28, 43]} The 2013 incidence of Merkel cell carcinoma in the United States was 0.7 case per 100,000 person-years, amounting to about 2488 cases per year, which is almost double the incidence reported in 2000.^{[8, 43]} The same period saw a 95.2% jump in the total number of Merkel cell carcinoma cases reported.^[43] The incidence is expected to exceed 3000 cases per year by 2025.^[43]

Geographically, Merkel cell carcinoma sustains a predilection for lighter-skinned patients living in areas with increased ultraviolet radiation (UVR) exposure. The majority of Merkel cell carcinomas in Australia seem to be mediated by UVR damage.^[34] In White patients, the age-adjusted incidence of Merkel cell carcinoma seems to be linearly correlated with the UVB radiation index, with the highest incidence rates reported in Hawaii.^[44]

In summary, Merkel cell carcinoma has a rising incidence, and it predominantly affects fair-skinned men in their mid 70s, most often occurring in sun-exposed areas. The annual increase in incidence is expected to continue, at least in part, owing to the aging population from the Baby Boomer generation.^[43]

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Prognosis

Merkel cell carcinoma is an aggressive cancer. At presentation, 26% and 8% of patients are found to have nodal and distant metastasis, respectively.^[27] Patients who present with node-positive disease experience a high rate of relapse, and approximately half of these patients die from the disease within 5 years. The most common site of recurrence is the draining nodal basin. The median time to recurrence is 7-9 months, with 80-90% of recurrences occurring within the first 2 years.^{[45, 46]} The literature reveals marked variation in reported recurrence rates, possibly attributable to inconsistent reporting methodologies and small sample sizes. Based on newer reports, overall recurrence after wide excision occurs in approximately 18-29%, inclusive of local, in-transit, regional, and distant recurrences.^{[47, 48, 49]} Studies from The Mayo Clinic (1981-2008) and Memorial Sloan-Kettering Cancer Center (1970-2002) provide a breakdown of overall recurrences by site, including local recurrence (8-10.4%), nodal recurrence (11.3-25%), and distant metastasis (21%).^{[45, 49]}

The extent of disease, tumor size, and tumor burden in the regional nodal basin correlates with worsening survival in Merkel cell carcinoma.^[50] In fact, the American Joint Committee on Cancer (AJCC) staging system for Merkel cell carcinoma was updated in 2017 to reflect the relatively new prognostic information summarized herein.^[51] The disease extent at presentation is predictive of 5-year overall survival (OS), with an estimated 51% for local disease, 35% for nodal disease, and 14% for distant disease.^[27] Regional metastatic involvement can be described by either pathologic or clinical evaluation of the lymph node basin (some patients, based on their comorbidities, require staging by clinical/radiologic evaluation alone). For local cutaneous disease, the prognosis is better for patients with negative lymph node disease using pathologic staging (62.8% 5-year OS) versus clinical staging (45% 5-year OS). Of those with regional metastasis, patients with clinically detectable lymph node involvement have poorer prognoses (27% 5-year OS) compared with those with clinically occult (microscopically detectable) nodal disease (42% 5-year OS). Thus, new clinical guidelines recommend sentinel lymph node biopsy (SLNB) for all biopsy-proven localized Merkel cell carcinoma patients without clinical or radiological evidence of regional lymph node metastasis.^[52] Accordingly, the updated AJCC staging system now incorporates pathologic stage in addition to clinical stage.

About 12-14% of patients with positive (clinically detected or clinically/radiologically occult) nodal disease present without a known primary tumor (unknown primary).^{[45, 50]} Cases of nodal disease with an unknown primary tumor have a better prognosis than cases of nodal disease with a known primary cutaneous tumor (5-year OS rates of 42% vs 27%, respectively).^[27] In cases of nodal disease with an unknown primary tumor, it is thought that the primary tumor might have spontaneously regressed, presumably due to successful tumor infiltration by the patient’s CD8⁺ cytotoxic T cells, signifying a favorable heightened immune response. Partial or complete spontaneous regression is a well-documented but rare phenomenon.^[53] Moreover, high intratumoral CD8⁺ T-cell infiltration has been shown to be independently associated with improved outcomes in primary and metastatic Merkel cell carcinoma.^[54]

Characteristics associated with lower survival rates include old age, male sex, Black race, advanced stage or increasing number of metastatic sites, primary tumor on the head/neck or trunk, and immunosuppression. Increasing tumor size, infiltrative (versus nodular) tumor growth pattern, increased tumor thickness, lymphovascular invasion, and lymph node involvement have also been associated with lower survival rates.^{[11, 27, 45, 55, 56, 57, 58, 59, 48]} Furthermore, multivariate analysis including age, sex, and immune status has shown that relative to virus-positive Merkel cell carcinomas, virus-negative Merkel cell carcinomas have a significantly increased risk of disease progression (hazard ratio = 1.77, 95% confidence interval [CI] = 1.20-2.62) and death from Merkel cell carcinoma (hazard ratio = 1.85, 95% CI = 1.19-2.89).^[60] Staining for tumor protein 63 (p63) has also been linked to a worse prognosis.^{[61, 62, 63]}

Patients who live in areas with a higher density of dermatologists are more likely to survive. Such communities also tend toward higher median household income and increased densities of hospitals, primary care physicians, and oncologists, alluding to the impact of socioeconomic status.^{[37, 57]} There is now a role for serology testing with regard to predicting recurrence and prognosis. In Merkel cell polyoma virus (MCPyV)‒mediated Merkel cell carcinoma, low levels of MCPyV VP1 antibody titers are associated with increased risk of recurrence and mortality, whereas increasing T-antigen antibody titers are associated with decreased risk of recurrence. MCPyV antibody positivity at baseline corresponds with a 42% decrease in the risk of recurrence.^{[17, 64]} In general, MCPyV-positive tumors have better prognosis compared with MCPyV-negative ones.^{[65, 66, 60]}

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Patient Education

For patient education resources, physicians and researchers who work with and study Merkel cell carcinoma have created a comprehensive, evidence-based online resource for patients at merkelcell.org.

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History

Merkel cell carcinoma typically presents as a rapidly enlarging, erythematous-to-violaceous nodule on the sun-exposed skin of an elderly fair-skinned individual.^{[3, 8]} Approximately two thirds of cases present with cutaneous disease, and up to 26% of patients present with lymph node metastases. Interestingly, approximately 13% of patients presenting with nodal disease have no known primary cutaneous tumor, presumably reflecting regression of the primary tumor.^[27] The primary skin lesion is generally asymptomatic, although sometimes tender.^[3] Along with rapid growth, ulceration and/or hyperkeratosis can sometimes be seen. A 2019 report suggests that ulceration and hyperkeratosis may help predict the presence of Merkel cell polyoma virus (MCPyV)‒negative disease (80% of MCPyV-negative Merkel cell carcinomas and none of the MCPyV-positive ones featured ulceration/hyperkeratosis).^[67] However, this association warrants additional research because of the small sample size (n=20).^[67] Papules (with or without telangiectasia), plaques, cystlike structures, pedunculated lesions, pruritic tumors on the lower extremities, and subcutaneous masses are other dermatologic manifestations of Merkel cell carcinoma.^{[68, 69, 70]} About 5-10% of Merkel cell carcinomas present in combination with scars or other skin neoplasms such as squamous cell carcinoma or trichoblastoma.^{[71, 72, 73]} Mucosal Merkel cell carcinoma, albeit rare, has also been reported and exhibits more aggressive behavior than its cutaneous counterpart.^[74]

Approximately 8% of patients present with disseminated disease.^[50] These patients may have constitutional symptoms (eg, fatigue), localizing signs (eg, hemoptysis, neurologic defect, adenopathy secondary to metastasis), or both. The mnemonic AEIOU encompasses the five most common clinical features, as follows^[75] :

• Asymptomatic/lacking tenderness
• Expanding rapidly (≤ 3 months)
• Immunosuppressed
• Over age 50 years
• Ultraviolet-exposed site (location)

A high index of suspicion is required to diagnose Merkel cell carcinoma in an efficient and accurate manner. Owing to the nonspecific and varied clinical features, it is often clinically misdiagnosed as a benign lesion (cyst, chalazion, pyogenic granuloma, dermatofibroma). Histopathologic and immunohistochemical evaluation is required to confirm a Merkel cell carcinoma diagnosis.

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Physical Examination

Skin - Primary lesion

Merkel cell carcinoma usually presents as a solitary, dome-shaped nodule or firm plaque (see image below).

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Large, violaceous nodule of Merkel cell carcinoma on the antecubital fossa. Courtesy of Dr. Jonathan Cook.

Most lesions are 1-2 cm in greatest dimension (43%), but they may be larger than 15 cm.^[75] Lesions are typically red to violaceous, or they can be bluish purple or flesh-colored. The epidermal surface is often shiny, and telangiectases may be seen, suggesting atrophy. Ulceration may be present, which may be preferentially associated with Merkel cell polyoma virus (MCPyV)‒negative disease.^[67]

Dermatoscopic features

Data on the dermatoscopic findings of Merkel cell carcinoma are limited, and dermatoscopic features specific to Merkel cell carcinoma have not been identified. However, findings from small retrospective series include linear irregular vessels, milky-red areas, and polymorphous vessels.^{[76, 77]} Dermatoscopy is not likely to facilitate early diagnosis of Merkel cell carcinoma, as the findings are nonspecific. Histopathologic and immunohistochemical evaluation is required for diagnosis.

Skin distribution

Lesions characteristically appear on the head or the neck (43%), followed by upper limbs and shoulders (23.6%), lower limbs and hips (15.3%), trunk (10.9%), and other skin sites.^[27] Any mucosal or cutaneous site can be affected.

Metastasis

Regional nodal metastases are usually the first site of dissemination. They may be detectable by palpation, which is the basis for the role of clinical lymph node evaluation in staging. Clinically and/or radiologically detected lymph node positivity [N1b] is identified clinically by means of palpation and/or imaging, and it is confirmed by pathology, whereas clinically occult lymph node disease is not palpable or visible on imaging (clinically node-negative), but is pathologically identified at sentinel lymph node biopsy (SLNB) [N1a(sn)] or following lymph node dissection (N1a).^[51] Increased primary tumor size correlates with an increased risk for metastasis, although all Merkel cell carcinomas carry substantial risk for occult metastasis. In a 2016 literature review,^[78] of 721 clinically node-negative patients who underwent sentinel node biopsy, 30% were positive for micrometastasis, supporting the use of SLNB for all such patients.^{[8, 52, 78]}

The most common distant metastatic sites are liver, skin, bone, brain, and lung.^{[14, 79]} The location of the primary lesion may be predictive of the location of metastasis. One study reports that primary tumors from the head and neck are more likely to metastasize to the liver.^[79]

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Complications

Complications secondary to metastasis depend on the anatomic sites of involvement.

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Approach Considerations

Since the cutaneous manifestations can resemble a variety of other skin conditions (see DDx), a high degree of clinical suspicion is required for the expedient diagnosis of Merkel cell carcinoma. In 2018, the National Comprehensive Cancer Network (NCCN) consensus guidelines incorporated new recommendations for the use of Merkel cell polyoma virus (MCPyV) as a biomarker and the use of checkpoint immunotherapies for treatment of advanced (metastatic or unresectable) cases.^[52]

During the history and physical examination, a complete skin and lymph node examination is recommended. Serologic quantitation of MCPyV oncoprotein antibodies may be considered as part of the initial workup. Seronegative patients may have a higher risk of recurrence; in seropositive patients, a rising titer may be an early indicator of recurrence.^{[17, 64]} Skin biopsy, commonly a punch biopsy (a small core of tissue) or a shave biopsy (a portion of the lesional surface is removed using a scalpel), is required to establish a histopathologic diagnosis. Evaluation of routine hematoxylin and eosin‒stained slides, along with a panel of immunohistochemically stained slides, is necessary to differentiate Merkel cell carcinoma from other morphologically similar entities. Results of a diagnostic immunohistochemical panel would likely feature CK20⁺, TTF-1^-, CK7^-, LCA^-, S100^-, and positivity in a neuroendocrine marker such as insulinoma-associated protein 1 (INSM-1), chromogranin, or synaptophysin.^{[10, 19, 80, 81]}

After pathologic diagnosis of Merkel cell carcinoma has been confirmed, another complete skin and regional lymph node evaluation with palpation for lymphadenopathy is performed. Imaging is important for evaluation for potential metastases, and the preferred imaging modalities include whole body positron-emission tomography with fluorodeoxyglucose (PET-FDG), possibly in combination with computed tomography (CT) with contrast of the neck, chest, abdomen, and pelvis, and/or brain magnetic resonance imaging (MRI) depending on the clinical scenario. Whole body PET-FDG offers improved sensitivity compared with CT alone, with an additional impact on management in 37% of patients.^[82]

Furthermore, the incidence of occult nodal metastasis without clinically detectable lymphadenopathy is high (~30%).^[78] Therefore, sentinel lymph node biopsy (SLNB) is recommended in all biopsy-proven Merkel cell carcinoma patients with no clinical evidence of regional lymph node involvement, unless surgery is contraindicated or declined.^{[52, 78]} Every effort should be made to perform SLNB prior to surgical intervention.^[52] The SLNB specimen should also be evaluated using immunohistochemical stains. Alternatively, patients with a Merkel cell carcinoma diagnosis who have clinically palpable or radiologically evident lymph node disease should undergo fine-needle aspiration (FNA) biopsy or core needle biopsy to enable pathologic confirmation of clinically positive nodes, again, with the help of immunohistochemical markers.^{[52, 78]}

Finally, if metastases are suspected upon evaluation of a biopsy-proven Merkel cell carcinoma patient, a multidisciplinary tumor board meeting is recommended to discuss enrollment in a clinical trial for systemic therapy (checkpoint immunotherapy preferred over chemotherapy) and/or radiation, palliation, or surgery.^{[13, 52]}

A detailed summary of the recommended workup and associated protocols for biopsy-proven Merkel cell carcinoma is provided in Table 1 below.^[52]

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Recommended workup and protocols for biopsy-proven Merkel cell carcinoma.

Considerations

Merkel cell carcinomas that are diagnosed at earlier stages have better outcomes. Because of the rarity of this carcinoma, consulting a dermatologist might improve the likelihood of efficient, accurate diagnosis. High dermatologist density has been associated with improved Merkel cell carcinoma‒specific survival, suggesting that provider familiarity with the disease may have a positive impact on patient outcomes.^{[37, 43]} The dermatopathologist evaluating the biopsy and excision specimens plays a crucial role in diagnosing and staging the disease. In cases with positive lymph nodes and/or distant metastases, it is recommended that a multidisciplinary tumor board be consulted to ensure high-quality, coordinated care based on the individual clinical scenario.^{[13, 52]}

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Imaging Studies

Imaging is helpful at various time points from workup to follow-up and when clinically indicated for evaluation of suspected metastasis or unresectable Merkel cell carcinoma (see Workup, Table 1). Baseline imaging is recommended soon after biopsy-proven diagnosis to identify and quantify any potential regional and distant metastasis, or it might be done after sentinel lymph node biopsy (SLNB) in cases without clinically evident lymphadenopathy. Whole-body positron-emission tomography with fluorodeoxyglucose (PET-FDG) combined with CT scanning (with contrast) of the neck, chest, abdomen, and pelvis is the preferred combination of modalities. In addition, brain MRI with contrast is recommended to evaluate for brain metastases. In the case of overt clinically suggestive lymphadenopathy with increased risk of metastasis, imaging with the same modalities may be performed to evaluate the extent of lymph node and/or visceral organ involvement. Imaging has the potential to affect staging and influence management decisions, including radiation field‒placement and dose selection.^[83] However, imaging is secondary to SLNB for staging purposes because it cannot identify subclinical disease.^{[52, 83]} Follow-up imaging studies are used as clinically indicated to ascertain treatment response and evaluate for recurrences.^[52]

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Procedures

Sentinel lymph node biopsy (SLNB) with pathologic evaluation using immunohistochemistry is indicated for all biopsy-proven Merkel cell carcinoma patients who have local cutaneous disease without clinically apparent lymphadenopathy.^{[52, 78]}

Fine-needle aspiration or core needle biopsy is indicated to confirm the presence of nodal metastases in those with clinically suggestive lymphadenopathy and may be helpful to assess for recurrence.^[52]

Radiation therapy (RT) is an alternative approach in patients who are not surgical candidates, and it is also an option for advanced unresectable metastatic disease. Adjuvant RT is indicated in select circumstances guided by the clinical situation (see Workup,Table 1).^[52] For example, in the head and neck region, there is an increased risk for false-negative results in SLNB; therefore, RT of the nodal beds is suggested after SLNB and in those cases in which SLNB is not possible, may be falsely negative, or may have been unsuccessful.^[52] In addition, adjuvant RT to the primary tumor site after wide local excision is associated with improved locoregional control and disease-free survival in multiple studies.^{[84, 85, 86]} However, in patients with small tumors (< 2 cm in greatest dimension) at low risk for recurrence, adjuvant RT may provide little additional benefit.^{[45, 48]} The National Comprehensive Cancer Network guidelines state that clinical observation without adjuvant radiotherapy may be considered for a subset of immunocompetent patients with low-risk tumors that are small (ie, < 1 cm), widely excised, and free of lymphovascular invasion.^{[13, 52]}

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Histologic Findings

Routine hematoxylin and eosin‒stained slides, as well as immunohistochemical stains, usually are required to diagnose Merkel cell carcinoma. It is primarily a dermal tumor, with frequent extension into the subcutaneous fat. The leading edges exhibit infiltrative or pushing borders, and there is often a lymphohistiocytic infiltrate accompanying the tumor cells.^[81] There is intraepidermal spread in about 10% of cases, with Pautrier-like microcollection formation (cutaneous T-cell lymphoma and superficial spreading melanoma enter the differential diagnosis).^[10] Purely intraepidermal (in situ) lesions have rarely been described. The tumor is quite often accompanied by reactive epidermal hyperplasia. The epidermis may feature a coexisting actinic keratosis or squamous cell carcinoma in situ.^[10]

Several architectural patterns are recognized, but there are three main histopathologic subtypes: intermediate, trabecular, and small-cell variants. The intermediate variant is the most common, and it exhibits large, solid nodules made up of diffuse sheets of basophilic round-to-polygonal cells with characteristic round-to-oval nuclei containing powdery chromatin and inconspicuous nucleoli. The trabecular pattern consists of delicate interconnecting strands of round-to-polygonal cells with abundant cytoplasm, round centrally located vesicular nuclei with inconspicuous nucleoli, common nuclear molding, and neoplastic aggregates resembling glands or neural rosettes.^[2] The least common is small-cell pattern, which consists of small, round blue cells with scant cytoplasm and oval, hyperchromatic nuclei with prominent nucleoli. The tumor cells form solid sheets and clusters with crush artifact and nuclear molding. A particular tumor often contains elements of all architectural patterns, with individual variation in the proportions represented.

See the images below.

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Histopathologic appearance of nodular Merkel cell carcinoma. Dermal nodule with a cohesive, expansive growth of basophilic cells.

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High-power view demonstrates an open chromatin pattern and a high mitotic index.

Regardless of histopathologic type, Merkel cell carcinoma is usually composed of small, round-to-polygonal basaloid cells with inconspicuous nucleoli and open chromatin with peripheral heterochromatin (salt-and-pepper nuclear pattern). Less commonly, Merkel cell carcinoma cells may simulate lymphoma, with a heavy lymphoid infiltrate and the presence of lymphoid follicles, or it may exhibit plasmacytoid, clear-cell, anaplastic, or spindle-cell features. Mitotic figures and apoptotic bodies are often numerous. Lymphovascular invasion is not uncommon and has been associated with a worse prognosis.^{[11, 51]} Other histopathologic variants of Merkel cell carcinoma include the desmoplastic, epidermotropic (resembling mycosis fungoides), and pagetoid (resembling Paget disease^[87] or melanoma) types, and tumors with focal true glandular or squamous differentiation.^{[88, 89, 90]} In uncommon cases, Merkel cell carcinoma is associated with squamous cell carcinoma, basal cell carcinoma, adnexal tumors, trichilemmal or follicular cysts, or trichoblastoma.^{[10, 71]} Combined Merkel cell carcinomas arising in association with squamous cell carcinoma seem to uniformly lack viral integration.^[72]

See the images below.

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Merkel cell carcinoma with a focus of squamous differentiation.

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Prominent in situ nested component of Merkel cell carcinoma, simulating malignant melanoma.

Several tumors might have small, round blue cell morphology, so immunohistochemistry is required for distinguishing Merkel cell carcinoma from other histopathologically similar tumors, including poorly differentiated primary cutaneous malignancies and metastases to the skin.^[81] Positive staining for cytokeratin (CK) 20 and neuroendocrine markers (ie, synaptophysin, chromogranin, neuron-specific enolase, insulinoma-associated protein-1 [INSM1]), along with negative staining for TTF-1, CK7, and lymphoid markers, are taken together to make the diagnosis of Merkel cell carcinoma.^{[19, 80, 81]} Of note, small cell carcinoma of the lung can rarely express CK20 (3%); conversely, Merkel cell carcinoma can exceptionally rarely be focally positive for TTF-1 or negative for CK20 (10%), or both. In challenging cases such as this, the whole complement of markers should be used for accurate diagnosis.^{[10, 19]}

Merkel cell carcinomas usually show positivity for CKs, including low-weight CKs (CAM 5.2, or AE1/AE3) and especially CK20, with a characteristic dotlike perinuclear pattern. Approximately 90% of Merkel cell carcinomas exhibit CK20 positivity.^[81] Neurofilament is another sensitive and specific marker (positive in approximately 80% of Merkel cell carcinomas), which is particularly helpful, paired with TTF-1, in the diagnosis of CK20-negative cases of Merkel cell carcinoma.^[81] Lack of S100 staining can distinguish Merkel cell carcinoma from melanoma or small-cell carcinoma, which feature 97% and 50% positive cases, respectively.^[10] Leukocyte common antigen (LCA) could be helpful for differentiating lymphoma, because 98% of lymphoma cases are positive for LCA, while Merkel cell carcinoma is nonreactive.^[10]

See the image below.

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Dotlike paranuclear pattern of cytokeratin immunolocalization.

A 2018 study of 52 cases demonstrates that the classic or expected immunohistochemical profile (CK20⁺, NF⁺, Chromo⁺,TTF-1^-, CK7^-) is observed more often in Merkel cell polyoma virus (MCPyV)‒positive Merkel cell carcinomas than MCPyV-negative ones (75% vs 25%, P=.002). Additionally, MCPyV-negative carcinomas less frequently express neurofilament (66.7% vs 100%, P=.001) and more often express TTF-1 (37.5% vs 3.6%, P=.003).^[91]  Fluorescence in-situ hybridization studies of MCPyV in the tumors can differentiate a punctate pattern, indicating viral integration correlated with moderate viral load, versus a combined punctate and diffuse pattern, which is associated with very high viral load.^[92]

Electron microscopic findings are also characteristic, revealing a lobulated nucleus that may contain proteinaceous filaments called rodlets. The cytoplasm is electron-lucent and contains a prominent Golgi apparatus and numerous ribosomes. Intermediate filaments are numerous and often assume a parallel or whorled arrangement near the nucleus, accounting for the dotlike pattern of CK distribution visualized by immunohistochemistry.^[93] Desmosomes may be present. Also characteristic are the dense core granules (80-120 nm in diameter), the source and the locus of the neuroendocrine peptides.

See the images below.

View Image

Electron micrograph of Merkel cell carcinoma showing a dense core granule (arrow).

View Image

Electron micrograph of Merkel cell carcinoma showing whorled bundles of intermediate filaments (arrow) near nucleus in Merkel cell carcinoma.

Cytologic preparations from fine-needle aspiration demonstrate a loosely cohesive pattern of small-to-intermediate‒sized cells with round nuclei, finely granular chromatin, a thin rim of cytoplasm, and, infrequently, pseudorosette formation. Immunocytochemistry may be helpful.^[94]

See the image below.

View Image

Pseudorosette formation in Merkel cell carcinoma.

• References

Staging

In patients with a biopsy-proven Merkel cell carcinoma diagnosis, further workup including physical examination, with complete skin and lymph node evaluation, imaging, and surgery is required to establish the American Joint Committee on Cancer (AJCC) stage. Prior to 2010, up to five different staging systems contributed variable criteria for Merkel cell carcinoma staging, which made it difficult to compare research results. The first consensus staging system, based on analysis of 5823 cases from the US National Cancer Database, was adopted for use by the AJCC in 2010.^[50] A 2017 update based on analysis of 9387 Merkel cell carcinoma cases, from the same database, comprises the current AJCC (8th edition) staging classification.^[27]

Accurate staging provides important information on prognosis, guides management strategies, and can determine eligibility for clinical trials. Patients with similar 5-year survival outcomes are grouped together, forming the basis for staging using the TNM (tumor, node, metastasis) system. The TNM system is based on the size and extent of the primary tumor (T), the extent of spread to regional lymph nodes (N), and the presence of metastases to distant sites (M). The T, N, and M stages are combined, and these are stratified into an overall numerical stage of I to IV, increasing with worsening severity and prognosis.

Stage I and II Merkel cell carcinomas are localized to the skin. Stage III of Merkel cell carcinoma includes metastases to the lymph nodes close in proximity to the primary tumor (regional lymph nodes), or in the unusual case of positive lymph nodes when no primary tumor is detected (unknown primary). Stage IV includes metastases to distant sites, other than the regional lymph nodes. The stages are each further subdivided into A and B categories to, again, reflect groups of patients with similar prognoses. Previously, the TNM staging system based its categories on clinical and imaging findings, but the 2017 updated 8th edition AJCC staging incorporates staging categories based on pathologic staging of lymph nodes. Pathologic staging provides more accurate information than clinical examination and/or imaging. Pathologic examination is required to detect micrometastasis in sentinel lymph node biopsy specimens or to confirm the presence of metastasis.^{[13, 52, 78]}

The current, AJCC 8th edition, four-stage system is summarized in Table 2 below.^{[27, 95]}

View Image

Summary of Merkel cell carcinoma AJCC, 8th Edition, Staging. Courtesy of https://merkelcell.org/ with permission.

Components of the pathology report

The pathology report contributes significantly to staging. However, at the present time, consistent histopathologic synoptic reporting for Merkel cell carcinoma is not widespread, which limits retrospective analysis of diagnostic and potentially prognostic parameters. Consequently, the AJCC strongly encourages synoptic reporting for Merkel cell carcinoma beyond that which is required for determination of T-stage. The College of American Pathologists (CAP) provides a complete synoptic protocol for cutaneous Merkel cell carcinoma.^{[52, 96]}

There are two elements required to ascertain the T-stage: (1) maximum tumor diameter (tumor size) and (2) tumor extension (invasion of the fascia, muscle, cartilage, and bone).^[52] The tumor should be measured clinically before resection to avoid underestimation of size due to shrinkage of formalin-fixed tissue. Evaluation by a pathologist is needed to determine extracutaneous extension. Although not required for staging, the AJCC strongly encourages the reporting of primary tumor thickness (measured microscopically), tumor site, peripheral and deep margin status, and lymphovascular invasion, all included in the CAP protocol. Primarily owing to possible prognostic potential, other recommended parameters include specimen laterality, mitotic rate, infiltrating lymphocytes (present/absent, brisk/nonbrisk), growth pattern (nodular/infiltrative), and presence of second malignancy.^{[11, 51, 52, 96]}

Staging SLNB

Sentinel lymph node biopsy (SNLB) specimens should be cut by serial sectioning, or “bread-loafing,” the node to increase observable surface area available for microscopic evaluation.^[81] Analysis of immunohistochemically stained slides is highly recommended.^[81] Because dendritic cells in the lymph nodes may express keratin and even microscopic tumor deposits are considered positive, cytokeratin (CK) 20 immunopositivity is useful to locate any nests of metastatic Merkel cell carcinoma [labeled N1a(sn), if detected via SLNB].^[94] A typical immunohistochemical panel of stains would include CK20 and/or NF, TTF-1, CK7, S100, and a neuroendocrine marker such as INSM-1, chromogranin, synaptophysin, or CD56.^{[80, 81, 91]} As in other solid tumors, positive sentinel lymph nodes correlate with impaired prognosis.^[50]

• References

Laboratory Studies

The most recent National Comprehensive Cancer Network guidelines (2018) introduce a role for serology for Merkel cell polyomavirus (MCPyV) antibodies when performing the initial skin biopsy and, subsequently, at follow-up visits for comparison.^[52] Low baseline values of antibodies to the major MCPyV capsid protein (VP1) correspond with a higher risk of recurrence and increased mortality, but do not vary with disease burden.^[64] Additionally, rising MCPyV T-antigen antibodies can predict and sometimes precede clinical detection of recurrent disease. In newly diagnosed Merkel cell carcinoma, the condition of rising T-antigen antibodies is associated with a 66-83% positive predictive value for increasing tumor burden, but falling titers have a negative predictive value of 97%.^[17] Therefore, baseline titers for both the MCPyV VP1 and T antigens may be helpful for patient risk stratification and prognostication.^{[15, 52]} Determining the viral status of a Merkel cell carcinoma may have prognostic value, in and of itself, because MCPyV-negative tumors might be more clinically aggressive with higher risk of recurrence, progression, and death from the carcinoma with putatively less immunogenicity than the virus-positive counterpart.^[60]

• References

Medical Care

Chemotherapy

For Merkel cell carcinoma, systemic therapy has traditionally included cytotoxic chemotherapy regimens similar to those used for small-cell carcinoma of the lung—usually a combination of taxanes, platinum-based drugs, anthracyclines, and/or etoposide.^[50] Although initial response rates range from 20-76%, the effects are rarely sustained and are not associated with improved survival.^{[14, 50]} Chemotherapy has known toxicities, especially in patients who are older than 65 years. The most common adverse effects are myelosuppression, sepsis, fatigue, alopecia, nausea, vomiting, and renal injury.^[97] Owing to toxicity, lack of durable response, or survival benefit, and the advent of promising immunotherapies, chemotherapy is currently reserved for patients who are not candidates for immunotherapy, and it is considered to have a palliative role.^{[13, 19, 83, 98]}

Radiation therapy

The role of radiation therapy (RT) in managing Merkel cell carcinoma remains controversial. RT may help control unresectable primary or metastatic lesions. A brief course of RT contributes to cancer control through DNA damage to tumor cells and immunomodulation.^[99] The increased immunogenicity associated with RT is attributed to amplified presentation of viral or tumor antigens, combined with enhanced T-cell priming in the draining lymph node basins. The CD8⁺ T cells that are recruited to the radiated area are not destroyed by subsequent radiation treatments, have improved function, and are thought to participate in direct tumor debulking because they are no longer inhibited by tumor cells.^{[99, 100, 101]} The phenomenon of the regression of distant, untreated metastasis following local RT is termed the abscopal effect, and it has been observed in the treatment of other solid tumors.^{[14, 15, 102]} Additional research points to a possible synergistic effect of RT combined with immune checkpoint inhibitor therapy.^{[99, 100, 101, 103, 104]}

RT has also been shown to improve local control when administered postoperatively to the primary site and the regional draining lymph node basin. Adjuvant RT reportedly reduces the local and regional recurrence rate and disease-free survival.^{[84, 85, 86]}

Immunotherapy

Genetic alterations have been shown to allow many cancers to produce antigens that can be recognized by the human immune system. In return, some tumors develop mechanisms to locally evade the immune system. Immunotherapies provide the chance to heighten antitumor cellular responses against certain cancers. This is of particular interest in Merkel cell carcinoma because both subtypes, Merkel cell polyomavirus (MCPyV)‒positive and MCPyV-negative tumors, produce potential targets for immune-mediated therapy.

Checkpoint therapy

The physiologic programmed death receptor 1 (PD-1)/programmed death ligand 1 (PD-L1) pathway allows nonharmful cells in the body from being attacked by the immune system through inhibition of T-cell activation and reduction of the CD8⁺/T-reg ratio. The PD-1/PD-L1 pathway represents an important immune checkpoint. In many cancers, tumor cells take advantage of this physiologic mechanism by expressing high amounts of PD-L1. Disguised as nonharmful cells, tumor cells cause increased inhibition of T-cell activation near tumor sites, thereby stifling the local immune response. However, therapeutic PD-1 or PD-L1 blockade reinvigorates T cells and activates an antitumor response.^[9] The efficacy of checkpoint inhibition therapy has been established in several cancers, including melanoma, renal cell carcinoma, bladder cancer, and non‒small cell lung cancer.^{[105, 106, 107, 108]} While circulating tumor-infiltrating lymphocytes and MCPyV-specific T cells express PD-1, about 50% of Merkel cell carcinomas comprising both subtypes have increased surface PD-L1 expression, facilitating evasion from an immune response.^{[109, 110]} Furthermore, PD-L1 is up-regulated in persistent viral infection. Checkpoint inhibition has shown efficacy and safety for treatment of advanced Merkel cell carcinoma, with two US Food and Drug Administration (FDA)‒approved therapies and others under investigation.^{[109, 111]}

Avelumab

Avelumab (Bavencio), an anti-PD-L1 IgG1 monoclonal antibody, was the first checkpoint inhibitor approved by the FDA, in March 2017, for metastatic Merkel cell carcinoma in adults and pediatric patients aged 12 years and older. Avelumab has also been approved by the European Union, Canada, and Japan for treatment of advanced Merkel cell carcinoma.^[111]  

Approval was based on the JAVELIN Merkel 200 Part A open-label, international, multicenter, single-arm study of 88 patients with stage IV metastatic Merkel cell carcinoma and disease progression on or after chemotherapy.^[111] Twenty-eight patients had objective responses, defined as either partial (20 patients) or complete response (8 patients) over approximately 10.4 months. The 6-month estimate of avelumab durability was 92%, compared with 6% and 7% in patients treated with chemotherapy. Overall, avelumab was found to have earlier responses, higher response rates, and an improved safety profile compared with cytotoxic chemotherapies.^[111]

With longer follow-up, avelumab continues to show durable response and promising survival outcomes in patients with distant metastasis after chemotherapy.^[112] JAVELIN Merkel 200 Part B evaluated avelumab’s efficacy as a first-line therapy for patients with metastatic Merkel cell carcinoma and found high rates of response and tolerability with no treatment-related deaths or serious adverse effects.^[110] Another analysis based on the JAVELIN Merkel cell Part A dataset found that early objective response to avelumab tended to have significantly longer overall survival.^[113]

Pembrolizumab 

Pembrolizumab (Keytruda), an anti-PD-1 humanized IgG monoclonal antibody, has shown efficacy and increased progression-free survival in metastatic Merkel cell carcinoma compared with historic chemotherapy data.^[109] In December 2019, it was granted approval by the FDA for adult and pediatric patients with recurrent, locally advanced, or metastatic Merkel cell carcinoma.^[114] Pembrolizumab also demonstrated durable tumor control, a manageable safety profile, and favorable overall survival compared with historical data on patients treated with first-line chemotherapy.^[115] Pembrolizumab is also FDA-approved for the treatment of advanced melanoma, non‒small cell lung cancer, urothelial carcinoma, head and neck squamous cell carcinoma, mediastinal B-cell lymphoma, Hodgkin lymphoma, cervical cancer, and gastric cancer.^[103]

Retifanlimab 

In March 2023, the FDA approved retifanlimab (Zynyz) for adults with metastatic or recurrent locally advanced Merkel cell carcinoma. 

Approval was based on data from the phase 2 POD1UM-201 trial, an open-label, multiregional, single-arm study that evaluated retifanlimab in adults with metastatic or recurrent locally advanced MCC who had not received prior systemic therapy for their advanced disease. Among chemotherapy-naive patients (n = 65), retifanlimab monotherapy resulted in an ORR of 52%. Among those who responded, 12 patients (18%) achieved CR, and 22 patients (34%) showed PR. Among the responding patients, the DOR ranged from 1.1 to over 24.9 months, and 76% (26/34) experienced a DOR of 6 months or longer, and 62% (21/34) experienced a DOR of 12 months or longer by landmark analysis. 

There are many ongoing clinical trials focusing on combination and investigational treatments. These include nivolumab, another PD-L1 inhibitor, already FDA-approved as a monotherapy for advanced melanoma, lung cancer, Hodgkin lymphoma, colorectal cancer, renal cell carcinoma, urothelial carcinoma, head and neck cancers, and hepatocellular carcinoma.^[103] For Merkel cell carcinoma, nivolumab is being studied alone and in combination with ipilimumab.^[128]  

Investigational therapies

Other immune targets for therapy

Ipilimumab is a cytotoxic T-lymphocyte‒associated protein 4 (CTLA-4) inhibitor that also potentiates an antitumor response.^{[83, 103]} Ipilimumab was the first FDA-approved immunotherapy for advanced melanoma (2011), but with the advent of PD-1/PD-L1 inhibitors, it is no longer considered for first-line monotherapy. Ipilimumab and other CTLA-4 inhibitors (tremelimumab/durvalumab and utomilumab) could be promising treatments for boosting the immune response, particularly in cases that do not respond well to PD-1/PD-L1 blockade.^{[83, 103]} Additionally, clinical trials are currently investigating the efficacy of PD-1/PD-L1 inhibitors and CTLA-4 inhibitors in the adjuvant and neoadjuvant setting after primary tumor resection with the aim of minimizing recurrence.^{[103, 116]} The toll-like receptor (TLR) is another crucial protein in the physiologic immune response. TLRs trigger proinflammatory cascades when they recognize pathogenic molecules. TLR 4, 7/8, and 9 agonists are being studied as potential immune targets.^[104]

Targeted molecular therapies

Targeted molecular therapies are being investigated for patients who do not respond well to immunotherapies, or have contraindications such as autoimmune disease with long-term immunosuppressive treatment. The mutational profiles of MCPyV-positive and MCPyV-negative carcinomas differ from each other, and it may be important to consider the tumor viral status when selecting an appropriate molecular target for therapy. Yet, frequently altered pathways have been identified in both tumor pathways, substantiating the feasibility of molecularly targeted therapies. Driver mutations are more likely to be found in MCPyV-negative tumors because they have a higher mutational burden. Even as no specific driver mutations have been distinguished for Merkel cell carcinoma, several tumor-associated molecules have been identified as potential therapeutic targets. Receptor tyrosine kinase inhibitors, somatostatin receptor analogs, mammalian target of rapamycin (mTOR) inhibitors, histone deacetylase 6 (HDAC6) and heat shock protein 90 (HSP90) inhibitors, and cyclin-dependent kinase inhibitors are currently being investigated, to name a few prospective molecularly targeted therapies.^{[9, 28, 83, 104]}

Talimogene laherparepvec

Talimogene laherparepvec (T-VEC) is a genetically modified herpes simplex virus, type 1, that replicates in tumor cells, expresses granulocyte-macrophage colony-stimulating factor, and promotes local and systemic antitumor response.^[117] It is the first oncolytic virus therapy to be FDA-approved for treatment of advanced melanoma.^[117] In two cases of advanced Merkel cell carcinoma, intralesional T-VEC was injected in all metastatic lesions as first-line therapy, and the patients had durable partial and complete responses, respectively. In a more recent case series, a patient with surgically incurable, recurrent Merkel cell carcinoma had a complete response to intralesional T-VEC, along with response in an uninjected lesion, demonstrating a potential systemic immune response.^[118] Durable complete responses were seen in an additional 4 patients, with median progression-free survival of 16 months without serious adverse events.^[119] Several clinical studies are recruiting patients to investigate intralesional T-VEC, with or without RT and pembrolizumab, or nivolumab.^{[83, 118, 119]}

Also see Workup, Table 1; Procedures; and Guidelines.

• References

Surgical Care

Wide local excision (WLE) is the recommended first-line treatment for primary cutaneous Merkel cell carcinoma.^[52] The goal of WLE is removal of the primary tumor in its entirety, while obtaining histopathologically negative margins.^{[13, 95]} The National Comprehensive Cancer Network (NCCN) and the European Association of Dermato-Oncology (EADO)−European Organisation for Research on the Treatment of Cancer (EORTC) guidelines recommend 1- to 2-cm margins down to the muscle fascia or pericranium (membranous covering of the skull) regardless of tumor size.^{[52, 120]} Definitive surgical excision should be performed after the sentinel lymph node biopsy (SLNB), if SNLB is indicated, and reconstructive surgeries should be performed after negative histologic margins have been confirmed.^[52] However, surgical excision is not always feasible, for example, in patients ineligible for extensive surgery under anesthesia. In addition, wide excisions at primary tumor sites near the head and neck might have deleterious cosmetic implications.

Some have recommended Mohs micrographic surgery (MMS) for its tissue-sparing effects and possible superior control of local disease; however, tumor deposits may be histopathologically noncontiguous, rendering this modality less effective in such cases.^[121] Nevertheless, the Mohs procedure is an alternative option for smaller tumors (T1) in the head and neck.^[122] MMS allows for the evaluation of peripheral and deep margins, while potentially achieving superior cosmetic outcomes. The survival outcomes for MMS are similar to those with WLE.^{[13, 123]}

SLNB is now the standard recommended approach for patients with biopsy-proven Merkel cell carcinoma without clinically or radiologically evident lymphadenopathy.^[52] While any effect on survival remains unclear, it does provide valuable prognostic information since the presence of metastasis is the dominant risk factor for death from disease.^{[124, 125]}

Complete lymphadenectomy is indicated in patients with confirmed lymph node metastases after positive SLNB or fine-needle aspiration (FNA) biopsies or core biopsies (performed in Merkel cell carcinoma patients with clinically detected lymphadenopathy). Although, some lymph node sparing is attempted in the head and neck regions because of the complicated anatomy in this area.^{[52, 120]} Prophylactic complete lymph node dissection, combined with WLE and adjuvant radiotherapy, contribute to improved survival outcomes in this subset of patients.^{[52, 126]}

• References

Consultations

If a primary care provider is the first to see a suggestive skin lesion, early referral to a dermatologist is advisable because a dermatologist often is more familiar with this cancer than other specialists who may be involved in patient care. The dermatologist can then serve to expediently coordinate care with a surgical or medical oncologist, radiologist, and radiation oncologist, contributing to the formation of a multidisciplinary team/tumor board. A dermatologist is also needed for ongoing skin surveillance and long-term follow-up of patients with Merkel cell carcinoma. A dermatologist can refer patients to an academic center or regional center with Merkel cell carcinoma‒specific expertise; several dozen such institutions exist around the world, where optimal multidisciplinary care can be delivered.^[127]

• References

Prevention

Photoprotection (eg, sunscreen, behavioral prevention) may help prevent Merkel cell carcinoma, but this has not been proven.

Also see Sunscreens and Photoprotection.

• References

Long-Term Monitoring

Surveillance and follow-up recommendations

Merkel cell carcinoma is associated with a high risk of local, regional, and distant recurrence. The National Comprehensive Cancer Network (NCCN) consensus panel recommends close clinical follow-up for patients starting immediately after treatment for Merkel cell carcinoma. Physical examination including complete skin and lymph node evaluation should be completed every 3-6 months for the first 3 years, graduating to every 6-12 months thereafter.^[52] Imaging studies should be performed as clinically indicated, for example in the setting of sudden-onset lymphadenopathy, elevated liver function tests, organomegaly, or development of new constitutional symptoms (eg, fatigue, neurologic defect, unexplained weight loss, lymphadenopathy). Routine imaging should be considered for high-risk patients. The updated NCCN guidelines offer a new indication for drawing periodic serologic titers of antibodies against Merkel cell polyomavirus (MCPyV) viral proteins as biomarkers of recurrence risk and disease progression (see Laboratory Studies).^[52]

• References

Guidelines Summary

Below is a combined summary of updated clinical guidelines on Merkel cell carcinoma by the National Comprehensive Cancer Network (NCCN) (2018) and a European consensus‒based interdisciplinary group (European Dermatology Forum, European Association of Dermato-Oncology [EADO], and European Organisation of Research and Treatment of Cancer [EORTC] [2015]).^{[13, 52, 120]}

Cutaneous clinical features are not sufficient to make a diagnosis of Merkel cell carcinoma. Rather, histopathological (including immunohistochemical) evaluation of a skin biopsy specimen is mandatory to establish a pathologic diagnosis.

Whole-body positron-emission tomography with fluorodeoxyglucose (PET-FDG) scanning; CT with contrast of the neck, chest, abdomen, and pelvis; and/or brain MRI with contrast (in the United States) and ultrasound of the locoregional lymph nodes (in Europe) are helpful tools to evaluate for the presence of metastasis in the initial workup. Sentinel lymph node biopsy (SLNB) is recommended for patients without clinical evidence of regional lymph node involvement, and fine-needle aspiration or core needle biopsy is recommended for those with clinically palpable lymphadenopathy.

Surgical excision with 1- to 2-cm margins is the recommended management for primary tumors, potentially with adjuvant radiation therapy.

Radical lymphadenectomy is recommended for patients who have regional lymph node involvement, and adjuvant radiotherapy can be considered based on risk factors, especially in patients with multiple affected lymph nodes or extracapsular extension.

In the case of regional or distant metastases or recurrence, a multidisciplinary tumor board should be consulted to ascertain an appropriate management.

Checkpoint immunotherapies are the preferred systemic therapy for metastatic disease, preferably through enrollment in a clinical trial. 

Multiple- or single-agent chemotherapy achieves high remission rates in unresectable, metastatic Merkel cell carcinoma; however, responses are usually short-lived.

Close clinical follow-up is critical, with complete skin and lymph node evaluation every 3-6 months for 3 years and every 6-12 months thereafter.

• References

Medication Summary

At this time, the US Food and Drug Administration (FDA) has approved several checkpoint inhibitor immunotherapies for the treatment of Merkel cell carcinoma, avelumab, pembrolizumab, and retifanlimab. Chemotherapy can be considered as a second-line, palliative option for patients with advanced, refractory disease (see Medical Care).

• References

Avelumab (Bavencio); EMD Serono/Pfizer

• Dosing, Interactions, etc.

Clinical Context:  Avelumab is an IgG monoclonal antibody against PD-L1, which was approved by the FDA for treatment of advanced Merkel cell carcinoma on March 23, 2017. It is indicated for metastatic Merkel cell carcinoma in adults and pediatric patients aged 12 years or older.

• References

Pembrolizumab (Keytruda); Merck

• Dosing, Interactions, etc.

Clinical Context:  Pembrolizumab is an IgG monoclonal antibody against PD-1. It blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2. The FDA approved pembrolizumab for treatment of adults and children with recurrent, locally advanced, or metastatic Merkel cell carcinoma on December 19, 2018.

• References

Retifanlimab (Zynyz)

• Dosing, Interactions, etc.

Clinical Context:  Indicated for adults with metastatic or recurrent locally advanced Merkel cell carcinoma.

• References

Class Summary

Programmed death receptor 1 (PD-1) and related target programmed death ligand 1 (PD-L1) are expressed on the surface of activated T cells under normal conditions. PD-L1/PD-1 interaction inhibits immune activation and reduces T-cell cytotoxic activity when bound. This negative feedback loop is essential for maintaining normal immune responses and limits T-cell activity to protect normal cells during chronic inflammation.

• References