Pathogenesis, clinical features, and diagnosis of Merkel cell (neuroendocrine) carcinoma

INTRODUCTION — Merkel cell carcinoma (MCC) is a rare, aggressive, cutaneous malignancy that predominantly affects older adults with light skin types and has a high propensity for recurrence and metastases [1].

The pathogenesis, clinical features, and diagnosis of MCC are discussed here. The staging, treatment, and surveillance of patients with locoregional MCC and the treatment of recurrent and metastatic MCC are discussed separately. (See "Staging, treatment, and surveillance of locoregional Merkel cell carcinoma" and "Treatment of recurrent and metastatic Merkel cell carcinoma".)

EPIDEMIOLOGY

Incidence — Multiple studies report increasing incidence of Merkel cell carcinoma (MCC) in several countries over the past decades [2-9]. Data from the Surveillance, Epidemiology, and End Results (SEER) Program database indicate that in the United States, the estimated annual incidence rate rose from 0.5 cases per 100,000 persons in 2000 (95% CI 0.4-0.5) to 0.7 cases per 100,000 persons in 2013 (95% CI 0.7-0.8). MCC incidence increases exponentially with advancing age, from 0.1 to 1 to 9.8 (per 100,000 person-years) among age groups 40 to 44, 60 to 64, and >85 years, respectively. Due to aging of the population, the United States' MCC incidence is predicted to climb to more than 3200 cases in 2025 [2].

Risk factors — Recognized risk factors for MCC include:

●Light skin color – MCC predominantly affects persons with light skin [10,11]. A study analyzing SEER data from 1973 to 2006 found that 95 percent of cases diagnosed during this interval arose in White individuals [10].

●Increasing age – MCC is typically seen in older individuals, with a mean age at diagnosis of 74 to 76 years [10,11]. MCC incidence increases in advanced age groups, with an almost 10-fold increase every 20 years of increasing age [11].

●Male sex – In general, the incidence of MCC is higher in males than in females. In an analysis of United States cancer registries including the National Program of Cancer Registries, the reported incidence rate was 4.2 per 100,000 persons for males and 1.9 per 100,000 persons for females, and the male-to-female ratio was 2.2 (95% CI 2.1-2.4) [9].

●Immunosuppression – The incidence of MCC is more frequent in immunosuppressed patients, such as organ transplant recipients [12-17], individuals infected with human immunodeficiency virus (HIV) [18,19], and those with hematologic malignancies [11,12,20]. MCC occurs at a younger age and higher incidence in immunosuppressed individuals [11-14,18-20]. Data from the United States Scientific Registry of Transplant Recipients and 15 population-based cancer registries indicate that transplant recipients have a 24-fold higher risk of MCC than immunocompetent patients [12]. The highest incidence occurs 10 or more years after transplant. Maintenance treatment with mammalian (mechanistic) target of rapamycin (mTOR) inhibitors and azathioprine or cyclosporine confers a higher risk of MCC [12]. (See 'Immunosuppression' below.)

●Other malignancies – The risk of MCC is significantly increased in patients with other malignancies, especially hematologic malignancies [20,21]. In a SEER database study of over two million patients with cancer, the risk of MCC was significantly increased in those with multiple myeloma, chronic lymphocytic leukemia, and malignant melanoma (standardized incidence ratio [SIR] 3.7, 6.9, and 3.1, respectively) [20]. Increased incidence of MCC in patients with hematologic malignancies is likely due to immunosuppression and immune dysregulation associated with those conditions [14]. A retrospective study of 4164 patients with chronic lymphocytic leukemia and 172 patients with MCC supported the association between these two disorders reported in the SEER database study [22]. Among patients with a diagnosis of chronic lymphocytic leukemia, the incidence of a subsequent diagnosis of MCC was greatly elevated (SIR 15.7, 95% CI 3.2-46). Patients with a preceding diagnosis of MCC also exhibited an increased risk for developing chronic lymphocytic leukemia (SIR 17.9, 95% CI 2.2-64.6).

●Germline variants – Germline variants in genes associated with cancer predisposition, such as MAGT1, ATM, BRCA1, BRCA2, and TP53, may be a risk factor for the development of MCC in individuals younger than 50 years [23]. Of note, ATM, BRCA1, BRCA2, and TP53 are all involved in deoxyribonucleic acid (DNA) repair.

PATHOGENESIS — Several factors have been associated with the development of Merkel cell carcinoma (MCC). These include infection with the Merkel cell polyomavirus (MCPyV), ultraviolet (UV) radiation exposure, and immunosuppression. (See 'Risk factors' above.)

Cell of origin — Based upon early histologic and ultrastructural studies, MCC has traditionally been believed to arise from Merkel cells, which are located in the basal layer of the epidermis and hair follicles and are associated with sensory neurites in the dermal papillae, the skin mechanoreceptors [24]. However, this hypothesis is controversial. An alternative hypothesis is that these tumors originate from an immature multipotent stem cell that acquires neuroendocrine features during malignant transformation [25]. Based on cancer genomic studies and an understanding of the two different etiologies of MCC (MCPyV-positive or MCPyV-negative MCCs), it is plausible that MCC tumors might not have a single cell of origin. MCPyV-positive MCCs might arise from dermal fibroblasts and MCPyV-negative MCCs from epidermal keratinocytes, but this is a highly controversial area [26,27]. In contrast, data clearly suggest that MCPyV-negative MCC tumors likely arise from keratinocytes [28]. (See 'Merkel cell polyomavirus' below.)

Merkel cell polyomavirus — Merkel cell polyomavirus (MCPyV) is a nonenveloped, double-stranded DNA virus that has been causally linked to the development of MCC (picture 1) [29-32]. Previous studies have consistently reported that MCPyV can be detected in approximately 80 and 60 percent of all MCCs by real-time polymerase chain reaction (PCR) and immunohistochemistry, respectively [33]. A 2015 meta-analysis of 23 studies found an overall MCPyV prevalence of 79 percent (95% CI 72-84 percent) in Merkel cell tumors versus 12 percent (95% CI 8-9 percent) in control skin samples [34].

MCPyV is a ubiquitous virus, with five specific geographically related genotypic variants [35]. MCPyV is thought to be part of the human skin microbiome and appears to be chronically shed from the skin in the form of assembled virions [36]. The seroprevalence of antibodies specific to the capsid viral protein 1 (VP1) appears to increase with age, from approximately 40 percent in children to up to over 80 percent in older individuals [32,37-39].

The observation that the integration of the virus into the tumor genome precedes the clonal expansion of tumor cells suggests that the virus is present at tumor initiation and that one or more viral proteins are oncogenic drivers [29,40]. MCPyV encodes two main oncoproteins, the large tumor (LT) antigen and small tumor (sT) antigen, which are both persistently expressed in MCC and have been implicated in oncogenesis through multiple mechanisms. Sequential events involved in the pathogenesis of MCPyV-positive tumors include clonal integration into the host genome, expression of sT, acquisition of mutations in the 3' end of LT, and evasion of a destructive immune response [1,41,42].

Mutations in LT result in a truncated molecule that lacks the DNA binding domain and the helicase domain, which renders the virus replication incompetent while preserving its retinoblastoma (RB1) gene binding property and the expression of the oncogenic viral proteins [43]. LT antigens with intact RB1 binding domain sequester and inactivate the tumor suppressor, resulting in sustained tumor growth.

MCPyV has been detected in normal-appearing skin and in other tumors, including cutaneous squamous cell carcinoma, chronic lymphocytic leukemia, and folliculotropic mycosis fungoides [44-50]. In one series of patients with MCC, skin samples taken from sites distant from the tumor were positive for the virus in 10 out of 14 cases (71 percent), a frequency higher than that was observed in six skin samples from unaffected individuals (17 percent) [44]. Importantly, outside of MCC, evidence of clonal integration of the virus and expression of viral proteins in tumor cells is almost invariably lacking in other cancers, suggesting that the occasional detection of the virus was likely coincidental rather than causal in non-MCC tumors [51].

Ultraviolet radiation — Ultraviolet (UV) radiation exposure, especially to the sun, is thought to play an important role in the etiology of many cases of MCC. The following observations are consistent with an etiologic role for UV radiation exposure:

●MCC has a predilection for sun-exposed areas. In a study of the clinical manifestations in 195 cases of MCC, the tumor arose in a UV-exposed region in 81 percent of assessable cases [11]. Furthermore, 98 percent of cases occurred in individuals with lightly pigmented skin.

●Regional incidence rates correlate with increasing sun exposure, as measured by the ultraviolet B (UVB) solar index [7,8,52,53].

●Presentation with other skin cancers, for which sun exposure is a major risk factor, is common [21,54]. (See "Basal cell carcinoma: Epidemiology, pathogenesis, clinical features, and diagnosis" and "Cutaneous squamous cell carcinoma: Epidemiology and risk factors".)

●MCC has been described in patients treated with psoralen plus ultraviolet A (PUVA) photochemotherapy [55].

●Multiple reports describe UVB signature mutations in MCC tumors [56-59].

UV radiation exposure may be especially relevant in the pathogenesis of the virus-negative subtype of MCC (see 'Virus-negative Merkel cell carcinoma' below). This hypothesis is supported by the observation that in Australia the incidence of MCC is highest, but the prevalence of MCPyV-positive tumors is much lower than in other geographic areas. An Australian study of 95 MCC reported a 23 percent prevalence of MCPyV positivity; the prevalence was even lower in tumors occurring in skin areas with evidence of sun damage (ie, elastosis, squamous dysplasia) [60].

Immunosuppression — The incidence of MCC is increased in immunosuppressed patients, including organ transplant recipients [12-17], individuals infected with HIV [18,19], and those with hematologic malignancies [11,12,20]. (See "Epidemiology and risk factors for skin cancer in solid organ transplant recipients", section on 'Merkel cell carcinoma' and "HIV infection and malignancy: Management considerations", section on 'Merkel cell carcinoma'.)

The mechanism by which immunosuppression interacts with MCPyV and UV radiation exposure in the pathogenesis of MCC is unknown. Immunosuppression may facilitate the replication of MCPyV and increase the chance of virus integration in the MCC progenitor cell. In addition, reduced immune surveillance may contribute to the survival and proliferation of atypical cells. Finally, immunosuppressive agents, such as azathioprine or calcineurin inhibitors, have been shown to act synergistically with UV radiation in inducing mutagenesis and promoting skin carcinogenesis in an immunosuppression-independent manner [61-65].

Virus-negative Merkel cell carcinoma — Some MCCs have low or negligible levels of MCPyV T antigen expression. The mechanisms of oncogenesis underlying MCPyV-negative MCC are incompletely understood, but they are thought to involve somatic mutations in tumor suppressor genes such as TP53 and retinoblastoma (RB1), as well as epigenetic alterations, such as DNA methylation and microRNAs, resulting in aberrant expression and activity of oncogenes [43,66-69]. Mutations in TP53 (encoding p53) occur infrequently in MCCs and have been found almost exclusively in tumors with low or complete lack of MCPyV LT antigen expression [58,70]. The expression of retinoblastoma protein (RB), a key cell cycle regulator, is low or absent in viral-negative tumors, whereas nearly all MCPyV-positive tumors are also RB-positive [70].

The frequency of TP53 mutations, either UV signature mutations or non-UV signature mutations, appears to be higher in MCPyV-negative MCCs than in MCPyV-positive tumors [71]. An analysis of MCPyV-positive and MCPyV-negative MCCs using next-generation sequencing found an overall high mutational burden in MCPyV-negative tumors compared with MCPyV-positive tumors [58]. In MCPyV-negative tumors, the majority of tandem substitutions were CC > TT substitutions, characteristic of UV mutational signature, whereas only one CC > TT tandem substitution was detected across all MCPyV-positive tumors. Activating oncogenic mutations in HRAS, PIK3CA, KNSTRN, PREX2, and RAC1 were found in six of eight MCPyV-negative tumors but only in two of eight MCPyV-positive tumors. Highly recurrent mutations in tumor suppressor genes, including TP53, RBI, NOTCH1, and PRUNE2, were also found in MCPyV-negative tumors. These findings suggest that genetic aberrations independent of MCPyV infection are involved in the pathogenesis of viral-negative MCCs.

CLINICAL FEATURES — Merkel cell carcinoma (MCC) typically presents in older patients with light skin tones as a rapidly growing, firm, nontender, shiny, flesh-colored or bluish-red, intracutaneous nodule (picture 2C and picture 2A-B). Ulceration and crusting are relatively infrequent. MCCs range in size from less than 1 cm to over 2 cm and are most often located in sun-exposed areas.

In an analysis of 9387 MCC cases from the National Cancer Database between 1998 and 2012 (median age 76 years), the most frequent anatomic locations for the primary tumor were the following [72]:

●Head and neck – 43 percent

●Upper limbs and shoulder – 24 percent

●Lower limbs and hip – 15 percent

●Trunk – 11 percent

●Other areas – 9 percent

In this series, patients presented with local disease only in 65 percent of cases, while 26 percent had regional lymph node involvement at presentation, and 8 percent had distant metastases; 3.6 percent had lymph node involvement with an unknown primary tumor and without distant metastases. In these patients, the primary tumor may have spontaneously regressed [73-76].

DIAGNOSIS — Merkel cell carcinoma (MCC) is often clinically misdiagnosed as a benign lesion (eg, cyst, lipoma, pyogenic granuloma) [11]. A high index of suspicion is required if the diagnosis is to be made without delay. An analysis of data from the Surveillance, Epidemiology, and End Results (SEER) registry from 1973 to 2014 on over 3400 patients with MCC found that younger age (<65 years), male sex, and location of the tumor on the trunk or extremities were all associated with late-stage disease at diagnosis [77].

Clinical — Lesion features that suggest a biopsy include a rapidly growing, nontender lesion on sun-exposed skin in an older person with lightly pigmented skin, particularly if chronic immune suppression is present. These features can be easily remembered by the acronym AEIOU, derived from a series of 195 cases seen over a period of 27 years [11]:

●Asymptomatic – 88 percent

●Expanding rapidly (significant growth in ≤3 months) – 63 percent

●Immune suppression (HIV infection, solid organ transplant recipient, chronic lymphocytic leukemia) – 8 percent

●Older than 50 years age – 90 percent

●Ultraviolet (UV)-exposed area in an individual with lightly pigmented skin – 81 percent

The presence of at least three of these features increases the suspicion of MCC. Lesion biopsy and histologic examination are necessary to establish the diagnosis. (See 'Histopathology' below.)

Dermoscopy — Data on the dermoscopic findings of MCC are limited, and features specific to a diagnosis of MCC have not been identified. Some of the dermoscopic findings reported in small, retrospective series include milky red areas; linear, irregular vessels; and polymorphous vessels (picture 3) [78-81]. However, dermoscopy is unlikely to be broadly useful for the clinical diagnosis of MCC due to a lack of specific features, the rarity of MCC, and the need for a highly experienced dermoscopist to potentially recognize features suspicious of MCC. (See "Overview of dermoscopy".)

Histopathology — Both routine studies with hematoxylin and eosin as well as immunohistochemical stains are usually required to distinguish MCC from other poorly differentiated tumors. MCC typically presents as a dermal mass that frequently extends into the subcutis. The epidermis is infrequently involved, and the overlying skin is rarely ulcerated.

The tumor is composed of strands or nests of monotonously uniform, round, blue cells, containing large basophilic nuclei with powdery dispersed chromatin and inconspicuous nucleoli, and minimal cytoplasm [82]. Other features may include single-cell necrosis, frequent mitoses, lymphovascular invasion, perineural invasion, and epidermal involvement via pagetoid spread. Ultrastructurally, MCC tumor cells, like normal Merkel cells, contain paranuclear electron-dense neurosecretory granules (dense core granules), 10 mm filaments, and desmosomes [83].

There are three main histologic patterns, which have not been demonstrated to have prognostic or therapeutic implications but may be helpful in differentiating MCC from other entities (picture 4) [82]:

●Intermediate type – This variant, which is the most common, shows large, solid nodules made of diffuse sheets of basophilic cells with the characteristic round to oval nucleus, powdery chromatin, and inconspicuous nucleoli.

●Small cell type – The small cell variant has small, round cells with scant cytoplasm, oval hyperchromatic nuclei, and prominent nucleoli. The tumor cells form a solid sheet or clusters, often with crush artifact and nuclear molding.

●Trabecular type – This variant, which is the least common, has round to polygonal cells with abundant cytoplasm; round, centrally located vesicular nuclei; and inconspicuous nucleoli arranged in an organoid, trabecular, or ribbon-like arrangement.

In rare cases, MCC may exhibit squamous, eccrine, glandular, and melanocytic differentiation [84,85]. The occurrence of focal areas of squamous or sarcomatous differentiation in MCC has been documented in several patients [86,87]. The histogenesis and pathogenesis of these tumors are incompletely understood. They are Merkel cell polyomavirus (MCPyV) negative and have high frequency of retinoblastoma (RB1) and TP53 mutations [87].

Immunohistochemistry — On immunohistochemistry, the Merkel cells show features of both epithelial and neuroendocrine cells [83]. They express epithelial markers, such as AE1/AE3, CAM 5.2, pan-cytokeratin, epithelial membrane antigen, and Ber-EP4, and may stain for various neuroendocrine markers, including chromogranin, synaptophysin, calcitonin, vasoactive intestinal peptide, and somatostatin receptor [88].

Immunoreactivity for low molecular weight cytokeratins (eg, CK20, CK5/6) distinguishes MCC from other undifferentiated tumors (table 1) [89]. MCC stains positively for low molecular weight CK20, which is a fairly specific and sensitive marker for MCC, with a characteristic paranuclear dot-like positivity (picture 5) [82].

MCPyV large tumor (LT) antigen expression can be detected by using the commercially available mouse monoclonal antibody CM2B4 (picture 1). The LT antigen expression is highly correlated with the viral load (amount of MCPyV DNA) measured by real-time polymerase chain reaction [33].

Cytogenetic and molecular analysis — Multiple chromosome abnormalities, including gains, losses, and rearrangements, have been detected in MCC. However, the relationship of these genetic changes to pathogenesis, natural history, and therapeutic outcomes is unclear.

The chromosomes most frequently affected are 1, 5, 6, 8, and 13 [43,90-92]. The pattern of chromosome gains and losses is similar to those seen in small cell cancer of the lung (SCLC) [91] (see "Pathobiology and staging of small cell carcinoma of the lung"). Structural abnormalities involving chromosome 1p have been noted in up to 40 percent of examined cases [93].

Somatic mutations in tumor suppressor genes, including RB1 and TP53, have been documented in subsets of MCCs. Mutations in TP53 have been found in 0 to 28 percent of MCCs, the majority of which represent single nucleotide polymorphisms or silent mutations of unknown clinical significance [43]. RB1-inactivating mutations occur in nearly all MCPyV-negative MCCs.

Other molecular alterations found with varying frequency in MCC include mutations in genes involved in the tyrosine kinase signaling (PIK3CA, KIT, and PDGFR) and microRNA expression [94,95]. Distinct expression profiles of microRNA (noncoding RNA sequences that silence translation of complementary messenger RNA transcripts) have been found in MCPyV-positive and -negative tumors, suggesting distinct molecular mechanisms in tumor development and progression based upon MCPyV status [96].

DIFFERENTIAL DIAGNOSIS — Clinically, Merkel cell carcinoma (MCC) may closely mimic many benign and malignant lesions occurring on sun-exposed skin, such as basal cell carcinoma, squamous cell carcinoma, keratoacanthoma, amelanotic melanoma, pyogenic granuloma, lipoma, and adnexal tumors. Histology can clarify the diagnosis in most cases. However, on conventional light microscopy, MCC is difficult to distinguish from other poorly differentiated cutaneous and noncutaneous "small, blue cell tumors," including [97,98]:

●Small cell carcinoma of the lung – In contrast to MCC, cutaneous metastases of small cell carcinoma of the lung do not stain with CK20 but are positive for CK7, neuron-specific enolase, and thyroid transcription factor-1 (table 1) [89,99]. (See "Pathobiology and staging of small cell carcinoma of the lung", section on 'Pathology'.)

●Small cell melanoma – Melanoma with small cell phenotype is a rare variant of melanoma that resembles MCC [100,101]. Positive staining for HMB-45, Melan-A, and S-100 protein confirms the diagnosis of melanoma. (See "Pathologic characteristics of melanoma", section on 'Rare variants'.)

In such cases, immunohistochemistry is required for a definitive diagnosis (table 1) [83,102,103]. (See 'Immunohistochemistry' above.)

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●Basics topic (see "Patient education: Non-melanoma skin cancer (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Epidemiology and pathogenesis – Merkel cell carcinoma (MCC) is a rare, cutaneous malignancy with a high propensity for local recurrence and distant metastases. It predominantly affects older individuals with light skin types. Multiple factors appear to contribute to the etiology of MCC, including the Merkel cell polyomavirus (MCPyV), ultraviolet (UV) radiation exposure, and immunosuppression. (See 'Epidemiology' above and 'Pathogenesis' above.)

●Clinical presentation – Patients with MCC typically present with a rapidly growing, painless, firm, nontender, shiny, flesh-colored or bluish-red, intracutaneous nodule commonly located in the sun-exposed area (picture 2A-C). (See 'Clinical features' above.)

●Diagnosis – The diagnosis of MCC requires a high index of suspicion, as it is often clinically misdiagnosed as a benign lesion (eg, cyst, lipoma, pyogenic granuloma). Clinical warning signs that should prompt a biopsy are summarized in the acronym AEIOU (asymptomatic lesion, expanding rapidly, immunosuppression, age older than 50 years, lesion on UV-exposed skin). The definitive diagnosis is made by histologic examination of a biopsy specimen and generally requires immunohistochemistry as well as routine staining to distinguish MCC from other poorly differentiated tumors (table 1). (See 'Diagnosis' above and 'Differential diagnosis' above.)

●Staging and management – The staging and management of patients with MCC are discussed separately. (See "Staging, treatment, and surveillance of locoregional Merkel cell carcinoma" and "Treatment of recurrent and metastatic Merkel cell carcinoma".)