Approach

MCC is a rare, aggressive cutaneous neuroendocrine malignancy that carries a high risk of metastasis to regional lymph nodes and distant organ sites and has a higher case fatality rate than melanoma.[3][19]​ The primary cutaneous tumor typically presents as a solitary, nonspecific, rapidly growing nodule or plaque, generally on sun-exposed white people who are >65 years of age and/or immunosuppressed.​[2][9][30][31][32][33][34][35][36][37][38]

The diagnosis is confirmed with skin biopsy and histopathologic evaluation.[3][19][39]​​

Diagnosis of MCC requires a high index of suspicion, because the primary tumor lacks distinguishing features and is usually asymptomatic.[3] Always ensure prompt biopsy of any asymptomatic nodule or plaque that is firm, red or flesh-colored, and expanding rapidly.​[2][7]

  • MCC is often initially misdiagnosed clinically as a benign lesion. In one prospective cohort study of 195 patients with MCC, 56% of lesions were presumed by the physician to be benign; the most common incorrect diagnosis (32%) was a cyst or acneiform lesion.[2]

  • The clinical differential diagnosis includes other types of skin cancer such as basal or squamous cell carcinoma, amelanotic melanoma, or a benign skin lesion such as an epidermal inclusion cyst or a pyogenic granuloma. Another differential diagnosis to consider would be cutaneous metastasis of a primary visceral tumor, such as metastatic small cell lung cancer, which has similar histopathology to MCC; immunohistochemistry, and sometimes imaging, is needed to distinguish between the two.[3]

It is important to diagnose MCC early because the 5-year overall survival for stage IV disease (distant metastases) has been reported at just 14% to 29%, whereas the prognosis is significantly better for earlier stages.​[10][19]

Use the mnemonic AEIOU to recall five common presenting features of MCC. The presence of three or more should prompt suspicion of the diagnosis.[2][40]​ Bear in mind that not all patients present with all five features; of 62 patients studied, 89% met ≥3 of the AEIOU criteria, 52% met ≥4 criteria, and 7% met all 5 criteria.[2]

  • Asymptomatic/lack of tenderness. One study of 195 patients with pathologically confirmed MCC found 88% of tumors were asymptomatic.[2]

  • Expanding rapidly over ≤3 months.

  • I mmunosuppressed. Immunosuppression is an important risk factor for MCC (although it is also important to note that most patients who develop MCC are not immunosuppressed).[30]​ Studies have reported that an estimated 6% to 12% of MCC cases are associated with immunosuppression.[7][19]​​

  • Older than 50 years of age. The median age of MCC diagnosis is 77 years.[6][7][10]​​

  • Ultraviolet (UV)-exposed site on a person with light skin. Less than 10% of MCCs occur on partially sun-protected areas (trunk, thighs, and hair-bearing scalp) or on highly sun-protected sites (e.g., buttocks).[7]

History

Take a detailed history with a particular focus on:

  • How long the lesion has been present, whether it has increased in size, and if any other changes have occurred.

    • Early growth of MCC lesions is typically rapid, over weeks or months.[7]

    • Although ulceration and bleeding are infrequent at first presentation, they might occur at advanced stages.[7][19]

  • Any associated pain or pruritus.

    • MCC is not typically tender or pruritic.

  • History of UV exposure.[30]

    • MCC is strongly associated with lower latitudes and a high UV radiation index.[13]

    • The primary tumor typically occurs on sun-exposed skin.[7] It may sometimes be commingled with or adjacent to other lesions caused by UV exposure.[3]

    • Note that UV induction is understood to be one of the two pathogenetic pathways for MCC development; the second pathway is associated with oncogenic transformation by Merkel cell polyomavirus.[7]

  • Immunosuppression, including any history of hematologic malignancies, HIV/AIDS, solid organ transplant, and use of immunosuppressant medications.[30]

    • MCC is strongly associated with immunosuppression, with an estimated 6% to 12% of all patients with MCC being immunosuppressed.[7] The European Society for Medical Oncology (ESMO) guideline states that 10% of patients with MCC are organ transplant recipients, or have either a hematologic malignancy or human immunodeficiency virus (HIV) infection.[19]

  • Other risk factors. These include:[7]

    • Advancing age. The median age at diagnosis is 77 years.​[6][10]​​ Incidence rates increase with age; the highest incidence is reported in those ages over 85 years.[6]

    • Light skin type. MCC is very rare in people who are not white.​[5][32]

    • Male sex. Studies have reported that 61% to 66% of cases are in men.​​​[1][4][5][9][10]

Physical exam

Perform a thorough examination of any suspicious lesion(s).

  • The primary cutaneous MCC tumor usually presents as a solitary, firm, rapidly-growing, erythematous or pink-to-violaceous or skin-colored papule or subcutaneous nodule.[19]

  • MCC most frequently develops on the sun-exposed areas of head and neck (29% to 44%) and the extremities (37% to 45%). Less than 10% of MCCs occur on partially sun-protected areas (trunk, thighs, and hair-bearing scalp) or highly sun-protected areas (buttocks). Extracutaneous sites (e.g., vulva, vagina, oral mucosa parotid gland, nasal cavity) are very rarely involved.[7] Note that in black and Hispanic patients, MCC more often presents on sites other than the head and neck.[41]

  • MCC lesions are usually asymptomatic and not tender to the touch.[7]

  • Measure the clinical size of the lesion prior to any biopsy, as the diameter of the primary tumor will determine the T-stage. Moreover, increased clinical tumor diameter and depth are associated with a worse prognosis.[42]​ The National Comprehensive Cancer Network (NCCN) guideline lists a primary tumor >1 cm as one of several adverse risk factors for a worse outcome, warranting different treatment recommendations.[3]

Dermoscopy for MCC is nonspecific, but can show prominent red or milky-red background color or smaller clods of milky-red areas, polymorphous vessels, and white areas.[7] It can be particularly helpful to use dermoscopy for patients with multiple skin lesions as MCC can sometimes be contiguous to, or intermingled with, other skin cancers that can be more easily identified with dermoscopy.[19]

[Figure caption and citation for the preceding image starts]: A primary MCC tumor in an 87-year-old man who presented with a large, fast-growing, red, eroded nodule on the right templeFrom the collection of Dr Kelly Harms and Dr Alison Lee, University of Michigan; used with patient consent [Citation ends].com.bmj.content.model.Caption@2cb4879[Figure caption and citation for the preceding image starts]: A rapidly-growing MCC on the right cheek of a 64-year-old man, which started as a small erythematous cyst-like papule then developed within a few months into a larger, violaceous nodule with associated pruritusFrom the collection of Dr Kelly Harms and Dr Alison Lee, University of Michigan; used with patient consent [Citation ends].com.bmj.content.model.Caption@5ce070b8​​[Figure caption and citation for the preceding image starts]: MCC on the left lower lip of a 68-year-old man. The asymptomatic tumor is an ill-defined reddish-pink, scaly plaque blurring the lower vermillion of the lipFrom the collection of Dr Kelly Harms and Dr Alison Lee, University of Michigan; used with patient consent [Citation ends].com.bmj.content.model.Caption@18005a47[Figure caption and citation for the preceding image starts]: Primary MCC on the right frontal scalp (asterisk) of a 73-year-old man, with a biopsy scar of an in-transit metastasis (arrow). The primary tumor initially presented as an asymptomatic, fast-growing subcutaneous nodule that was misdiagnosed as an epidermoid cystFrom the collection of Dr Kelly Harms and Dr Alison Lee, University of Michigan; used with patient consent [Citation ends].com.bmj.content.model.Caption@2e425046[Figure caption and citation for the preceding image starts]: MCC presenting as a well-defined, rapidly growing, asymptomatic, brightly violaceous nodule on the left cheek of a 71-year-old man. The patient developed a golf-ball sized subcutaneous mass in the left parotid (original biopsy site marked with blue ink, subcutaneous metastasis marked with arrow). Fine needle aspiration of the mass in the left parotid gland confirmed MCCFrom the collection of Dr Kelly Harms and Dr Alison Lee, University of Michigan; used with patient consent [Citation ends].com.bmj.content.model.Caption@564f0d9​​[Figure caption and citation for the preceding image starts]: A 2 cm red, nodular MCC with varied vessel patterns on the right upper arm of an 80-year-old manFrom the collection of Dr Kelly Harms and Dr Alison Lee, University of Michigan; used with patient consent [Citation ends].com.bmj.content.model.Caption@49c47ffd

[Figure caption and citation for the preceding image starts]: MCC on the right posterior ankle of a 66-year-old African-American man, which presented as a subtle 1.5 cm subcutaneous nodule without overlying epidermal changes. This can often be confused with benign entities such as an epidermal cyst or a lipomaFrom the collection of Dr Kelly Harms and Dr Alison Lee, University of Michigan; used with patient consent [Citation ends].com.bmj.content.model.Caption@4d48350c

[Figure caption and citation for the preceding image starts]: A 2x3 cm MCC lesion in a white man aged in his late 60s who had a history of taking immunosuppressive medication for psoriasis. The nodule was violaceous with central ulceration, tan crusting, and serous drainage. Note that ulceration is unusual in MCCTomtschik J et al. BMJ Case Reports CP 2022; 15: e249288; used with permission [Citation ends].com.bmj.content.model.Caption@15e40ee7

Biopsy

Any nontender nodule with nonspecific morphology that is fast growing should be biopsied rather than monitored.[7]

  • Skin biopsy confirms the diagnosis and provides prognostic information.

  • Ensure the clinical size of the lesion is measured prior to biopsy as this has implications for the T-staging, prognosis, and recommended treatment pathway.[3][42]

A punch, incisional, or excisional biopsy should be performed on any suspicious lesion.​[3][7][39][43]​​​​ The most appropriate method will depend on the size and location of the tumor.

  • Immunohistochemistry (IHC) must be used in conjunction with hematoxylin and eosin (H&E) for confirmation of the diagnosis and to rule out histologic mimics (most notably other small cell tumors, including basal cell carcinoma, small cell lung cancer, and small cell melanoma).​[3][7][29][39][43]​​​​​ Staining that is positive for cytokeratin 20 (CK20) and negative for thyroid transcription factor (TTF-1) is usually considered sufficient to confirm the MCC diagnosis, although variations are sometimes reported.[3]

  • H&E typically shows a dermally-based tumor of small round blue cells with hyperchromatic nuclei, a "salt and pepper" chromatin pattern, and high mitotic activity.[7]​​[40][43]

[Figure caption and citation for the preceding image starts]: Histologic features of MCC from biopsy of a primary tumor. Image B shows small round blue cells and image C shows characteristic nuclei, finely granular and dusty “salt and pepper” chromatin, and abundant mitotic figuresMauzo SH et al. J Clin Pathol 2016; 69: 382-90; used with permission [Citation ends].com.bmj.content.model.Caption@3adaae0

Subsequent diagnostic workup

​Once the diagnosis of MCC is confirmed, consult with the multidisciplinary team.[3][7] Clinical exam and initial imaging studies (if indicated) are used to make an initial determination of the clinical N-stage and M-stage, which then determines the recommended approach to pathologic evaluation of lymph nodes.[3]

Staging

Initial staging involves a complete examination of the patient's skin and palpation of lymph nodes, which may reveal clinical signs of metastatic disease.[2][3][7][19]​​​​[29][44]

  • Clinical size of the primary tumor lesion, as measured prior to biopsy, is needed for T-staging.[45]

  • MCC presents with a primary tumor without regional metastases in 65.4% of cases. However, it has a high risk of loco-regional metastasis, and presents with nodal and distant metastasis in 26.3% and 8.3% of patients, respectively.[10]

  • Cutaneous satellite or in-transit metastases present as smaller papules or nodules surrounding the primary tumor. In-transit metastases are defined as lesions that are discontinuous from the primary tumor, located between the primary tumor and the draining regional nodal basin or distal to the primary tumor site.[3] Regional lymph node metastases present as enlarged lymph nodes or masses in the draining nodal lymph node basin.

  • In addition, MCC can present with clinically detectable metastatic disease in a lymph node without a primary tumor (unknown primary MCC).​[35][46][47]​​ Around 11% of patients with MCC have no identifiable primary lesion.[19] These patients have significantly higher survival rates compared with those who have a similar extent of disease but with a known primary lesion.[29]

Histopathologic confirmation of metastatic disease with biopsy is recommended.[3][7][48]​​

  • A skin biopsy should be performed on suspected satellite/in-transit metastases.[3][7]

  • Fine-needle aspiration (FNA) or core biopsy should be performed on suspected lymph node metastases.[3][7]

Imaging

Imaging is recommended for most cases of MCC to evaluate for regional lymph node metastases and distant disease and for staging of the disease.[3][44]

  • This is because occult metastatic disease has been detected in 12% to 20% of patients who presented with no suspicious findings on history and examination.[3][48]

  • Data indicate that whole-body fluorodeoxyglucose-positron emission tomography (FDG-PET) with fused axial imaging is the most reliable method for detecting occult metastatic MCC at baseline.[49][50]​​​ It is therefore recommended as the preferred cross-sectional imaging modality, if available, to assess local and distant disease.[3][19]

  • An acceptable alternative is CT with contrast of chest/abdomen/pelvis (and neck if the primary tumor is on the head/neck).[3][19]

  • Use MRI of the brain with or without contrast if there is clinical suspicion of brain metastases (e.g., if the patient has neurologic symptoms).[3]

  • European guidelines recommend ultrasound of the regional lymph nodes in patients with clinical stage I or II disease to further evaluate for regional lymph node involvement.[19]

Imaging is also an important tool to evaluate for underlying, noncutaneous, visceral neuroendocrine tumor mimics such as small cell lung cancer that may have metastasized to the dermis.

Sentinel lymph node biopsy (SLNB)

SLNB is recommended for any patient who presents without detectable metastatic disease and who is a candidate for surgery.[19]​​[33][34][35][42][44][51]​​​​ It is performed prior to, or at the time of, excision of the primary tumor.[3][7]​​​

  • SLNB is the most reliable tool to identify subclinical metastatic disease in the regional nodal basin.[3][7]

  • SLNB has been demonstrated to detect lymph node spread in up to one third of patients who would have otherwise been staged as node-negative.[52]

Merkel cell polyomavirus (MCPyV) serology

Consider baseline serum testing of antibodies to MCPyV (AMERK test), if available.[3] Virus-positive MCC is one of two subtypes of the disease and carries a better prognosis than UV-induced MCC.[7]

  • The AMERK test can be considered as part of initial workup, and if used, should be undertaken within 3 months of initial treatment.[3]

  • A proportion of patients with MCC caused by MCPyV develop antibodies to MCPyV oncoproteins.[53]​ In these patients, antibody titers can be monitored to detect changes in MCC disease burden.[53][54]​​

  • Among those who are seropositive, titers are expected to decrease after the elimination of clinically evident disease, hence a rising titer may be an early indicator of recurrent disease. Consider re-testing every 3 months for surveillance, to detect recurrence and to help determine frequency of radiologic imaging.[53][54]

  • Among those who are seronegative, more intensive surveillance is indicated as virus-negative patients have a worse prognosis.[3][7]

Integration of MCPyV into the host genome is associated with up to 70% to 80% of MCC tumors in North America and Europe. The proportion of virus-positive cases is lower in Australia, where the UV index is higher.[7]​​[12][14][19]​​​

  • MCPyV is a ubiquitous virus, with seroprevalence in the adult population of 60% to 80%.[20]​ Oncogenic transformation by MCPyV is a rare event and requires viral integration into the host genome, resulting in inactivation of a viral replication protein.

Emerging test

Circulating tumor DNA (ctDNA) analysis, which measures circulating cell-free DNA from tumor cells, is an emerging blood test for molecular disease monitoring of different cancers, including MCC.[55][56]​​​ Additional studies are needed to further define its role in MCC.

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