Skin Cancer - Merkel Cell Carcinoma 

Updated: Jul 22, 2019
Author: James M Pearson, MD; Chief Editor: Arlen D Meyers, MD, MBA 

Overview

Practice Essentials

Merkel cell carcinoma (MCC) is the eponym for primary cutaneous neuroendocrine carcinoma, a dermal neoplasm with cytoplasmic, dense-core neuroendocrine granules and keratin filaments. A rare cancer, Merkel cell carcinoma (MCC) is an aggressive cutaneous neoplasm that lacks distinguishing clinical features. More than half of Merkel cell carcinomas (MCCs) occur in the head and neck of elderly people, in areas of actinically damaged skin. The most common site of occurrence is the periorbital region. Merkel cell carcinoma (MCC) has a propensity to recur and to cause local and distant metastases. Distant metastases indicate a condition that is nearly always fatal.[1]

Current treatment consists of wide local excision with adjuvant irradiation. Neck dissection is used for clinically positive nodes, and chemotherapy is given for advanced disease.[2]

If the prognosis of patients with (MCC) is to be improved, early diagnoses are needed, and further understanding of the roles of neck dissection, radiation therapy, and chemotherapy must be attained.[3]

Symptoms of Merkel cell carcinoma

Merkel cell carcinoma (MCC) commonly appears as a painless mass on or just under the skin surface. Appropriate clinical diagnosis is often delayed because of a lack of symptoms. The tumor may take on an erythematous or violaceous appearance. Bleeding and superficial ulceration are late findings suggestive of advanced disease. Regional lymph node metastasis is common, even with tumors smaller than 2 cm.

Workup in Merkel cell carcinoma

Baseline laboratory studies should include a complete blood count (CBC), a chemistry profile, and liver function tests.

No optimal imaging algorithm has been defined. However, because of the difficulties in distinguishing metastatic oat cell carcinoma from Merkel cell carcinoma (MCC), chest radiography should be performed. Obtain computed tomography (CT) scans of the chest, abdomen, and pelvis to rule out metastases.

Light microscopy, electron microscopy, and immunohistochemistry may be needed to confirm the diagnosis of Merkel cell carcinoma (MCC).

No universally accepted staging system for Merkel cell carcinoma (MCC) exists. Some have used the American Joint Committee on Cancer Staging System for skin cancer to stage Merkel cell carcinoma (MCC). Others employ a staging system developed by the Memorial Sloan Kettering Cancer Center or the system suggested by Yiengpruksawan et al (1991).

Management of Merkel cell carcinoma

For patients with operable disease, most agree that surgery is the treatment of choice. As with most tumors, treatment is based on the stage.

Guidelines released in 2015 by a collaborative group of multidisciplinary experts from the European Dermatology Forum (EDF), the European Association of Dermato-Oncology (EADO), and the European Organization of Research and Treatment of Cancer (EORTC) included the following with regard to the management of Merkel cell carcinoma (MCC)[4] :

  • The primary tumor should be excised with 1-2 cm margins
  • In patients with regional lymph node involvement, radical lymphadenectomy is recommended
  • Adjuvant radiation therapy may be considered in patients with multiple affected lymph nodes of extracapsular extension
  • In unresectable metastatic Merkel cell carcinoma, monochemotherapy or polychemotherapy achieve high remission rates; however, responses are usually short-lived
  • Treatment within clinical trials is regarded as a standard of care in disseminated Merkel cell carcinoma

Complications

In addition to metastasizing to the lymph nodes, Merkel cell carcinoma (MCC) can also spread to the brain, bones, liver, and lungs, thus affecting their function.[5] As stated above, distant metastases indicate a condition that is nearly always fatal.[1]

Avoidance

As with other skin cancers, the risk of developing Merkel cell carcinoma (MCC) can likely be decreased via protection from ultraviolet (UV) light. This can be accomplished through the following[5, 6] :

  • Reduction of sun exposure during peak daylight hours
  • Application and reapplication of sunscreen
  • Use of protective clothing during sun exposure
  • Avoidance of tanning beds and sunlamps

Individuals can also regularly check themselves for skin changes, contacting a doctor if any occur.[6] Nonetheless, it remains unproven whether Merkel cell carcinoma (MCC) is associated with sun exposure,[5] and the disease has been reported in areas not exposed to the sun, such as the nasal cavity, buccal mucosa, gingiva, hard palate, and postauricular skin.

History of the Procedure

Freidrich Sigmund Merkel, a German histopathologist, first described the Merkel cell in 1875. He fixed and stained the skin of geese and ducks and demonstrated touch cells in the snouts of pigs. These clear-staining cells at the dermoepidermal junction were near myelinated nerve fibers. Merkel postulated that these cells acted as mechanoreceptors in all animals.

Cyril Toker first described Merkel cell carcinoma (MCC) in 1972.[7] On the basis of the histologic characteristics of the tumor, he named it trabecular cell carcinoma of the skin.

Subsequent studies involving immunohistochemistry and electron microscopy revealed that these tumors originate from the Merkel cell.

Problem

Merkel cell carcinoma (MCC) is a deadly disease with a poor likelihood for survival. Local recurrence occurs in 44% of patients; multiple local recurrences occur in 15%. These tumors appear as rapidly growing, painless nodules in elderly Caucasian individuals or in young adults with ectodermal dysplasia syndromes. The mean age at presentation is 68 years, and no sex bias is observed. Merkel cell carcinomas (MCCs) usually appear as indurated plaques or violaceous (red or deep purple) solitary and dome-shaped nodules. The surface is typically shiny, with telangiectasias and possibly ulceration. Most tumors measure 0.7-1.2 cm in diameter.

Merkel cell carcinomas (MCCs) usually occur in sun-damaged skin. They are often found near other lesions of actinically damaged skin, including skin involved with Bowen disease, squamous cell carcinoma, basal cell carcinoma, solar keratoses, or lentigo maligna. Merkel cell carcinoma (MCC) has also been linked to previous radiation exposure and B-cell lymphoma.

Approximately 53% of Merkel cell carcinomas (MCCs) occur in the head and neck; 35% occur in the extremities. In the head and neck, 46% of tumors occur in the periorbital region; 29%, on the cheek; 18%, on the eyelid; and 17%, on the forehead. Other sites in the head and neck include the lips (9%), ears (7%), nose and neck (5.4%), and scalp (4%). Common distribution of Merkel cell carcinoma in the head and neck is shown in the image below.

Common distribution of Merkel cell carcinoma in th Common distribution of Merkel cell carcinoma in the head and neck.

Tumors have also been reported in areas not exposed to the sun, such as the nasal cavity, buccal mucosa, gingiva, hard palate, and postauricular skin.

About 3% of patients with Merkel cell carcinoma (MCC) have tumors at several sites. Approximately 11-15% of patients present with clinically positive nodes. About 75-83% of patients eventually develop regional nodal and distant metastases during their illness.

The nonspecific characteristics of Merkel cell carcinoma (MCC) lead to a lengthy differential diagnosis that includes basal cell carcinoma, squamous cell carcinoma, keratoacanthoma, amelanotic melanoma, epidermal cysts, lymphoma, and metastatic carcinoma of the skin. As a result, Merkel cell carcinoma (MCC) is rarely diagnosed until biopsy is performed.

Complications

In addition to metastasizing to the lymph nodes, Merkel cell carcinoma (MCC) can also spread to the brain, bones, liver, and lungs, thus affecting their function.[5] As stated above, distant metastases indicate a condition that is nearly always fatal.[1]

Epidemiology

Frequency

Since Merkel cell carcinoma (MCC) was first described in 1972, more than 600 cases have been reported in the literature; over 320 of these cases have involved the head and neck.

The reported annual incidence of Merkel cell carcinoma (MCC) is 0.2-0.45 case per 100,000 population. This rare cancer occurs 100 times less frequently than does melanoma.

Evidence suggests that the incidence of Merkel cell carcinoma (MCC) is increasing. In an analysis of the Surveillance, Epidemiology and End Results (SEER) database, Hodgson (2005) reported that the incidence of Merkel cell carcinoma (MCC) increased 3-fold between 1986 and 2001.[8]  Moreover, a study by Uitentuis et al reported that in the Netherlands, between 1993 and 2016, the incidence of Merkel cell carcinoma (MCC) rose from 0.17 per 100,000 person-years to 0.59 per 100,000 person-years.[9]

Etiology

The Merkel cell is found in the skin of fish, amphibians, reptilians, avians, and mammals. It is an ovoid or round cell in the basal layer of the epidermis, lying parallel to the surface. The cell has scant cytoplasm and a round or oval nucleus with fine, evenly dispersed chromatin. The cells cluster in areas of sensory perception, such as fingertips, the tip of the nose, and tactile hair follicles.

Ultrastructural evaluation of the Merkel cell reveals desmosomal connections with surrounding keratinocytes; intracytoplasmic aggregates of intermediate filaments; and numerous, membrane-bound, dense core granules located in short, spinous, cytoplasmic processes that synapse with adjacent terminal nerve endings.

Immunohistochemical studies of the Merkel cell have demonstrated the presence of neuron-specific enolase (NSE), an amine precursor uptake and decarboxylation (APUD) cell marker. Studies have also shown staining for cytokeratins 8, 18, and 19.

The origin of the Merkel cell is still controversial. The cell has both epithelial and neuroendocrine elements. This finding has led some to hypothesize that the cell is derived from an epidermal stem cell in the basal layer of the epidermis that is capable of differentiation along either lineage. An alternative hypothesis, one stimulated by the presence of calcitonin and other hormones, suggests that the cell may be of neural crest origin.

The exact function of the Merkel cell has yet to be delineated, but most believe that it acts to modulate mechanoreception.

Recently, a polyomavirus was found to be integrated into the genome of MCC and has been postulated to play a role in the pathogenesis and progression of this disease.[10, 11, 12, 13, 14]

Presentation

Merkel cell carcinoma (MCC) commonly appears as a painless mass on or just under the skin surface. Appropriate clinical diagnosis is often delayed because of a lack of symptoms. The tumor may take on an erythematous or violaceous appearance. Bleeding and superficial ulceration are late findings suggestive of advanced disease. Regional lymph node metastasis is common, even with tumors smaller than 2 cm.

In a representative case that demonstrates common findings, a patient was an 89-year-old Caucasian woman with a 6-month history of an enlarging painless mass involving the right side of her nose. No pain or bleeding was associated with this mass. Her medical history included no previous cutaneous malignancies or sun exposure.

Physical examination revealed a smooth violaceous discolored mass measuring 2 X 3 cm involving the right nasal ala. The mass deeply invaded the full thickness of the nasal skin, with evidence of right nasal obstruction as seen in the image below. The rest of her facial skin contained no additional lesions. The bilateral intraparotid and jugulodigastric nodes were normally sized.

Merkel cell carcinoma affecting the right nasal al Merkel cell carcinoma affecting the right nasal ala.

The patient underwent right-sided partial rhinectomy, with at least 5-mm margins from the visible borders of the tumor. Frozen sections revealed that all margins were free of disease. Reconstruction was accomplished immediately with a nasolabial flap. The patient's postoperative treatment included radiation therapy of 45 Gy for 5 weeks. The patient was free from recurrence at 2 years after surgery, when she died from causes unrelated to this mass.

 

Workup

Approach Considerations

Guidelines on the diagnosis and treatment of Merkel cell carcinoma were released in 2015 by a collaborative group of multidisciplinary experts from the European Dermatology Forum (EDF), the European Association of Dermato-Oncology (EADO), and the European Organization of Research and Treatment of Cancer (EORTC). Diagnostic guidelines included the following[4] :

  • Clinical features of the cutaneous/subcutaneous nodules contribute little to the diagnosis of Merkel cell carcinoma

  • The diagnosis is made by histopathology, and an incisional or excisional biopsy is mandatory

  • Immunohistochemical staining contributes to clarification of the diagnosis

  • Initial work-up consists of ultrasonography of the locoregional lymph nodes and total body scanning examinations

  • In patients without clinical evidence of regional lymph node involvement, sentinel node biopsy is recommended, if possible, and will be taken into account in a new version of the American Joint Committee on Cancer classification

Laboratory Studies

Baseline laboratory studies should include a complete blood count (CBC), a chemistry profile, and liver function tests.

Imaging Studies

See the list below:

  • No optimal imaging algorithm has been defined.

  • Because of the difficulties in distinguishing metastatic oat cell carcinoma from Merkel cell carcinoma (MCC), chest radiography should be performed.

  • Obtain CT scans of the chest, abdomen, and pelvis to rule out metastases.

  • Some have suggested that obtaining octreotide scanning may also be helpful for ruling out metastases. However, this study is not part of the standard evaluation.

  • The role of [18 F]2-fluoro-D-2-deoxyglucose (FDG) positron emission tomography (PET) remains undefined.

    • Recent reports indicate that FDG-PET may aid in the staging and following up Merkel cell carcinomas (MCCs).

    • Yao et al (2005) reported that pretreatment FDG-PET scans revealed metastatic disease in subcentimeter lymph nodes that were not appreciated on initial CT images.[15] Likewise, posttreatment FDG-PET scans revealed responses to therapy, with the level of FDG uptake correlating with complete responses to treatment and with residual disease.

Histologic Findings

Diagnosing Merkel cell carcinoma (MCC) is difficult and requires a high degree of suspicion. Light microscopy, electron microscopy, and immunohistochemistry may be needed to confirm the diagnosis.

Light microscopy

On occasion, Merkel cell carcinomas (MCCs) may be diagnosed with histology alone, but confirmation with immunohistochemistry and/or electron microscopy is always encouraged. Diagnosis by means of light microscopy alone is difficult because the appearance of Merkel cell carcinomas (MCCs) is similar to that of many other undifferentiated small-cell neoplasms, especially other APUD tumors, such as metastatic oat cell carcinoma. In fact, 66% of Merkel cell carcinomas (MCCs) are misdiagnosed when studied with light microscopy alone.

These points emphasize the need to consider Merkel cell carcinoma (MCC) when small cell tumors are being diagnosed with light microscopy. Light microscopy reveals round-to-polygonal neoplastic cells that are compactly arranged. Rare fusiform cells are also observed. A ball-in-mitt arrangement of cells is often described, where 1 or 2 crescentic tumor cells wrap around a round tumor cell. A grenz zone usually separates the tumor from the epidermis. As a result, the epidermis is commonly spared because the Merkel cell carcinoma (MCC) alternatively extends into the subcutaneous tissues, vessels, and lymphatics.

Gould et al (1985) described a widely accepted histologic classification of Merkel cell carcinoma (MCC).[16] The classification details 3 specific cellular patterns.

The most common pattern is the intermediate cell type; observed in over 50% of patients with Merkel cell carcinoma (MCC). These tumors display a large nest of cells without organoid architecture or recognizable palisading. A distinct disassociation exists between cells. Areas of focal necrosis and lymphocytic invasion are typical. Cytoplasm is moderate, nuclei are vesicular, and mitoses are abundant.

The trabecular cell type is observed in 25% of Merkel cell carcinomas (MCCs). It is believed to be the original tumor Toker described (1972).[7] In this class, the cells are arranged in organoid clusters with interconnected trabeculae separated by strands of connective tissue. Clusters may show glandlike organization. Individual cells are compactly arranged round-to-polygonal cells. Cytoplasm is abundant, and the nuclei are round, centrally located, and vesicular. Pleomorphism and mitotic activity is mild to moderate.

The final and least common class is the small cell variation. This pattern consists of solid sheets and clusters of cells separated by abundant stroma, with large areas of necrosis. The cells are small with scant cytoplasm and hyperchromatic nuclei. Pleomorphism and mitoses are common.

Electron microscopy

Because of the difficulty in diagnosing Merkel cell carcinoma (MCC) with light microscopy, electron microscopy plays an important role in the diagnosis of Merkel cell carcinoma (MCC). The ultrastructure of the tumor is similar to that of the normal Merkel cell. The cells are round to ovoid and intimately apposed to adjacent tumor cells, with desmosomal junctions to surrounding keratinocytes. One of the most consistent findings is the aggregation of intermediate filaments in a paranuclear location. Other characteristic findings are membrane-bound, dense core granules. The granules are usually concentrated in the periphery or in dendritelike processes.

Immunohistochemistry

Immunohistochemistry is often used to confirm Merkel cell carcinoma (MCC). Merkel cell tumors stain positively for NSE, as would any APUD cell tumor. They also demonstrate perinuclear staining with antikeratin antibodies to low-molecular-weight cytokeratins 8, 18, and 19. These 2 markers are the most constant immunohistochemical markers and are often said to be present in 100% of Merkel cell carcinomas (MCCs). A third marker, neurofilament protein, is used to distinguish Merkel cell carcinoma (MCC) from oat cell carcinoma. Neurofilament protein is seen in nearly all Merkel cell carcinomas (MCCs) but few oat cell carcinomas.

Other markers present with variable frequency are chromogranin, synaptophysin, vasoactive intestinal peptide (VIP), calcitonin, bombesin, corticotropic hormone (ACTH), met-encephalon, gastrin, and somatostatin.

Finally, the absence of certain markers also helps in the diagnosis of Merkel cell carcinoma (MCC) by ruling out other tumors. S-100 is seen in melanoma, whereas leukocyte common antigen is present in lymphoma. Neither of these is found in Merkel cell carcinoma (MCC).

Staging

No universally accepted staging system for Merkel cell carcinoma (MCC) exists. Some have used the American Joint Committee on Cancer Staging System for skin cancer to stage Merkel cell carcinoma (MCC). Others use a staging system developed by the Memorial Sloan Kettering Cancer Center. This article uses the widely-used system suggested by Yiengpruksawan et al (1991), as follows:[17]

  • Stage I - Absence of lymphadenopathy

    • Stage IA - Tumors < 2 cm

    • Stage IB - Tumors >2 cm

  • Stage II - Positive regional lymphadenopathy

  • Stage III - Evidence of distant metastases

At presentation, most patients have stage I disease (55%), followed by stage II (31%), and stage III (6%).

 

Treatment

Approach Considerations

The aforementioned 2015 European guidelines on the diagnosis and management of Merkel cell carcinoma included the following regarding treatment[4] :

  • The primary tumor should be excised with 1-2 cm margins

  • In patients with regional lymph node involvement, radical lymphadenectomy is recommended

  • Adjuvant radiation therapy may be considered in patients with multiple affected lymph nodes of extracapsular extension

  • In unresectable metastatic Merkel cell carcinoma, monochemotherapy or polychemotherapy achieve high remission rates; however, responses are usually short-lived

  • Treatment within clinical trials is regarded as a standard of care in disseminated Merkel cell carcinoma

A study by Bishop et al indicated that treatment for Merkel cell carcinoma of the head and neck that includes radiation therapy provides effective local and regional control of the disease. The study, which included 106 patients with the condition who underwent radiation treatment, found that the 5-year actuarial rates for local and regional control of Merkel cell carcinoma were both 96%. In addition, no regional recurrences were found among 22 patients with gross nodal disease who received radiation therapy but no neck dissection.[18]

A study by Chen et al of 4815 patients with Merkel cell carcinoma of the head and neck indicated that postoperative adjuvant therapy with chemoradiotherapy offers greater improvement in the overall survival rate than does postoperative radiotherapy alone in patients with male sex, tumor size of at least 3 cm, and positive margins.[19]

Avelumab (Bavencio), an anti–programmed death ligand-1 (anti-PD-L1) immunoglobulin G1 (IgG1) monoclonal antibody, was approved by the US Food and Drug Administration (FDA) in March 2017 for metastatic Merkel cell carcinoma in adults and pediatric patients aged 12 years or older.

Approval of avelumab was based on the JAVELIN Merkel 200 open-label, single-arm, multicenter study in 88 patients in whom metastatic Merkel cell carcinoma had been histologically confirmed and in whom the disease had progressed on or after administration of chemotherapy for distant metastatic disease. The overall response rate (ORR) reached 33% (29 patients), partial response rate was 22%, and complete response rate (CRR) was 11%. Eight-six percent of tumor responses lasted at least 6 months (25 patients), and 45% lasted at least 12 months (13 patients). The duration of response (DOR) lasted from 2.8 to over 23.3 months.[20]

Pembrolizumab (Keytruda), another PD-L1 inhibitor, was approved by the FDA in December 2018 for adults and children with metastatic or recurrent, locally advanced Merkel cell carcinoma.[21] The drug’s pediatric efficacy was extrapolated from adult study data.

Results from a multicenter, nonrandomized, open-label trial by Nghiem et al formed the basis for pembrolizumab’s approval. In patients who underwent pembrolizumab monotherapy who had not received prior systemic treatment, the ORR, CRR, and partial response rates were 56%, 24%, and 32%, respectively. Among responding patients, the DOR for 6 months or longer and 12 months or longer was 96% and 54%, respectively, with median DOR not reached in the study.[22]

Avoidance

As with other skin cancers, the risk of developing Merkel cell carcinoma (MCC) can likely be decreased via protection from ultraviolet (UV) light. This can be accomplished through the following[6, 5] :

  • Reduction of sun exposure during peak daylight hours
  • Application and reapplication of sunscreen
  • Use of protective clothing during sun exposure
  • Avoidance of tanning beds and sunlamps

Individuals can also regularly check themselves for skin changes, contacting a doctor if any occur.[6] Nonetheless, it remains unproven whether Merkel cell carcinoma (MCC) is associated with sun exposure,[5] and the disease has been reported in areas not exposed to the sun, such as the nasal cavity, buccal mucosa, gingiva, hard palate, and postauricular skin.

Surgical Therapy

For patients with operable disease, most agree that surgery is the treatment of choice. As with most tumors, treatment is based on the stage. The Yiengpruksawan system is used here.[17]

Stage I

Aggressive wide local excision is the treatment of choice for the primary tumor. A 2- to 3-cm margin is recommended because it is thought to decrease the risk of recurrence. (However, in a study of patients with Merkel cell carcinoma, 35.4% of whom had primary head and neck lesions, Perez et al found that, in comparing resection margins of 1 cm, 1.1-1.9 cm, and 2 cm or more, the 1 cm margins were not associated with a greater rate of local recurrence or significantly different rates of disease-specific and overall survival.[23] ) All margins should be confirmed with frozen sections.

The role of elective neck dissection in the absence of clinically positive nodes is controversial.[24] Because of the low incidence of Merkel cell carcinoma (MCC), most reports are based on retrospective or anecdotal studies. Lymph node metastases develop in approximately 55% of patients; therefore, some authors recommend prophylactic neck dissection in all patients. Others recommend neck dissection after the tumor reaches 2 cm in diameter.

Silva et al (1984) recommend neck dissection for tumors with 10 or more mitoses per high-power field, for cases of lymphatic invasion, or for tumors composed of small cells.[25] Cotlar et al (1986) recommend lymphadenectomy for tumors present longer than 6 weeks.[26] Tumors in the midline present the problem of bilateral drainage. Goepfert et al (1984) and Hitchcock et al (1988) recommend that patients with such lesions undergo a bilateral neck dissection.[27, 28]

Recent studies have been conducted to investigate the efficacy of sentinel node biopsy to determine whether neck dissection is necessary. These studies have been small, but their results indicate that a negative sentinel node may obviate the need for neck dissection.

When one contemplates neck dissection, realize that no indications are universally accepted and that the effect of regional lymphadenopathy on overall survival is uncertain.

Merkel cell carcinoma (MCC) is a radiosensitive tumor, and radiotherapy is currently used as an adjuvant. Most clinical studies demonstrate better local control rates with adjuvant radiotherapy after surgery. Numerous authors have recommended postexcision irradiation of the primary site and primary areas of lymph node drainage. Adjuvant radiotherapy is routinely given by some practitioners, whereas other practitioners only give it to patients considered to be high risk, which is inconsistently defined as demonstrating any of the following: (1) primary tumor >1.5 cm; (2) positive margins; (3) margins < 2 mm; (4) evidence of lymphatic, vascular, or perineural invasion; or (5) regional lymph node involvement.

The recommended dosing schedule is 45-50 Gy for 5 weeks; this is increased to 56-65 Gy for tumors with positive margins. These doses are similar to those used to treat squamous cell carcinoma. Therapy for recurrent localized disease or extensive unresectable stage I disease is similar to that given for stage II disease because lymphadenopathy is more likely to occur in this situation than in primary disease.

Stage II

A widely accepted practice is for patients with regional node metastases or local or regional recurrence to undergo excision of the primary lesion and lymph node dissection. Adjuvant radiation therapy to the primary site and regional nodes is generally recommended in addition to neck dissection.

Chemotherapy is generally not currently advocated for stage II disease.

Stage III

The development of distant metastases portends a poor prognosis, with a mean life expectancy of 5 months. Many types of chemotherapeutic agents have been used with brief success in treating stage III disease, with no increase in the survival rate. Because of the morphologic and immunohistochemical similarities of Merkel cell carcinoma (MCC) to small cell lung cancer, these regimens have been used as treatment models.

Pharmacologic agents most commonly used are doxorubicin and cyclophosphamide. Other agents are cisplatin, vincristine, etoposide, methotrexate, bleomycin, and 5-fluorouracil. However, reports of these treatments to date have consisted of small studies and anecdotal evidence. Merkel cell carcinomas (MCCs) often respond to chemotherapy; however, as with small cell carcinoma, remission is brief. No chemotherapeutic protocol has notably increased survival rates.

The role of radiation therapy in disseminated disease is to achieve palliation.

Follow-up

After treatment, monitor patients closely. Recommended follow-up is every month for 6 months, every 3 months for the next 2 years, and every 6 months thereafter.

Outcome and Prognosis

Merkel cell carcinoma (MCC) is a deadly disease with a poor outlook for survival. Local recurrence occurs in 44% of patients; multiple local recurrences occur in 15%. These recurrences usually happen within 5 months after the primary lesion is treated. About 15% of patients have palpable nodes at the time of diagnosis. Lymph node metastases eventually develop in 55% of patients, and distant metastases develop in 34%. Most metastases occur before the eighth month after diagnosis.

The areas where metastases are most likely to occur are the liver, bone, brain, and lung. The presence of distant metastases is the only factor that is consistently predictive of the outcome. The mean time to death after the discovery of distant metastases is 5 months. Mortality rates for patients with distant metastases are 75-100%. In patients without distant metastases, mortality rates are 4%.

The aforementioned study by Uitentuis et al found that in the Netherlands, out of a cohort of 1977 patients, the relative 5-year survival rate for individuals with Merkel cell carcinoma (MCC) was 63.0%, with greater mortality seen in males (hazard ratio [HR] 1.24), in patients of higher age (HR 1.07), in individuals with nodal invasion (HR 1.26), and in patients with distant disease spread (HR 2.44).[9]

A review of a prospective database of 500 patients with Merkel cell carcinoma (MCC) treated at a single institution reported a median age at diagnosis of 71 years and 5-year overall survival and disease-specific death (DSD) rates of 56% and 30%, respectively. (The staging system for this study was based up on the American Joint Committee on Cancer [AJCC], 7th edition, 2010.) Pathologic stage and lymphovascular invasion were independent predictors of DSD. Patients with metastatic disease (stage 4) or clinically positive lymph nodes (stage 3b) demonstrated increased DSD compared with patients with lower-staged disease. Of note, no difference was noted in DSD demonstrated for stage 3a or 2 compared with stage 1. Also of note, only 1 of 132 patients without lymphovascular invasion died of MCC. The authors note that overall survival is a poor measure of the influence of MCC on life expectancy.[29]

Future and Controversies

Future directions for the treatment of Merkel cell carcinoma (MCC) that are still under investigation include Mohs surgery for excision of the primary lesion, lymphoscintigraphy, intraoperative mapping of lymph nodes, biopsy of sentinel lymph nodes to treat and stage occult neck disease, as well as to further define the role of chemotherapy.

O'Connor et al (1997) compared the efficacy of Mohs surgery to that of wide local excision.[30] Following up 86 patients, they determined that Mohs surgery fared well compared with the standard treatment of wide local excision.

When weighing the choice between wide local excision and Mohs surgery, one must consider the advantage of Mohs surgery because it allows for histologic control of margins of the tumor, minimizing the extent of excision. In the head and neck, conservation of tissue is imperative to preserve vital structures. Considering this information, many authors now advocate Mohs excision in lieu of wide local excision.

In Merkel cell carcinoma (MCC), the prognosis and the treatment of the disease is largely based on the presence or absence of metastases. To facilitate appropriate treatment and staging, the clinician must determine the state of the regional lymphatics in the clinically negative neck. At present, prophylactic neck dissection is advocated, but the procedure entails morbidity. In addition, because drainage patterns in the head and neck are notoriously ambiguous and difficult to predict, which lymph node basins should be dissected is often unclear.

For the treatment of melanomas of the head and neck, preoperative lymphoscintigraphy and intraoperative lymphatic mapping have been used to successfully identify draining lymph node basins and localize the sentinel lymph node for biopsy. Preliminary studies have demonstrated that, in Merkel cell carcinoma (MCC), the status of the sentinel node is predictive of the status of the remaining lymph node basin.

Recent work in this area by Schmalbach et al (2005) supports these preliminary findings.[31] Regional failure in the setting of negative findings on sentinel lymph node biopsy was observed in 1 (13%) of 8 patients. This rate of regional recurrence compares favorably with mean rates of regional recurrence reported in the literature. If data from large studies confirm these findings, sentinel lymph node biopsy may provide an accurate and less morbid alternative to neck dissection for the treatment and staging of regional occult neck disease in Merkel cell carcinoma (MCC).

However, elective lymph node dissection may still be warranted in Merkel cell carcinoma (MCC) patients with head and neck primaries because of the complex and unpredictable nature of lymphatic drainage patterns in these areas. The best conclusion at this point is that sentinal node biopsy may allow for more selective lymphadenectomy and may help determine the need for elective radiotherapy to the proper nodal basins.

The role of adjuvant chemotherapy remains unresolved. Palliative chemotherapy is often used for unresectable or recurrent disease. No prospective randomized, case-controlled phase III studies exist to clearly define the role of chemotherapy in the treatment of Merkel cell carcinoma (MCC). Recently, the National Institutes of Health approved a phase II trial of imatinib mesylate (Gleevac) in treating metastatic or unresectable Merkel cell carcinoma (MCC).

 

Medication

Medication Summary

In 2017, avelumab became the first drug approved by the FDA for metastatic Merkel cell carcinoma in adults and children aged 12 years or older. It is a programmed death 1 (PD-1) inhibitor.[20] In 2018, another PD-1 inhibitor, pembrolizumab, was approved for adults and children with metastatic or recurrent, locally advanced Merkel cell carcinoma.[22, 21]

Platinum-based chemotherapy regimens have been also been used, but clinical efficacy is limited and brief.

PD-1/PD-L1 Inhibitors

Class Summary

Programmed cell death-1 (PD-1) and related target PD-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.

Avelumab (Bavencio)

Anti-PD-L1 IgG1 monoclonal antibody. It is indicated for metastatic MCC in adults and pediatric patients aged 12 years or older.

Pembrolizumab (Keytruda)

Monoclonal antibody that targets PD-1. It blocks PD-1 from interacting with ligands PD-L1 and PD-L2. Indicated for adults and children with metastatic or recurrent, locally advanced Merkel cell carcinoma.

 

Questions & Answers

Overview

What is Merkel cell carcinoma (MCC)?

What are the symptoms of Merkel cell carcinoma (MCC), and how is it diagnosed and treated?

What are the complications of Merkel cell carcinoma, and how can the disease be avoided?

How and when was the Merkel cell first identified?

How is Merkel cell carcinoma (MCC) characterized?

Where do Merkel cell carcinomas (MCCs) most commonly occur?

Why is Merkel cell carcinoma (MCC) difficult to diagnose?

What is the incidence of Merkel cell carcinoma (MCC) involving the head and neck?

What is the incidence of Merkel cell carcinoma in comparison to melanoma?

Is the incidence of Merkel cell carcinoma (MCC) increasing or decreasing?

What are the characteristics of the Merkel cell?

What is the origin of the Merkel cell?

What is the function of the Merkel cell?

Which physical findings are associated with Merkel cell carcinoma (MCC)?

Workup

What are the diagnostic guidelines for Merkel cell carcinoma (MCC)?

Which lab studies may be performed in the diagnosis of Merkel cell carcinoma (MCC)?

Which imaging studies may be performed in the diagnosis of Merkel cell carcinoma (MCC)?

Which histologic studies may be required to confirm a diagnosis of Merkel call carcinoma (MCC)?

What is the role of light microscopy in the diagnosis of Merkel cell carcinoma (MCC)?

What are the histological classifications of Merkel cell carcinoma (MCC)?

What is the role of electron microscopy in the diagnosis of Merkel cell carcinoma (MCC)?

What is the role of immunohistochemistry in the diagnosis of Merkel cell carcinoma?

What staging systems can be used for Merkel cell carcinoma (MCC)?

Treatment

What are the treatment guidelines for Merkel cell carcinoma (MCC)?

Which treatment approaches to Merkel cell carcinoma (MCC) are supported by research results?

What is the role of avelumab (Bavencio) and pembrolizumab (Keytruda) in the treatment of Merkel cell carcinoma (MCC)?

When is surgery indicated in the treatment of Merkel cell carcinoma (MCC)?

What is the recommended treatment for stage I Merkel cell carcinoma (MCC)?

What is the role of radiotherapy in the treatment of Merkel cell carcinoma (MCC)?

What is the recommended treatment for stage II Merkel cell carcinoma (MCC)?

What is the recommended treatment for stage III Merkel cell carcinoma (MCC)?

What is the recommended follow-up after treatment for Merkel cell carcinoma (MCC)?

What is the prognosis of Merkel cell carcinoma (MCC)?

Where are metastases most likely to occur in Merkel cell carcinoma (MCC), and what is the mortality rate of metastatic MCC?

What are the survival and disease-specific death (DSD) rates associated with Merkel cell carcinoma (MCC)?

What is the role of Mohs surgery in the treatment of Merkel cell carcinoma (MCC)?

What is the role of sentinel lymph node biopsy in the management of Merkel cell carcinoma (MCC)?

What is the role of chemotherapy in the treatment of Merkel cell carcinoma (MCC)?

Medications

What is the role of avelumab and pembrolizumab in the treatment of Merkel cell carcinoma (MCC)?

Which medications in the drug class PD-1/PD-L1 Inhibitors are used in the treatment of Skin Cancer - Merkel Cell Carcinoma?