Merkel Cell Tumors of the Head and Neck

Updated: Mar 28, 2017
  • Author: Arjun S Joshi, MD; Chief Editor: Arlen D Meyers, MD, MBA  more...
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Overview

Overview

Merkel cell carcinoma (MCC) is an unusual and highly aggressive skin cancer and often appears in the elderly population. More than one half of all MCCs occur on the head and neck. MCC has a high propensity for local recurrence, as well as regional and distant metastases. One third to one half of patients with MCC eventually die from the disease. [1]

See the following image depicting Merkel cell carcinoma.

Large, violaceous nodule of a Merkel cell carcinom Large, violaceous nodule of a Merkel cell carcinoma on the antecubital fossa (photo courtesy of Dr Jonathan Cook).

Toker first described MCC more than 3 decades ago. Since then, it has been referred to as cutaneous neuroendocrine carcinoma, small cell tumor of the skin, primary undifferentiated carcinoma of the skin, anaplastic carcinoma of the skin, murky cell carcinoma, neuroendocrine tumor of the skin, or cutaneous APUDoma (a tumor composed of cells with amine precursor uptake and decarboxylation [APUD] cytochemical properties). The cell of origin is still a topic of debate, though most agree that MCC is of neuroendocrine origin. [2] Recent literature over the last 5 years has uncovered a strong association between MCC and a newly found polyomavirus (now named the Merkel cell polyomavirus, abbreviated MCV or MCPyV).

For excellent patient education resources, visit eMedicineHealth's Cancer Center. Also, see eMedicineHealth's patient education articles Skin Cancer and Skin Biopsy.

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Pathophysiology and Etiology

Merkel cells and their origin

Merkel cells are nondendritic, nonkeratinocytic epithelial cells located primarily in or near the basal layer of the epidermis. A few of these cells are also found in the dermis and portions of ectodermally derived mucosa. Merkel cells are scarce in normal skin, but they are commonly found in innervated clusters around hair follicles. These cells are thought to function as slowly adapting mechanoreceptors that mediate the senses of touch and hair movement.

The origin of Merkel cells is unclear, as they share both epidermal and neuroendocrine features. Research suggests that they may be derived from pluripotential stem cells of the dermis or, as an alternative, from neural crest cells. Cytologic and immunohistochemical data support both contentions.

Merkel cells display paranuclear staining for cytokeratins, which are also found in other neuroendocrine tumors. Osmiophilic granules contain neuropeptide, such as neuron-specific enolase, chromogranins, and synaptophysin. Evidence suggests that Merkel cells communicate with nerve terminals by means of a glutamatergic pathway, implying that they may have a neuroendocrine origin.

The general assumption is that MCC originates from Merkel cells, though this does not appear to be entirely correct. For example, MCC develops almost exclusively in the dermis, whereas the overwhelming majority of Merkel cells are found in the epidermis, a site rarely involved with MCC. Some suggest that the cells of origin may be immature pluripotential stem cells found in the dermis. These stem cells share phenotypic similarities with Merkel cells, though they do not appear to communicate with nerve terminals. It is postulated that these cells may acquire neuroendocrine features during malignant transformation.

In 2008, a paper by Feng et al found an association between MCC and a polyomavirus. This association has been a major topic of the literature over the past 5 years. The virus, now named Merkel cell polyomavirus (MCV or MCPyV), was consistently found to be clonally integrated in 80% of MCC tumors. [3, 4, 5] There is strong evidence for a causative role of this virus. [6] Research into the genome of MCV is expanding and specific proteins are being explored for their clinical utility. For example, it was found that the large T antigen (LT) of MCV is critical for carcinogenesis. The LT can now be used for immunohistochemical diagnosis and is the target for future treatment. [7, 8, 9, 10]

Histologic features

Ultrastructural and immunohistochemical studies provide support for each hypothesis. Merkel cells and MCCs have similar neuroendocrine markers, such as neuron-specific enolase, chromogranin, and synaptophysin. However, MCC expresses neurofilament proteins not observed in normal Merkel cells. MCC seldom expresses vasoactive intestinal peptide or metenkephalin, 2 markers found in healthy Merkel cells. See image shown below.

Histologic appearance of nodular Merkel cell carci Histologic appearance of nodular Merkel cell carcinoma. This dermal nodule has a cohesive, expansile growth of basophilic cells.

Risk factors for MCC

Risk factors for MCC include exposure to sun and UV light. MCC appears to be correlated with the UV-B index. The increased incidence of MCC among populations with regular sun exposure supports this correlation. In addition, exposure to methoxsalen and UV-A (which are used to treat psoriasis), as well as arsenic, appear to be factors in the development of MCC.

Immunosuppression appears to be a significant risk factor for MCC. Patients who have undergone organ transplantation and who are taking immunosuppressive drugs long term appear to be at increased risk for developing MCC. Further supporting this relationship are the observations that rates of MCC rise among people with human immunodeficiency virus (HIV) infection (13.4-fold increase in the relative risk) and in those with chronic lymphocytic leukemia.

MCC has a notable genetic component. Myriad chromosomal abnormalities have been reported with MCC. The most common abnormality is deletion of the short arm of chromosome 1 (1p36). This deletion is also found in neuroblastoma and melanoma, a finding that provides further evidence of a link between MCC and neural crest tissue. Trisomy 1, trisomy 6, trisomy 18, and the deletion of chromosome 7 have also been reported. Loss of heterozygosity has been observed in chromosome 3 (3p21, which is also seen in small cell cancer of the lung), as well as in chromosomal arm 10q and chromosome 13. The relevance of these chromosomal changes and their effect on cancer development remains unclear.

MCC is associated with the Merkel cell polyomavirus (MCV), with studies showing up to 80% involvement in MCC tumors. [3, 4, 5] Although evidence suggests a causative link between MCV and MCC, [6] further research is needed to evaluate the absolute risk of cancer. Infection with the virus is common during childhood and is usually asymptomatic. MCV is present in 35% of 13-year-olds [11] and increases to 80% at age 50 years. [12]

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Clinical Features

MCC are typically painless, firm, shiny, raised intradermal nodules that vary from red to violet. The overlying epidermis is usually intact, though advanced lesions may become ulcerated. Ulceration suggests rapid growth, which is common with MCCs.

Diagnosis can be difficult. Because of the nonspecific appearance of the tumor, its true nature is generally not established except after biopsy specimens are examined. An MCC can be mistaken for a basal cell carcinoma, squamous cell carcinoma, malignant melanoma, lymphoma, or small cell carcinoma of the skin. Most MCCs are provisionally diagnosed as basal cell carcinomas before biopsy. As a result, the margin of excision is often inadequate, and repeat excision is necessary to prevent local recurrence.

The characteristic violaceous nodule on sun-exposed portions of the body suggests the diagnosis (see image below). In addition, the fact that MCC tends to grow rapidly narrows the differential diagnosis. In patients who present with rapidly growing lesions, the most common neoplastic diagnoses are lymphoma, Merkel cell tumor, and giant keratoacanthoma. Biopsy is mandatory.

Large, violaceous nodule of a Merkel cell carcinom Large, violaceous nodule of a Merkel cell carcinoma on the antecubital fossa (photo courtesy of Dr Jonathan Cook).

MCC has a propensity to invade the dermal lymphatic system, often resulting in the formation of satellite lesions. About 70-80% of patients with MCC present with localized disease. Approximately 9-25% of patients have local-regional metastases, which manifest as enlarged, firm, painless lymph nodes. Around 1-4% present with widely metastatic disease, which most often involves the skin, lungs, liver, bone, and brain.

The early course of MCC is usually asymptomatic. As a result, a delay in diagnosis is not uncommon until regional adenopathy or widely metastatic disease is noted. As many as one third of patients present with a neck mass without an obvious primary lesion. In rare cases, MCC have been associated with superior vena cava (SVC) syndrome.

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Epidemiology

MCC is a rare neoplasm. In the United States, the estimated annual incidence of MCC is 0.23 per 100,000 Caucasian individuals; this rate roughly translates to 470 new cases yearly. The tumor is rare in people of other races. For example, African Americans have an annual incidence of 0.01 per 100,000 population.

The tumors most often arise in the sixth and seventh decades of life (mean age, 67.8 y; age range, 15-97 y).

The head and neck is the most common site of occurrence (50%), followed by the lower limbs (30%), the upper limbs (15%), and the trunk (5%). On the face, the eyelids are the most common sites for MCC. The increased incidence in sun-exposed areas suggests that UV light exposure plays a role in the etiology of MCC. However, reports of MCC uncommonly occurring in unexposed sites, such as the genitalia or the oral mucosa, suggest that other factors must play a role.

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Diagnosis and Evaluation

Physical examination

Perform thorough physical examination, with careful attention to the cheeks, nose, mouth, and eyelids because these are the most common sites of MCC involvement.

Evaluate for a red or violet nodule with telangiectasias and intact skin. In some cases, ulceration may be present.

It is also important to evaluate the mucous membranes of the oral cavity, though these are not common sites for MCCs.

Biopsy and histology

Biopsy must be performed to confirm the diagnosis.

On light microscopy, MCC appears as small, round, basophilic cells arranged in sheets, rests, or trabeculae (see image below) involving the dermis and usually sparing the epidermis.

Note the small, round, basophilic cells arranged i Note the small, round, basophilic cells arranged in sheets, rests, or trabeculae in this Merkel cell carcinoma. The cells possess hyperchromatic nuclei, minimal cytoplasm, and frequent mitotic and apoptotic figures (hematoxylin-eosin stain).

The cells possess hyperchromatic nuclei, minimal cytoplasm, and frequent mitotic and apoptotic figures, which suggest a rapid growing neoplastic process. MCC cells positive for Merkel cell polyomavirus (MCV) may have less nuclear polymorphism and less cytoplasm than their MCV-negative counterparts. [13]

MCC can resemble and be confused with other poorly differentiated small cell carcinomas, such as metastatic small cell carcinoma of the lung, Ewing sarcoma, neuroblastoma, melanoma, or basal cell carcinoma.

As the tumor advances, it infiltrates into underlying subcutaneous fat, fascia, and muscle. Vascular and lymphatic invasion is common.

Three histologic subtypes of MCC have been described: intermediate, small cell, and trabecular. The intermediate subtype is the most common. Of note, subtypes are not clinically useful because they do not help in predicting the patient's outcome or survival.

Immunohistochemistry

Definitive diagnosis is based on the presence of antibodies to cytokeratin (CK) 20 (in the form of a perinuclear dotlike pattern typical of neuroendocrine tumors), neuron-specific enolase, synaptophysin, and chromogranin. CK19 expression is increased in tumors positive for the Merkel cell polyomavirus and may help in diagnosis of CK20-negative tumors. [14]

The absence of S-100 protein and homatropine methylbromide marker essentially excludes the diagnosis of malignant melanoma. Likewise, the absence of leukocyte common antigen excludes cutaneous lymphoma.

Epithelial membrane antigen and BEP-EP4 can also be found in MCC.

Cytokeratin 7 is found in bronchial small cell carcinoma and not in MCC.

MCC tumors infected with the Merkel cell polyomavirus (MCV) characteristically show immunoreactivity with monoclonal antibodies against the MCV large T (LT) antigen [9] in up to 97% of cases. [15]

Electron microscopy

Electron microscopy can be used to confirm the diagnosis of MCC, when needed.

The most characteristic findings are perinuclear bundles of intermediate filaments and electron-dense neurosecretory granules (see image below). These features virtually confirm the diagnosis of MCC.

Electron photomicrograph of a Merkel cell carcinom Electron photomicrograph of a Merkel cell carcinoma shows a dense core granule (arrow).

Computed tomography /positron emission tomography

CT has a limited role in the evaluation of localized disease.

CT may reveal regional nodal involvement, or systemic involvement with metastases to the lung, bone, liver, etc. The sensitivity, specificity, positive predictive value, and negative predictive value of CT for regional lymph node involvement is 47%, 97%, 94%, and 68%, respectively. Sensitivity is increased 83% using18 F-Fluorodeoxyglucose (FDG) positron emission tomography (PET). [16] FDG-PET/CT can also uncover metastatic disease (mostly to bone/bone marrow) that is undetected on CT. [17]

MRI

In the evaluation of MCC, MRI accurately identifies metastases to soft tissue sites, brain, and bone marrow and should be performed is there is any suspicion for central nervous system involvement. [18]

Selective sentinel lymph-node lymphoscintigraphy and biopsy (SSLNB)

SSLNB is effective in the evaluation of regional micrometastatic disease in cutaneous melanoma.

Colloids labeled with technetium-99m (99m) are intradermally injected into the primary excision site. A gamma camera with a large-field view is used to localize lymphatic drainage to sentinel nodes in the regional nodal basins. The identified sentinel nodes can be tattooed before surgery.

Intraoperative localization of the sentinel nodes can also be performed in a similar manner by using a hand-held gamma counter.

As an alternative, vital blue dyes can be injected just before the operation to localize the sentinel nodes. During surgery, pale-blue staining marks afferent lymphatics, which are followed to the sentinel nodes.

A meta-analysis of patients with MCC who were undergoing SSLNB revealed that two thirds had negative biopsy results and that 97% remained disease-free 7 months after biopsy. Of the third who had positive biopsy results, 33% had some form of local, regional, or systemic recurrence at 12 months.

SSLNB positivity appears to be correlated with an increased short-term risk of recurrence or metastasis.

Somatostatin receptor lymphoscintigraphy

Scanning with radiolabeled octreotide (a somatostatin analog) has been used in the evaluation of disease extension.

The efficacy of this study is currently under investigation.

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Clinical Course and Prognostic Factors

Aggressiveness and spread of MCCs

MCCs are aggressive malignancies with courses more similar to those of malignant melanomas than to those of other skin cancers. Similar to melanoma, MCC has a high propensity for local recurrence, spread to regional lymph nodes, and distant metastasis.

MCC spreads in a predictable fashion. Initial spread is to first-echelon lymph nodes. Subsequent spread involves higher-order nodal regions and then distant sites.

Staging and outcomes

The most commonly used clinical staging system, first described by Yiengpruksawan, is as follows:

  • Stage I - Isolated local disease
    • Stage Ia - Tumor ≤2 cm in diameter
    • Stage Ib - Tumor ≥2 cm in diameter
  • Stage II - Evidence of regional nodal spread
  • Stage III - Evidence of distant metastasis

About 75% of patients initially present with localized stage I disease. Nearly 20% of patients present with stage II disease, and 4% of patients present with distant stage III disease. During follow-up, 34% of patients develop regional metastases, whereas 27% developed distant metastases.

After primary surgical excision, local recurrence develops in 27-60% of patients, regional nodal involvement develops in 45-91% of patients at some time during the course of the disease, and distant metastases occur in 18-52%.

The overall 5-year survival rate is 50-70%. The presence of regional nodal or distant metastases adversely affects survival.

Prognostic factors

Poor prognostic factors include the stage of disease at presentation, which is influenced by presence of nodal and/or distant disease. In particular, the presence of nodal disease influences survival and the likelihood of metastatic disease. Median survival for patients with positive nodes is 13 months, compared with 40 months for those with negative nodes. Primary tumor size does not predict nodal disease. [19]

The location of the primary tumor also appears to be a poor prognostic factor. Within the head and neck, lip tumors have a high rate of invasion into bone, cartilage, and muscle and are associated with decreased survival. [20] Lesions affecting the lower limbs are associated with a high rate of local-regional failure because of the difficulty of surgical resection and radiation therapy at these sites. In addition, lesions on the lower extremities have a propensity for early dermal lymphatic infiltration. Other poor prognostic factors are age older than 60 years, male sex, a primary lesion >2 cm, and a lack of radiation therapy.

Tumor thickness is a significant risk factor for 5-year mortality. Patients with tumors thicker than 10 mm have 18% survival over 5 years compared with 69% in patients with tumors thinner than 10 mm. [21]

MCC is associated with the Merkel cell polyomavirus (MCV), with studies showing up to 80% involvement in MCC tumors. [3, 4, 5] The prognostic risk associated with MCV is unclear, as there has been conflicting data on the subject. [14]

Certain transcription factors, such as HATH-1 and Brn-3c, are being studied as prognostic factors for MCC. Whether these are linked to MCC is unknown at this time. Expression of p63, a transcription factor within the p53 family, is associated with reduced overall survival. [22] P-cadherin expression is associated with increased recurrence-free survival. [23]

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Treatment & Management

Approach Considerations

MCC is an aggressive malignant tumor with a high propensity for local recurrence, regional nodal involvement, and distant metastases. Treatment depends on the clinical stage at presentation and may involve surgery, radiation therapy, and/or chemotherapy. Multimodal therapy for MCC is often challenging because many patients are elderly and cannot tolerate aggressive treatments. [24] Problems with healing, as well as surgical-site morbidity, must be taken into account to create an effective, individualized therapeutic regimen.

Surgical Treatment

The treatment of choice for the primary lesion in MCC is surgical excision. Because of the high propensity for local recurrence, wide local excision including 2-3 cm of normal-appearing skin is the standard recommendation for reducing the incidence of recurrence. However, this margin is not always possible in the head and neck region. In practice, a disease-free margin appears to be most important factor in the evaluation of patient outcomes.

For the reasons just discussed, Mohs micrographic surgery followed by radiation therapy has proven to be an equally effective option for small primary facial MCCs. This surgical approach has the advantage of sparing as much normal adjacent tissue as possible, an important consideration when the primary lesion occurs on cosmetically important areas of the head and neck. Studies have demonstrated equivalent rates of local disease control with Mohs surgery and radiation therapy, as compared with standard surgical excision.

Treatment of first- and second-echelon nodal basins for the clinically negative neck (stage I) is controversial. Some suggest that prophylactic lymphadenectomy should not be performed routinely. Although prophylactic lymphadenectomy substantially decreases the local recurrence rate, it does not appear to affect disease survival. Some surgeons recommend prophylactic neck dissection for aggressive tumors, that is, those >2 cm, those with >10 mitotic figures per high-power field, and/or those with histologic evidence of lymphatic involvement.

Most surgeons are now performing intraoperative lymphoscintigraphy in most cases, reserving neck dissection for cases involving nodal positivity. Lymphoscintigraphy may spare patients from unnecessary lymphadenectomy, and it theoretically improves accuracy in staging clinically localized MCC. This treatment has been described in only a few centers, and its role in the routine management of MCC remains undefined.

Radiation Therapy

MCC is a radiosensitive tumor. Doses of 45-60 Gy are administered in standard fractions to the surgical site and to the regional lymphatic bed.

A study by Bishop et al indicated that treatment for MCC 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 MCC were both 96%. [25]

As the sole treatment for localized (stage I) lesions, radiation therapy has been used with some success. In the Bishop study, no regional recurrences were found among 22 patients with gross nodal disease who received radiation therapy but no neck dissection. [25] However, some studies have demonstrated high rates of local-regional recurrence in patients treated with radiation alone. [26]

Radiation therapy is not recommended as treatment for primary disease in patients able to undergo surgery. It is used as a primary treatment when patients are unable to tolerate surgery or when wide resection is required to remove the disease with a negative margin.

Radiation therapy is most often used an adjunctive therapy after surgical resection of the primary lesion and/or affected nodal basins. In a recent study, postoperative radiation therapy appeared to reduce local recurrence rates from 44% to 12%. A meta-analysis of 333 reports in the literature concluded that surgery plus radiotherapy decreases the rates of local and regional recurrence as compared to surgery alone. [27]

Radiation therapy may also be used in the palliative setting to reduce symptoms of pain, bleeding, ulceration, and secondary infection.

Chemotherapy

Chemotherapy has primarily been used for the palliation of advanced-stage MCC. Although most cases of advanced disease have some response to chemotherapy, the effect is not long term. Complete cure is extremely rare in patients with locally advanced disease or metastasis.

Chemotherapy with radiation therapy is being used to treat locally advanced or recurrent disease. A study by Chen et al of 4815 patients with MCC 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. [28]

Chemotherapy for MCC is based on previous experience with small-cell lung carcinoma, which is pathologically similar to MCC. Common regimens include cyclophosphamide, doxorubicin, vincristine or etoposide, and cisplatin. Partial response rates approach 75%, and complete response rates are observed in 40% of patients with locally recurrent or advanced disease. Chemotherapy appears to be more effective for patients with locally advanced disease (response rate, 69%) than for those with metastatic disease (response rate, 57%).

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 MCC 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 MCC 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 reached 33% (29 patients), partial response was 22%, and complete response was 11%. Eight-six percent of tumor responses lasted at least 6 months (25 patients), and 45% lasted at least 12 months (13 patients). Response duration lasted from 2.8 to over 23.3 months. [47]

Future treatments

Upcoming medical treatment of MCC may involve the Merkel cell polyomavirus. In tumor cells positive for Merkel cell polyomavirus, type I interferon has been shown to increase their apoptotic cell death in vivo through interference of the large T antigen of MCV . [29] Other proteins are the target of experimental vaccines. [30] Further exploration of virus-specific therapy will provide exciting new modes of treatment of this malignant cancer.

Treatments by Stage

Stage I

Therapeutic options for stage I disease include surgical excision and radiation therapy. Adjuvant chemotherapy is generally used postoperatively, especially when wide surgical margins are unattainable or when the surgical margins were involved with tumor.

Stage II

Patients with clinical stage II disease present with clinically positive regional nodes. Fine-needle aspiration can be used to confirm regional metastatic spread. Most authorities recommend complete lymphadenectomy and postoperative radiation therapy given to the regional site.

Biopsy of any suggestive lesion at the primary site is performed to confirm local recurrence. If recurrence is present, treatment involves repeat excision with a 2-cm margin or with Mohs micrographic surgery. Administer additional radiation therapy if possible.

Biopsy of suggestive nodes is also done to confirm regional recurrence. If present, treatment includes repeat dissection of the lymph node basin and further radiation therapy, if possible. Adjuvant chemotherapy is used to manage regional recurrence.

Stage III

Distant metastatic disease (stage III) most often occurs in the lungs, liver, bone, or brain. The prognosis for patients with stage III disease is poor, with a mean survival time of 8 months.

MCC is a chemosensitive tumor. Because MCC is histochemically similar to small cell carcinoma of the lung, the chemotherapeutic regimens to treat them are similar. Carboplatin and etoposide have displayed promising results with comparatively less toxicity. In the setting of advanced disease, chemotherapy has produced good response rates, including complete remission; however, such favorable responses are usually short-lived. Nevertheless, occasional cases of long-term remission justify the use of systemic therapy in patients who can tolerate the toxicities of the chemotherapeutic agents. In March 2017, the PD-1/PD-L1 inhibitor avelumab became the first drug approved by the US Food and Drug Administration for metastatic MCC. [47]

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