1

Introduction

Merkel cell carcinoma (MCC) is a rare and aggressive neuroendocrine tumor that typically arises from the skin [ ]. Merkel cells are found in the basal layer of the epidermis and responsible for light touch sensation [ ]. These tumors appear as a red or violaceous nodule often with overlying telangiectasia [ ]. The most common locations are sun-exposed areas, with 50% of tumors occurring in the head and neck region [ ]. Merkel cell carcinoma is characterized by an aggressive behavior with frequent local recurrence, regional lymph node and distant metastasis [ ]. Non-cutaneous MCC has been reported in different locations infrequently [ ]. In this paper, we report a case of primary Merkel Cell Carcinoma of the parotid gland and provide a comprehensive review of the literature of this rare entity.

2

Case report

A 71 years old white man who presented to the oral and maxillofacial surgery/head and neck oncology outpatient clinic at our institution complaining of a painless, slowly growing mass on the right side of his face of four months duration. The referring primary care physician obtained Fine-Needle Aspiration (FNA), computed tomography (CT) with intravenous contrast, and subsequently the patient was referred to our clinic.

At presentation, the patient reported a painless right facial mass with slight enlargement. He denied trauma, infection, drainage, dysphagia, dysphonia, xerostomia, or any other related symptoms. His medical history was significant for urinary bladder cancer, which was treated with surgical resection and chemotherapy five years ago. In addition, he has history of diabetes mellitus (II), hypertension, aortic valve replacement, and hip replacement. He was a former smoker (quit 5 years prior to presentation), drank alcohol socially, denied recreational drugs use, and his family history was noncontributory. He reported no known allergies and was on aspirin 81mg, atorvastatin, docusate, empagliflozin, insulin, metformin, metoprolol, and pantoprazole. No personal or family history of skin cancer was reported.

Clinical examination revealed a 2 × 3 cm firm, nontender, mobile mass of the right parotid gland with intact, normal overlying skin. No skin lesions were identified, and no cervical lymphadenopathy was noted. The facial nerve function was intact. The intraoral exam was unremarkable, patent, non-inflamed Stenson’s duct with clear salivary flow. The CT showed 35 × 19.5 × 18.7 mm mass in the superficial lobe of the right parotid gland and no lymph node involvement ( Fig. 1 ). FNA cytology was inconclusive; however, it demonstrated some atypical small blue cell proliferation.

Computed Tomography with IV contrast showing right parotid mass.

Right superficial parotidectomy with facial nerve dissection and preservation was planned. However, intraoperatively, the lesion was found to be firm and infiltrative and a subtotal parotidectomy with facial nerve dissection and preservation was performed ( Fig. 2 ). Histologically, the tumor showed predominantly round to oval cells arranged in sheets and trabecular pattern. Nuclear overlapping and molding were noted. The cytoplasm was thin and extremely scant. The chromatin was finely granular and evenly distributed. The nucleolus was inconspicuous. The histomorphological features were diagnostic of Merkel cell carcinoma ( Fig. 3 A and B). In immunohistochemical analysis, the tumor cells were positive for cytokeratin (CK20) and showed a paranuclear dot-like pattern which is characteristic for MCC ( Fig. 4 ). Also, it was positive for Anti-Cytokeratin (CAM 5.2) and other neuroendocrine markers like synaptophysin. Furthermore, it was negative for Leukocyte Common Antigen (LCA), ruling out lymphoma and tumors of lymphoid origin. Tumor cells were also negative for small cell carcinoma, melanoma, and metastatic tumor markers.

Right parotid gland merkel cell carcinoma.

A&B: H&E histopathology slides of the tumor. Low power magnification 40x (3A) and High power magnification (3B): Tumor cells arrange in trabecular pattern. These cells have scant cytoplasm, round to oval nuclei, and evenly distributed chromatin. Nucleoli are inconspicuous.

Tumor cells showing the paranuclear dotlike pattern immunoreactivity for CK 20 immunohistochemical stains. This pattern is diagnostic of Merkel cell carcinoma.

Postoperative course was uneventful, the patent was discharged home. However, after one week, the patient presented to the clinic with a dehiscence in the surgical site that required debridement. The patient had a relatively prolonged healing time. Another formal skin evaluation was performed, no skin lesions were found. Positron-Emission Tomography (PET) scan was obtained and was negative for any other lesions. The case was presented to the multidisciplinary tumor board. Due to the aggressive behavior and uncommon location of the tumor, post-operative radiation therapy was recommended and completed.

3

Discussion

Merkel cell carcinoma (MCC) is a rare primary neuroendocrine neoplasm of the skin that demonstrates aggressive behavior and dismal prognosis [ ]. It was first reported by Toker as “Trabecular Carcinoma of the skin” in 1972 [ , ]. Tang and Toker in 1976, proposed that this carcinoma was arising from the Merkel cell, a mechanoreceptor of the hair follicle [ , ]. The name “Merkel” refers to Friedrich Sigmund Merkel, a German pathologist, who first described the Merkel cell in the skin of geese and ducks in 1875 [ , ]. Merkel cell is an epidermal, nondendritic, nonkeratinocytic cell of neuronal origin, found within the basal layer of the epidermis, functioning as a type I mechanoreceptor involved in light tough sensation and hair movement [ , , ]. The embryologic origin of these cells was hypothesized in two different theories, one proposed that the origin is epidermal stem cells with neuroendocrine differentiation, while the other recent theory suggest that these cells originate from the neural crest [ ].

Even though MCC is considered a rare tumor, the incidence has been increasing in the last two decades [ ]. It increased from 0.22 cases per 100,000 in 1986 to 0.79 cases per 100,000 in 2011, this may be the result of greater recognition and improved techniques for diagnosis [ ]. In the United States, approximately 1600 to 2500 cases of MCC are diagnosed annually [ ]. MCC mostly occurs in elderly (older than 50 years), immune suppressed patients, particularly in organ transplant recipients and sun-exposed areas, with 50% of tumors occurring in the head and neck region [ , ]. It has a slight male predominance and is more common in the Caucasian (0.23 per 1,00,000) than African American (0.01 per 1,00,000) population [ ]. MCC typically invades both lymphatic channels and blood vessels, which subsequently leads to both regional and distant metastasis and, overall poor prognosis [ ]. 5-years overall survival of head and neck MCC ranges between 40% and 68% and the overall mortality rate is twice that observed in cutaneous melanoma (33% vs. 15%) [ , ]. Common sites of metastasis have been described as lymph nodes, mediastinum, lung, liver, and bone [ ].

Although MCC most commonly affect the skin, approximately 4.5% of MCCs arise on mucous membranes [ ]. In the infrequent non-cutaneous presentation of MCC, the challenge is to identify whether it represents a metastatic MCC of unknown primary or a primary MCC in a non-cutaneous site [ ]. In about 8–14%, MCC presents as a metastasis in a lymph node (most common presentation) or visceral site, without a known primary cutaneous tumor [ ]. Akhtar et al. reviewed 875 cases of MCC from 36 reports and found MCC of unknown primary in 5% of the cases [ ]. Various case reports of atypical sites of primary MCC in the head and neck include the tongue, upper lip, lower lip, alveolar mucosa, hard palate, nasal fossa, floor of the mouth and parotid gland [ ]. De novo MCC of the parotid gland is extremely rare [ ]. Szeder et al. proposed the origin of MCC from neuroendocrine cells due to migration of neural crest cells where they differentiate into mature Merkel cells [ ]. This process would potentially make it possible for MCCs to develop in non-cutaneous sites, including the parotid gland [ ]. Moreover, malignant transformation is another possible mechanism for the development of MCCs at atypical sites [ ]. Fornelli et al. reported two patients of parotid gland MCC, both had no cutaneous primary tumor and assumed that these tumors developed from the neuroendocrine component of Warthin tumor [ ]. In 2013, Gioacchini et al. reported a systemic review of MCC presentation in the head and neck/ENT area and only identified five cases of MCC in which the parotid gland was the primary site [ ]. Furthermore, a review from Germany by Knopf et al., in 2016, reported 91 parotid gland malignancies and only eight patients had primary parotid gland MCC [ ]. In their review, there were no differences in Recurrence Free Interval (RFI) and Overall Survival (OS) between primary parotid MCC and other primary parotid gland malignancies [ ]. However, it was noted that patients with primary parotid MCC were significantly older (75±4 years) and had significantly more distant metastases at the time of diagnosis [ ].

High-grade neuroendocrine carcinoma of the parotid can be classified based on their immunophenotype to “Merkel Cell type” and “Pulmonary type” [ ]. Those that express cytokeratin 20 (CK20) are referred to as “Merkel cell type,” as this protein is characteristically expressed by histologically similar high grade neuroendocrine (Merkel cell) carcinomas of the skin [ ]. The other type is known as “pulmonary type,” as CK20 is not expressed by neuroendocrine carcinomas of lung origin [ ].

Moreover, chromosomal alterations in MCC are found to be similar to that seen in small cell lung cancers [ ]. The most frequent genetic alterations in MCC involve the short arm of chromosome 1, where deletions and unbalanced translocations happen in about 40% of the cases [ ].

There is considerable diagnostic confusion between parotid gland Merkel Cell Carcinoma and Cutaneous Merkel Cell Carcinoma since the morphologic and immunohistochemical overlap between the two is essentially the same [ ].

Cutaneous MCCs of the head and neck commonly metastasize to lymph nodes that are in or adjacent to the parotid gland, thus making a metastasis difficult to be distinguished from a primary parotid gland MCC [ ]. Moreover, it is complicated due to the fact that the parotid gland is rich in lymph nodes that are intimately associated with the glandular parenchyma unlike other salivary glands [ ]. A history of a primary cutaneous MCC is often used to make the distinction [ ]. In addition, PET scan is being used to rule out any other lesions. In our case, the patient denied any history of cutaneous MCC or any history of skin cancer. A comprehensive dermatological examination did not reveal any skin lesion and his PET scan was negative for any other lesions.

The etiology of MCC has been attributed to ultraviolet B (UVB) radiation exposure, immunosuppression and more recently to Merkel Cell PolyomaVirus (MCPyV) [ ]. Ultraviolet B (UVB) radiation exposure for long duration (older patients) has been shown to correlate with the development of the disease [ ]. For instance, white people living in Hawaii, where the UVB index is the highest, have the highest incidence of MCC [ ]. It is assumed that the head and neck is the region of the body that tends to be the least protected from sun exposure [ ]. Chronic repeated insults may lead to development of MCC [ , ]. Immunocompromised conditions, iatrogenic or acquired, have a strong correlation to the development of MCC [ ]. Solid-organ transplant patients are at high risk for developing MCC with an average of 7 years after transplantation [ , ]. Moreover, patients with acquired immunodeficiency disease have been shown to have increased risk of developing MCC, the relative risk has been reported as 13.4 when compared to the general population [ , ]. It is well established that immunosuppression is an independent risk factor for the development of MCC [ , ]. In our case, the patient had a history of urinary bladder cancer that was treated with surgery and chemotherapy five years ago. It is possible that his immunocompromised condition led to the development of parotid gland MCC.

The viral etiology of Merkel cell polyomavirus (MCPyV) was proposed by Feng et al., in 2008 [ , ]. The virus was found to be integrated at various locations in the MCC tumor genome in a clonal pattern, which illustrated that infection of the cells occurred prior to their clonal expansion [ ]. MCPyV has been found in up to 80% of cutaneous MCCs and is clonally integrated into the host genome [ , , ]. Moreover, Chernock et al. evaluated seven cases of primary parotid gland high-grade neuroendocrine carcinomas, with the aim to distinguish it from cutaneous MCC [ ]. They concluded that “Merkel cell” type primary parotid neuroendocrine carcinomas develop through different biological pathways than most cutaneous MCCs, which appear to be virally driven [ ]. They found that MCPyV is clonally integrated but not capable of replicating in Merkel cell carcinomas [ ]. Viral infection and integration must occur prior to tumor development and thus, is presumed to play an important role in oncogenesis but its exact role is not entirely clear [ ].

The classic histologic appearance of Merkel cell carcinoma consists of small round to oval cells arranged in sheet and in trabecular pattern. These cells are monotonous with minimal cytoplasm and finely stippled (salt and pepper) neuroendocrine chromatin. Molding, hyperchromatic nuclei, with abundant mitotic figures and apoptosis are usually seen [ , , , ]. In immunohistochemistry, MCCs express keratin in a classic paranuclear dotlike pattern with Cytokeratin 20 (CK20) which is a highly specific and sensitive marker for MCC [ ]. Also, MCCs express the classic neuroendocrine markers including chromogranin A, neuron-specific enolase (NSE), and synaptophysin [ ]. MCC is negative for Leukocyte Common Antigen (LCA), CD20, CD3 which are used to rule out lymphoma and tumors of lymphoid origin [ , ]. MCC is negative to thyroid transcription factor 1 to exclude small cell carcinoma of the lung and negative to metastatic tumor markers such as estrogen receptors, mammaglobin, p63, CK7, and AE1/AE3 [ , ]. It is essential to note that there are no differences in the histological and immunohistochemical profile between the cutaneous and parotid gland Merkel Cell Carcinomas [ ]. The histologic and immunohistochemical presentation in our case are consistent with the typical MCC and illustrated in Figs. 3A and B &4 .

A multidisciplinary team approach in the management of MCC is essential [ ]. The mainstay treatment of cutaneous MCC includes resection with 1-to 2-cm margins and adjuvant radiation therapy to improve locoregional control and minimize recurrence [ ]. However, obtaining such wide margins in the head and neck area may be difficult to achieve [ ]. Recent guidelines emphasize the role of sentinel lymph node biopsy for clinically node-negative patients [ , ]. Patients with positive sentinel lymph nodes will undergo lymph node dissection or radiotherapy to the nodal basin [ , ]. In general, chemotherapy neither reduced the risk of recurrence/distant metastasis, nor improved the overall survival [ ]. Adjuvant Chemotherapy is not recommended because it does not produce a durable response and is generally preserved for palliation of stage IV disease [ , ]. New immunotherapy with avelumab, an anti-PD-L1 agent, and anti-PD-1 agents pembrolizumab and nivolumab, may provide more durable treatment responses [ , ]. Due to the rarity of Parotid MCCs, treatment guidelines are not yet established. Several reports include wide local excision via superficial, subtotal and total parotidectomy with facial nerve preservation or sacrifice have been reported in the literature [ , , , ]. Neck dissection was performed in cases who had a preoperative diagnosis of parotid MCC. However, for cases without preoperative diagnosis, the neck was treated with postoperative radiotherapy [ , , , , ]. Some of these reports also added chemotherapy regimen to their patients [ , ]. Patient with parotid MCC generally do not benefit form facial nerve sacrifice to extend tumor free margins [ ]. In our case, we did not have a preoperative diagnosis of MCC and there was no lymph node involvement. The patient underwent a subtotal parotidectomy with facial nerve preservation and postoperative adjuvant radiation therapy. In general, patients with parotid MCC should be treated following the guidelines of salivary glands malignancies.

In conclusion, primary Merkel Cell Carcinoma of the parotid gland is extremely rare and might present clinically as benign parotid tumors, as in this case. Immunohistochemistry staining and exclusion of other primary lesions through a thorough clinical cutaneous exam are essential for the diagnosis. Multimodal treatment is highly recommended. Surgical excision via superficial, subtotal or total parotidectomy with adequate margins with facial nerve preservation and adjuvant radiation therapy is generally acceptable. Due to the high risk of metastasis and aggressive behavior of parotid MCCs, the regional lymph nodes basin should undergo either elective neck dissection, irradiation, or sentinel lymph node biopsy. Chemotherapy is preserved for advanced stage disease; immunotherapy might provide reasonable response in the future.

Proof of consent

The case is written as non- identifiable. consent is available upon request.