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Merkel cell carcinoma in situ: Begin the beguine?

DII small banner By Warren R. Heymann, MD
May 26, 2017

I have to admit, the concept of Merkel cell carcinoma in situ (MCCIS) was “below my radar screen,” until I read the intriguing article, from Jason Lee’s group, questioning whether an intraepidermal proliferation of Merkel cells (MC) within a seborrheic keratosis is MCCIS or MC hyperplasia (1). Every Merkel cell carcinoma (MCC) I have diagnosed has been dermal (unless I unwittingly missed an epidermal component).

According to Pulitzer, “MCC most often presents in an older white population with a male predominance. The median age of presentation falls within the late seventh decade, despite a broad age range (fourth to tenth decades). Sun-exposed sites, including the head/neck and limbs, are the most common sites of presentation. There seem to be 2 patterns of clinical presentation that align with either MCV-positive, morphologically monophenotypic, and/or cytokeratin 20 (CK20)-positive tumors versus MCV-negative, often morphologically heterogeneous, tumors. The first, more prevalent group (80% of cases) arises in a slightly younger population and is equally present on the limbs and head/neck, sometimes found on the buttock or other non–sun-exposed sites. These tumors are often (>45%) indeterminate to clinically benign flesh-colored to violaceous dome-shaped nodules with chief differential diagnoses of cysts, pimples, dermatofibromas, lipomas, and lymphomas; 10% are suspected to be nonmelanoma skin cancer. The second group of patients more commonly presents with tumors in sun-damaged skin of the head and neck, in a background of other nonmelanoma skin cancers, and are clinically more likely to be diagnosed as a new nonmelanoma skin cancer (58%), with only 15% suspected to be benign. Clinical features, such as overlying scale and nearby actinic keratoses, solar lentigines, and telangiectasia, are common. A third, smaller group of patients presents with nodal adenopathy, eventuating in a biopsy-diagnosis of apparently metastatic MCC of unknown primary skin site.” (2)
In a review of 132 cases of MCC, Smith et al identified an intraepidermal component in 11 (8.33%). (3). Pure MMCIS, however, has only rarely been reported. An example was the case of a 71-year-old man with a history of melanoma and basal cell carcinoma, who was found to have MCCIS (CK7, [partial] CK20, EMA, and synaptophysin positive; MC polyomavirus negative) associated with Pagetoid Bowen disease, from a pink, pearly papule of the left zygoma. As Miraflor et al note, MCs, which are essential mechanoreceptors for light touch, are present in the basal layer, often near nerve ending, and within the hair follicle. They surmise that cases  of MCC with epidermal and dermal involvement may initiate from the epidermis (4).

A similar case was reported by Tammie Ferringer et al, describing the case of a 76 year-old man, with a history of non-melanoma skin cancers and melanoma, with MCCIS associated with an actinic keratosis (5). MCCIS has also been reported within a benign trichilemmal cyst (6). Dr. Ferringer’ s case was reported in 2005, 3 years prior to the discovery that 80% of MCCs are associated with a polyomavirus. In pure cases of MCCIS published since 2008, I am not aware of any that have been linked to the Merkel cell polyomavirus. According to Miraflor et al, with the exception of a solitary case in reference 3, all reported cases of MCCIS have shown no evidence of recurrence or metastasis after excision (4). (To my reading, I am not sure if the case in question in reference 3 was pure MCCIS or a lesion with a dermal component).
Pure cases of MCCIS (no dermal component) raise many questions that warrant further study. Given the paucity of reports, it is difficult to reach any conclusions other than the following: 1) Intraepidermal Merkel cells may be found in lesions exposed to ultraviolet light — most characteristically associated with non-melanoma skin cancer, but also within benign lesions such as seborrheic keratoses or pilar cysts.; 2) It remains to be determined if these are incidental hyperplasias or MCCIS; 3) Such lesions may due to another mechanism(s) rather than infection with the Merkel cell polyomavirus.

Although I suspect that such lesions are incidental hyperplasias rather than incipient MCCs, until such time that hypothesis is unequivocally proven, it makes sense recommending a complete excision of these lesions, reassuring patients that their prognosis is excellent. Much research remains to be performed to ascertain the implications of clusters of intraepidermal MCs and their relationship to neighboring keratinocytes. Could this be the beginning of an intricate dance (such as the Beguine) of carcinogenesis? Any misstep could prove potentially detrimental. Fortunately, you will see perfect synchronization between Eleanor Powell and Fred Astaire in the following link: https://youtu.be/DWW6QeeVzDc — if we could only get our cells coordinate this way, there would never be a problem!

1. McFalls J, et al. Intraepidermal proliferation of Merkel cells within a seborrheic keratosis: Merkel cell carcinoma in situ or Merkel cell hyperplasia? J Cutan Pathol 2017; 44: 480-5.
2. Pulitzer M. Merkel cell carcinoma. Surg Pathol Clin 2017; 10: 399-408.
3. Smith KJ, et al. Neuroendocrine (Merkel cell) carcinoma with an intraepidermal component. Am J Dermatopathol 1993; 528-33.
4. Miraflor AP, et al. Intraepidermal Merkel cell carcinoma with Pagetoid Bowen’s disease. J Cutan Pathol 2016; 43: 921-6.
5. Ferringer T, et al. Merkel cell carcinoma in situ. J Cutan Pathol 2005; 162-5.
6. Su W, et al. Merkel cell carcinoma in situ arising in a trichilemmal cyst: A case report and literature review. Am J Dermatopathol 2008; 30: 458.

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