Review Article
The Toker Tumor: Spectrum of morphologic features in primary neuroendocrine carcinomas of the skin (Merkel cell carcinoma)

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Abstract

Primary neuroendocrine carcinoma of the skin is a relatively rare tumor that was first described by Cyril Toker in 1972. Since the seminal paper by Toker based on simple morphologic observations and detailed clinical correlation, our understanding of the clinical, morphological, and biological attributes of these lesions has grown exponentially with their increased awareness by pathologists and clinicians as well as with the many contributions of modern diagnostic techniques. The present review focuses principally on the various morphologic appearance that these tumors are able to adopt, the role of modern special techniques for diagnosis, and the conditions that need to be considered in their differential diagnosis.

Introduction

Primary neuroendocrine carcinoma of the skin (PNECS) is a rare skin cancer of neuroendocrine origin that was first described by Toker in 1972 [1] under the designation of trabecular carcinoma of the skin. This tumor is commonly known as Merkel cell tumor, although it has also gone by a variety of other names including APUDoma, primary small-cell carcinoma of the skin, primary undifferentiated carcinoma of the skin, and the Toker tumor [2]. Tang and Toker [6] were the first to postulate that these tumors might be derived from Merkel cells, which are normally found in the skin and in parts of mucosal surfaces derived from the ectoderm. Merkel cells are thought to be of neuroectodermal origin and function as slow-acting mechanoreceptors in the basal layer of the epidermis to provide information about touch and hair movement [3], [4], [5].

The histogenesis of this tumor is still a matter of controversy. The most commonly accepted hypothesis is the one postulated by Tang and Toker in 1978 [6], who found dense core neurosecretory granules in the tumor cells by electron microscopy and suggested a neural crest derivation, most likely from Merkel cells. Other authors, however, have challenged this concept because neuroendocrine carcinomas of the skin arise primarily in the dermis and not from the epidermis, where Merkel cells are most commonly found [7], [8], [9], [10], [11], [12].

Primary neuroendocrine carcinoma of the skin occur primarily in elderly white patients with a slight male predilection; however, some studies have demonstrated equal incidence in men and women. The average age of presentation is 69 years, and only 5% of cases occur before age 50. Clinically, it presents as a rapidly growing, solitary, purple dome-shaped papule or plaque on sun-exposed skin frequently localized in the head and neck region, followed by the extremities and trunk. Primary neuroendocrine carcinoma of the skin is a high-grade, aggressive cutaneous malignancy with a propensity for local recurrence and regional lymph node metastasis [4], [10], [13]. In fact, the original description of the tumor was prompted by the observation of tumors that showed a tendency to repeated local recurrences before metastasizing, thus indicating that the tumor was most likely a primary lesion rather than repeated metastases to the same site from an occult primary. The latter phenomenon is anecdotally referred to as “the Toker principle.”

The incidence of PNECS increases with sun exposure, but the presence of lesions in non–sun-exposed areas of the body suggests that factors other that ultraviolet light may be involved in its pathogenesis. Arsenic exposure is another factor that has been thought to predispose to PNECS [14]. Primary neuroendocrine carcinoma of the skin shows higher aggressiveness in patients who are immunosuppressed [15]. These tumors have also been associated with the human immunodeficiency virus [16]. Transplant patients also develop PNECS; the tumors in this setting seem to behave in a much more aggressive manner than in the general population [17]. A significant percentage of patients with PNECS are at risk of developing other types of epithelial neoplasms, mainly squamous cell carcinoma (SCC), ovarian and breast carcinoma, Bowen disease, actinic keratosis, basal cell carcinomas, and sweat gland tumors [4], [5], [18], [19], [20], [21]. Hematologic neoplasms have also been associated with PNECS, such as Hodgkin lymphoma, B-cell lymphoma, and chronic lymphocytic leukemia [22].

Section snippets

Morphologic features of PNECS

Primary neuroendocrine carcinoma of the skin is generally categorized in the group of “small round blue cell tumors” together with small-cell carcinoma, malignant lymphoma, Ewing sarcoma, rhabdomyosarcoma, and neuroblastoma. The original description by Toker made emphasis on the striking trabecular growth pattern that these lesions can adopt [1]. With increased experience and advances in diagnostic methods and ancillary techniques, however, other morphologic appearances were also recognized.

Histologic variants of PNECS

Many histological variants of PNECS have been described in the literature. The tumor can be associated with a variety of cytologic appearances, morphologic growth patterns, stromal changes, and other unusual features such as foci of aberrant or heterologous differentiation (Table 1).

Differential diagnosis and role of immunohistochemistry in PNECS

Primary neuroendocrine carcinoma of the skin can easily be confused with many other neoplasms such as lymphomas, leukemia, metastatic small-cell carcinoma of the lung, neuroblastoma, poorly differentiated cutaneous malignancies, malignant melanoma with small-cell growth pattern, neuroepithelioma, retinoblastoma, carcinoid tumor, rhabdomyosarcoma, and Ewing sarcoma. For the most part, PNECS needs to be differentiated from cutaneous metastases of neuroendocrine carcinomas from internal organs and

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