Major Review

SURVEY OF OPHTHALMOLOGY VOLUME 35. NUMBER 3 - NOVEMBER-DECEMBER 1990 MAJOR REVIEW The Merkel Cell and Associated Neoplasms in the Eyelids and Periocular Region TERO KIVEL& M.D., AND AHTI TARKKANEN, M.D. Department of Ophthalmology, Helsinki llniversity Central Hospital, Helsinki, Finland Abstract. Merkel cells are clear oval cells in the epidermis and outer root sheaths of hair follicles, which are probably of epithelial origin, share ultrastructural features with neuroendocrine cells, and are found in association with touch receptors. In the eyelid, they occur singly in the epidermis and external root sheaths of hairs and eyelashes, and in specialized touch spots alternating with eyelashes. Their typical electron microscopical and antigenic features include dense-core granules, intranuclear rodlets, spinous processes, and a positive reaction for specific cytokera- tins, epithelial membrane antigen, neuron-specific enolase, chromogranin and synaptophysin. Merkel cell carcinoma probably develops from precursor cells which give rise to keratinocytes and Merkel cells, and nearly one out of ten Merkel cell carcinomas occur in the eyelid and periocular region. They tend to be bulging lesions near the lid margin ofelderly patients, reddish in color, and erythematous with telangiectatic vessels. The diagnosis is based on the frequent presence of neurofilaments and paranuclear aggregates of intermediate filaments in addition to features typical of normal Merkel cells. The tumor often mimics lymphoma or undifferentiated carcinoma and frequently invades lymphatic vessels. One third of Merkel cell carcinomas recur, almost two thirds give rise to regional node metastases, and up to one half metastasize widely and result in death. Initial treatment should be prompt and aggressive, with wide resection and routine postoperative irradiation. Although metastatic lesions often respond to radiation therapy and cytostatic drugs. these treatments are mainly of palliative value. (Surv Ophthalmol 35:171-187, 1990) Key words. electron microscopy l eyelid tumors l immunohistochemistry l Merkel cell l neuroendocrine carcinoma . small cell carcinoma l touch receptor Merkel cells are specialized epidermal cells of Merkel cells might also give rise to malignant neo- probable epithelial origin, which resemble neuro- plasms.‘38 In fact, such a tumor had already been endocrine cells ultrastructurally and can be found described in 1972 by Toker,lz5 even though initially in the skin and cutaneous appendages both in ver- it was thought to derive from sweat glands, and the tebrates and invertebrates.38*78~‘9s Together with ultrastructural similarity to normal Merkel cells was Langerhans cells and melanocytes they form the demonstrated only in 1978 by Tang and Take? dendritic cell population in the epidermis.” They and others.” Since then, Merkel cell carcinoma has were first described by Friedrich Merkel in 1875.” been established as an important and highly malig- Shortly afterward, Pinkus described aggregates of nant primary neoplasm of the skin, which most Merkel cells near hair follicles, which he designated probably derives from an epithelial precursor Haarscheiben,‘04 and favored the suggestion of cell.3s*86 Merkel that these cells were touch receptors. In It has not been commonly appreciated, however, 1973, Winkelmann and Breathnach postulated that that both Merkel cells and Merkel cell carcinomas 171 172 Surv Ophthalmol 35 (3) November-December 1990 KIVELA, TARKKANEN are common in the eyelids. Almost one out of ten Merkel cell tumors affects either the eyelids or the periocular region, making it an ophthalmologic en- tity. They are regularly misdiagnosed clinically and often histopathologically. Recurrent and metastatic lesions are common; thus, surgery combined with radiation therapy and, when metastases are present, chemotherapeutic regimens are mandatory in their treatment. I. The Normal Merkel Cell A. DISTRIBUTION IN THE HUMAN BODY 1. Epidermis and Mucous Membranes Merkel cells occur singly and in groups in the basal and, rarely, in the suprabasal layer of rete ridges, especially in crista profunda intermedia or glandular ridges.4g,7’*73@~g’They concentrate in acral areas, such as the nose, fingertips and toes, 4g*50~‘05*‘38but are also present on most other cutaneous locations,71~73~86~g2~“8as well as on mucous membranes of the lip, gingiva and oral cavity.26*27.g3 Single Merkel cells are found in the epidermis of the eyelids, but not in the occlusal surface and con- junctiva.g’ Under the light microscope, Merkel cells are oval in shape and have a clear cytoplasm. They are larg- er than keratinocytes and have their long axis par- allel to the skin surface.73’g18”8 Most of them form a complex with a dermal nerve ending.47*85,g’ Mature Merkel cells divide only infrequently, possibly be- cause they need to maintain connections with their nerve terminals. s*,‘*‘They are difficult to identify by light microscopy and are easily confused with other epidermal cell populations (e.g., Langerhans cells, melanocytes and infiltrating lymphocytes,50*58 but can be identified in experimental studies with the vital dye quinacrine’5*g5 or with a monoclonal antibody of human origin.“‘,“’ 2. Epidermal Appendages Merkel cells can be found below the opening of the sebaceous gland in the outer root sheath of small vellus hair follicles, including those of the ex- Fig. 1. Localization of putative Merkel cells in normal ternal cutaneous surface of the eyelids (Fig. human skin relative to epidermal keratinocytes. A: Most 1). 7’~g’~g8~“o~‘30They are also present in external root immunoreactive cells are situated at the basal layer of the sheath collars of eyelashes, but possibly largely epldermls (arrowhead) adjacent to the basement mem- without innervation.43*g’ brane (X230). B: Occasional immunoreactive cells can be observed adjacent to the basal layer (arrowhead) and in 3. Specialized Aggregates the suprabasal layer (arrow) (X230). C: A small number of similar cells (arrowhead) are labeled in the dermis near Merkel touch spot (Tastscheibe) is a prominent hair follicles (X230). All putative Merkel cells shown here rete ridge, which projects into the dermis and con- occur in or near the outer root sheath collar of follicular tains several Merkel cell-neurite complexes inner- epithelium close to the opening of the sebaceous gland vated by myelinated nerve fibers.g’ In the human (sb) in human eyelid and were identified by an antibody eyelid, touch spots occur regularly throughout the against cytokeratin types 8, 18 and 19 (Clone CAM5.2; entire palpebral margin between successive eye- Becton-Dickinson). MERKEL CELL AND NEOPLASMS I 73 lashes.“’ They are somewhat more prominent in velop from bristle-coated secretory granules, which monkey and rat eyelids.4J,“” Merkel rete papillae in form in the Golgi apparatus.‘6~50~‘09 Crinophagic or the oral mucosa and glabrous digital skin are mor- multivesicular bodies are secondary lysosomes, phologically similar to touch spots.433138 which contain remnants of dense-core granules, Tactile hair disc (Haarscheibe) is a specialized suggesting their continuous lysis and turnover.92.“‘y thickened region of the epidermis in the hairy skin Small clear vesicles similar to presynaptic vesicles of of mammals, which is demarcated by prominent neurons are also present.” rete ridges and consists of a vascularized dermal Another characteristic feature is short spine-like core with many large myelinated nerve fibers, that cytoplasmic processes containing an axis of intracy- contact Merkel cell clusters located in the epider- toplasmic microfilaments, which typically indent ~~~~~?,~H.lli.l04.lIX.llY Even though hair discs are con- surrounding keratinocytes”.‘“l*’ and might be asso- stantly associated with large tylotrich hairs and vi- ciated with the function of Merkel cells.92 Short mi- brissae in many mammals, they are inconspicuous crovilli and many interstitial processes without a and lack a constant relationship to hairs in hu- filamentous core extend freely in the intercellular mans~5x.Ys.IIx.IIo Hair discs have not been found in space between keratinocytes.“,“’ Desmosomes, the eyelids,I","I,"" which lack attached tonofilaments and are signifi- cantly shorter than those between adjacent keratin- 4. Dermal Merkel Cells ocytes, connect epidermal Merkel cells and neigh- Whether Merkel cells can be found in the dermis boring keratinocytes;- ~“7..50.9’.92.“8as well as dermal has been a matter of dispute.‘0~105~‘0”~‘38Subsequent Merkel cells and Schwann cells.“‘~“’ to their appearance in the epidermis during the The basal portion of the Merkel cell is situated 12th gestational week, a population of Merkel cells within a meniscoid nerve terminal (Merkel apparently penetrates the basal membrane and mi- disc).'".9I,I IX The myelinated dermal nerve fiber grates into the dermis.“’ During the 17th to 24th loses its myelin sheath and extends between the gestational weeks, dermal Merkel cells are most Merkel cell and the epidermal basal lamina, cov- abundant, comprising about one fifth of the epider- ered by its own basement membrane and Schwann cell cytoplasm~7",9'.Y?m ma1 population.‘” Thereafter they diminish in num- It contains many mitochon- ber, and Merkel-like cells with dense-core granules dria and glycogen granules, but synaptic vesicles or have rarely been found in adult human dermis,38,7’, specialized membrane junctions have rarely been 74~R0*9X.’‘“.“l” including that of the eyelids (Fig. 1 C).” described in humans.‘6~“‘~Y2~“HIn other species,

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