SURVEY OF OPHTHALMOLOGY

MAJOR

VOLUME 35. NUMBER 3 - NOVEMBER-DECEMBER

1990

REVIEW

The Merkel Cell and Associated Neoplasms in the Eyelids and Periocular Region TERO KIVEL& M.D., AND AHTI TARKKANEN,

Department

of Ophthalmology,

Helsinki

M.D.

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 cytokeratins, 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 cell neuroendocrine carcinoma l

l

immunohistochemistry eyelid tumors small cell carcinoma touch receptor l

.

l

Merkel

l

Merkel cells are specialized epidermal cells of probable epithelial origin, which resemble neuroendocrine cells ultrastructurally and can be found in the skin and cutaneous appendages both in vertebrates and invertebrates.38*78~‘9s Together with Langerhans cells and melanocytes they form the dendritic cell population in the epidermis.” They were first described by Friedrich Merkel in 1875.” Shortly afterward, Pinkus described aggregates of Merkel cells near hair follicles, which he designated and favored the suggestion of Haarscheiben,‘04 Merkel that these cells were touch receptors. In 1973, Winkelmann and Breathnach postulated that

Merkel cells might also give rise to malignant neoplasms.‘38 In fact, such a tumor had already been described in 1972 by Toker,lz5 even though initially it was thought to derive from sweat glands, and the ultrastructural similarity to normal Merkel cells was demonstrated only in 1978 by Tang and Take? and others.” Since then, Merkel cell carcinoma has been established as an important and highly malignant primary neoplasm of the skin, which most probably derives from an epithelial precursor cell.3s*86 It has not been commonly appreciated, however, that both Merkel cells and Merkel cell carcinomas 171

172

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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 entity. 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 but are also present on most other toes, 4g*50~‘05*‘38 cutaneous locations,71~73~86~g2~“8 as 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 conjunctiva.g’ Under the light microscope, Merkel cells are oval in shape and have a clear cytoplasm. They are larger than keratinocytes and have their long axis parallel 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 because 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 external cutaneous surface of the eyelids (Fig. 7’~g’~g8~“o~‘30 They are also present in external root 1). sheath collars of eyelashes, but possibly largely without innervation.43*g’ 3. Specialized Aggregates Merkel touch spot (Tastscheibe) is a prominent rete ridge, which projects into the dermis and contains several Merkel cell-neurite complexes innervated by myelinated nerve fibers.g’ In the human eyelid, touch spots occur regularly throughout the entire palpebral margin between successive eye-

Fig. 1. Localization of putative Merkel cells in normal human skin relative to epidermal keratinocytes. A: Most immunoreactive cells are situated at the basal layer of the epldermls (arrowhead) adjacent to the basement membrane (X230). B: Occasional immunoreactive cells can be observed adjacent to the basal layer (arrowhead) and in the suprabasal layer (arrow) (X230). C: A small number of similar cells (arrowhead) are labeled in the dermis near hair follicles (X230). All putative Merkel cells shown here occur in or near the outer root sheath collar of follicular epithelium close to the opening of the sebaceous gland (sb) in human eyelid and were identified by an antibody against cytokeratin types 8, 18 and 19 (Clone CAM5.2; Becton-Dickinson).

MERKEL

CELL AND

NEOPLASMS

I 73

lashes.“’ They are somewhat more prominent in monkey and rat eyelids.4J,“” Merkel rete papillae in the oral mucosa and glabrous digital skin are morphologically similar to touch spots.433138 Tactile hair disc (Haarscheibe) is a specialized thickened region of the epidermis in the hairy skin of mammals, which is demarcated by prominent rete ridges and consists of a vascularized dermal core with many large myelinated nerve fibers, that contact Merkel cell clusters located in the epider~~~~~?,~H.lli.l04.lIX.llY Even though hair discs are constantly associated with large tylotrich hairs and vibrissae in many mammals, they are inconspicuous and lack a constant relationship to hairs in humans~5x.Ys.IIx.IIo Hair discs have not been found in the eyelids,I","I,"" 4. Dermal Merkel Cells Whether Merkel cells can be found in the dermis has been a matter of dispute.‘0~105~‘0”~‘38 Subsequent to their appearance in the epidermis during the 12th gestational week, a population of Merkel cells apparently penetrates the basal membrane and migrates into the dermis.“’ During the 17th to 24th gestational weeks, dermal Merkel cells are most abundant, comprising about one fifth of the epiderma1 population.‘” Thereafter they diminish in number, and Merkel-like cells with dense-core granules have rarely been found in adult human dermis,38,7’, 74~R0*9X.’ ‘“.“l” including that of the eyelids (Fig. 1C).” These cells are constantly associated with dermal nerve endings.3X~“~7’~H”~“~yK~“o Subepithelial Merkel cells are also seen in the oral mucosa and glans penis.!” B. SPECIFIC

IDENTIFICATION

1. Ultrastructural

METHODS

Characteristics

Merkel cells have a relatively electron-lucent cytoplasm, which contains many free ribosomes, sparse endoplasmic reticulum, and the normal complement of intracellular organelles, including a relatively prominent Golgi complex.?6~‘7~50~“2 lntermediate filaments are randomly distributed and form no paranuclear aggregates, a hallmark of Merkel cell carcinoma.‘6~‘7~x6~y2.‘30Tonofilaments have been found in putative fetal Merkel cells in animal species only. =.” Rare melanosomes are interpreted as evidence of phagocytosis.“‘The nucleus is oval, often lobulated, and may contain a characteristic intranuclear rodlet.25-87.“2 Merkel cells typically have cytoplasmic densecore granules, which are morphologically identical to those of neuroendocrine cells and measure 70-110 I’m in diameter.,, 5R.26."7,50,7',74.8fi.92.lO9,"X.l.lll These are often seen in cytoplasmic processes and along the basal cell membrane.“~‘6~7’~R6~92~“X They de-

velop from bristle-coated secretory granules, which form in the Golgi apparatus.‘6~50~‘09Crinophagic or multivesicular bodies are secondary lysosomes, which contain remnants of dense-core granules, suggesting their continuous lysis and turnover.92.“‘y Small clear vesicles similar to presynaptic vesicles of neurons are also present.” Another characteristic feature is short spine-like cytoplasmic processes containing an axis of intracytoplasmic microfilaments, which typically indent surrounding keratinocytes”.‘“l*’ and might be associated with the function of Merkel cells.92 Short microvilli and many interstitial processes without a filamentous core extend freely in the intercellular keratinocytes.“,“’ Desmosomes, space between which lack attached tonofilaments and are significantly shorter than those between adjacent keratinocytes, connect epidermal Merkel cells and neighas well as dermal boring keratinocytes;- ~“7..50.9’.92.“8 Merkel cells and Schwann cells.“‘~“’ The basal portion of the Merkel cell is situated within a meniscoid nerve terminal (Merkel disc).'".9I,I IX The myelinated dermal nerve fiber loses its myelin sheath and extends between the Merkel cell and the epidermal basal lamina, covered by its own basement membrane and Schwann cell cytoplasm~7",9'.Y?m It contains many mitochondria and glycogen granules, but synaptic vesicles or specialized membrane junctions have rarely been described in humans.‘6~“‘~Y2~“HIn other species, however, complex intercellular junctions with supposed presynaptic neurosecretory granules and postsynaptic small clear vesicles have been likened to reciprocal synapses.15,2".9".~7,H~,"7 2. Immunohistochemical

Characteristics

The epithelial properties of Merkel cells are reflected in their antigenic profile. Merkel cells can be labeled with antibodies to low-molecular weight cytokeratins 8, 18 and 19 characteristic of simple and glandular epithelia (Fig. l), while they lack the cytokeratin types (previously often called prekeratins) normally found in keratinocytes of stratified epithelia.“x~x”~gs~y”~“’ The cytokeratin filaments are evenly distributed throughout the cytoplasm without forming any aggregates. The same cytokeratin types are also found in embryonic human skin and some positive cells may theoretically be stem cells of Merkel cells are also positive for keratinocytes.X”~yo~y” desmoplakins,“g but, at least in rabbits, they lack the bullous pemphigoid antigen, produced by adjacent basal keratinocytes7” Merkel cells express several antigens common to the diffuse neuroendocrine system. They react positively with antibodies to neuron-specific enolase. 4’~‘x.79.‘90an antigen also found in malignant

174

Surv

CASE

Ophthalmol

SEX

35 (3) November-December

AGE LOCATION (Y)

1 2 3 4 5 6 7 6 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31

Fern Mal Mal Mal Fern Fern Mal Mal Mal Fern Fern Fern Fern Fern Fern Fern Fern Fern Fern Fern Fern Mal Fern Fern Mal Mal Fern Fern

89 71 88 73 83 83 72 57 80 73 95 59 88 82 82 65 79 80 62 79 75 61 74 78 77 85 83 54

DURATION SIZE (months) (mm)

FIEF

n/a n/a n/a n/a n/a 20 5 6 n/a 6x15 10 8x15 20 4x8 8x23 15 6 35x35

n/a n/a n/a n/a n/a 5 n/a 2 n/a 24 >2 2 4-8 3-4 3 1 4 4 n/a n/a n/a 8 n/a n/a n/a I2 n/a n/a n/a n/a n/a >24 n/a n/a

15 10 45 n/a n/a n/a n/a 15 n/a

45 45 45 61 9 9 123 145 63

45 46 47 48 49 50

Fern Fern Mal Mal Fern Fern

56 71 64 69 65 62

Supraorbiial Infraorbital lnfraorbital Infraorbital lnfraorbiial lnfraorbital

da n/a n/a n/a 12 n/a

n/a 30 n/a n/a 10x15 n/a

145 68 97 97 127 19

Mal

L 70 65 65 81

KIVEIJi, TARKKANEN

1990

TREATMENT AND CLINICAL COURSE e

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.

Merkel cell carcinomas in the eyelid and periocular region. R, recurrence; N, regional lymph node metastasis; M, extraregional metastasis; < RNM > , recurrence, nodal and extraregional metastasis present after an unspecified time interval; i, incision; b, biopsy; e, excision; w, wide excision; x, exenteration; n, neck dissection; p, parotidectomy; r, radiation therapy; c, cryotherapy; [l], dead of Merkel cell carcinoma; [2], dead of intercurrent disease with evidence of active Merkel cell carcinoma; and 3, dead of unrelated disease without evidence of Merkel cell carcinoma. Eops, presented by Prof. Cunha-Vaz at the 27th meeting of the European Ophthalmic Pathology Society, 1988. In a few cases, the size of the tumor and the follow-up time were estimated from the data presented. N/a, data not available and can not be estimated. Fig. 2.

MERKEL

CELL AND NEOPLASMS

melanomas

but

not in most normal melanoIn humans, Merkel cells react strongly with antibodies to chromogranins, a major family of secretory proteins of dense-core granules, 4x.sy.’’ ‘,‘97and more weakly for synaptophysin, a membrane protein of small clear vesicles in neuroendocrine cells and neurons.“,‘00*‘“6 Merkel cells are negative for neurofilaments, which are frequently expressed in Merkel cell carcinoma.s6,g”.’ ’ ’ In rabbits they also lack vimentin, desmin and glial fibrillary acidic protein.“’ Attempts to detect a putative transmitter substance in the cytoplasmic granules of Merkel cells have been wrought with difflculties.‘5 Although met-enkephalin has been found in monkey and several rodent species, it has not been detected in humans.‘“x4” Positive reaction has been obtained with antisera to vasoactive intestinal polypeptide, whereas neurotensin, somatostatin, corticotropin, secretin, alpha-melanocyte stimulating hormone, gastrin, cholecystokinin, glucagon, substance P and bombesin have not been detected in adult or fetal human Merkel cells.“H*4X,“” Cyt~~~:4X.42.45.73.10~,llo,l~~~

C. ORIGIN

AND FUNCTION

It was initially suggested that Merkel cells would originate from neural crest and migrate along peripheral nerves through the dermis into the epidermis and outer root sheaths of hair follicles. This theory was based on the presence of cytoplasmic granules similar to those of neuroendocrine cells in Merkel cells, their approximity to neurons and Schwann cells, and the occasional dermal Merkel cells. “” However, it has since been shown that Merkel cells appear in the epidermis before they can be detected in the dermis, that there is no evidence ofa migration from the dermis into the epidermis, and that at least some invertebrates may develop Merkel cells in the absence of neural crest (for a review see reference 38). Although transitional cells resembling keratinocytes and Merkel cells have been described in animal studies only, it is now widely believed that Merkel cells and keratinocytes ma) originate from a common epidermal stem cell.sx~*6~g!’ Merkel cells have classically been described as slowly adapting mechanoreceptors mediating the sense of touch and, possibly, the direction of hair movement.7x~“‘4 There is, indeed, abundant evidence for the fact that Merkel cell-neurite complex is a touch receptor, although the precise function of the Merkel cell itself remains unclear.‘6~SR*‘3XFirm morphological and biochemical evidence for synaptic transmission is lacking in humans, and recent experimental electrophysiological studies have concluded that Merkel cells are not directly responsible for the transducer function, even in laboratorv

17.5 anjmals

15.54.76

Alternative hypotheses have been that Merkel cells might have a trophic function for keratinocytes and dermal nerve endings, they might act as neuromodulators, or they may have a tropistic function and act as targets in axonal arborization during development with subsequent passive role. '6.38,7R.Xfi.I38

II. Merkel Cell Carcinomas A. INCIDENCE

AND DEMOGRAPHY

1. Age and Sex Distribution Merkel cell carcinoma is a relatively frequent primary malignant neoplasm of the skin. It is difficult to give an accurate number of the published cases, because many patients have been reported multiple times by different groups of authors. However, we estimate that about 600 cases have been described during the last eight years. Merkel cell carcinomas typically occur in the elderly population, The average age at the time of diagnosis has ranged from 66 to 73 years, and about three fourths of patients are sixty-five years of age or older.. 9.2l~."7.:)L',44.5'.fi2.6X.77,~~.'f~', IO'L.ll4.llf~.IL'4,l'LX.ISJ Rarely, the tumor affects young adults, some of whom may have an antecedent cutaneous disorder such as the hypohidrotic ectoderma1 dysplasia syndrome.“~77~‘“” The patients with eyelid tumors (Fig. 2) have been on an average 77 years old (range 54 to 95 years) and those with eyebrow lesions 7 1 years old (range 3 1 to 86 years). In many series, females have been affected nearly

Fig. 3. ‘Typical clinical appearance of a Merkel cell carcinoma affecting the left upper eyelid of a 72-year-old woman. The tumor had progressively enlarged during three months and measured 23 x 8 x 8 mm. (Case 15; Courtesy of Prof. William R. Lee, University of Glasgow, Scotland).”

176

Surv Ophthalmol

35 (3) November-December

twice as often as males,20~27~45~8g~‘0’~‘02~‘16 and this is also true for lesions in the eyelid and periocular region (Fig. 2). Analysis of published cases, however, has generally revealed no consistent difference in this respect. 44,5’,‘15Merkel cell carcinomas are exceedingly rare in the black population.‘3,32*56,“5,“6

1990

KIVEL&

TARKKANEN

may appear erythematous and is characteristically red in color, with hues ranging from pink to violalts sur_ ceous and purple. 12.17,20,27,32,63,72,103,114.124,133 face is smooth and frequently shiny, sometimes nodular, and very often characterized by dilated telang.iecmtic blood vessels.‘,‘2,‘7,23,59,63,69,‘03,’ ‘2.139The

red color and dilated vessels may relate to the frequently observed inflammation and invasion of local lymphatic channels. ‘I4 The overlying epidermis About one half of Merkel cell carcinomas occur in the head and neck region.9,20,32,44,45,51,62,68,77. is usually intact, but it occasionally may be ulcerated.31~32~40~103*‘07~‘28 These features form a recognizg6~"4~'16~124*133 In almost one fifth of these patients, or able pattern, especially for tumors involving the one tenth of all cases, the tumor affects either the eyelid, and should lead to a high index of suspicion eyelid or the periocular region, which appear to be of Merkel cell carcinoma, which helps the patholopredilection sites of Merkel cell carcinoma (Fig. 2).* gist to proceed accordingly. The eyelid, preferentially the upper one, has been 2. Location

involved in 31 patients, whereas four tumors have affected the canthus, nine have localized to the eyebrows, and six have been removed from the orbital rim (Fig. 2). Elsewhere in the body, Merkel cell carcinomas tend to involve the extremities, and only about one tenth affect the trunk or mucous Occasional_ membranes. 9~20~27~44~51~62~68~77~96~102~114~124~133 ly there may be widely distributed multiple skin lesions, a condition sometimes termed cutaneous ~~~~~~~~~~~~~~~~30~57~l16~129~131~l40

B. CLINICAL

PRESENTATION

The tumor is generally a solitary dermal skin nodule, which is painless, nontender and often probulging or dome-shaped.7~‘7*20*23,32~63* tuberant, 6g~‘03~“2~‘24~133 In the eyelid (Fig. 3 and 4A), it arises near the lid margin’7,23~“3~6g~72~~~1 I2 and either spares or causes partial loss of the eyelashes.‘2~63~6g*72~“2 Several eyelid tumors have been pedunculated17~23*72 and two have mimicked chalazia.5gs72 The tumor

*The notion that periocular Merkel cell carcinoma is a relatively frequent tumor is substantiated by the fact that five new cases have been reported since submission of this manuscript. A 95-year-old woman, who had a 10 mm tumor involving upper evelid, died of unrelated causes 8 months after local excision. 5oa An 82-year-old woman had a large tumor in the inner canthus, which was operated and irradiated. It recurred and sent nodal metastases in 2 months, and she died one year later with evidence of distant metastasis. la A 60-year-old man had in his upper eyelid a 4 mm tumor, which was excised. Nodal metastasis was biopsied and irradiated after 3 months. Testicular metastasis occurred after 9 months, followed by chemotherapy with complete response. He is alive 3 years after initial diagnosis. Ia A 65year-old man had in his upper lid an 18 mm tumor that developed after incision for presumed chalazion. He is alive and well one year after wide excision. la A tumor in the upper eyelid of a 67-year-old patient was excised and irradiated, and there is no evidence of disease after 8 months. 70a Case 10 is reported to be well one year after therapy to5= and our own Case 28 has no evidence of disease after 3 years.

C. HISTOPATHOLOGIC

DIAGNOSIS

1. Light Microscopy Merkel cell carcinomas originate in the reticular or papillary dermis and frequently extend into the subcutaneous fat and muscle.‘,20,27.41,46,64,1 14,ll7,126~ 130*‘33 In the eyelid, they typically invade the orbicularis muscle and spare the tarsal plate (Fig. 4B). 63~6g~103~’ 12,’I5 The overlying epidermis may be attenuated, but it is generally separated from the tumor by a narrow rim of papillary dermis,7*‘7*20*23,27,45* 5g~87,‘o’~‘14~133 and ulceration is present in a minority Pilosebaceous fol_ of cases only. 40~45~~6~~~6~~‘03~‘~7~‘12~tt4 licles and sweat glands persist within the tumor, but may become compressed.20.23,4~.8’,’ ‘%‘l4,l t5zt22 very

rarely, pagetoid invasion of the epidermis2~35~“2~72~‘07~ 114-“6~12’or follicular epithelium115*“6 has been observed, twice associated with an eyelid tumor.72,“5 The arrangement of the tumor cells varies.27s3s The “classical” organoid pattern of interconnecting trabecular cords separated from each other by connective tissue strands, which led to the initial designation of trabecular carcinoma,‘22r125 has since been found to be infrequent, and is observed in less than one-fourth of cases.4’38~46,52,87,‘02,“4~“6 In these tumors, the trabecular cords may form pseudorosettes or pseudoglandular patterns.‘7.27,64,81,103,107*‘14, ‘22,‘25~‘33Most Merkel cell carcinomas form large nests of cells (Fig. 4C), which may show some arrangement in their peripheral trabecular F’ parts. 2327, 38.46,59,68,75,87,102,114,121,133 mally, some consist of diffusely infiltrating neoplastic cells (Fig. large cell lympho4D, E), which resemble mas. 4,27,41,102.112.114-116,128 A finding of considerable clinical importance is the frequently observed vascular62*103*“4and, in parlymphatic ~~~~~~~~~27~56~64~68~103~107~114-116~133~ ticular, ‘35~‘3g The latter is thought to underlie the high frequency of local recurrences and regional nodal metastases so characteristic of Merkel cell carcinoma.g*“4 When specifically searched for, tumor cells

MERKEL CELL AND NEOPLASMS may be observed in lymphatic vessels in more than one half of the tumors,‘7~6*~“‘7~“4 and such invasion has also been reported for eyelid tumors.z7,5g.“5 The tumor is also frequently surrounded by a more or less dense infiltration of lymphocytes and plasma

177 12,17,L’0,27.31.41,~9.Xl.l0~~,l14.1l~.12H.I~~9.1:(~~

cells, which may cause further difficulties in differential diagnosis with respect to lymphoma (Fig. 4D and E). The tumor generally consists of round cells of intermediate size, ranging from 12 to 25 km in

A rapidly growing tumor developed within three months in the right upper lid of an otherwise healthy 54-year old woman (Case 28). The tumor was biopsied and diagnosed as a lymphoma by an experienced senior pathologist. It grew further and finally measured 10 x 18 mm. A: Clinically the recurrence adhered to the tarsus, the skin was intact. and the bulging tumor reddish in color with telangiectatic vessels. It was excised with liberal margins, the eyelid repaired with a tarsal graft and frontal skin flap, and postoperative radiotherapy given (50 Gy in 25 fractions during 5 weeks). B: The tumor (mc) occupied the dermis and infiltrated the orbicular muscle, but it did not involve either the epidermis or tarsus (tar). Eyelashes (arrowheads) were also spared (HE, x 10). C: The tumor cells form a solid mass of uniformly round cells with pale vesicular nuclei, sparse cytoplasm, and many mitotic figures (arrowheads) (HE, X 250). D: In other areas. noncohesive tumor cells infiltrate among abundant lymphocytes and plasma cells (HE, x 250). E: Fibers of the orbicular muscle (or) are present among small tumor cell nests and associated inflammatory infiltrate (HE, x 250). F: Many tumor cells (arrowheads) show some perinuclear granular positivity in the Grimelius staining after formalin fixation ( X 250).

Fig. 4.

178

Surv Ophthalmol

35 (3) November-December

TABLE

1

Antigenic Properties of Merkel Cell Carcinomas. ’ Antigen

Immunoreactive tumors

Epithelial anti ens Cytokeratin 8 203/212(96%) Epithelial membrane antigen 44/49(90%) Desmoplakins 4/8(50%) Carcinoembryonic antigen3 203 (-) Grimelius stain4 108/210(51%) Neurofilaments5 77/146(53%) Neuroendocrine antigens Neuron-specific enolase 220/254(87%) Chromogranins’ 53/88(61%) 6114146%) Synaptophysin’ 2/19(11%) HNK-1 carbohydrate epitope6 Putative neurotransmitters7 ACTH (corticotropin) 5/94(5%) Bombesin l/57(2%) 24/121(20%) Calcitonin Cholecystokinin o/22 (-) B-Endorphin O/22(-) Gastrin 7/55(7%) Glucagon O/36 (-) a-Human chorionic gonadotropin o/17 (-) Insulin 0136 (-) Leu-enkephalin 2/24(8%) B-Lipotropin O/6 (-) Met-enkephalin 3/67(5%) Nerve growth factor o/3 (-) Neurotensin O/32 (--) l/41(2%) Pancreatic polypeptide Serotonin O/70 (-) 10/87(12%) Somatostatin l/56(2%) Substance P Vasoactive intestinal polypep20/60(33%) tide Miscellaneous antigens 18/117(15%) S- 100 protein Leucocyte common antigen o/93 (-) Vimentin o/34 (-) Glial fibrillary acidic protein o/12 (-) Laminin O/8 (-)

[15%]

KIVEL&

1990

TAKKKANEN

diameter.23,31~37,5g*60~75”03 They have scant amphophilic and slightly metachromatic, occasionally faintly granular cytoplasm with indistinct borders 23.27,31.101,103,112.~14,122,125.133 The large nuclei (Fig. 4C). are vesicular, round to oval, and have a sharply defined, often indented membrane, finely granular chromatin and l-3 mostly inconspicuous nucleoli.20~‘3~‘7~3’~75*“5 Many tumors contain a population of small round to spindle-shaped cells with hyperchromatic nuclei resembling those of bronchial oat cell carcinoma '~17~36~38~~2~68~102~103~114~116~141~133 The rate of mitosis is generally very high, ranging from 3-l 5 mitoses per high power field (Fig. 4C).‘7*23,‘7*3’~ 59~60~63~6~~69~~2~'5~101.103,128 Individuaj

4C)

and

apoptosis

cell necrosis

(Fig.

are also common,23~27*37~64~ but areas of confluent necrosis

68,69.107.115.116,128,130,143

[ 13%] [ lOO%] [45%]

[55%]

[ lOO%] [lOO%]

[5%] [25%] [5%] [40%0]

‘Data from references [4, 11, 12, 17, 19, 20,23, 27, 28, 31,35-37,39-41,45,46,52-57,60,64,67-69,73,75,81, 83,84,87,89,101,102,107,108,113,114, 117,120,123, 124, 126, 128, 130-133, 137, 139, 142, 1431 and the case presented in Fig. 4 and 6. 2Positive for simple epithelial types 8, 18 and 19 only; diffuse perinuclear and/or focal immunoreaction in fibrous bodies depending on the antibody used.

3Selective immunoreactivity in squamous and eccrine elements seen in exceptional cases only. 4Modified argyrophilic stain, all specimens; 36137 Bouin- and 22152 formalin-fixed specimens positive

when fixation reported. 51mmunoreaction almost exclusively in fibrous bodies. “Generally focal immunoreaction in a proportion of cells. 7Peptides are notoriously difficult to demonstrate; second percentage [in brackets] excludes papers in which all specimens were negative.

are infrequent. 7~2',103~114-116,133 one study claims that a ball-in-mitt arrangement, in which one or two crescentic tumor cells are closely wrapped around a central round one, would be typical of Merkel cell carcinoma.“’ Small areas showing squamous differentiation and keratin pearls have been described in exceptional Merkel cell carcinomas.27~35*66~1’5.“6Furthermore, primordial sweat gland differentiation with eccrine tubules and ducts containing keratohyalin granules and showing focal keratinization has been detected in a few cases.35S62S1’6 More often, however, Merkel cell carcinoma is associated with a concurrent or antecedent invasive squamous cell carcinoma,3,33,56,ffl,“6.‘21,142 with an intraepithelial squamous carcinoma in the overlying epidermis27~62~64’107~ ‘14.“6 or with an adnexal neoplasm,‘16~‘20 suggesting the possibility of a common carcinogenic influence in addition to divergent lines of differentiation. Merkel cell tumors frequently occur in patients who cell epitheliomas.13~29~32*33~ have had basal 75~‘02~‘07*133~‘35~14z In this respect it is of interest that rare basal cell epitheliomas that have features suggestive of neuroendocrine function have been described.‘4S70

2. Special Staining Features Grimelius stain for argyrophilic granules (Fig. 4F) is positive in at least one half of cases (Table I). The specimen should optimally be Bouin-fixed, since routine fixation in formalin may quench the reaction. 17~27~60~116 The tumor cells are negative in Fontana-Masson stain for argentafhn granules and in other melanin reactions.* "3 v27.31,36,63.64.75,101~117,122, 123s133 Although most cases do not stain for glyco31.36.65.64,lOllipids,63,'Z~myloid,~l,36,IOI,I16 and

mu_

gen, copolysaccharides,23~z’,3’.3’*54*63.64 spurious positive reactions may be observed.‘3*64.‘4’ Certain lectins also label Merkel cell carcinomas.s~‘O’

MERKEL

CELL

AND NEOPLASMS

Fig. 5. Schematic representation of characteristic ultrastructural features in Merkel cell carcinoma. The diagnosis is generally based on dense-core cytoplasmic granules (A), paranuclear aggregates of intermediate filaments (B; fibrous bodies), spike-like cytoplasmic processes with actin filaments (C), and rare intranuclear rodlet-like inclusions (D). The nucleus is convoluted and contains small nucleoli (E). Additionally, the cells have a relatively prominent Colgi complex (F), abundant free polyribosomes (G), sparse smooth and rough endoplasmic reticulum (H), small clear vesicles (I), some poorly formed desmosomes (J), dispersed intermediate filaments (K), as well as several dendritic cytoplasmic processes (L) and occasional microvilli (M).

3. Electron

Microscopic

Characteristics

brane and in dendritic cytoplasmic processes 36.37,40,60.68,75,89,101.107,114.116,1l7,l33 Although The ultrastructure of neoplastic cells in Merkel dense-core granules are diagnostic, in a minority of cell carcinoma closely resembles that of normal Merkel cell carcinomas none or only very few are Merkel cells (Fig. 5). The tumor cells are generally detected.23,27,28.36’59.68.121 Furthermore, if formalinpolygonal in shape. They often have indented nufixed and paraffin-embedded tissue must be salclei with evenly dispersed sparse euchromatin, a vaged for electron microscopy, the granules have thin rim of heterochromatin, and multiple small nucleoli 7~25~46~59~63~107~115~133lntranuclear often been destroyed.46*“4,“7*‘42 Small clear vesicles rodlets are have also been described in Merkel cell carcinorarely encountered.60*“5.‘39 The cytoplasm is distinma.11'57 guished by abundant ribosomes and polyriboA consistent feature of Merkel cell carcinoma is somes, but the smooth and rough endoplasmic reticulum are generally ~pa~~e.7~27~31~46~59~107~112~115,122r130paranuclear aggregates of intermediate filaments, The Golgi apparatus is most often well-develcilia,133 oped. 17.27.57~63,107~115~133~135~139Centrioles,l33'135 glycogen granules,3”‘43 lipid droplets,‘7,23~40~12’and paracrystalline granules reminiscent of premelanosomes’40 are occasionally found. The diagnosis of Merkel cell carcinoma is classically based on the presence of cytoplasmic densecore granules averaging from 80-l 50 nm in diameter (range 75 to 240 nm). 17.27.31.36.46.57.59.68.75,101.107,114"7~122~'28~130

They

concentrate

along

the cell mem-

often designated fibrous bodies,46.60.68,75.8g,‘07,“4. “5.130,‘42which frequently enclose a few dense-core l4sl33.135 Immunoelectron micros_ granules. 2’137.46,60,1 copy shows that these are composed of cytokeratins and neurofilaments, either alone or in combination.75*87 Even though some tumors appear to be degranulated, they still have a prominent fibrous body, and only rare tumors diagnosed as Merkel cell carcinoma have been reported to lack these Fibrous bodies are perinuclear aggregates. 68,*7,10’.114

180

Surv Ophthalmol

35 (3) November-December

particularly useful because they usually survive fixation in formalin and embedding in paraffin, and can be used later for electron microscopic diagnosis that was not originally planned.4”,“4,‘33 Intermediate filaments are also found dispersed in the cytop~as~,37,40,68,87,103,116.128 but their arrangement seldom bears resemblance to tonofilaments.66~sg*“4*“5 Specialized intercellular junctions are variable. Most often they are reported to be sparse and poordesmosomes, 27,66,75,81,87,89.115.121,122,142.143 ly formed and hemidesmosomes,3’*‘22’130 or they are described as primitive. 23,40.56,103,112,116,121 Maculae adherzonulae adherentes27,46 entes 59,60,72, l15.130.133.135 and have also been described, and the tumor cells occasionally have rudimentary basal laminae.57r’2” 122~‘30,‘33~135 Dendritic cytoplasmic processes, some of which contain actin microfilaments and resemble cytoplasmic spikes of normal Merkel cells,1g@,68S “4~‘23,*30 are frequent. 7.23,27,36,37,40,75,101.112,114.117,130,133,143 Focal microvilli may be present.7,35*66.115.‘33S’35 4. Antigenic Profile

Merkel cell tumors resemble normal Merkel cells in expressing cytokeratin polypeptides 8, 18 and 19 typical of simple and glandular epithelia (Table 1; Fig. 6A and B), as judged both by immunohistoand immu_ chemistry 2.20,35,37,45,52,68.87,102,113~123~124~126~128 noblotting. 52,87In contrast, cytokeratin antibodies reacting exclusively with stratified squamous epithelia do not label Merkel cell carcinoma.37~52~56~60~84~87~“3*‘23 Unlike normal Merkel cells, most Merkel cell tumors additionally express some of the three neurofilament proteins, which invariably aggregate to form the paranuclear whorls seen microscopy (Fig. 6C).4,‘8.20*45,52, by electron 64,67~9.81.87,113,123,l24.l26,128 Both

types

of

filament

are

simultaneously present in many neoplastic cells,52,81*87and cytokeratins can often be found in the fibrous bodies, although this can not be shown with all antibodies (Fig. 6A and B).4,‘7,‘8*45*46, 52,67,68,75,81,87,102,113.124,126,128 Such whorls are characteristic of Merkel cell carcinoma and are seldom found in other neuroendocrine tumors.4’45,64,88,‘34Vimentin, desmin and glial fibrillary acidic protein are not found in Merkel cell tumors.37~38~52~81~84~87~8g~‘23 Antibodies to neuron-specific enolase react with weak to strong intensity with almost all Merkel cell carcinomas (Fig. 6D; Table 1). Although chromogranins (Fig. 6E) and synaptophysin are more specific than neuron-specific enolase as neuroendocrine markers, positive reaction is often focal and present in a proportion of Merkel cell carcinomas only. 4.28,35,39,67,102,131.132.131The HNK- 1 carbohydrate epitope, another antigen associated with neuroendocrine cells, is likewise demonstrable in some Merkel cell carcinomas.20,83

1990

KIVEti,

T-EN

Putative neuropeptides have been detected in only a minority of cases (Table 1). Vasoactive intestinal polypeptide is found in about one third37*38,40,67@*“4and calcitonin in one fifth of Merkel cell carcinomas.3~38.67,68,“7 Other peptides that have been occasionally demonstrated include ACTH, ‘6*3*,‘7~~“7bombesin,37*” gastrin,yO leu_enke_ phalin,37*38 met-enkephalin,23z40 pancreatic polypeptide,‘14 somatostatin,20*36”‘7 and substance P.‘l’ Elelevels of serum ACTH5* and vated calcitonin36~55*‘08~‘43have been reported, although these have never been found in association with a clinical paraneoplastic syndrome.36,54,55*108.“7’13g~143 The variability and rarity of neuropeptides in Merkel cell carcinomas means that they are of little diagnostic importance, although when elevated serum levels are present, they may help in detecting recurrent disease.3”p’43 Antibodies to epithelial membrane and related antigens react with most Merkel cell carcinomas Carcinoembryonic antigen (Fig. 6F). 20.23~124*‘28,‘3’ and human large-molecular weight salivary mucins have been detected only in those rare cases which show eccrine differentiation.s5 Laminin was not found in tumor cells in one particular study,45 but desmoplakins may be observed.87 Leukocyte common antigen (Fig. 6G) and other lymphocyte markers have been constantly absent from Merkel cell carcinoma.4*20*67~68,154.126,128 Although antibodies

Fig. 6. (Page 181) Antigenic properties of Merkel cell carcinoma (immunoperoxidase, x 250). A: Almost all tumor cells react positively for the cytokeratin polypeptides 8, 18 and 19, giving a diffuse cytoplasmic immunoreaction in addition to some perinuclear aggregates (arrowheads) (Clone CAM5.2; Becton-Dickinson). B: A monoclonal antibody recognizing a conformational epitope on most types of cytokeratin reveal perinuclear aggregates of intermediate filaments (fibrous bodies) in most neoplastic cells (Clone Lu5; Boehringer Mannheim). C: The high-molecular weight neurofilament triplet protein can also be detected in the fibrous bodies in a proportion of the neoplastic cells (Clone lA3; Labsystems). D: A polyclonal antiserum to neuron-specific enolase gives a moderate immunoreaction in the majority of tumor cells (A589; Dakopatts). E: Monoclonal antibody to chromogranin reveals a granular cytoplasmic immunoreaction (arrowheads) in a minority of neoplastic cells (Clone LK2HlO; Hybritech). F: Murine antibodies to epithelial membrane antigen label the entire tumor cell population (Clone lA4; Dakopatts). G: Antibodies to leukocyte common antigen do not react with Merkel cell carcinoma (mc), but label infiltrating lymphocytes (DAKO-LC; Dakopatts). H: In addition to occasional histiocytes (arrowheads), many tumor cells react weakly with a polyclonal antiserum to S-100 protein (2311; Dakopatts).

MERKEL

1x1

CELL AND NEOPLASMS

agi nst S-100 protein will give a negative reaction in 4,":~,37..~?.AS.IOP.l~4,l?~ a faint positive reaction mc t cases, ma sometimes be observed (Fig. 6H).20.‘2X D. (:)RIGIN

AND HISTOGENESIS

Merkel cell carcinomas

were originally

thought

to derive either from fully developed epidermal Merkel ce~~s?0.S~~.~J,l~l.12~.l~~0.1~~ Or from dermal neuro_ endocrine cells, which have migrated from the neural CreSt~4.~..iL’.XI.I:~o While ultrastructural and immunohistochemical studies show that Merkel cell carcinomas share most of the essential features of

182

Surv Ophthalmol

35 (3) November-December

normal Merkel cells, such an origin has been denied on the basis of the exclusively dermal localization of most Merkel cell carcinomas, lack of neuroendocrine peptides typical of normal Merkel cells, and the presence of neurofilament proteins.27,52,62,“4, “7,‘23 Indeed, it is considered more likely that Merkel cell carcinomas develop from epidermal stem cells, which are still capable of squamous and primitive sudoriferous differentiation.35*40*62*‘03~“5 This theory is consistent with the fact that Merkel cell carcinoma is often associated with epithelial, but not with melanocytic tumors, the latter being of neural crest origin.“’ It must be presumed that the tumor cells may invade the dermis, as do normal fetal Merkel cells during development.86 The carcinogens responsible for the malignant transformation remain unknown, although sunlight has been suggested as one possible causative agent.‘g,“3V’15.13’ E. DIFFERENTIAL

DIAGNOSIS

Although the light microscopic appearance of Merkel cell carcinoma is fairly characteristic,“‘*62. 68*‘30it must be distinguished from other poorly differentiated round cell tumors (especially lymphomas), metastatic and small cell carcinomas, as well as carcinoid tumors. Clinically, Merkel cell carcinoma in the eyelid may mimic lymphoma, sebaceous carcinoma or even chalazion,‘g*23~5g~72 while metastatic neuroendocrine carcinoma and carcinoid tumor are very uncommon in the periocular region. Other neoplasms that more rarely enter into the differential diagnosis include basal cell, squamous and various adnexal carcinomas, adult neuroblastoma, amelanotic malignant melanoma, and Ewin practice, the diag_ ing’s sarcoma. 4'~53~68~'5,"2~'30~'39 nosis must often be confirmed using electron microscopy and immunohistochemistry, followed by exclusion of other primary neoplasms.‘7’3’,4’* 64,75~‘30 One should note, however, that patients with Merkel cell carcinoma are usually elderly and may concurrently have other malignant neoplasms as well 44,51,62,75,'02,"5,"6 1. Malignant Lymphoma Merkel cell carcinoma has often been clinically and histopathologically misdiagnosed as lymphoma. 4,313 54,'0','08,114,"5,'24,'30 Lymphadenopathy, characteristic for many lymphomas, is frequently present in Merkel cell carcinoma due to regional nodal metastases. A further pitfall in the diagnosis may be that the patient can have a concurrent lymphoproliferative disorder.44~5’~62~‘02~“5*“6 The tumor closely resembles a large cell or lymphoblastic lymphoma, when it consists of diffusely infiltrating and loosely arranged uniform round cells, particularly if the associated lymphocytic infiltrate is heavy.

1990

RIVEti,

TARREANEN

Poorly differentiated plasmocytoma63*‘15 and leukemic infiltrates’30 must also be excluded. Merkel cell carcinomas generally lack chromatin clumps, have very scant cytoplasm, and have rather uniform nuclei compared to lymphomas.53*63~68~“2~“5~‘30 They are positive for leukocyte common and other lymphocyte antigens, and lack neuroendocrine and epithelial markers. 2. Bronchogenic Oat Cell Carcinoma Histopathologically, Merkel cell carcinoma closely resembles other small cell neuroendocrine carcinomas, especially metastatic pulmonary oat cell carcinoma, one tenth of which eventually have skin metastases.“5,‘34 They consist of small round to spindle shaped cells, which commonly show extensive necrosis and crush artifact.53~“2*“5 Although their antigenic profile may be identical to Merkel cell carcinoma,‘j4 most authors would consider perinuclear whorls of cytokeratins and neurofilaments exceptional for oat cell carcinoma.4*18*64~88,‘34 Nevertheless, the differential diagnosis ultimately rests on careful systemic work-up for other primary neoplasms. 4,'0'.'03,'33 3. Carcinoid Tumors Carcinoid tumors closely resemble Merkel cell carcinoma in their light microscopic and immunohistochemical pattern, including even occasional paranuclear aggregates of intermediate filaments.4*65*‘34They tend to have more pleomorphic and larger neurosecretory granules than Merkel cell carcinomas, and give stronger Grimelius and chromogranin reactions.4*68 Again, meticulous systemic work-up for other primary tumors is mandatory. 4. Sebaceous Carcinoma Merkel cell carcinoma in the eyelid may be confused with sebaceous carcinoma.‘g,23 Both neoplasms often present as an erythematous nodule affecting the upper eyelid of elderly patients and sometimes simulate a large chalazion.5g~72 Sebaceous carcinoma involves the tarsus, grows in more solid and often lobular pattern, and shows squamous differentiation much more frequently.“2~“4 In addition to lack of neuroendocrine features by electron microscopy and immunohistochemistry, frozen sections stained for intracellular lipids will make the diagnosis.“* F. PROGNOSIS Merkel cell carcinomas be slowly growing tumors that may behave for a long tumors.30*‘03~‘3qIt has since

were initially thought to of low-grade malignancy time as locally aggressive been documented, how-

MERKEL CELL AND NEOPLASMS ever, that the incidence of local recurrence and early extensive nodal metastasis is high even when the primary

tumor

is ~mall.l3~"Z~"l~96~lOZ~lO6.'I4~I41 Although

183

have died of Merkel cell carcinoma, and the estimated five-year survival rate is 38%.44.“1 Only six patients with an eyelid tumor and five patients with an eyebrow lesion have been observed at least for two years or until death with metastasis (Fig. 2). Two patients in both groups have died of Merkel cell carcinoma, and two additional patients with primary eyebrow lesions had evidence of metastatic disease at the time of death, which was thought to be due to an intercurrent disease. Five putative spontaneous regressions of Merkel cell carcinoma have been reported.g~‘02~14’ No clinical or histopathological classification has been presented that would consistently correlate with prognosis of Merkel cell carcinoma.77~10’~“4 Features tentatively suggested as prognostic indicators include large size of the tumor,44’“4.“” location in the head and neck region,lz4 metastases at the lymphatic invasion,3'."" in_ time of diagnosis, 10~~116 complete excision, 32,51,116 and either male or female sex of the patient.“‘.“‘“.“’ Although some authors have felt that tumors of the trabecular type are less aggressive than those of the small cell type,‘i8~“6B191 such a relationship has not been very strong in other series.“‘”

many Merkel cell carcinomas in the eyelids and periocular region have not had an extended follow-up period (Fig. Z), it appears likely that malignant melanoma, Merkel cell carcinoma and sebaceous carcinoma are the three most malignant primary tumors of the eyelid. However, clinical data currently available on periocular Merkel cell carcinoma is scanty, and future cases should be published with an adequate description of treatment and a sufficiently long follow-up period. Local recurrence and satellite lesions occur in about one third of all patients, usually within one year of initial surgery. 9,13.27,32.51.62,77.96.102.103,ll4llfi~124~133Recurrences are often multiple and may be especially frequent when the tumor has been associated with a squamous cell carcinoma.33 Five out of 18 eyelid tumors and four out of 12 periocular lesions that have been observed for at least six months after therapy have recurred (Fig. 2). Five patients, at least one of whom had a periorbital primary lesion, have died from direct intracranial spread of the recurrent tumor.77,“6 About two thirds of patients with Merkel cell carcinoma have had regional lymph node metastases, G. TREATMENT either at the time of diagnosis or, more often, within eighteen months after initial therapy.g~L3~20*27~“z~ 1. Localized Disease 44.50b.51.62.77.96.101,104.106.114.116.117 The metastases may oc_ Merkel cell carcinoma demands prompt and aginitial therapy for a favorable outgressive casionally be delayed for several years.‘0?*“4 Six out surgical excision of the pri_ come. IJ.3".5'~116~l"3Wide of 18 eyelid, and six out of 12 periocular tumors mary tumor should be carried out whenever poswith a follow-up of six months or more have given sible.9,I3.:1".51.77.96,I?4.I:~3 In the case of an eyelid tumor, rise to regional metastases (Fig. 2). this means full-thickness resection followed by a reHematogenous distant metastases from Merkel constructive procedure.5”~“3~7’~l” Frozen section cell carcinoma have eventually developed in more one control may be helpful in ensuring the deep margin than one third of cases:’ 9 13,3?,44.51.77,101,102.106.114,116 of the excision, but it does not guarantee complete half of patients followed for two years or more have removal due to the frequent early lateral disseminaextraregional disease.“’ Extraregional metastases tion through lymphatic channels, leading to satelusually appear within two years of initial diagnos~~~9~3~,~l,62.96.114.1 I6 lite lesions and multiple recurrences.y*92~77~96A furThey involve most frequently the ther operation has sometimes been considered skin, bone, brain, liver and lung, but have also been necessary to ensure complete removal when the tufound in meninges, spinal cord, mediastinum, mor has been clinically misdiagnosed,“‘.“4”” and pleura, pericardium, myocardium, retroperitoexenteration has twice been deemed necessary for a neum, kidney, pancreas, stomach, small and large recurrent eyelid tumor.g6.“5 bowel, thyroid, parathyroids, adrenals, testes, ovaMerkel cell carcinomas generally respond well to ries, pelvis, large blood vessels and tonSOme have sils 9,24~27.'?9~~~L'~62~lO6~li6~lZ9~l~~~~~l4l radiation therapy, 4,12.61.102.105,1?6although Orbital metastasis has recurred in the radiation field or during radiotherbeen reported at least twice,“.‘” while cutaneous metastasis to eyelids”” and a clinically diagnosed choapy. “.I’.“” It may be used as primary treatment if the patient does not tolerate surgery or the tumor enroidal metastasis’ have both been described once. croaches vital structures,‘.y”.‘24 such as the eye.‘.“.‘“’ The overall mortality parallels the incidence of In these cases, aspiration cytology may be used to systemic metastaseslW and ranges from one fifth to establish the diagnosis in addition to ordinary biopone third of all cases.’ 9 1'127.32,JOb,A?.77.96.IOl,lO2.lO6.ll6.ll7.l3:i According to two critical literature surveys, nearl) sy. ‘.w~’ Adjunctive radiotherapy may also be effectively used to obviate the necessity for extensive one half of patients followed for three years or more

184

Surv Ophthalmol

surgical procedures.gs’” Indeed, surgery combined with prophylactic local radiotherapy may have a success rate superior to surgery alone, even when a wide excision has been performed.13 It has been recommended that the tissues between the tumor and first regional lymphatic nodes should be routinely irradiated (50 to 60 Gy in 20 to 25 fractions Over 4-6 weeks).g,13.32.51.96,' 16 Patients need regular follow-up for early detection of possible lymph node spread.51,“4.‘33 While some authors have suggested that prophylactic dissection of regional lymph nodes might be carried this is probably not advisable due to out, ‘3~32~5’*‘06~‘14 the advanced age of most patients, the fact that many cases are cured by treatment of the primary tumor only, and the radiosensitivity of Merkel cell carcinoma.g*62~g6~10z~‘24~‘4’ It has been suggested that adjuvant chemotherapy be considered in younger patients, but there is no evidence yet that this approach increases surviva1.24.g6.‘4’ 2. Regional

Nodal

to ten years after a complete therapy_‘.%’ 14.141

Disease

response

to chemo-

References 1. Alexander

la.

2.

3.

E III, Rossitch E Jr, Small K, et al: Merkel cell carcinoma. Long term survival in a patient with proven brain metastasis and presumed choroid metastasis. Clin Neural Neurosurg 91:3 17-320, 1989 Arnaud B, Zaghloul K, Dupeyron G, Malrieu C: Tumeurs palpebrales a cellules de Meikel. Apropos de 3 cas. Bull Sot Ophtalmol Fr 89:979-984, 1989 Ashby MA, Jones DH, Tasker AD, Blackshaw AJ: Primary cutaneous neuroendocrine (Merkel cell or trabecular carcinoma) tumour of the skin: a radioresponsive tumour. Clin Radio1 40:85-87, 1989 Auriol M, Diner P, Degois G, et al: Tumeur B cellules de tierkel associee a un $tht+lioma spinocellulaire. Apropos d’une observation. Rev Slomatol Chir Marillofac 87:276-28 I, 1986 Battifora H, Silva EC: The use of antikeratin antibodies in the immunohistochemical distinction between neuroendocrine (Merkel cell) carcinoma of the skin, lymphoma, and oat cell carcinoma. Cancer 58:1040-1046, 1986 Beiras A, Garcia-Caballero T, FernOndez-Redondo V, Gallego R: Morphometric characterization of the human neuroendocrine Merkel cells. J Invest Dermatol88:766-768, 1987 Beiras A, Garcia-Caballero T, Gallego R, Ros6n E: Staining of neuroendocrine Merkel cells of human epidermis using the uranaflin reaction. J Invest Dermalol89:36f%368, 1987 Beyer CK, Goodman M, Dickersin CR, Dougherty M: Merkel cell tumor ofthe eyelid. Aclinicopathologic case report. Arch Ophthalmol IOl:lO98-1101, 1983 Bosca AR, Cavero FV, Peris VT, Rodellas AC: Marcaje mediante lectinas de un tumor de celulas de Merkel. Med Cutan Ibero Lat Am 16:125-127, 1988 Bourne RG, O’Rourke MGE: Management of Merkel cell tumour. Aust NZ J Surg 58:971-974, 1988 Breathnach AS: Branched cells in the epidermis: an overview. J Invest Dermatol 75:6-l 1, 1980 Buffa R, Rindi G, Sessa F, et al: Synaptophysin immunoreactivity and small clear vesicles in neuroendocrine cells and related turnours. Mol Cell Probes 2:367-381, 1988 Champion R, Gloor F, Speiser P, Bosshard Ch: Merkelzelltumor des Lides. Klin Monatsbl Augenheilkd 320:480- 482, 1982 Cotlar AM, Gates JO, Gibbs FA Jr: Merkel cell carcinoma: combined surgery and radiation therapy. Am Surg 52: 159-164, 1986 Dardi LE. Memoli VA, Gould VE: Immuohistochemical demonstration of neuroendocrine cells in basal celi carcinomas. J Cutan Path01 8:335, 1981 Diamond J, Holmes M, Nurse CA: Are Merkel cell-neurite reciprocal synapses involved in the initiation of tactile responses in salamander skin? J Physiol (Land) 376:101-120, 1986 Diamond J, Mills LR, Mearow KM: Evidence that the Merkel cell is not the transducer in the mechanosensory Merkel cell-neurite complex. Progr Brain Res 74:51-56, 1988 Dhermy P, Sterkers M, Morax S, et al: Localisation palp& brale de la tumeur g cellules de Merkel (carcinome trab&J

4.

5.

6.

7.

8.

9. 10.

Chemotherapeutic regimens have been used for Il. extensive local or recurrent disease and for distant metastases. No treatment protocol has been found 12. to be superior to others, and most have included adriamycin, vincristine, cyclophosphamide and 13. doxorubicin.9~Z4~3O~5I,lO6.141 Although some authors have reported little success with chemotherapy,“” 14. most Merkel cell carcinomas respond well, with a complete response in about one half of patients and partial response in most others.9~24~29,30.51,106,IP4,126.l4~15. The tumor has a great tendency to recur after cessation of treatment, however, and current chemotherapeutic regimens are mainly of palliative value in management of Merkel cell carcinoma.g~24~‘g~30*32~ 51,61,62,'02,106,114,124.'26.'41 Nevertheless, a few patients have enjoyed longterm disease-free survival of up

TARKKANEN

The benefits of chemotherapy should be balanced against the possible side effects in elderly patients. However, it should be given serious consideration if the patient is a reasonable candidate for this treatment modality, especially in the younger age group. g,24Radiotherapy can also be used in palliative treatment of metastatic Merkel cell carcinoma and a radioactive episcleral iodine plaque has given a good response in a case of a presumed choroidal metastasis (8806 cGy to tumor apex).’

Disease

Several authors have felt that resection of any grossly abnormal regional lymph nodes found at the time of diagnosis is indicated and may effectively control the disease.g~32,5’.‘24Lymph node dissection either alone or in combination with radiation therapy has also been used in patients who have later developed regional metastases.32’“‘.77*96*‘02* 106*107,‘24 Irradiation alone for regional metastases, although initially effective, does not always cure the disease.62.“4 As is the case with primary lesions, the evidence suggests that surgery combined with radiation therapy may be superior to either treatment modality alone.g~3’~77Lymph node metastases without other systemic disease do not necessarily signify poor prognosis, and some patients have survived for several years after treatment.g6”02”‘4 3. Extraregional

KIVEti,

35 (3) November-December

16.

17.

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Outline [. The normal A.

Merkel ceII Distribution in the human

body 1. Epidermis and mucous membranes 2. Epidermal appendages 3. Specialized aggregates 4. Dermal Merkel cells B. Specific identification methods 1. Ultrastructural characteristics 2. lmmunohistochemical characteristics C. Origin and function II. Merkel cell carcinomas A. Incidence and demography 1. Age and sex distribution 2. Location B. Clinical presentation C. Histopathologic diagnosis 1. Light microscopy 2. Special staining features 3. Electron microscopic characteristics 4. Antigenic profile D. Origin and histogenesis E. Differential diagnosis 1. Malignant lymphoma 2. Bronchogenic oat cell carcinoma 3. Carcinoid tumors 4. Sebaceous carcinoma F. Prognosis G. Treatment 1. Localized disease 2. Kegional nodal disease J. Extraregional disease

Reprint address: Tero KivelP, M.D., Department of Ophthalmology, Helsinki University Central Hospital, Haartmaninkatu 4