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 epider- mis 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 pres- ent, 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 anti- body 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~‘09Crinophagic 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, These cells are constantly associated with dermal however, complex intercellular junctions with sup- nerve endings.3X~“~7’~H”~“~yK~“oSubepithelial Merkel posed presynaptic neurosecretory granules and cells are also seen in the oral mucosa and glans postsynaptic small clear vesicles have been likened penis.!” to reciprocal synapses.15,2".9".~7,H~,"7
B. SPECIFIC IDENTIFICATION METHODS 2. Immunohistochemical Characteristics 1. Ultrastructural Characteristics The epithelial properties of Merkel cells are re- Merkel cells have a relatively electron-lucent cy- flected in their antigenic profile. Merkel cells can be toplasm, which contains many free ribosomes, labeled with antibodies to low-molecular weight cy- sparse endoplasmic reticulum, and the normal tokeratins 8, 18 and 19 characteristic of simple and complement of intracellular organelles, including a glandular epithelia (Fig. l), while they lack the cyto- relatively prominent Golgi complex.?6~‘7~50~“2lnter- keratin types (previously often called prekeratins) mediate filaments are randomly distributed and normally found in keratinocytes of stratified epithe- form no paranuclear aggregates, a hallmark of lia.“x~x”~gs~y”~“’The cytokeratin filaments are evenly Merkel cell carcinoma.‘6~‘7~x6~y2.‘30Tonofilaments distributed throughout the cytoplasm without have been found in putative fetal Merkel cells in forming any aggregates. The same cytokeratin animal species only. =.” Rare melanosomes are in- types are also found in embryonic human skin and terpreted as evidence of phagocytosis.“‘The nucle- some positive cells may theoretically be stem cells of us is oval, often lobulated, and may contain a char- keratinocytes.X”~yo~y”Merkel cells are also positive for acteristic intranuclear rodlet.25-87.“2 desmoplakins,“g but, at least in rabbits, they lack the Merkel cells typically have cytoplasmic dense- bullous pemphigoid antigen, produced by adjacent core granules, which are morphologically identical basal keratinocytes7” to those of neuroendocrine cells and measure Merkel cells express several antigens common to 5R.26."7,50,7',74.8fi.92.lO9,"X.l.lll 70-110 I’m in diameter.,, the diffuse neuroendocrine system. They react These are often seen in cytoplasmic processes and positively with antibodies to neuron-specific eno- along the basal cell membrane.“~‘6~7’~R6~92~“XThey de- lase. 4’~‘x.79.‘90an antigen also found in malignant 174 Surv Ophthalmol 35 (3) November-December 1990 KIVEIJi, TARKKANEN
CASE SEX AGE LOCATION DURATION SIZE FIEF TREATMENT AND CLINICAL COURSE (Y) (months) (mm) e NM tl] 1 Fern 89 Eyelid n/a n/a 20 130 2 Mal 71 Eyelid n/a n/a 32 L 70 Outer canthus 9 n/a 17 wr Nnpr M, 111 33 Mal 65 Inner canthus 2 12 28 br 34 Mal 65 Inner canthus 4 30 196 I 35 Mal 81 Canthus n/a n/a 33 e fjn 36 Fern 86 Eyebrow >I2 15 45 e fjn 45 Fern 56 Supraorbiial da n/a 145 46 Fern 71 Infraorbital n/a 30 68 47 Mal 64 lnfraorbital n/a n/a 97 48 Mal 69 Infraorbital n/a n/a 97 49 Fern 65 lnfraorbiial 12 10x15 127 eerRw 50 Fern 62 lnfraorbital n/a n/a 19 6mo tY 2y 4Y 6y . Fig. 2. 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. MERKEL CELL AND NEOPLASMS 17.5 melanomas but not in most normal melano- anjmals 15.54.76 Cyt~~~:4X.42.45.73.10~,llo,l~~~ In humans, Merkel cells react Alternative hypotheses have been that Merkel strongly with antibodies to chromogranins, a major cells might have a trophic function for keratino- family of secretory proteins of dense-core gran- cytes and dermal nerve endings, they might act as ules, 4x.sy.’’ ‘,‘97 and more weakly for synaptophysin, a neuromodulators, or they may have a tropistic membrane protein of small clear vesicles in neuro- function and act as targets in axonal arborization endocrine cells and neurons.“,‘00*‘“6 Merkel cells during development with subsequent passive are negative for neurofilaments, which are fre- role. '6.38,7R.Xfi.I38 quently expressed in Merkel cell carcinoma.s6,g”.’ ’ ’ In rabbits they also lack vimentin, desmin and glial II. Merkel Cell Carcinomas fibrillary acidic protein.“’ A. INCIDENCE AND DEMOGRAPHY Attempts to detect a putative transmitter sub- 1. Age and Sex Distribution stance in the cytoplasmic granules of Merkel cells have been wrought with difflculties.‘5 Although Merkel cell carcinoma is a relatively frequent pri- met-enkephalin has been found in monkey and sev- mary malignant neoplasm of the skin. It is difficult eral rodent species, it has not been detected in hu- to give an accurate number of the published cases, mans.‘“x4” Positive reaction has been obtained with because many patients have been reported multiple antisera to vasoactive intestinal polypeptide, where- times by different groups of authors. However, we as neurotensin, somatostatin, corticotropin, secre- estimate that about 600 cases have been described tin, alpha-melanocyte stimulating hormone, gas- during the last eight years. Merkel cell carcinomas trin, cholecystokinin, glucagon, substance P and typically occur in the elderly population, The aver- bombesin have not been detected in adult or fetal age age at the time of diagnosis has ranged from 66 human Merkel cells.“H*4X,“” 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~', C. ORIGIN AND FUNCTION IO'L.ll4.llf~.IL'4,l'LX.ISJRarely, the tumor affects young It was initially suggested that Merkel cells would adults, some of whom may have an antecedent cu- originate from neural crest and migrate along pe- taneous disorder such as the hypohidrotic ectoder- ripheral nerves through the dermis into the epider- ma1 dysplasia syndrome.“~77~‘“” The patients with mis and outer root sheaths of hair follicles. This eyelid tumors (Fig. 2) have been on an average 77 theory was based on the presence of cytoplasmic years old (range 54 to 95 years) and those with granules similar to those of neuroendocrine cells in eyebrow lesions 7 1 years old (range 3 1 to 86 years). Merkel cells, their approximity to neurons and In many series, females have been affected nearly Schwann cells, and the occasional dermal Merkel cells. “” However, it has since been shown that Mer- kel 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 resem- bling keratinocytes and Merkel cells have been de- scribed in animal studies only, it is now widely be- lieved 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 evi- dence 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 Fig. 3. ‘Typical clinical appearance of a Merkel cell carci- morphological and biochemical evidence for synap- noma affecting the left upper eyelid of a 72-year-old tic transmission is lacking in humans, and recent woman. The tumor had progressively enlarged during experimental electrophysiological studies have con- three months and measured 23 x 8 x 8 mm. (Case 15; cluded that Merkel cells are not directly responsible Courtesy of Prof. William R. Lee, University of Glasgow, for the transducer function, even in laboratorv Scotland).” 176 Surv Ophthalmol 35 (3) November-December 1990 KIVEL& TARKKANEN twice as often as males,20~27~45~8g~‘0’~‘02~‘16and this is may appear erythematous and is characteristically also true for lesions in the eyelid and periocular red in color, with hues ranging from pink to viola- region (Fig. 2). Analysis of published cases, howev- ceous and purple. 12.17,20,27,32,63,72,103,114.124,133 lts sur_ er, has generally revealed no consistent difference face is smooth and frequently shiny, sometimes in this respect. 44,5’,‘15Merkel cell carcinomas are ex- nodular, and very often characterized by dilated ceedingly rare in the black population.‘3,32*56,“5,“6 telang.iecmtic blood vessels.‘,‘2,‘7,23,59,63,69,‘03,’‘2.139 The red color and dilated vessels may relate to the fre- 2. Location quently observed inflammation and invasion of lo- About one half of Merkel cell carcinomas occur cal lymphatic channels. ‘I4 The overlying epidermis in the head and neck region.9,20,32,44,45,51,62,68,77. is usually intact, but it occasionally may be ulcerat- g6~"4~'16~124*133In almost one fifth of these patients, or ed.31~32~40~103*‘07~‘28These features form a recogniz- one tenth of all cases, the tumor affects either the able pattern, especially for tumors involving the eyelid or the periocular region, which appear to be eyelid, and should lead to a high index of suspicion predilection sites of Merkel cell carcinoma (Fig. 2).* of Merkel cell carcinoma, which helps the patholo- The eyelid, preferentially the upper one, has been gist to proceed accordingly. involved in 31 patients, whereas four tumors have C. HISTOPATHOLOGIC DIAGNOSIS affected the canthus, nine have localized to the eye- brows, and six have been removed from the orbital 1. Light Microscopy rim (Fig. 2). Elsewhere in the body, Merkel cell Merkel cell carcinomas originate in the reticular carcinomas tend to involve the extremities, and or papillary dermis and frequently extend into the only about one tenth affect the trunk or mucous subcutaneous fat and muscle.‘,20,27.41,46,64,1 14,ll7,126~ 9~20~27~44~51~62~68~77~96~102~114~124~133 Occasional_ membranes. 130*‘33 In the eyelid, they typically invade the orbic- ly there may be widely distributed multiple skin ularis muscle and spare the tarsal plate (Fig. lesions, a condition sometimes termed cutaneous 4B). 63~6g~103~’12,’I5 The overlying epidermis may be at- ~~~~~~~~~~~~~~~~30~57~l16~129~131~l40 tenuated, but it is generally separated from the tu- mor by a narrow rim of papillary dermis,7*‘7*20*23,27,45* B. CLINICAL PRESENTATION 5g~87,‘o’~‘14~133and ulceration is present in a minority The tumor is generally a solitary dermal skin of cases only. 40~45~~6~~~6~~‘03~‘~7~‘12~tt4Pilosebaceous fol_ nodule, which is painless, nontender and often pro- licles and sweat glands persist within the tumor, but tuberant, bulging or dome-shaped.7~‘7*20*23,32~63* may become compressed.20.23,4~.8’,’ ‘%‘l4,l t5zt22 very 6g~‘03~“2~‘24~133In the eyelid (Fig. 3 and 4A), it arises rarely, pagetoid invasion of the epidermis2~35~“2~72~‘07~ near the lid margin’7,23~“3~6g~72~~~1I2 and either spares 114-“6~12’or follicular epithelium115*“6 has been ob- or causes partial loss of the eyelashes.‘2~63~6g*72~“2Sev- served, twice associated with an eyelid tumor.72,“5 eral eyelid tumors have been pedunculated17~23*72 The arrangement of the tumor cells varies.27s3s and two have mimicked chalazia.5gs72 The tumor The “classical” organoid pattern of interconnecting trabecular cords separated from each other by con- nective tissue strands, which led to the initial desig- nation 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~“6In these tu- mors, the trabecular cords may form pseudoro- *The notion that periocular Merkel cell carcinoma is a rela- settes or pseudoglandular patterns.‘7.27,64,81,103,107*‘14, tively frequent tumor is substantiated by the fact that five new cases have been reported since submission of this manuscript. A ‘22,‘25~‘33Most Merkel cell carcinomas form large 95-year-old woman, who had a 10 mm tumor involving upper nests of cells (Fig. 4C), which may show some evelid, died of unrelated causes 8 months after local excision. 5oa trabecular arrangement in their peripheral An 82-year-old woman had a large tumor in the inner canthus, 2327, 38.46,59,68,75,87,102,114,121,133 F’ which was operated and irradiated. It recurred and sent nodal parts. mally, some con- metastases in 2 months, and she died one year later with evi- sist of diffusely infiltrating neoplastic cells (Fig. dence of distant metastasis. la A 60-year-old man had in his 4D, E), which resemble large cell lympho- upper eyelid a 4 mm tumor, which was excised. Nodal metastasis 4,27,41,102.112.114-116,128 was biopsied and irradiated after 3 months. Testicular metastasis mas. occurred after 9 months, followed by chemotherapy with com- A finding of considerable clinical importance is plete response. He is alive 3 years after initial diagnosis. Ia A 65- the frequently observed vascular62*103*“4and, in par- year-old man had in his upper lid an 18 mm tumor that devel- lymphatic ~~~~~~~~~27~56~64~68~103~107~114-116~133~ oped after incision for presumed chalazion. He is alive and well ticular, one year after wide excision. la A tumor in the upper eyelid of a ‘35~‘3g The latter is thought to underlie the high fre- 67-year-old patient was excised and irradiated, and there is no quency of local recurrences and regional nodal me- 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 tastases so characteristic of Merkel cell carcino- evidence of disease after 3 years. ma.g*“4 When specifically searched for, tumor cells MERKEL CELL AND NEOPLASMS 177 may be observed in lymphatic vessels in more than cells, 12,17,L’0,27.31.41,~9.Xl.l0~~,l14.1l~.12H.I~~9.1:(~~ which may one half of the tumors,‘7~6*~“‘7~“4 and such invasion cause further difficulties in differential diagnosis has also been reported for eyelid tumors.z7,5g.“5 The with respect to lymphoma (Fig. 4D and E). tumor is also frequently surrounded by a more or The tumor generally consists of round cells of less dense infiltration of lymphocytes and plasma intermediate size, ranging from 12 to 25 km in Fig. 4. 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). 178 Surv Ophthalmol 35 (3) November-December 1990 KIVEL& TAKKKANEN TABLE 1 diameter.23,31~37,5g*60~75”03They have scant ampho- Antigenic Properties of Merkel Cell Carcinomas. ’ philic and slightly metachromatic, occasionally faintly granular cytoplasm with indistinct borders Immunoreactive 23.27,31.101,103,112.~14,122,125.133 Antigen tumors (Fig. 4C). The large nuclei are vesicular, round to oval, and have a sharply Epithelial anti ens defined, often indented membrane, finely granular Cytokeratin 8 203/212(96%) Epithelial membrane antigen 44/49(90%) chromatin and l-3 mostly inconspicuous nu- Desmoplakins 4/8(50%) cleoli.20~‘3~‘7~3’~75*“5Many tumors contain a popula- Carcinoembryonic antigen3 203 (-) [15%] tion of small round to spindle-shaped cells with hy- Grimelius stain4 108/210(51%) perchromatic nuclei resembling those of bronchial Neurofilaments5 77/146(53%) oat cell carcinoma '~17~36~38~~2~68~102~103~114~116~141~133The Neuroendocrine antigens Neuron-specific enolase 220/254(87%) rate of mitosis is generally very high, ranging from Chromogranins’ 53/88(61%) 3-l 5 mitoses per high power field (Fig. 4C).‘7*23,‘7*3’~ Synaptophysin’ 6114146%) 59~60~63~6~~69~~2~'5~101.103,128Individuaj cell necrosis (Fig. HNK-1 carbohydrate epitope6 2/19(11%) 4C) and apoptosis are also common,23~27*37~64~ Putative neurotransmitters7 68,69.107.115.116,128,130,143but areas of confluent necrosis ACTH (corticotropin) 5/94(5%) [ 13%] 7~2',103~114-116,133 one study claims that Bombesin l/57(2%) [ lOO%] are infrequent. Calcitonin 24/121(20%) [45%] a ball-in-mitt arrangement, in which one or two Cholecystokinin o/22 (-) crescentic tumor cells are closely wrapped around a B-Endorphin O/22(-) central round one, would be typical of Merkel cell Gastrin 7/55(7%) [55%] carcinoma.“’ Glucagon O/36 (-) a-Human chorionic gonado- Small areas showing squamous differentiation tropin o/17 (-) and keratin pearls have been described in excep- Insulin 0136 (-) tional Merkel cell carcinomas.27~35*66~1’5.“6Further- Leu-enkephalin 2/24(8%) [ lOO%] more, primordial sweat gland differentiation with B-Lipotropin O/6 (-) eccrine tubules and ducts containing keratohyalin Met-enkephalin 3/67(5%) [lOO%] Nerve growth factor o/3 (-) granules and showing focal keratinization has been Neurotensin O/32 (--) detected in a few cases.35S62S1’6More often, however, Pancreatic polypeptide l/41(2%) [5%] Merkel cell carcinoma is associated with a concur- Serotonin O/70 (-) rent or antecedent invasive squamous cell carcino- Somatostatin 10/87(12%) [25%] ma,3,33,56,ffl,“6.‘21,142with an intraepithelial squamous Substance P l/56(2%) [5%] Vasoactive intestinal polypep- carcinoma in the overlying epidermis27~62~64’107~‘14.“6 tide 20/60(33%) [40%0] or with an adnexal neoplasm,‘16~‘20 suggesting the Miscellaneous antigens possibility of a common carcinogenic influence in S- 100 protein 18/117(15%) addition to divergent lines of differentiation. Mer- Leucocyte common antigen o/93 (-) kel cell tumors frequently occur in patients who Vimentin o/34 (-) Glial fibrillary acidic protein o/12 (-) have had basal cell epitheliomas.13~29~32*33~ Laminin O/8 (-) 75~‘02~‘07*133~‘35~14zIn this respect it is of interest that rare basal cell epitheliomas that have features sug- gestive of neuroendocrine function have been de- ‘Data from references [4, 11, 12, 17, 19, 20,23, 27, 28, scribed.‘4S70 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 2. Special Staining Features presented in Fig. 4 and 6. 2Positive for simple epithelial types 8, 18 and 19 only; Grimelius stain for argyrophilic granules (Fig. diffuse perinuclear and/or focal immunoreaction in fi- 4F) is positive in at least one half of cases (Table I). brous bodies depending on the antibody used. The specimen should optimally be Bouin-fixed, 3Selective immunoreactivity in squamous and eccrine since routine fixation in formalin may quench the elements seen in exceptional cases only. reaction. 17~27~60~116 4Modified argyrophilic stain, all specimens; 36137 The tumor cells are negative in Bouin- and 22152 formalin-fixed specimens positive Fontana-Masson stain for argentafhn granules and when fixation reported. in other melanin reactions.* "3 v27.31,36,63.64.75,101~117,122, 51mmunoreaction almost exclusively in fibrous bodies. 123s133 Although most cases do not stain for glyco- “Generally focal immunoreaction in a proportion of 31.36.65.64,lOl 16 and mu_ gen, lipids,63,'Z~myloid,~l,36,IOI,I cells. 7Peptides are notoriously difficult to demonstrate; sec- copolysaccharides,23~z’,3’.3’*54*63.64 spurious positive ond percentage [in brackets] excludes papers in which all reactions may be observed.‘3*64.‘4’ Certain lectins specimens were negative. 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 pro- The ultrastructure of neoplastic cells in Merkel cesses 36.37,40,60.68,75,89,101.107,114.116,1l7,l33 Although cell carcinoma closely resembles that of normal dense-core granules are diagnostic, in a minority of Merkel cells (Fig. 5). The tumor cells are generally Merkel cell carcinomas none or only very few are polygonal in shape. They often have indented nu- detected.23,27,28.36’59.68.121Furthermore, if formalin- clei with evenly dispersed sparse euchromatin, a fixed and paraffin-embedded tissue must be sal- thin rim of heterochromatin, and multiple small vaged for electron microscopy, the granules have nucleoli 7~25~46~59~63~107~115~133lntranuclear rodlets are often been destroyed.46*“4,“7*‘42 Small clear vesicles rarely encountered.60*“5.‘39 The cytoplasm is distin- have also been described in Merkel cell carcino- guished by abundant ribosomes and polyribo- ma.11'57 somes, but the smooth and rough endoplasmic re- A consistent feature of Merkel cell carcinoma is ticulum are generally ~pa~~e.7~27~31~46~59~107~112~115,122r130paranuclear aggregates of intermediate filaments, The Golgi apparatus is most often well-devel- often designated fibrous bodies,46.60.68,75.8g,‘07,“4. oped. 17.27.57~63,107~115~133~135~139Centrioles,l33'135 cilia,133 “5.130,‘42which frequently enclose a few dense-core glycogen granules,3”‘43 lipid droplets,‘7,23~40~12’and granules. 2’137.46,60,1l4sl33.135 Immunoelectron micros_ paracrystalline granules reminiscent of premelano- copy shows that these are composed of cytokeratins somes’40 are occasionally found. and neurofilaments, either alone or in combina- The diagnosis of Merkel cell carcinoma is classi- tion.75*87 Even though some tumors appear to be cally based on the presence of cytoplasmic dense- degranulated, they still have a prominent fibrous core granules averaging from 80-l 50 nm in diame- body, and only rare tumors diagnosed as Merkel ter (range 75 to 240 nm). 17.27.31.36.46.57.59.68.75,101.107,114- cell carcinoma have been reported to lack these "7~122~'28~130 They concentrate along the cell mem- perinuclear aggregates. 68,*7,10’.114Fibrous bodies are 180 Surv Ophthalmol 35 (3) November-December 1990 KIVEti, T-EN particularly useful because they usually survive fix- Putative neuropeptides have been detected in ation in formalin and embedding in paraffin, and only a minority of cases (Table 1). Vasoactive intes- can be used later for electron microscopic diagnosis tinal polypeptide is found in about one that was not originally planned.4”,“4,‘33 Intermedi- third37*38,40,67@*“4and calcitonin in one fifth of Mer- ate filaments are also found dispersed in the cyto- kel cell carcinomas.3~38.67,68,“7 Other peptides that p~as~,37,40,68,87,103,116.128 but their arrangement sel- have been occasionally demonstrated include dom bears resemblance to tonofilaments.66~sg*“4*“5 ACTH, ‘6*3*,‘7~~“7 bombesin,37*” gastrin,yO leu_enke_ Specialized intercellular junctions are variable. phalin,37*38 met-enkephalin,23z40 pancreatic polypep- Most often they are reported to be sparse and poor- tide,‘14 somatostatin,20*36”‘7 and substance P.‘l’ Ele- ly formed desmosomes, 27,66,75,81,87,89.115.121,122,142.143 vated serum levels of ACTH5* and and hemidesmosomes,3’*‘22’130 or they are described calcitonin36~55*‘08~‘43have been reported, although as primitive. 23,40.56,103,112,116,121 Maculae adher- these have never been found in association with a entes 59,60,72, l15.130.133.135 and zonulae adherentes27,46 clinical paraneoplastic syndrome.36,54,55*108.“7’13g~143 have also been described, and the tumor cells occa- The variability and rarity of neuropeptides in Mer- sionally have rudimentary basal laminae.57r’2” kel cell carcinomas means that they are of little diag- 122~‘30,‘33~135Dendritic cytoplasmic processes, some of nostic importance, although when elevated serum which contain actin microfilaments and resemble levels are present, they may help in detecting recur- cytoplasmic spikes of normal Merkel cells,1g@,68S rent disease.3”p’43 “4~‘23,*30are frequent. 7.23,27,36,37,40,75,101.112,114.117,130,133,143 Antibodies to epithelial membrane and related Focal microvilli may be present.7,35*66.115.‘33S’35 antigens react with most Merkel cell carcinomas (Fig. 6F). 20.23~124*‘28,‘3’Carcinoembryonic antigen 4. Antigenic Profile and human large-molecular weight salivary mucins Merkel cell tumors resemble normal Merkel cells have been detected only in those rare cases which in expressing cytokeratin polypeptides 8, 18 and 19 show eccrine differentiation.s5 Laminin was not typical of simple and glandular epithelia (Table 1; found in tumor cells in one particular study,45 but Fig. 6A and B), as judged both by immunohisto- desmoplakins may be observed.87 Leukocyte com- chemistry 2.20,35,37,45,52,68.87,102,113~123~124~126~128and immu_ mon antigen (Fig. 6G) and other lymphocyte mark- noblotting. 52,87 In contrast, cytokeratin antibodies ers have been constantly absent from Merkel reacting exclusively with stratified squamous epi- cell carcinoma.4*20*67~68,154.126,128Although antibodies thelia do not label Merkel cell carcino- ma.37~52~56~60~84~87~“3*‘23Unlike normal Merkel cells, most Merkel cell tumors additionally express some of the three neurofilament proteins, which invari- Fig. 6. (Page 181) Antigenic properties of Merkel cell ably aggregate to form the paranuclear whorls seen carcinoma (immunoperoxidase, x 250). A: Almost all tu- by electron microscopy (Fig. 6C).4,‘8.20*45,52, mor cells react positively for the cytokeratin polypeptides 64,67~9.81.87,113,123,l24.l26,128 Both types of filament are 8, 18 and 19, giving a diffuse cytoplasmic immunoreac- simultaneously present in many neoplastic tion in addition to some perinuclear aggregates (arrow- cells,52,81*87and cytokeratins can often be found in heads) (Clone CAM5.2; Becton-Dickinson). B: A mono- clonal antibody recognizing a conformational epitope on the fibrous bodies, although this can not be shown most types of cytokeratin reveal perinuclear aggregates with all antibodies (Fig. 6A and B).4,‘7,‘8*45*46, 52,67,68,75,81,87,102,113.124,126,128 of intermediate filaments (fibrous bodies) in most neo- Such whorls are character- plastic cells (Clone Lu5; Boehringer Mannheim). C: The istic of Merkel cell carcinoma and are seldom found high-molecular weight neurofilament triplet protein can in other neuroendocrine tumors.4’45,64,88,‘34Vimen- also be detected in the fibrous bodies in a proportion of tin, desmin and glial fibrillary acidic protein are not the neoplastic cells (Clone lA3; Labsystems). D: A poly- found in Merkel cell tumors.37~38~52~81~84~87~8g~‘23 clonal antiserum to neuron-specific enolase gives a mod- Antibodies to neuron-specific enolase react with erate immunoreaction in the majority of tumor cells weak to strong intensity with almost all Merkel cell (A589; Dakopatts). E: Monoclonal antibody to chromo- carcinomas (Fig. 6D; Table 1). Although chromo- granin reveals a granular cytoplasmic immunoreaction granins (Fig. 6E) and synaptophysin are more spe- (arrowheads) in a minority of neoplastic cells (Clone cific than neuron-specific enolase as neuroendo- LK2HlO; Hybritech). F: Murine antibodies to epithelial membrane antigen label the entire tumor cell population crine markers, positive reaction is often focal and (Clone lA4; Dakopatts). G: Antibodies to leukocyte com- present in a proportion of Merkel cell carcinomas 4.28,35,39,67,102,131.132.131 mon antigen do not react with Merkel cell carcinoma only. The HNK- 1 carbohydrate (mc), but label infiltrating lymphocytes (DAKO-LC; Da- epitope, another antigen associated with neuroen- kopatts). H: In addition to occasional histiocytes (arrow- docrine cells, is likewise demonstrable in some Mer- heads), many tumor cells react weakly with a polyclonal kel cell carcinomas.20,83 antiserum to S-100 protein (2311; Dakopatts). MERKEL CELL AND NEOPLASMS 1x1 agi nst S-100 protein will give a negative reaction in to derive either from fully developed epidermal 4,":~,37..~?.AS.IOP.l~4,l?~ Merkel ce~~s?0.S~~.~J,l~l.12~.l~~0.1~~ Or from dermal neuro_ mc t cases, a faint positive reaction ma sometimes be observed (Fig. 6H).20.‘2X endocrine cells, which have migrated from the neu- ral CreSt~4.~..iL’.XI.I:~o While ultrastructural and immu- D. (:)RIGIN AND HISTOGENESIS nohistochemical studies show that Merkel cell M erkel cell carcinomas were originally thought carcinomas share most of the essential features of 182 Surv Ophthalmol 35 (3) November-December 1990 RIVEti, TARREANEN normal Merkel cells, such an origin has been denied Poorly differentiated plasmocytoma63*‘15 and leuke- on the basis of the exclusively dermal localization of mic infiltrates’30 must also be excluded. Merkel cell most Merkel cell carcinomas, lack of neuroendo- carcinomas generally lack chromatin clumps, have crine peptides typical of normal Merkel cells, and very scant cytoplasm, and have rather uniform nu- the presence of neurofilament proteins.27,52,62,“4, clei compared to lymphomas.53*63~68~“2~“5~‘30They “7,‘23 Indeed, it is considered more likely that Mer- are positive for leukocyte common and other lym- kel cell carcinomas develop from epidermal stem phocyte antigens, and lack neuroendocrine and cells, which are still capable of squamous and primi- epithelial markers. tive sudoriferous differentiation.35*40*62*‘03~“5 This theory is consistent with the fact that Merkel cell 2. Bronchogenic Oat Cell Carcinoma carcinoma is often associated with epithelial, but Histopathologically, Merkel cell carcinoma close- not with melanocytic tumors, the latter being of ly resembles other small cell neuroendocrine carci- neural crest origin.“’ It must be presumed that the nomas, especially metastatic pulmonary oat cell car- tumor cells may invade the dermis, as do normal cinoma, one tenth of which eventually have skin fetal Merkel cells during development.86 The car- metastases.“5,‘34 They consist of small round to cinogens responsible for the malignant transforma- spindle shaped cells, which commonly show exten- tion remain unknown, although sunlight has been sive necrosis and crush artifact.53~“2*“5 Although suggested as one possible causative agent.‘g,“3V’15.13’ their antigenic profile may be identical to Merkel cell carcinoma,‘j4 most authors would consider per- E. DIFFERENTIAL DIAGNOSIS inuclear whorls of cytokeratins and neurofilaments Although the light microscopic appearance of exceptional for oat cell carcinoma.4*18*64~88,‘34Never- Merkel cell carcinoma is fairly characteristic,“‘*62. theless, the differential diagnosis ultimately rests on 68*‘30it must be distinguished from other poorly dif- careful systemic work-up for other primary neo- ferentiated round cell tumors (especially lympho- plasms. 4,'0'.'03,'33 mas), metastatic and small cell carcinomas, as well as carcinoid tumors. Clinically, Merkel cell carcino- 3. Carcinoid Tumors ma in the eyelid may mimic lymphoma, sebaceous Carcinoid tumors closely resemble Merkel cell carcinoma or even chalazion,‘g*23~5g~72while meta- carcinoma in their light microscopic and immuno- static neuroendocrine carcinoma and carcinoid tu- histochemical pattern, including even occasional mor are very uncommon in the periocular region. paranuclear aggregates of intermediate fila- Other neoplasms that more rarely enter into the ments.4*65*‘34They tend to have more pleomorphic differential diagnosis include basal cell, squamous and larger neurosecretory granules than Merkel and various adnexal carcinomas, adult neuroblas- cell carcinomas, and give stronger Grimelius and toma, amelanotic malignant melanoma, and Ew- chromogranin reactions.4*68 Again, meticulous sys- ing’s sarcoma. 4'~53~68~'5,"2~'30~'39in practice, the diag_ temic work-up for other primary tumors is nosis must often be confirmed using electron mandatory. microscopy and immunohistochemistry, followed by exclusion of other primary neoplasms.‘7’3’,4’* 4. Sebaceous Carcinoma 64,75~‘30One should note, however, that patients with Merkel cell carcinoma in the eyelid may be con- Merkel cell carcinoma are usually elderly and may fused with sebaceous carcinoma.‘g,23 Both neo- concurrently have other malignant neoplasms as plasms often present as an erythematous nodule well 44,51,62,75,'02,"5,"6 affecting the upper eyelid of elderly patients and sometimes simulate a large chalazion.5g~72 Seba- 1. Malignant Lymphoma ceous carcinoma involves the tarsus, grows in more Merkel cell carcinoma has often been clinically solid and often lobular pattern, and shows squa- and histopathologically misdiagnosed as lym- mous differentiation much more frequently.“2~“4 phoma. 4,313 54,'0','08,114,"5,'24,'30 Lymphadenopathy, In addition to lack of neuroendocrine features by characteristic for many lymphomas, is frequently electron microscopy and immunohistochemistry, present in Merkel cell carcinoma due to regional frozen sections stained for intracellular lipids will nodal metastases. A further pitfall in the diagnosis make the diagnosis.“* may be that the patient can have a concurrent lym- phoproliferative disorder.44~5’~62~‘02~“5*“6The tumor F. PROGNOSIS closely resembles a large cell or lymphoblastic lym- Merkel cell carcinomas were initially thought to phoma, when it consists of diffusely infiltrating and be slowly growing tumors of low-grade malignancy loosely arranged uniform round cells, particularly that may behave for a long time as locally aggressive if the associated lymphocytic infiltrate is heavy. tumors.30*‘03~‘3qIt has since been documented, how- MERKEL CELL AND NEOPLASMS 183 ever, that the incidence of local recurrence and ear- have died of Merkel cell carcinoma, and the esti- ly extensive nodal metastasis is high even when the mated five-year survival rate is 38%.44.“1 Only six primary tumor is ~mall.l3~"Z~"l~96~lOZ~lO6.'I4~I41 Although patients with an eyelid tumor and five patients with many Merkel cell carcinomas in the eyelids and pe- an eyebrow lesion have been observed at least for riocular region have not had an extended follow-up two years or until death with metastasis (Fig. 2). period (Fig. Z), it appears likely that malignant Two patients in both groups have died of Merkel melanoma, Merkel cell carcinoma and sebaceous cell carcinoma, and two additional patients with pri- carcinoma are the three most malignant primary mary eyebrow lesions had evidence of metastatic tumors of the eyelid. However, clinical data cur- disease at the time of death, which was thought to rently available on periocular Merkel cell carcino- be due to an intercurrent disease. Five putative ma is scanty, and future cases should be published spontaneous regressions of Merkel cell carcinoma with an adequate description of treatment and a have been reported.g~‘02~14’ sufficiently long follow-up period. No clinical or histopathological classification has Local recurrence and satellite lesions occur in been presented that would consistently correlate about one third of all patients, usually within one with prognosis of Merkel cell carcinoma.77~10’~“4 year of initial surgery. 9,13.27,32.51.62,77.96.102.103,ll4- Features tentatively suggested as prognostic indica- llfi~124~133Recurrences are often multiple and may be tors include large size of the tumor,44’“4.“” location especially frequent when the tumor has been associ- in the head and neck region,lz4 metastases at the ated with a squamous cell carcinoma.33 Five out of time of diagnosis, 10~~116lymphatic invasion,3'."" in_ 18 eyelid tumors and four out of 12 periocular le- complete excision, 32,51,116and either male or female sions that have been observed for at least six months sex of the patient.“‘.“‘“.“’ Although some authors after therapy have recurred (Fig. 2). Five patients, have felt that tumors of the trabecular type are less at least one of whom had a periorbital primary le- aggressive than those of the small cell type,‘i8~“6B191 sion, have died from direct intracranial spread of such a relationship has not been very strong in oth- the recurrent tumor.77,“6 er series.“‘” About two thirds of patients with Merkel cell car- cinoma have had regional lymph node metastases, G. TREATMENT either at the time of diagnosis or, more often, within 1. Localized Disease eighteen months after initial therapy.g~L3~20*27~“z~ 44.50b.51.62.77.96.101,104.106.114.116.117The metastases may oc_ Merkel cell carcinoma demands prompt and ag- casionally be delayed for several years.‘0?*“4 Six out gressive initial therapy for a favorable out- of 18 eyelid, and six out of 12 periocular tumors come. IJ.3".5'~116~l"3Wide surgical excision of the pri_ with a follow-up of six months or more have given mary tumor should be carried out whenever pos- rise to regional metastases (Fig. 2). sible.9,I3.:1".51.77.96,I?4.I:~3In the case of an eyelid tumor, Hematogenous distant metastases from Merkel this means full-thickness resection followed by a re- cell carcinoma have eventually developed in more constructive procedure.5”~“3~7’~l” Frozen section than one third of cases:’ 9 13,3?,44.51.77,101,102.106.114,116one control may be helpful in ensuring the deep margin half of patients followed for two years or more have of the excision, but it does not guarantee complete extraregional disease.“’ Extraregional metastases removal due to the frequent early lateral dissemina- usually appear within two years of initial diagno- tion through lymphatic channels, leading to satel- s~~~9~3~,~l,62.96.114.1I6 They involve most frequently the lite lesions and multiple recurrences.y*92~77~96A fur- skin, bone, brain, liver and lung, but have also been ther operation has sometimes been considered found in meninges, spinal cord, mediastinum, necessary to ensure complete removal when the tu- pleura, pericardium, myocardium, retroperito- mor has been clinically misdiagnosed,“‘.“4”” and neum, kidney, pancreas, stomach, small and large exenteration has twice been deemed necessary for a bowel, thyroid, parathyroids, adrenals, testes, ova- recurrent eyelid tumor.g6.“5 ries, pelvis, large blood vessels and ton- Merkel cell carcinomas generally respond well to sils 9,24~27.'?9~~~L'~62~lO6~li6~lZ9~l~~~~~l4lOrbital metastasis has radiation therapy, 4,12.61.102.105,1?6although SOme have been reported at least twice,“.‘” while cutaneous me- recurred in the radiation field or during radiother- tastasis to eyelids”” and a clinically diagnosed cho- apy. “.I’.“” It may be used as primary treatment if the roidal metastasis’ have both been described once. patient does not tolerate surgery or the tumor en- The overall mortality parallels the incidence of croaches vital structures,‘.y”.‘24 such as the eye.‘.“.‘“’ systemic metastaseslW and ranges from one fifth to In these cases, aspiration cytology may be used to 9 1'127.32,JOb,A?.77.96.IOl,lO2.lO6.ll6.ll7.l3:i one third of all cases.’ establish the diagnosis in addition to ordinary biop- According to two critical literature surveys, nearl) sy. ‘.w~’ Adjunctive radiotherapy may also be effec- one half of patients followed for three years or more tively used to obviate the necessity for extensive 184 Surv Ophthalmol 35 (3) November-December KIVEti, TARKKANEN surgical procedures.gs’” Indeed, surgery combined to ten years after a complete response to chemo- with prophylactic local radiotherapy may have a therapy_‘.%’ 14.141 success rate superior to surgery alone, even when a The benefits of chemotherapy should be bal- wide excision has been performed.13 It has been anced against the possible side effects in elderly pa- recommended that the tissues between the tumor tients. However, it should be given serious consid- and first regional lymphatic nodes should be rou- eration if the patient is a reasonable candidate for tinely irradiated (50 to 60 Gy in 20 to 25 fractions this treatment modality, especially in the younger Over 4-6 weeks).g,13.32.51.96,' 16 age group. g,24Radiotherapy can also be used in pal- Patients need regular follow-up for early detec- liative treatment of metastatic Merkel cell carcino- tion of possible lymph node spread.51,“4.‘33 While ma and a radioactive episcleral iodine plaque has some authors have suggested that prophylactic dis- given a good response in a case of a presumed cho- section of regional lymph nodes might be carried roidal metastasis (8806 cGy to tumor apex).’ out, ‘3~32~5’*‘06~‘14this is probably not advisable due to References the advanced age of most patients, the fact that 1. Alexander E III, Rossitch E Jr, Small K, et al: Merkel cell many cases are cured by treatment of the primary carcinoma. Long term survival in a patient with proven tumor only, and the radiosensitivity of Merkel cell brain metastasis and presumed choroid metastasis. Clin carcinoma.g*62~g6~10z~‘24~‘4’It has been suggested that Neural Neurosurg 91:3 17-320, 1989 la. Arnaud B, Zaghloul K, Dupeyron G, Malrieu C: Tumeurs adjuvant chemotherapy be considered in younger palpebrales a cellules de Meikel. Apropos de 3 cas. Bull Sot patients, but there is no evidence yet that this ap- Ophtalmol Fr 89:979-984, 1989 proach increases surviva1.24.g6.‘4’ 2. Ashby MA, Jones DH, Tasker AD, Blackshaw AJ: Primary cutaneous neuroendocrine (Merkel cell or trabecular car- cinoma) tumour of the skin: a radioresponsive tumour. 2. Regional Nodal Disease Clin Radio1 40:85-87, 1989 3. Auriol M, Diner P, Degois G, et al: Tumeur B cellules de Several authors have felt that resection of any tierkel associee a un $tht+lioma spinocellulaire. Apropos grossly abnormal regional lymph nodes found at d’une observation. Rev Slomatol Chir MarillofacJ 87:276-28 I, the time of diagnosis is indicated and may effective- 1986 4. Battifora H, Silva EC: The use of antikeratin antibodies in ly control the disease.g~32,5’.‘24 Lymph node dissec- the immunohistochemical distinction between neuroendo- tion either alone or in combination with radiation crine (Merkel cell) carcinoma of the skin, lymphoma, and therapy has also been used in patients who have oat cell carcinoma. Cancer 58:1040-1046, 1986 5. Beiras A, Garcia-Caballero T, FernOndez-Redondo V, Gal- later developed regional metastases.32’“‘.77*96*‘02* lego R: Morphometric characterization of the human 106*107,‘24Irradiation alone for regional metastases, neuroendocrine Merkel cells. J Invest Dermatol88:766-768, although initially effective, does not always cure the 1987 6. Beiras A, Garcia-Caballero T, Gallego R, Ros6n E: Staining disease.62.“4 As is the case with primary lesions, the of neuroendocrine Merkel cells of human epidermis using evidence suggests that surgery combined with radi- the uranaflin reaction. J Invest Dermalol89:36f%368, 1987 ation therapy may be superior to either treatment 7. Beyer CK, Goodman M, Dickersin CR, Dougherty M: Mer- kel cell tumor ofthe eyelid. Aclinicopathologic case report. modality alone.g~3’~77Lymph node metastases with- Arch Ophthalmol IOl:lO98-1101, 1983 out other systemic disease do not necessarily signify 8. Bosca AR, Cavero FV, Peris VT, Rodellas AC: Marcaje poor prognosis, and some patients have survived mediante lectinas de un tumor de celulas de Merkel. Med Cutan Ibero Lat Am 16:125-127, 1988 for several years after treatment.g6”02”‘4 9. Bourne RG, O’Rourke MGE: Management of Merkel cell tumour. Aust NZ J Surg 58:971-974, 1988 3. Extraregional Disease 10. Breathnach AS: Branched cells in the epidermis: an over- view. J Invest Dermatol 75:6-l 1, 1980 Chemotherapeutic regimens have been used for Il. Buffa R, Rindi G, Sessa F, et al: Synaptophysin immuno- extensive local or recurrent disease and for distant reactivity and small clear vesicles in neuroendocrine cells and related turnours. Mol Cell Probes 2:367-381, 1988 metastases. No treatment protocol has been found 12. Champion R, Gloor F, Speiser P, Bosshard Ch: Merkelzell- to be superior to others, and most have included tumor des Lides. Klin Monatsbl Augenheilkd 320:480- 482, adriamycin, vincristine, cyclophosphamide and 1982 doxorubicin.9~Z4~3O~5I,lO6.141 13. Cotlar AM, Gates JO, Gibbs FA Jr: Merkel cell carcinoma: Although some authors combined surgery and radiation therapy. Am Surg 52: have reported little success with chemotherapy,“” 159-164, 1986 most Merkel cell carcinomas respond well, with a 14. Dardi LE. Memoli VA, Gould VE: Immuohistochemical demonstration of neuroendocrine cells in basal celi carci- complete response in about one half of patients and nomas. J Cutan Path01 8:335, 1981 partial response in most others.9~24~29,30.51,106,IP4,126.l4~15. Diamond J, Holmes M, Nurse CA: Are Merkel cell-neurite The tumor has a great tendency to recur after cessa- reciprocal synapses involved in the initiation of tactile re- sponses in salamander skin? J Physiol (Land) 376:101-120, tion of treatment, however, and current chemo- 1986 therapeutic regimens are mainly of palliative value 16. Diamond J, Mills LR, Mearow KM: Evidence that the Mer- in management of Merkel cell carcinoma.g~24~‘g~30*32~ kel cell is not the transducer in the mechanosensory Mer- 51,61,62,'02,106,114,124.'26.'41 kel cell-neurite complex. Progr Brain Res 74:51-56, 1988 Nevertheless, a few patients 17. Dhermy P, Sterkers M, Morax S, et al: Localisation palp& have enjoyed longterm disease-free survival of up brale de la tumeur g cellules de Merkel (carcinome trab&- MERKEL CELL AND NEOPLASM!3 1X5 ulaire).] Fr Ophtalmol 10:155-164, 1987 antibody as a single and reliable histologic marker. Am ,/ 18. Domagala W, Lubinski J, Lasota J, et al: Neuroendocrine Path01 204:63-68, 1981 (Merkel-cell) carcinoma of the skin. Cytology, intermediate 43. Halata Z, Munger BL: The sensory innervation of primate filament typing and ultrastructure of tumor cells in fine eyelid. Anat Rrc I98:657-670, 1980 needle aspirates. Acta Cy?l (Baltimore) 31:267-275, 1987 44. Halioua B, Ortonne J-P: Les carcinomes neuroendocrines 19. von Domarus H, Johamsson R, Schmauz R: Merkel cell cutan&. Ann Dermatol Venereal 115:1305-1322, 1988 carcinoma of the face. Case report and review of the litera- 45. Hall PA, D’Ardenne AJ, Butler MG, et al: Cytokeratin and ture. 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Hartschuh W, Weihe E: Multiple messenger candidates GraefeA Arch Clan Exp Ophthalmol 224:330-335, 1986 and marker substances in the mammalian Merkel cell-axon 24. Feun LG, Savaraj N, Legha SS, et al: Chemotherapy for complex: a light and electron microscopic study. Progr metastatic Merkel cell carcinoma. Review of the M. D. An- Brai?z Res 74:181-187, 1988 derson Hospital’s experience. Cancer 62683-685, 1988 49. Hartschuh W, Weihe E, Yanaihara N, Reinecke M: lm- 25. Fortman GJ, Winkelmann RK: A Merkel cell nuclear inclu- munohistochemical localization of vasoactive intestinal sion. J Inrwst Dermutol 61:334-338, 1973 polypeptide (VIP) in Merkel cells of various mammals: evi- 26. Fortman GJ, Winkelmann RK: The Merkel cell in oral dence for a neuromodulator function of the Merkel cell.,] human mucosa. J Dent RP.T 56:1303-1312, 1977 fnzjesl Dermatol 81~361-364, 1983 27. Frigerio B, Capella C, Eusebi V, et al: Merkel cell carcino- 50. 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