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Merkel cell carcinoma is a relatively rare neoplasm of the skin. The present study describes three cases of Merkel cell carcinoma diagnosed by fine-needle aspiration cytology and reviews their histologic, cytologic, and ultrastructural features. The advantages of using fine-needle aspiration to diagnose Merkel cell carcinoma (and other cutaneous neoplasms) are emphasized.
The Merkel cells in the taste organ of the frog were investigated by immunohistochemistry using neuron-specific enolase (NSE) antiserum. NSE-immunoreactivity was found exclusively in the Merkel cells lying at the base of the taste organ. The distribution and the profiles of the NSE-immunoreactive Merkel cells coincided with serotonin-containing cells previously reported at the same place.
Merkel cell development was studied in the regenerative labial mucous membrane of adult rabbits. Fullthick wounds were made on the inferior labial mucous membrane of the rabbits, then the regenerative mucous membrane was examined by electron and light microscopy at time intervals of 2, 7, 10, 14, 21 and 30 days after the injury. By 7 days, the regenerative area of the mucous membrane was replaced with a dense lamellar connective tissue, which was mainly composed of alternately arranged collagen fiber layers and fibroblasts, and an overlying stratified squamous epithelium. No Merkel cell was found 7 days after the injury. Ten days after the injury, a few very immature Merkel cells were identified in the regenerative epithelium. The Merkel cells increased in number and matured in structure during the course of the following regenerative period. Thirty days after the injury, the wounded area healed without forming a scar tissue, and the regenerated epithelial ridges usually included regular type Merkel cells. As adult animals were used in this experiment, the reproduction of the Merkel cell in the regenerative epithelium seemed to be independent of the undifferentiated neuroectodermal tissue.
We have previously described the establishment of a number of cell lines from Merkel cell carcinoma (MCC), also known as small cell cancer of the skin or neuroendocrine carcinoma of the skin. These cells, all of which grew as suspension cultures, were found to resemble small cell lung cancer (SCLC) lines types 1, 2 and 3 by their morphology and growth characteristics. We now report 4 more MCC cell lines which resemble the SCLC type 4 cell lines in that they grow as adherent monolayers. These MCC lines would belong to the variant subgroup as they no longer express most neuroendocrine markers, grow at low cell density and have population doubling times of 1-5 days in contrast to the MCC suspension lines which have doubling times of 6-12 days. MCC14/1 and MCC14/2 were established from the same metastatic node and would appear to represent 2 clones of the tumour which differ in morphology, histochemical markers and DNA content. We present details of the morphology, DNA content and immunohistochemistry of these 4 lines and compare their growth patterns with those of SCLC and MCC lines which grow in suspension.
Merkel cell carcinoma (MCC) is an aggressive skin neoplasm of neuroendocrine origin. To clarify those factors important in improving survival, we retrospectively reviewed the charts of all patients with Merkel cell carcinoma treated at two tertiary referral centers. Eighty percent of the patients with stage I disease were initially treated with local therapy alone, while all of the patients with stage II disease were treated with local and regional therapy. The overall survival rate for all patients was 64%. Regardless of stage, patients treated with local excision alone had a 52% 5-year survival rate, while patients treated with local excision and lymph node dissection had an 87% survival rate. We conclude that the aggressive nature of this tumor warrants radical therapy.
Many cases of Merkel cell carcinoma have recently been reported, and most of them have been localized on the facial skin. In this study, we investigated Merkel cells in the vellus hair follicles of facial region to characterize these cells in human subjects. Skin specimens doubly stained with cytokeratin (CK) 20 and either protein gene product (PGP) 9.5 or vasoreactive intestinal polypeptide (VIP) were examined by confocal laser microscopy. Many of the Merkel cells in the vellus hair follicles of the facial skin were localized in the bulge area. Some of these cells were attached to nerve terminals, although most of them were not associated with them. Our results suggest that there are two types of Merkel cells in the bulge area of the vellus hair follicles of facial skin: cells wholly unassociated with the nerve terminals and cells associated with thin nerve fibers. We postulate that the former cells may be undifferentiated (immature) and the latter differentiated (mature). If this is so, there is a chance that Merkel cell carcinoma originates from the undifferentiated Merkel cells in the bulge of the vellus hair with the formation of tumor masses in the dermis and no involvement of the epidermis. The Merkel cells connected with nerve fibers may secrete endocrine substances via a regulation of autonomic nerves.
Merkel cell carcinoma is a rare malignancy of the skin in predominantly elderly patients, frequently missed because of its inconspicuous aspect. The histological diagnosis is not always easily made. Four case histories are presented. Literature shows the aggressive biological behaviour of this tumour: the rate of local recurrence is 40%, of regional metastatic disease over 50%, while approximately half the patients with a Merkel cell carcinoma will die of this skin tumour.
Merkel cell carcinoma is a primary cutaneous neuroendocrine carcinoma occurring commonly in the head and neck of middle-aged and elderly patients. While not very rare, this disease has never been reported in Taiwan. We report the clinical and pathologic features of three patients with Merkel cell carcinoma. The patients included one male (aged 56) and two females (aged 70, 80). The primary sites of the tumors were the hand in one patient and the head and neck in two. Two patients had regional lymph node metastasis. Case 1 had concurrent chronic arsenicalism with multiple Bowen's disease and squamous cell carcinoma of the skin. Histopathology revealed tumor cell infiltration throughout the dermis. In two cases, the tumor cells were small, round and non-cohesive, like lymphocytic infiltrates. In Case 3, however, they were large, oval and formed in nests. The tumor cells were keratin (AE1), neuron-specific enolase and chromogranin positive by immunohistochemical staining. Electronmicroscopy in Case 1 revealed a few cytoplasmic intermediate filaments and neurosecretory granules. Therapy consisted of radiation in 2 patients and surgery in 1; one died during radiotherapy, the other two survived and showed no signs of recurrence at 10 and 21 months.
To delineate fully opioid peptide function in cutaneous inflammatory and nociceptive responses, it is necessary to know first which opioid peptides are present in the skin and which cellular elements in the skin store and secrete them. Merkel cells are cutaneous neuroendocrine cells, which may derive from the neural crest or from undifferentiated keratinocytes with stem cell character. The neuroendocrine character of Merkel cells is supported by their immunoreactivity for chromogranin A (CGA) and a variety of neuropeptides, among them the opioid peptide [Met]enkephalin as shown in guinea-pig and mouse. This study investigates in the rat whether the preprodynorphin derived opioid peptide dynorphin A is expressed in cutaneous Merkel cells and possibly related to an aminergic phenotype. Light microscopic immunohistochemistry revealed dynorphin A immunoreactivity in Merkel cells to be codistributed with immunoreactivity for calcitonin gene-related peptide (CGRP) and CGA, two well-established merker peptides of mammalian Merkel cells. Vibrissal Merkel cells stained for the neuroendocrine vesicular monoamine transporter isoform 1 (VMAT1) but not for the predominantly neuronal isoform 2 (VMAT2). Merkel cell staining for dynorphin A, VMAT1, CGA, and CGRP was unaffected by experimental denervation. Dynorphin A and a still unidentified monoamine, possibly serotonin, may cofunction as autocrine or paracrine mediators in the mechanosensory Merkel cell--axon complex and are potentially involved in peripheral analgesia.
Cytokeratin 20 (CK20) is a low-molecular-weight cytokeratin (CK) that shows restricted expression in the gastrointestinal epithelium, urothelium, and Merkel cell. Recent studies have suggested that since Merkel cell (primary cutaneous neuroendocrine) carcinomas are consistently CK20-positive, this feature may help to distinguish it from pulmonary small cell carcinomas. However, only limited numbers of these tumors have been studied, and the pattern of CK20 expression in other small cell carcinomas has not been established. Therefore, we studied CK20 expression in small cell carcinomas from a wide variety of sites. Immunohistochemical study was performed on paraffin sections using CK20 antibody, coupled with antigen retrieval by pressure cooking in citrate buffer. The cases included 34 Merkel cell carcinomas and 89 small cell carcinomas from various sites (pulmonary, 37; gastrointestinal tract, nine; pharynx and tongue, two; sinonasal tract, three; salivary gland, five; larynx, nine; breast, two; thymus, three; uterine cervix and corpus, 12, prostate, three; urinary bladder, two; kidney, one; pancreas, one). In addition, all cases were immunostained with pan-CK (MNF-116) and low-molecular-weight CK (CAM5.2) antibodies to ascertain their epithelial nature. With the exception of one case, all Merkel cell carcinomas were CK20-positive; and 30 of the 33 cases showed a punctate pattern. Almost 100% of tumor cells were positive, except for two cases that showed staining of 10% and 30% of tumor cells, respectively. Among the other small cell carcinomas, only five cases were CK20-positive, including one of 37 pulmonary (40% cells positive in punctate pattern), one of 11 cervical (10% cells positive), and three of five salivary gland (100% cells positive). We conclude that CK20-positivity in a small cell carcinoma of uncertain origin strongly predicts a diagnosis of Merkel cell carcinoma, especially if the majority of tumor cells are positive. A negative CK20 reaction can practically rule out Merkel cell carcinoma, provided that an effective antigen retrieval technique is used and appropriate staining is obtained with other cytokeratin antibodies. The frequent CK20 positivity observed in salivary gland small cell carcinomas in this series suggests that at least some of them may be more closely related biologically to Merkel cell carcinoma than to pulmonary-type small cell carcinoma. This may explain why they are far less clinically aggressive than other small cell carcinomas.
Merkel cell carcinoma is an aggressive cutaneous neoplasm with neuroendocrine differentiation that carries a poor prognosis. Its homogeneous morphology is easily confused with lymphoma, leukemia, metastatic small cell carcinoma, and poorly differentiated cutaneous malignancies. Histopathologic diagnosis frequently requires support by immunohistochemistry. The authors investigated cytokeratins (CKs) 5/6, 7, 17, and 20 staining in paraffin sections of 26 Merkel cell carcinomas to expand the knowledge of the CK staining profile of this entity. Reactivity with anti-CK 20 was demonstrated in 23 of 26 Merkel cell carcinomas (88%). All three CK 20-negative tumors showed punctate staining with anti-keratin CAM5.2. Six of 26 tumors (23%) were positive for CK 7, a finding not previously reported. The staining patterns for both CKs 20 and 7 ranged from punctate (perinuclear) to localized (confined to half of the cytoplasm) to diffuse. Punctate CK 20 staining was seen in 17 of 26 cases but was the predominant pattern in only 10 cases. Antibodies to CKs 5/6 and 17 were each negative in the 13 cases for which these stains were performed. Both the positive and negative elements of the CK profile of this distinctive neoplasm provide additional useful diagnostic information for the differential diagnosis between Merkel cell carcinoma and other carcinomas that may simulate it. The authors note that the classically described perinuclear dotlike keratin staining pattern is not universally seen with CK 20 and that CK 7 staining may be seen in a subset of Merkel cell carcinomas.
Of the 42 Merkel cell carcinomas that we studied, two showed numerous tubular structures within sheets and nests of small cells. The small cells stained for both neuron-specific enolase and keratin. The keratin decorated a dot-like paranuclear structure. The ducts stained positively for carcinoembryonic antigen (CEA) and CF-1 (cystic fibrosis-1, a monoclonal antibody that only stains eccrine duct and acrosyringium). Electron microscopy performed on one case showed cytoplasmic dense-core neurosecretory granules and intercellular lumina lined by cells containing microvilli. These ultrastructural and immunohistochemical features support the concept of eccrine differentiation in these tumors. A third case contained foci of typical keratinizing squamous cell carcinoma admixed with sheets of small cells. The immunohistochemical and ultrastructural characteristics of this tumor were essentially similar to those of a conventional Merkel cell carcinoma. Our findings suggest that Merkel cell carcinomas, similar to neuroendocrine tumors from other anatomic sites arise from a primitive totipotential stem cell that has the capacity to differentiate along different cell lines.
This paper first elucidated the overall morphology of Merkel cells in the rat touch dome with scanning electron microscopy (SEM). Quinacrine-fluorescent Merkel cells in the touch dome were exposed by enzymatic treatment following application of dithiothreitol, photographed and then fixed. By referring to the photograph, the same fluorescent cells were easily identified under the SEM. Enzymatically isolated Merkel cells were also examined with SEM. Unlike quinacrine negative, ordinary epidermal cells, the Merkel cells had numerous finger-like processes, ranging from 0.1 to 0.25 micron in diameter and attaining to 2.5 microns in length.
We present 11 cases of primary neuroendocrine (Merkel cell) carcinoma of the skin with an intraepidermal component that were identified in a larger review of Merkel cell carcinomas. Among these is a case with a follow-up of over 11 years in which the primary lesion appeared as bowenoid dysplasia, with subsequent recurrences as intraepidermal Merkel cell carcinoma with focal tubular differentiation, and then with dermal invasion and lymph node metastasis. In addition to immunohistochemical markers commonly used in the identification of Merkel cell carcinomas (neuron-specific enolase and cytokeratin), these tumors stained with Ber-EP4, an immunohistochemical marker used to identify carcinomas. We believe that these histopathologic and immunohistochemical features further confirm that Merkel cell carcinomas represent an epithelial tumor with the potential for neuroendocrine and adnexal differentiation.
The present study was performed in order to re-examine the possible Merkel cell dependency upon the anterior pituitary by a combined ultrastructural and NSE immunohistochemical analysis of Merkel cells in normal toads, and following pars distalis ablation. Ultrastructurally, toad Merkel cells appeared similar to those in previous reports. They were found in normal as well as in operated toads, but with lower frequency in the latter group. By NSE immunohistochemistry, Merkel cells were seen in normal toads only. Even in individual, operated toads, in which Merkel cells were found with relative high frequency by electron microscopy, no NSE could be demonstrated immunohistochemically. It is discussed whether the amount of NSE present depends upon the physiological state of the Merkel cell and in some cells occurs in so low an amount that the NSE antigen cannot be detected by the immunocytochemical method applied. If it is so, the failure to demonstrate Merkel cells in the operated toads by means of the specific marker NSE may be interpreted as an inhibition of NSE expression following pars distalis ablation. This interpretation combined with the lower number of Merkel cells found ultrastructurally in operated toads support a previous indication of an influence of the anterior pituitary--directly or indirectly--upon toad Merkel cell function.
A case of a Merkel cell tumor of the vulva is presented. In addition to the typical microscopic, immunohistochemical, and ultrastructural features of Merkel cell tumor, there were areas of squamous and glandular differentiation. This is the ninth reported case of a vulvar Merkel cell tumor, and the first where squamous and glandular differentiation were seen. The findings support an origin of Merkel cell tumors from pluripotential stem cells.
BACKGROUND: Merkel cell carcinomas are rare neoplasm of neuroendocrine origin, usually observed in elderly people in areas with abundant sunlight, and predominantly located on the head and neck, extremities, and trunk. In many patients, a local recurrence after resection of the primary tumour and even distant metastases can be found. CASE PRESENTATION: We report an unusual occurrence of pancreatic metastases from a previously diagnosed Merkel cell carcinoma with the discovery of a concomitant insulinoma. An 82-year old lady suffered from recurrent attacks of hypoglycemia and presented with an abdominal mass, 2 years prior she had an excision done on her eyebrow that was reported as Merkel cell carcinoma. An extended distal pancreatectomy and splenectomy along with resection of the left flexure of the colon for her abdominal mass was carried out. Final histopathology of the mass was a poorly differentiated endocrine carcinoma in the pancreatic tail, in the peripancreatic tissue and in the surrounding soft tissue consistent with metastatic Merkel cell carcinoma in addition to an insulinoma of the pancreatic body. CONCLUSION: This is the first documented case of a metastatic Merkel cell carcinoma and a concomitant insulinoma, suggesting either a mere coincidence or an unknown neuroendocrine tumor syndrome.
The Merkel cell is a distinctive nondendritic, nonkeratinocytic, epithelial clear cell believed to migrate from the neural crest to the epidermis and dermis, which is usually located in or near the basal layer of the epidermis and associated with nerve terminations. Merkel first described these cells in 1875 as "Tastzellen" occurring in the snout of a mole. They are believed to function as slowly adapting mechanoreceptors that mediate the sense of touch. Tumors arising from Merkel cells have been reported to occur on the head and neck area, the trunk, arms, and legs, and resemble a primary cutaneous lymphoma or cutaneous metastasis of a lymphoma or a carcinoma. Electron microscopy, to locate the characteristic membrane-bound, dense core neurosecretory granules, is needed for accurate diagnosis. These tumors must be treated aggressively to minimize the chance of local recurrence and nodal or visceral metastases. The authors present a case of Merkel cell tumor occurring on the eyelid. The clinical history, light and electron microscopic findings are shown.