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PubMedDate not supplied

Synaptophysinlike immunoreactivity in the Merkel cells of pig-snout skin.

Synaptophysin is a membrane glycoprotein (Mr 38,000) found in small vesicles with clear content. It is present in neurons and in a variety of neuroendocrine cells and neoplasms, including the neuroendocrine carcinoma of the skin (Merkel cell tumor). We report the presence of synaptophysinlike immunoreactivity in normal Merkel cells of the pig-snout epidermis and vibrissae. The immunostaining was primarily localized in the Merkel cell side opposite to the nerve terminal. This fact suggests that in Merkel cells, as well as in other neuroendocrine cells, synaptophysin could occur in small clear vesicles (accumulated in Merkel cells in the side opposite to the neurite) and not in the secretory granules themselves (which are concentrated in the cellular side apposed to the neurite).

Animals↗
PubMed2000

Nuclear localization of E-cadherin expression in Merkel cell carcinoma.

CONTEXT: Cadherins are cell-cell adhesion proteins that act as tumor suppressor genes and have a critical role in cell sorting and tissue formation during organogenesis. The pattern of cadherin expression constitutes a useful diagnostic and prognostic tool in the evaluation of tumors and for determining the histogenesis of tumor cells. We have previously characterized the cell types of several tumors based on the expression of individual cadherins. OBJECTIVE: To investigate the expression of cadherins in Merkel cell carcinomas. DESIGN: Paraffin immunohistochemical analysis of the 3 best-studied cadherins was performed on 35 cases of Merkel cell carcinoma. RESULTS: E-cadherin was expressed in 34 (97%) of 35 Merkel cell carcinomas examined, N-cadherin was expressed in 22 (63%) of 35 cases, and P-cadherin was expressed in 15 (43%) of 35 cases. This frequency of cadherin expression was similar to a group of small cell and neuroendocrine tumors from other primary sites. Interestingly, the localization of E-cadherin expression was unique in Merkel cell carcinomas compared with other primary neuroendocrine tumors. Merkel cell carcinomas showed marked preference for nuclear versus membrane localization, whereas small cell tumors from other sites showed fewer cases of nuclear E-cadherin expression. The nuclear localization of E-cadherin did not correlate with cadherin-associated protein beta-catenin nuclear expression. CONCLUSIONS: Our findings show that E-cadherin is the most frequently expressed cadherin in Merkel cell carcinoma, followed in frequency by N-cadherin then P-cadherin. The pattern of nuclear E-cadherin expression is more frequent for Merkel cell carcinoma than small cell tumors of other primary sites. These observations suggest that E-cadherin expression and function are altered in Merkel cell carcinoma, and this finding has potential use in the differential diagnosis of these tumors.

Breast Neoplasms↗
PubMed2003

Merkel cell carcinomas: expression of S-phase kinase-associated protein 2 (Skp2), p27, and proliferation markers.

Merkel cell carcinomas are rare and aggressive tumors about which the expression of cell cycle regulatory proteins are not well known. We evaluated the clinicopathologic features of Merkel cell carcinomas and examined the expression of the cell cycle regulatory markers p27 and S-phase kinase-associated protein 2 (Skp2) and the proliferation markers Ki-67 and DNA topoisomerase II alpha (topo II alpha) in a group of these tumors. Thirty-nine cases of Merkel cell carcinoma were studied, 19 from the Mayo Clinic, Rochester, MN, and 20 from the University of Torino, Torino, Italy. Although the University of Torino patients tended to be slightly older at time of surgery compared to the Mayo Clinic patients, no clinical, pathologic, or immunohistochemical feature was statistically significantly different between the two groups. Of the 39 patients, 20 were male and 19 were female. The age at surgery averaged 72 yr. Formalin-fixed paraffin-embedded archival tissues from the 39 Merkel cell carcinomas were analyzed by immunohistochemistry for p27, Skp2, Ki-67, and topo II alpha with the avidin-biotin peroxidase system. The distribution of immunoreactivity was analyzed by quantifying the percentage of positive nuclei, which was expressed as the labeling index. There was a statistically significant inverse relationship between p27 and Skp2 (p = 0.005). Most tumors with increased levels of Skp2 were associated with reduced p27, and tumors with high levels of p27 expression were associated with reduced levels of Skp2. These results suggest that Skp2 regulates p27 expression in Merkel cell carcinomas. Tumors showing increased Skp2 expression were not always correlated with increased proliferation as evaluated by Ki-67 and topo II alpha, suggesting that Skp2 may be involved in Merkel cell tumorigenesis, but that other factors may also influence cell proliferation in these tumors.

Aged↗
PubMed1999

The existence of Merkel cells in the lingual connective tissue of the Surinam caiman, Caiman crocodilus crocodilus (order Crocodilia).

The tongue of the Surinam caiman (a reptilian species) was studied by light microscopy including immunohistochemistry for protein gene product 9.5 (PGP 9.5), and transmission electron microscopy. The connective tissue immediately under taste buds housed a cluster of cells immunoreactive for PGP 9.5. These cells synapsed on nerves, and their cytoplasm contained characteristic granules of 90 nm in the mean diameter, glycogen particles, and bundles of intermediate filaments. In light of these ultrastructural features, they were identified as Merkel cells. The Merkel cells were also surrounded by Schwann cells. These findings indicate that the present Merkel cell-neurite-Schwann cell complex is comparable to the avian Merkel corpuscle. On the basis of the granule localization in the cytoplasm, the caiman Merkel cell was presumed to be involved in not only mechanoreception but also endocrine or paracrine functions.

Alligators and Crocodiles↗
PubMed1994

Merkel cell tumour of the eyelid and reconstruction with the Cutler-Beard technique: a clinicopathologic case report.

A case of Merkel cell tumour that developed on the left upper lid of a 76-year-old white man is reported. The diagnosis was ultrastructurally made by demonstrating characteristic light microscopic features of Merkel cell carcinoma; such as large, round nuclei and frequent mitoses. Immunohistochemically, the tumour cells were shown to possess simple epithelia-type keratin intermediate filaments. Merkel cell tumour probably develops from precursor cells which give rise to keratinocytes and Merkel cells, and nearly one out of 10 Merkel cell tumours occur in the eyelid and periocular region. They tend to be bulging lesions near the lid margin of elderly patients. The condition can be misdiagnosed as lymphoma, oat cell carcinoma, malignant melanoma, sweat gland tumours, neuroblastoma and Ewing's sarcoma, and frequently invades lymphatic vessels. Nearly one out of three Merkel cell tumours recur and two thirds cause regional lymph node metastases. Wide surgical resection and reconstructive procedures, should be followed by routine postoperative irradiation. This patient was treated with wide resection and the Cutler-Beard technique, then scheduled for radiotherapy.

Aged↗
PubMed1991

Chemotherapy of metastatic Merkel cell carcinoma: case report and review of the literature.

Merkel cell carcinoma is a skin cancer that bears histologic, ultrastructural, and immunohistochemical resemblance to small cell lung cancer. Although this tumor is often localized and may be treated with wide excision, metastatic Merkel cell carcinoma does appear in 18%-28% of patients and may be aggressive and lethal. We report a case of metastatic Merkel cell carcinoma who responded to treatment with cisplatin/etoposide. Review of the literature reveals that doxorubicin/cyclophosphamide-based regimens and cisplatin-based regimens have been most commonly studied. Complete and partial responses are often achieved although the duration of response tends to be short. Further investigation of chemotherapeutic regimens similar to those used in small cell lung cancer should be undertaken.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2001

Management and prognosis of Merkel cell carcinoma of the eyelid.

OBJECTIVE: To evaluate the clinical presentation, treatment, and long-term follow-up of eyelid Merkel cell carcinoma. DESIGN: Retrospective noncomparative interventional case series. PARTICIPANTS: Fourteen patients with primary eyelid Merkel cell carcinoma. METHODS: Cases of Merkel cell carcinoma for which long-term follow-up was available were solicited from members of the American Society of Ophthalmic Plastic and Reconstructive Surgery through an on-line e-mail/news group. MAIN OUTCOME MEASURES: Follow-up period, treatment history, presence and type of recurrence, and mortality. RESULTS: Average follow-up was 33.4 months. Of the 14 cases identified, only 2 patients (14%) received prophylactic therapy beyond wide surgical excision. Three patients (21%) had recurrences, none of whom initially received prophylactic therapy (i.e., radiation therapy, lymph node dissection, and/or chemotherapy) beyond wide surgical excision. One patient (7%) died of metastatic Merkel cell carcinoma. CONCLUSIONS: Merkel cell carcinoma is a rare skin malignancy that occasionally affects the eyelid, with the potential for regional and distant metastasis. Consideration should be given to the use of prophylactic adjunctive therapies beyond wide surgical excision while simultaneously considering the morbidity of these therapies.

Aged↗
PubMed2003

[Merkel cell carcinoma. Clinical and histological differential diagnosis, diagnostic approach and therapy].

Merkel cell carcinomas are rare tumors of the skin with an aggressive behavior and frequent regional and distant metastases. Typically, the primary is a fast-growing, painless, reddish nodule with an iceberg-like effect, broadening in the depth. On the trunk and the buttocks, deep clinically rather inconspicuous nodules can occur. The clinical differential diagnosis of the Merkel cell carcinoma includes skin metastases, malignant lymphomas, malignant adnexal tumors and cysts when the tumor is located deep in the soft tissue (e.g. on the buttocks). Histological and immunohistochemical analysis is necessary for the diagnosis. The demonstration of cytokeratin 20 in the typical globular distribution pattern is of main importance in the diagnosis of Merkel cell carcinoma. Because they are very rare, Merkel cell carcinomas are infrequently diagnosed clinically, in spite of the rather characteristic picture. Diagnostic excision with a safety margin of 3 cm is recommended followed by an adjuvant radiotherapy. The radiation field should include the area of the draining vessels and the first regional lymph nodes. There are some reports concerning the advantage of sentinel lymph node biopsy. In distant metastases, the therapy is multimodal and palliative including surgery, radiation and chemotherapy. Because of the high incidence of regional and distant metastases, regular follow-up is important.

Adult↗
PubMedDate not supplied

Radiotherapy for Merkel cell carcinoma of the skin of the head and neck.

BACKGROUND: Merkel cell carcinoma is a relatively rare neuroendocrine carcinoma of the skin. It arises in the head and neck region in approximately 50% of cases. Its aggressive behavior predisposes patients to local-regional recurrence and distant metastases after surgical excision alone. In this article, we describe our experience with Merkel cell carcinoma of the head and neck. METHODS: Of 18 patients with Merkel cell carcinoma treated in the Department of Radiation Oncology at the University of Florida, 12 patients who had primary tumors in the head and neck region are reported. Eight patients were treated at initial diagnosis (group A), and four were treated at the time of local-regional recurrence (group B). RESULTS: Local-regional control was achieved in seven of eight patients in group A and all four patients in group B. One patient in group A and all patients in group B developed distant metastases and eventually died of their disease. Bone exposure developed in one patient, requiring surgical debridement and hyperbaric oxygen treatment. CONCLUSION: Patients with Merkel cell carcinoma of the head and neck should be treated aggressively. Our data suggest that local-regional recurrence is a harbinger of distant metastases. We recommend that these patients receive treatment to both the primary site and draining lymphatics at initial presentation. The role of chemotherapy remains unclear.

Aged↗
PubMed2005

Merkel cell carcinoma of the Bartholin's gland.

BACKGROUND: There are a few cases of "small cell neuroendocrine carcinoma" of the Bartholin's gland as well as Merkel cell carcinoma of the vulva reported in the gynecologic oncology literature, most with aggressive clinical behavior. Merkel cells were originally described in the epidermis with neuroendocrine properties. Merkel cell carcinoma is different from the neuroendocrine small cell (oat cell) tumor arising in the lung and other internal organs based on morphology and immunohistochemistry. CASE: A 49-year-old female was diagnosed with a FIGO stage I Merkel cell carcinoma of the Bartholin's gland. The tumor originated from the duct and stained with endocrine markers and cytokeratin 7 and 20. She was treated with radical wide local excision and bilateral inguinal lymph node dissection followed by radiation therapy to the pelvis, perineum, vulva, and inguinal regions. Two years after the diagnosis, she is alive with no evidence of recurrent disease. CONCLUSION: This is a case of Merkel cell carcinoma of the Bartholin's gland discovered in the early stage with a survival of 2 years following diagnosis and treatment with no evidence of disease recurrence.

Bartholin's Glands↗
PubMed1995

Dynamics of Merkel cell patterns in developing hair follicles in the dorsal skin of mice, demonstrated by a monoclonal antibody to mouse keratin 8.

In order to explore the origin and significance of Merkel cells in the hairy skin of mammals, the development of Merkel cells and nerve endings in the dorsolateral skin of C57BL mouse embryos was studied in serial cryostat sections. At 13 and 14 days of gestation, application of a monoclonal antibody to mouse keratin 8 (mK8) resulted in specific immunofluorescence of all cells in the epidermis and periderm. The periderm retained specific staining until it was shed, around 18 days. At 15 days, mK8-specific staining elsewhere was restricted to scattered immature Merkel cells in the developing tylotrich follicles and the adjacent epidermis. Between 16 and 17 days, these cells assembled within the basal epidermal layer, caudal to each tylotrich follicle, to form a disc-shaped rudiment of a 'haarscheibe' or touch dome. No Merkel cells were found in association with the later developing awl and zigzag follicles. In mice homozygous or hemizygous for the Tabby mutation, in which tylotrich follicles never form, no Merkel cells were found in any part of the dorsolateral skin. In mice homozygous for the recessive downy mutation, in which all three types of hair are present but reduced in size, Merkel cell development was the same as in wild-type mice. Nerve endings were located in the upper dermal mesenchyme by a monoclonal antibody to neural cell adhesion molecule. This antibody also stained plasma membranes in specific parts of the hair follicles during their development. From 14 to 19 days, none of the nerve endings were seen in contact with the epidermis or the follicle epithelium, even in areas where Merkel cells were located. These findings support the view that both location and early differentiation of Merkel cells in the dorsolateral epidermis are independent of neural influences but linked to the development of tylotrich follicles.

Animals↗
PubMed1986

Merkel cell tumor of the skin: an immunohistochemical study.

Skin biopsy specimens from 12 elderly patients with Merkel cell tumors were investigated. Conventional light microscopy and immunohistochemical techniques were used. All of the tumors had similar morphologic features. Immunoreactivity for neuronspecific enolase, gastrin, calcitonin, and epithelial membrane-like antigen was demonstrated, and both neurofilaments and keratin filaments were observed. The immunohistochemical findings supported a Merkel cell origin for these Merkel cell tumors. The co-expression of neuroendocrine and epithelial markers in Merkel cell carcinomas is suggestive of neuroendocrine differentiation in a neoplasm of epithelial origin. Merkel cell carcinomas share many characteristics with neuroendocrine tumors of the bronchopulmonary and gastrointestinal tracts. All of these neoplasms may originate from cells of similar types that are present in several organs.

Aged↗
PubMed1999

Immunohistochemical investigation of the different developmental stages of trichofolliculoma with special reference to the Merkel cell.

The morphologic features of trichofolliculoma are variable, reminiscent of the anagen, catagen, and telogen phases of a normal hair follicle in its cycle. We recently described an early, fully developed stage and late stages of trichofolliculoma. Using immunohistochemical examination, we sought to demonstrate hyperplasia of Merkel cells in all three stages of trichofolliculoma. We found this to be the most striking in small lesions of the late stage. The distribution of the Merkel cells in several stages of trichofolliculoma coincided with the known arrangement of normal follicular Merkel cells during the follicular cycle. However, antibodies against neurofilaments failed to detect innervated Merkel cells, in contrast to normal follicular Merkel cells. Antibodies against Ki67 did not reveal proliferative Merkel cells in any of the trichofolliculomas, but for unknown reasons, a distinct cytoplasmic staining of Merkel cell processes sometimes occurred. Nuclear Ki67 was strongly expressed in the nuclei of follicular keratinocytes of the fully developed trichofollicullomas, whereas those at a late stage showed a markedly decreased staining pattern. Our finding of Merkel cells in all trichofolliculomas underlines their classification as hamartomas with follicular differentiation. Hyperplasia of Merkel cells, even in trichofolliculomas at a late stage, as regressing lesions might implicate hitherto unknown regulatory functions of this neuroendocrine cell.

Adult↗
PubMed1999

Diagnostic relevance of chromosomal in-situ hybridization in Merkel cell carcinoma: targeted interphase cytogenetic tumour analyses.

AIMS: To resolve the conflicting diagnoses of five pathologists (which included well-differentiated neuroendocrine carcinoma, malignant carcinoid, undifferentiated small-cell carcinoma, primitive neuroectodermal tumour, metastases of small-cell lung carcinoma (SCLC) and Merkel cell carcinoma (MCC)), and tumour-free lungs after necropsy, we investigated an alarmingly metastasizing MCC in a 32-year-old Caucasian man using chromosomal in-situ hybridization (CISH). Differences in incidence and course in males and females also prompted targeted analyses for chromosomes X and Y. The lesion was also analysed for p53 gene mutations. METHODS AND RESULTS: Paraffin sections of the thorax, buccal lymph nodes and scalp tumours were stained with haematoxylin and eosin. Immunohistochemistry was performed with antibodies against pancytokeratin, keratin 20, neuron-specific enolase (NSE), chromogranin, neurofilaments and vimentin, among others. Sections (5-6 microm) of the tumours were analysed with alpha-satellite probes for chromosomes 1, 6, 7, 11, 12, 17, 18, X and Y using CrSH; and exons 5-9 of the p53 gene were examined by polymerase chain reaction and single strand conformation polymorphism (PCR-SSCP) methods. Although positive for pancytokeratin, keratin 20, chromogranin, NSE, synaptophysin and vimentin, the similarity in antigen profiles expressed by SCLC and MCC prevented a definitive tumour diagnosis. Chromosomal in-situ hybridization, however, revealed trisomies 1 and 11, two frequent aberrations in MCC, and trisomy 18. Moreover, 71% of the tumour cells had two to three copies of X, whereas 98% of the cell nuclei in the hair follicles and normal epidermis (purported Merkel cell origins) displayed one X chromosome. No mutations were detected in the five exons of the p53 gene examined. CONCLUSIONS: Had CISH been performed earlier, treatment may have been tailored specifically to suit MCC, since MCC and SCLC have different therapeutic strategies. Finally, chromosome X may be of prognostic relevance in MCC, which apparently predominates in females and yet shows poorer prognosis in males, and hence be worthy of further investigation.

Adult↗
PubMed1991

Immunocytochemical evidence of a met-enkephalin-like substance in the dense-core granules of mouse Merkel cells.

The electron-microscopic immunogold method was applied to Merkel cells of adult mice to demonstrate the subcellular localization of met-enkephalin-like immunoreactivity. Post-embedding incubation with metenkephalin antisera showed that the gold particles were associated with the dense-core granules of the Merkel cells. The majority, but not all, of the dense-core granules were strongly labelled. Osmication caused a significant reduction in the number of gold particles on these granules. The nerve terminal associated with the Merkel cell did not show met-enkephalin-like immunoreactivity. To the best of our knowledge, this is the first report of the ultrastructural localization of a positive met-enkephalin immunoreactivity in the dense-core granules of Merkel cells in mice.

Animals↗
PubMed2005

Merkel cell carcinoma arising from the subcutaneous fat of the arm with intact skin.

BACKGROUND: Merkel cell carcinoma is a rare malignant neuroendocrine neoplasm characteristically arising from the dermis of sunlight-exposed skin. It rarely arises outside the skin. OBJECTIVE: We present a patient with primary Merkel cell carcinoma arising from subcutaneous fat, with no involvement of the overlying skin. We describe the clinical manifestations and magnetic resonance imaging (MRI) findings. METHODS: We report a 63-year-old woman with a primary lesion of Merkel cell carcinoma that arose from the subcutaneous fat layer of the left arm. The lesion presented as a subcutaneous nodule with intact overlying skin. MRI showed that the nodular lesion was located entirely in the subcutaneous fat layer, with no involvement of the dermis. Peritumoral infiltration around the lesion and enlarged lymph nodes deep to the lesion were noted. The patient received wide excision of the lesion with dissection of the regional lymph nodes and adjuvant radiotherapy and chemotherapy. RESULTS: Histopathologic examination confirmed the diagnosis of Merkel cell carcinoma with local lymphatic metastasis, and the lesion was completely located in the subcutaneous fat, with no involvement of the dermis. These findings were well correlated with MRI findings. CONCLUSION: Primary Merkel cell carcinoma may arise from the subcutaneous fat and present as an entirely subcutaneous lesion with intact skin. MRI is helpful to evaluate the local extension of the lesion and regional lymphatic metastasis.

Arm↗
PubMed2001

The number and distribution of Merkel cells in rudimentary polydactyly.

BACKGROUND: Rudimentary polydactyly histologically reveals a marked neural proliferation in the dermis and a large number of Meissner corpuscles in the dermal papillae. OBJECTIVE: Our study was performed to determine whether this neural proliferation is related to Merkel cells. METHOD: Using an antibody to cytokeratin 20, we examined the number and distribution of Merkel cells in 5 cases of rudimentary polydactyly, including an immature case without Meissner corpuscles. RESULTS: Only the case without Meissner corpuscles had a markedly large number of Merkel cells and some dermal Merkel cells. CONCLUSION: The normal number of Merkel cells in the mature cases suggests that abundant Merkel cells may appear at first and disappear after the development of neural proliferation. Merkel cells may be associated with the generation of cutaneous nerve plexus and nerve endings in the upper dermis, and possibly with the development of Meissner corpuscles, at the early stage of rudimentary polydactyly.

Adult↗