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PubMed1997

Merkel cell carcinoma of the vulva.

Merkel cell carcinoma is a very rare tumor. This is why it is not known whether this neoplasm behaves differently in the vulvar location than at other sites. We present a patient with a Merkel cell carcinoma assessed with a light optical microscope, immunohistochemistry, and electron microscope. Only eight previous cases have been reported in the literature. We discuss pathologic findings, such as histologic trabecular pattern under the optical microscope and neurosecretory granules (similar to Merkel cell carcinoma of the skin) under the electron microscope. Also discussed are the results of immunohistochemistry for low-molecular-weight cytokeratin, neuron-specific enolase, chromogranin, and Leu 7, and molecular study of N-ras, K-ras, N-myc, and p53 genes. Little is known about Merkel cell carcinoma of the vulva, but it seems to have a more aggressive behavior and poorer prognosis than Merkel cell carcinoma at other sites.

Aged↗
PubMed1998

Identification of Merkel cells by an antibody to villin.

Merkel cells represent a population of epithelial cells in the skin and oral mucosa. Although Merkel cells are reliably distinguishable from other epithelial cells at the ultrastructural level, these cells are usually not discernible by standard light microscopy and need special techniques for their identification. Villin is an actin-crosslinking protein that is associated with the actin filament cores of brush border microvilli. In this study we show that an antibody against villin is an excellent marker of Merkel cells and their microvilli even at the light microscopic level. The surrounding keratinocytes and subepithelial connective tissue cells do not show any significant affinity for the antibody against villin. Confocal laser micrographs reconstructed from serial images 0.5 microm thick of Merkel cells that were immunostained with villin clearly reveal the three-dimensional morphology of Merkel cells and their microvilli. The presence of villin in Merkel cell microvilli lends support to the idea that these cells might have a mechanoreceptor function.

Animals↗
PubMed1982

Unusual cutaneous carcinoma with features of small cell (oat cell-like) and squamous cell carcinomas. A variant of malignant Merkel cell neoplasm.

Three unusual primary neoplasms in the skin that occurred in elderly patients (64, 77, and 69 years of age) are presented. Two histologic components were found in each of the three neoplasms, one being small cell or oat cell-like carcinoma and the other squamous cell carcinoma. Study by electron microscopy revealed neurosecretory granules, though few, in the small cell component. The lack of clinical evidence of oat cell carcinoma elsewhere, the autopsy finding of two histologic components in one patient, and the findings by conventional and electron microscopy lead us to conclude that these three neoplasms are primary in the skin and of Merkel cell origin. We suggest further that small cell carcinoma of the skin represents a poorly differentiated counterpart of trabecular carcinoma. The spectrum of malignant Merkel cell neoplasm is, therefore, expanding. Two of our three patients died of their neoplasms 2 and 2 1/2 years, respectively, after the initial diagnosis.

Adenocarcinoma↗
PubMed1990

Human Merkel cell regeneration in skin derived from cultured keratinocyte grafts.

Human Merkel cell regeneration in epidermis derived from cultured keratinocyte autografts was studied from 6 days to 6 years after transplantation. Cultured keratinocyte sheets derived from skin of the sole, axilla, groin, or scalp were transplanted to full-thickness wounds in 20 pediatric patients treated for massive burns or giant congenital nevi. Normal age- and site-matched skin as well as meshed split-thickness autografts from the same patients served as controls. Merkel cells were identified by immunohistochemistry using antibodies to cytokeratins #8 and #18. Cultured keratinocytes in vitro expressed no neuroendocrine markers, but nonspecific, simple-epithelial cytokeratin expression was observed in about 20% of cells. After transplantation, Merkel cells were identified only in cultured grafts derived from sole skin and appeared in the epidermis as early as 21 days postgrafting. Dermal Merkel cells were rarely observed, but their appearance invariably succeeded that of intraepidermal Merkel cells. Regenerated Merkel cells were never innervated, and their emergence was unrelated either spatially or temporally to epidermal reinnervation. In skin bridges of meshed split-thickness grafts, Merkel cells survived after degeneration of associated neurites, but no Merkel cells appeared within re-epithelialized interstices. Among the neuroendocrine markers tested, Merkel cells in cultured grafts, meshed skin grafts or normal pediatric skin expressed only neuron-specific enolase. They failed to stain for calcitonin, chromogranin A, Leu-7, synaptophysin, bombesin, or vasoactive intestinal polypeptide by immunohistochemistry. These findings suggest that: (a) Merkel cells derive from keratinocyte precursors which undergo neuroendocrine differentiation in the epidermis; (b) that keratinocyte stem cells are capable of undergoing Merkel cell differentiation postnatally; (c) that postnatal Merkel cell differentiation may be body-site dependent; and (d) that Merkel cell development and maintenance is independent of neural induction.

Antibodies, Monoclonal↗
PubMed1995

Radiation sensitivity of Merkel cell carcinoma cell lines.

PURPOSE: Merkel cell carcinoma (MCC), being a small cell carcinoma, would be expected to be sensitive to radiation. Clinical analysis of patients at our center, especially those with macroscopic disease, would suggest the response is quite variable. We have recently established a number of MCC cell lines from patients prior to radiotherapy, and for the first time are in a position to determine their sensitivity under controlled conditions. METHODS AND MATERIALS: Some of the MCC lines grew as suspension cultures and could not be single cell cloned; therefore, it was not possible to use clonogenic survival for all cell lines. A tetrazolium based (MTT) assay was used for these lines, to estimate cell growth after gamma irradiation. Control experiments were conducted on lymphoblastoid cell lines (LCL) and the adherent MCC line, MCC13, to demonstrate that the two assays were comparable under the conditions used. RESULTS: We have examined cell lines from MCC, small cell lung cancer (SCLC), malignant melanomas, Epstein Barr virus (EBV) transformed lymphocytes (LCL), and skin fibroblasts for their sensitivity to gamma irradiation using both clonogenic cell survival and MTT assays. The results show that the tumor cell lines have a range of sensitivities, with melanoma being more resistant (surviving fraction at 2 Gy (SF2) 0.57 and 0.56) than the small cell carcinoma lines, MCC (SF2 range 0.21-0.45, mean SF2 0.30, n = 8) and SCLC (SF2 0.31). Fibroblasts were the most sensitive (SF2 0.13-0.20, mean 0.16, n = 5). The MTT assay, when compared to clonogenic assay for the MCC13 adherent line and the LCL, gave comparable results under the conditions used. CONCLUSION: Both assays gave a range of SF2 values for the MCC cell lines, suggesting that these cancers would give a heterogeneous response in vivo. The results with the two derivative clones of MCC14 (SF2 for MCC14/1 0.38, MCC14/2 0.45) would further suggest that some of them may develop resistance during clonogenic evolution.

Carcinoma, Merkel Cell↗
PubMed2003

Expression of MUC 1 and Ep-CAM in Merkel cell carcinomas: implications for immunotherapy.

The Merkel cell carcinoma (MCC) is a highly malignant carcinoma of the skin that is characterized by granules containing neuroendocrine peptides and by the expression of simple epithelial type cytokeratins. The glycoprotein Ep-CAM is a homophilic cell-cell adhesion molecule, present in most simple, pseudostratified and transitional epithelia and the tumors derived therefrom. MUC 1 is a well-established marker for squamous cell carcinomas and is generally secreted by glandular epithelial cells. We compared the expression of Ep-CAM and MUC 1 in Merkel cells and 33 cases of MCC and 12 MCC metastases using immunohistochemistry on paraffin-embedded sections. In addition, we examined the glycosylation status of MUC 1 with specific monoclonal antibodies. MUC 1 and Ep-CAM were expressed in Merkel cells and in about 82% and 70% of all MCC irrespective of clinical outcome. Both antigens were expressed in 66% of metastases. Similar to breast cancer, the presence of MUC 1 was not correlated with clinical outcome, but the staining intensity of monoclonal antibodies against glycosylation-independent and hypoglycosylated epitopes was. In MCC we found an altered glycosylation pattern in the immunodominant APDTR region of MUC 1 as compared to normal Merkel cells. Hyperglycosylated MUC 1 epitopes were not present in either MCC or normal Merkel cells. There was no correlation between glycosylation pattern and clinical outcome. Ep-CAM expression seemed to be stronger in primary MCC that metastasized than in those that did not. In conclusion, Merkel cells and the majority of MCC express Ep-CAM and MUC 1. This opens the door for treatments based on monoclonal antibodies or vaccination strategies against these antigens, already established for other tumor entities.

Antibodies, Monoclonal↗
PubMed2003

CD56: a useful marker for diagnosing Merkel cell carcinoma.

BACKGROUND: Merkel cell carcinoma (MCC) of the skin is an aggressive but rare malignant neuroendocrine tumor. For its pathological diagnosis, we use a panel of immunohistochemical markers, such as cytokeratin 20 (CK 20), epithelial membrane antigen (EMA), chromogranin A, neuron specific enolase (NSE), synaptophysin, and Leu7 (CD57) to demonstrate its epithelial and neuroendocrine features. CD56, or neural cell adhesion molecule (NCAM), has been demonstrated recently as the tumor marker of the pulmonary neuroendocrine cell system. Its expression in MCC, however, has still rarely been investigated. Furthermore, in such very few previous studies on NCAM expression in MCC, all the tumor cells were not necessarily demonstrated to express NCAM. OBJECTIVES: To study the immunoreactivity of CD56 in MCC, especially using a monoclonal antibody of a clone 1B6, different from those adopted in the previous reports. METHODS: We reexamined CD56 expression immunohistochemically in five MCC cases, along with the conventional panel of markers described above, using paraffin-embedded tissue sections. RESULTS: CD56 revealed the most diffuse and intense positive staining, which was noted along the cell borders, in all specimens compared with other neuroendocrine tumor markers. CONCLUSIONS: The results of our study indicate that CD56, especially a new monoclonal antibody (clone 1B6), is a useful immunohistochemical marker for MCC.

Aged↗
PubMed2006

Immunohistochemical study of apoptosis markers and involvement of chemokine CXCR4 in skin Merkel cell carcinoma.

BACKGROUND: Merkel cell carcinoma (MCC) is a rare, aggressive cancer of the skin that mainly affects elderly patients. Because of its rarity, there is no established treatment or proven markers to guide therapy or prognosis. Immunohistochemical expression of apoptosis proteins is considered a useful marker of both malignancy and tumour progression. Apoptosis plays a fundamental role in skin homeostasis, and apoptotic cells have been detected in normal and diseased skin. Chemokines possess a wide range of biological activities and CXCR4 is expressed in some cancer cells, where it plays an efficient role in metastasis formation. OBJECTIVE: To identify immunohistochemical parameters that can help clinicians select the most suitable therapy for skin MCC. DESIGN: Antibodies against ki67, bcl-2, p53, survivin, p16 and CXCR4 were tested to assess the usefulness of these antigens as indices of proliferation potential and predictors of prognosis. METHODS: Immunohistochemical detection of apoptosis inhibitors and CXCR4 was performed on tissue from 12 patients with primary MCC. After excision of the primary lesion, five survived and had no metastases, and seven experienced local recurrence or lymph node metastases. RESULTS: Expression of ki67 and survivin was increased in patients with local recurrence or metastasis (retrospectively classified as 'poor prognosis') compared with those with a 'good prognosis', and bcl-2 expression was significantly greater (P=0.003). P53 and p16 immunostaining was moderate in both groups. A positive correlation was observed between survivin and mutant p53 in the poor prognosis group (r=0.593, P=0.033; regression coefficient). High values of p53 were measured in patients with high levels of survivin and vice versa. CXCR4 was not detected at all. CONCLUSIONS: Our results show strong MCC cell apoptosis inhibition and a high cell proliferation capacity. The positive correlation between survivin and p53 may be a predictor of MCC spread via the lymphatic network. Absent CXCR4 expression may reflect a less aggressive form, with less efficient development of distant and non-organ-selective metastasis formation.

Apoptosis↗
PubMed2006

An unusual presentation of periocular Merkel cell carcinoma.

AIM: Merkel cell carcinoma (MCC) is an uncommon but potentially aggressive tumor. We describe a rare presentation of MMC of the upper lid. METHODS: A 63-year-old male presented with a 3-month history of right upper lid fullness. Examination revealed a large multinodular mass protruding into the conjunctival aspect of the eyelid. An enlarged right submandibular lymph node was also noted. RESULTS: An incisional biopsy was suggestive of MCC. Staged surgical excision with rapid paraffin sections was performed. The tumor cells were seen invading the tarsal plate and adjacent to the palpebral conjunctiva but not into the epidermis. MCC was confirmed using immunohistochemical stains and neuroendocrine markers (cytokeratins Cam 5.2, AE1/3, CK20, chromogranin, synaptophysin, and Leu 7). The lymph node biopsy was also confirmed as metastatic MCC. The patient was treated with postsurgical chemotherapy and radiotherapy, with no recurrence during a 6 months follow-up period. CONCLUSION: Although uncommon, periocular MCC may present as an atypical conjunctival multinodular mass.

Biomarkers, Tumor↗
PubMed1992

[Case reports on the importance of the locoregional radiotherapy of Merkel cell tumor].

The Merkel cell tumor is becoming an increasingly diagnosed primary neoplasm of the skin. This subepidermal tumor is commonly located on the head and neck or extremities of elderly patients. Occasionally misinterpreted as cutaneous metastases, they show a high rate of local recurrence (27 to 52%) and distant metastatic spread (18 to 52%). The definitive diagnosis can be made with immunohistochemistry. Wide surgical excision with postoperative irradiation to the local site and regional lymphatics is the therapy of choice. In seven patients we describe management strategies and discuss their clinical results.

Adult↗
PubMed1998

Clinical management and treatment outcomes of Merkel cell carcinoma.

BACKGROUND: Merkel cell carcinoma (MCC), first described in 1972, is an uncommon, highly malignant tumour of skin. Its aetiology is unknown although the tumour occurs most frequently in sun-exposed sites. This skin cancer is characterized by a high incidence of metastases, local and regional recurrence and has a high mortality. Few survival data beyond 3 years are available. Treatment strategies include wide local excision of the primary and lymph node dissection, as indicated together with adjuvant radiotherapy. The tumour has also been shown to be chemosensitive. Definitive treatment is inconclusive due to the relative rarity of this malignancy. METHODS: A retrospective study was undertaken between the years 1985 and 1996 of 33 patients with MCC at Concord Repatriation General Hospital (CRGH). Demographic details were noted, together with the site and appearance of the primary lesion and the sites and date of metastases. The response and outcome to various modalities of treatment were documented. RESULTS: There were 27 men and six women with an average age of 80 years (range: 60-86 years). The primary lesion in the present series most often resembled a basal cell carcinoma (BCC), with 53% occurring in the head and neck region. Twenty-seven patients (82%) developed metastatic disease, with an average interval of 13.4 months between diagnosis of the primary lesion and the development of metastases. The incidence of locoregional recurrence in the present series was 42%. Radiation combined with surgery achieved locoregional control in 15 of 19 patients with primary, regional or recurrent locoregional disease. Fourteen patients died of MCC and five others from unrelated causes. The 14 survivors have a mean survival of 54 months with six patients surviving more than 5 years. CONCLUSIONS: Local excision together with regional lymph node clearance as indicated, combined with adjuvant radiation treatment was associated with an improved survival. The role of chemotherapy remains unclear.

Aged↗
PubMed2001

Second neoplasms in patients with Merkel cell carcinoma.

BACKGROUND: Merkel cell carcinoma (MCC) has been associated with a high incidence of other skin tumors and hematological malignancies. The purpose of this study was to analyze data from the Israel Cancer Registry regarding the incidence of second neoplasms in patients with MCC and their impact on survival. METHODS: Sixty-seven patients in whom MCC was diagnosed between 1983 and 1999 were included. Data were collected on age, gender and ethnic origin, dates of diagnosis of MCC and any other neoplasm, and date and cause of death, if applicable. Comparison of MCC-specific survival, estimated by the Kaplan-Meier product limit method, between patients with no other neoplasm and those with second primary tumors was performed by log rank test. Age-specific standardized incidence ratio (SIR) was calculated using 5751 age- and ethnic-matched malignant melanoma patients as a control group. RESULTS: Seventeen patients (25%) had a second neoplasm before, concomitant with, or after the diagnosis of MCC; 2 of them also had a third primary tumor. The SIR was 2.8 (95% CI; range, 1.38-4.22), significantly higher than the control group. Almost half the tumors were squamous cell carcinomas, either skin or head and neck, and most of the remainder were hematological malignancies or breast and ovarian adenocarcinomas. On univariate analysis, the presence of another neoplasm, regardless of its chronology, was associated with higher MCC-specific mortality (65% vs. 40% for patients with MCC only; P = 0.022). Analysis of only those patients in whom a second neoplasm developed during follow-up after treatment for MCC yielded an estimated actuarial risk of developing a second primary of 2.1% for each year of observation. CONCLUSIONS: There is a high incidence of second neoplasms, including noncutaneous solid tumors, in patients with MCC. The presence of these neoplasms, whether they appear before, after, or simultaneously with MCC, is associated with a higher MCC-specific mortality.

Adult↗
PubMed1992

Immunohistochemical studies of Merkel cell carcinoma of the eyelid.

Merkel cell carcinoma of the eyelid is a rare malignant tumor. Immunohistochemical studies can be helpful in establishing the diagnosis of this tumor. We encountered a case of Merkel cell carcinoma of the eyelid and conducted an immunohistochemical analysis for clarification of its cell properties. The patient in this study was a 78-year-old man who noted a small mass on his right upper eyelid, which was subsequently removed. However, the lesion recurred and progressively enlarged. The results of a biopsy indicated the possibility of a highly malignant tumor. The lesion was removed by orbital exenteration. Merkel cell carcinoma was finally diagnosed by using light and electron microscopy. In immunohistochemical studies, the tumor cells showed both neuron-specific enolase and cytokeratin. Most of the cells were also labeled with antibodies against the protein gene product 9.5, endocrine granule constituent and chromogranin A. However, no neuropeptides were labeled. The properties of the tumor cells appeared virtually the same as those of normal human Merkel cells.

Aged↗
PubMed2000

Applicability of the sentinel node technique to Merkel cell carcinoma.

BACKGROUND: Merkel cell carcinoma (MCC) resembles malignant melanoma in several ways. Both are cutaneous lesions of the same embryonic origin. Both have an unpredictable biologic behavior, early regional lymph node involvement, early distant metastases, and high recurrence rate. OBJECTIVE: To apply the sentinel node technique described for melanoma to MCC in light of the common biologic features of these two tumors. METHODS: Preoperative lymphoscintigraphy, intraoperative lymphatic mapping, and sentinel node biopsy and frozen section histology were performed to guide the surgical treatment of three patients with MCC. RESULTS: Application of this approach in patients with MCC is feasible, reproducible, and seems reliable. CONCLUSION: The use of the sentinel node technique for MCC will reduce the number of unnecessary lymphadenectomies, will enable identification of microscopic metastases to lymph nodes, and will improve the stratification and accrual of patients into adjuvant treatment protocols. It may even lead to a survival benefit.

Aged↗
PubMed2005

Cyclooxygenase-2 expression in primary Merkel cell carcinoma.

BACKGROUND: Merkel cell carcinoma (MCC) is a highly malignant neuroendocrine skin tumor. The typical course of MCC is rapid progression of the primary tumor and metastatic dissemination to the regional lymph nodes. Thus far, no biological, prognostic marker has been established for this aggressive neoplasm. Cyclooxygenase-2 (Cox-2) is undetectable in most normal tissues, but it is induced in various cell types by inflammation and carcinogenesis. Although the expression and function of Cox-2 have been studied extensively in several carcinomas, little is known about Cox-2 expression in neuroendocrine carcinomas. The aim of the present report was to study Cox-2 expression in MCC and find out whether this expression correlates with outcome. METHODS: Immunohistochemical analysis for Cox-2 was performed on 22 primary MCC samples. RESULTS: Almost 70% of the samples showed positive staining. Protein expression of Cox-2 was sparse and low in intensity. We found a tendency for enhanced Cox-2 expression in tumors located in sun-exposed areas. Cox-2 expression had no significant statistical correlation with clinical parameters. CONCLUSIONS: MCC expresses Cox-2 in low levels, and the expression did not prove to be a prognostic factor. Furthermore, the low expression suggests that the primary treatment option for MCC is not therapeutic inhibition of Cox-2.

Aged↗
PubMed2000

Lymphoscintigraphy, sentinel lymph node biopsy, and Mohs micrographic surgery in the treatment of Merkel cell carcinoma.

BACKGROUND: Merkel cell carcinoma (MCC) is an aggressive cutaneous malignancy with a high incidence of occult nodal metastases. MCC is believed to be similar in natural history to thick or ulcerated melanomas in its propensity for locoregional recurrence and early lymph node metastasis. Studies have shown that nodal status is statistically correlated to survival in MCC. Radiolocalization and superselective lymph node biopsy is a recent technique that has been proven to be of great value in evaluating the status of occult lymph node disease in malignant melanoma and breast cancer patients. OBJECTIVE: In previously untreated patients, an orderly progression of metastases is observed for both cutaneous carcinomas and malignant melanomas and is anticipated for MCC. METHODS/RESULTS. We present two patients with MCC of the head and neck who underwent simultaneous Mohs micrographic surgery and sentinel lymph node biopsy with intraoperative radiolocalization. CONCLUSION: Sentinel lymph node biopsy and intraoperative lymphoscintigraphy may prove to be a useful technique in evaluating occult nodal involvement and in limiting the potentially unnecessary morbidity of more comprehensive lymph node dissections in MCC patients who do not yet have metastatic involvement.

Aged↗
PubMed1996

Merkel cell carcinoma.

BACKGROUND: Merkel cell carcinoma is an aggressive tumor with nonspecific clinical features. The prognosis in general is worse than malignant melanoma. Local recurrence rates are high with one-third of patients having recurrence within one year of excision. The tumor invades blood vessels and lymphatics. This frequent lymphatic dissemination leads later to satellite lesions and recurrence. Distant metastases occur in one-third of patients. One-,two- and three-year survival rates are poor, being estimated at 88%, 72%, and 55%, respectively. OBJECTIVE: To increase awareness of the behavior of this uncommon tumor. METHODS: A review of the current literature and recommendations regarding this tumor. RESULTS: Wide local excision with 3-cm margin shows significant reduction in local recurrence compared with 2-cm margins. Two-thirds of patients with local recurrence ultimately die from their disease. Radiation therapy has a role to play in the local and regional clearance of the tumor. CONCLUSION: Prompt diagnosis and surgical excision are necessary to improve survival. Mohs micrographic surgery offers potential advantages in evaluating both the lateral and the deep margins. Follow-up studies of patients treated with this modality will be beneficial.

Carcinoma, Merkel Cell↗
PubMed2001

Prognostic and therapeutic implications of sentinel lymphonodectomy and S-staging in Merkel cell carcinoma.

BACKGROUND: Merkel cell carcinoma (MCC) is a rare but very aggressive neuroendocrine neoplasm of the skin with a high propensity for early lymph node metastasis and subsequent distant spread. Optimal treatment and prognostic factors are poorly defined. OBJECTIVE: The purpose of this study is to assess the prognostic and therapeutic relevance of sentinel lymphonodectomy in MCC. METHODS: Five patients with biopsy-proven MCC underwent gamma-probe-guided sentinel lymphonodectomy assisted by lymphatic mapping. From each sentinel lymph node (SLN), a series of paraffin sections was histologically and immunohistochemically examined for the presence of micrometastases, which were then staged according to the recently published S classification. RESULTS: Four of the 5 patients showed metastatic disease in the SLNs, 3 of which were classified as S(2), 1 as S(3). Only 1 of the S(2) patients demonstrated additional positive nodes at completion lymphonodectomy. The patient staged as S(3) refused a radical lymph node dissection and died within 1 year due to widespread metastasis. CONCLUSIONS: Sentinel lymphonodectomy is a low-morbidity procedure which enables an early detection and exact staging of regional lymph node metastases with potentially high prognostic and therapeutic relevance in MCC.

Aged↗