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PubMed2005

Complete spontaneous regression of Merkel cell carcinoma.

Merkel cell carcinoma (MCC) is a very aggressive primary cutaneous neoplasm most often occurring on the head and neck of the elderly. Spontaneous regression of MCC was first described in 1986. A 79-year-old woman with MCC on the right cheek underwent spontaneous regression of the malignancy, documented by photographic follow-up, computed tomography, and histologic studies. A review of the literature is presented. Complete clinical and histologic regression of MCC was observed in the present case. Although the literature documents 11 similar cases, only 6 can be regarded as complete spontaneous regressions following exclusive performance of a biopsy (primary complete spontaneous regression). Primary complete spontaneous regression of MCC is infrequent, and most case reports describe this phenomenon in women with MCC on the cheek. The reasons underlying regression are unknown.

Aged↗
PubMed1998

[Merkel cell carcinoma].

Merkel cell carcinoma (MCC) is a malignant cutaneous neuroendocrine tumor which may be difficult to diagnose. It mostly occurs in old patients and the commonest sites are the skin of the head and neck and the extremities. MCC appears as a solitary violaceous dome-shaped nodule or indurated plaque. Histopathologic diagnosis may be difficult and three main patterns have been described. With immunohistochemistry studies, MCC express both epithelial (cytokeratins, EMA) and neuroendocrine (NSE, chromogranin, ...) markers. The tumor develops an aggressive course not unlike an aggressive melanoma. Local recurrence and regional lymph node metastases occur in 40 to 75% of cases. Long-term prognosis is unfavorable (3-year survival rate is 55%). Wide surgical excision associated with radiotherapy is the treatment of choice, regional lymph node metastases should be treated by lymph node excision and radiotherapy; chemotherapy should be used in systemic disease.

Adolescent↗
PubMed1999

Lymphoscintigraphy with sentinel lymph node biopsy in cutaneous Merkel cell carcinoma.

Merkel cell carcinoma (MCC) is a rare cutaneous malignancy characterized by an aggressive clinical behavior with high rates of locoregional and systemic recurrence. Regional disease and distant metastases are associated with poor prognosis. Despite a predisposition of MCC to spread via the lymphatics, prophylactic lymph node dissection in the absence of clinically apparent lymph node involvement is controversial. The value of lymphoscintigraphy in cutaneous melanoma is established in lesions with ambiguous lymphatic drainage patterns. When used with sentinel lymph node biopsy (SLNB), it can identify subjects with occult regional node metastasis. The authors present 2 patients with MCC who underwent regional node staging with lymphoscintigraphy-directed SLNB. Both patients had sentinel nodes that were positive for metastatic disease. In patients with MCC, minimally invasive regional node staging SLNB may be useful in limiting the sequelae of routine lymphadenectomies. Whether early identification and treatment of patients with occult regional node disease can influence survival in MCC is not known.

Aged↗
PubMed2003

Diagnostic value of microtubule-associated protein-2 in Merkel cell carcinoma.

Merkel cell carcinoma (MCC) is a rare, aggressive cutaneous carcinoma with neuroendocrine differentiation and a propensity for early spread to regional lymph nodes. Since surgical resection is the mainstay of treatment of MCC, differentiation of MCC from malignant lymphoma, metastatic small cell carcinoma, basal cell carcinoma, and malignant melanoma is very important and is sometimes challenging with routine histologic examination. Immunohistochemical studies may be required to differentiate MCC from other primary and metastatic skin neoplasms. Previously, the authors reported that microtubule-associated protein-2 (MAP-2) is a sensitive and specific marker for pulmonary neoplasms with neuroendocrine differentiation. Because MCC is also a neuroendocrine carcinoma, the authors hypothesized that MAP-2 may be expressed in MCC and therefore may be a useful marker in establishing an accurate diagnosis. MAP-2 staining was demonstrated in all 14 MCCs with diffuse (10 cases) to focal (4 cases) patterns of immunoreactivity. No MAP-2 immunoreactivity was observed in any lymphoma (14 cases), basal cell carcinoma (20 cases), or squamous cell carcinoma (14 cases). CK20 reactivity was present in 12 of 14 cases with focal (2 cases) to diffuse (10 cases) staining having the characteristic perinuclear dot-like pattern. NSE was positive in 13 of 14 cases, SYN was positive in all 14 cases, CHR was positive in 8 of 14 cases, CK7 was positive in 4 of 14 cases, and CD99 was focally positive in 2 cases and diffusely positive in 3 cases. MAP-2 showed a diffuse or focal staining of MCC with a +1 to +4 intensity in most cases. MAP-2 was positive in two cases of MCC that were negative for CK20 and CHR and negative or only slightly positive for SYN and NSE. Therefore, MAP-2 may be a valuable ancillary study in skin tumors suspicious for neuroendocrine origin with faint or negative staining with the antibodies traditionally used for diagnosing MCC. The authors believe this is the first study to demonstrate the utility of MAP-2 in the immunohistochemical workup of MCC. The authors recommend that MAP-2 be added to immunohistochemical panels to confirm the diagnosis of MCC.

Aged↗
PubMed2004

c-kit expression in primary and metastatic merkel cell carcinoma.

Merkel cell carcinoma (MCC) is an aggressive neuroendocrine tumor of the skin that is associated with a high incidence of recurrence and metastasis. The therapeutic arsenal for this malignancy is limited and once it spreads, there is no effective treatment. c-kit expression has been demonstrated previously in primary MCCs thus raising the possibility of treating MCCs with imatinib mesylate, the tyrosine kinase inhibitor that has shown promise in the management of c-kit expressing tumors. In this study we examine 25 additional primary MCCs and also 6 of their lymph node metastases. Formalin-fixed, paraffin-embedded tissues were stained immunohistochemically with an antibody directed against the KIT receptor. Percentage and intensity of staining were analyzed semiquantitatively using a three-tiered system. Twenty-one of the 25 (84%) primary tumors stained positively for KIT, of which 14 (67%) showed widespread positivity. Five of the 6 lymph nodes (83%) were similarly positive. High mitotic rate and vascular invasion in the primary tumors tended to be associated with prominent staining in the lymph node metastases. No association was found between c-kit expression and outcome. We confirm that the majority of primary MCCs express c-kit and further find that metastases are positive for the KIT receptor as well. Thus, c-kit expression may be an early event in the transformation of MCC, but not a marker for tumor progression.

Aged↗
PubMed2006

Clinical added-value of 18FDG PET in neuroendocrine-merkel cell carcinoma.

Merkel cell carcinoma (MCC) is a rare and highly malignant skin cancer with neuroendocrine differentiation. We studied the potential value of 18FDG PET in the management of MCC. Eleven patients with MCC were examined by 18FDG PET and PET-CT for staging purpose (n=4) or for detection of recurrence (n=7). Qualitative and quantitative interpretation of PET studies was performed routinely. 18FDG PET observations were compared to clinical and radiological findings. In 6 patients, PET findings were also compared to histology. In 7 patients, the 18FDG tumor uptake was compared to the MCC proliferative activity expressed by the Ki-67 index. 18FDG PET was contributive in 10/11 MCC patients. In 7 patients, 18FDG PET detected focal lesions or a disseminated stage of the disease including dermal, nodal and visceral metastases. In 3 patients, a normal 18FDG PET confirmed complete remission of disease. Most MCC patients exhibited highly 18FDG-avid sites suggestive of increased glucose metabolism. This imaging pattern was related to a high proliferative activity (Ki-67 index >50%). In 1 patient with a weakly proliferative nodal MCC (Ki-67<10%), a false negative result was yielded by metabolic imaging. In 4/11 patients, 18FDG PET revealed an unsuspected second neoplasm in addition to MCC. It is concluded that whole-body 18FDG PET may be useful in the management of MCC patients. However, a normal 18FDG PET aspect cannot rule out MCC with low proliferative activity.

Aged↗
PubMed2002

Role of postoperative radiotherapy in the management of Merkel cell carcinoma.

Merkel cell carcinoma (MCC) is a rare, aggressive neuroendocrine tumor of the skin with a high potential of locoregional relapse after surgery alone. This report is an update of our experience in the treatment of MCC. From January 1990 to May 2000, 31 patients with MCC, 13 men and 18 women aged between 34 and 92 years, were treated at the University of Cologne, Germany. Primary tumor sites were in the head and neck region in 13 patients, limbs in 13, and trunk in 5. The tumors were stage I in 26 of 31 patients, stage II in 4 of 31 and stage III in 1 of 31. Treatment included surgery alone in 14 of 31 patients, adjuvant postoperative radiotherapy in 16 of 31 patients, 1 of them had incomplete surgery, and definitive radiotherapy in 1 of 31 patients (stage III). Median overall survival (OS) after first diagnosis was 32 months (95% confidence interval: 0-75 months) with a 3-year OS rate of 47% (95% CI: 25-69%). Six of 31 patients relapsed locally after a median of 4 months, 10 of 31 patients developed regional node metastases, and 7 of 31 patients distant metastases. Nine patients died as a direct result of MCC. Locoregional control and disease-free survival were significantly improved in the group with postoperative radiotherapy (p = 0.023). Uni- and multivariate analysis revealed that head and neck location of the tumor and the lack of postoperative radiotherapy are unfavorable prognostic factors. Postoperative radiotherapy to the primary tumor region and the regional lymphatics is effective in the prevention of locoregional recurrence. Prospective clinical trials should be performed to confirm these observations.

Adult↗
PubMed2004

Expression of adhesion molecules and cytokeratin 20 in merkel cell carcinomas.

Merkel cell carcinoma (MCC) is an aggressive neuroendocrine carcinoma of the skin. MCCs often show characteristic paranuclear dot-like immunopositivity for cytokeratin 20 (CK20), a globular aggregation of CK20 intermediate filaments. These aggregates typically form rhabdoid features and fibrous bodies and may be associated with a down-regulation in adhesion molecules (AMs). To date, the relationship between the expression of AMs and CK20 and clinicopathological findings in MCC has not been well examined. In this immunohistochemical study, we assessed the expression of AMs, CK20, and chromogranin A (CgA) on MCCs in 8 men and 23 women with this disease, and also characterized their clinicopathological features. This study is the largest of its kind that has been undertaken to date in Japanese patients. Compared to normal tissue, E-cadherin and alpha- and beta-catenins showed reduced membranous expression in 95.7%, 46.7%, and 45.2% of MCCs, respectively. Nuclear E-cadherin localization was seen in four tumors, all of which predominantly showed a CK20 dot pattern. However, there was no significant relationship between the membranous expression of AMs and a CK20 dot pattern. E-cadherin expression was significantly lower in tumors of > or =2 cm, and tumors negative for E-cadherin more frequently developed outside of the head and neck than within those regions. CgA was more intensely expressed in tumors with uniform nuclei and a dense lymphocytic infiltrate than in those that showed pleomorphisms and that had few, if any, infiltrating lymphocytes. These findings suggest that MCCs have a reduced expression of AMs and that down-regulation of E-cadherin expression may correlate with increased tumor aggressiveness. The fact that no significant relationship was demonstrable between the membranous expression of AMs and the CK20 expression pattern suggests that the mechanism of aggregation of intermediate filaments may be different in different types of tumors.

Aged↗
PubMed1999

Multimodality management of Merkel cell carcinoma.

HYPOTHESIS: Merkel cell carcinoma is a rare dermal neuroendocrine carcinoma whose optimal treatment and prognostic factors are poorly defined. We hypothesize that high-risk patients with Merkel cell carcinoma are best treated with multimodality therapy. DESIGN: A retrospective review of all patients (N = 33) with Merkel cell carcinoma treated at the Massachusetts General Hospital from January 1, 1980, to August 24,1997. Median follow-up time was 37 months (range, 6-157 months). PATIENTS: Adequate data for evaluation were available for 31 patients. Male to female distribution was 14 men and 17 women, with a median patient age of 68 years. MAIN OUTCOME MEASURE: Stage at presentation; factors associated with recurrence; and the effects of surgery, radiation therapy (XRT), and chemotherapy on recurrence, salvage, and survival rates. RESULTS: There were 12 extremity, 11 head and neck, and 8 truncal tumors. There were 22 isolated primary tumors, 8 with additional clinically positive lymph nodes, and 1 with distant disease. Therapy was local excision with or without XRT in 19 patients, local resection and lymphadenectomy with or without XRT in 8 patients, and XRT alone in 4 patients with head and neck tumors. Fifteen patients developed recurrences (7 local, 8 nodal, and 10 distant). Median time to recurrence was 8 months (range, 3-48 months). There were 7 tumor-related deaths, 6 of which were associated with truncal lesions (P<.001). No locoregional recurrences occurred in patients with margins of resection of 2 cm or greater or adequate XRT. A multivariate analysis selected truncal location (P = .005) and nodal disease (P = .05) as predictors of mortality. Remission was possible in 5 patients with locoregional and 2 patients with distant recurrences. CONCLUSIONS: Merkel cell carcinoma is an aggressive dermal cancer with frequent nodal metastases; truncal tumors have the worst prognosis. Locoregional recurrence correlates with inadequate margins and lack of XRT, but remission is possible with multimodality therapy.

Aged↗
PubMed1999

Intraoperative lymphatic mapping and sentinel lymph node biopsy for Merkel cell carcinoma.

BACKGROUND: Merkel cell carcinoma is a rare cutaneous neoplasm which commonly spreads to the regional lymph nodes. The feasibility of identifying the sentinel node in patients with clinically node-negative Merkel cell carcinoma was evaluated. METHODS: Sentinel lymphatic mapping was performed in 18 patients with stage 1 Merkel cell carcinoma using the combination of isosulphan blue dye and 99mTc-radiolabelled sulphur colloid. Patients with tumour metastasis in the sentinel node underwent complete dissection of the remainder of the lymph node basin. RESULTS: Eighteen patients underwent removal of 35 sentinel nodes. Two patients demonstrated metastatic disease in the sentinel lymph nodes; complete dissection of the involved nodal basin revealed no additional positive nodes suggesting that the sentinel lymph node had been identified. The node-negative patients received no further surgical therapy, with no evidence of recurrent disease in the sentinel nodal basin at a median of 7 months' follow-up. CONCLUSION: Sentinel node biopsy is feasible in patients with Merkel cell carcinoma. It can be used to stage patients and provides important prognostic information. In those with subclinical nodal disease, it may direct early regional lymphadenectomy but the effect of such surgery on survival remains unclear.

Adult↗
PubMed2002

A meta-analysis of the prognostic significance of sentinel lymph node status in Merkel cell carcinoma.

BACKGROUND: Merkel cell carcinoma is an aggressive cutaneous neoplasm with a high propensity to metastasize to lymph nodes. OBJECTIVE: The objective of this study was to determine the prognostic significance of sentinel lymph node status in patients with Merkel cell carcinoma. METHODS: A meta-analysis of case series of patients with Merkel cell carcinoma managed with sentinel lymph node biopsy was performed. RESULTS: Forty of 60 patients (67%) had a biopsy-negative sentinel lymph node; 97% of this group had no recurrence at 7.3 months median follow-up. Twenty patients (33%) had a biopsy-positive sentinel lymph node; 33% of this group experienced local, regional, or systemic recurrence at 12 months median follow-up. Risk of recurrence or metastasis was 19-fold greater in biopsy-positive patients (odds ratio, 18.9; p = 0.005). None of 15 biopsy-positive patients who underwent therapeutic lymph node dissection experienced a regional recurrence; 3 of 4 who did not receive therapeutic lymphadenectomy experienced regional recurrence. CONCLUSION: Sentinel lymph node positivity is strongly predictive of a high short-term risk of recurrence or metastasis in patients with Merkel cell carcinoma. Therapeutic lymph node dissection appears effective in preventing short-term regional nodal recurrence. Aggressive adjuvant treatment should be considered for patients with positive sentinel lymph nodes.

Carcinoma, Merkel Cell↗
PubMed2003

Radiotherapy alone for primary Merkel cell carcinoma.

BACKGROUND: Merkel cell carcinoma is a rare and potentially aggressive cancer of the skin. Cumulative data from small retrospective series have supported treatment by wide excision and adjuvant radiotherapy. However, wide excision may be difficult to perform in patients with tumors of the head and neck or in older populations with comorbidities that may be incompatible with general anesthesia. OBSERVATIONS: Nine patients (group 1) with stage I (without lymph node involvement) Merkel cell carcinoma primary tumors were treated in our center by radiotherapy alone. The rate of recurrence was compared between this group and 17 additional patients (group 2) with stage I Merkel cell carcinoma who received conventional treatment (surgery followed by radiotherapy). RESULTS: The median follow-up was 3.0 years (range, 8 months to 7 years) for group 1 and 4.6 years (range, 5 months to 11 years) for group 2. During this period, we observed 1 relapse and 1 progression of disease in group 2. No statistical difference was found in overall and disease-free survival between the 2 groups of patients. CONCLUSION: This study demonstrates the possibility of treating inoperable Merkel cell carcinoma by radiotherapy alone, with outcomes similar to those of classic treatment.

Aged↗
PubMed1980

Development of rat Merkel cells.

The ultrastructure of Merkel cells and cutaneous nerves was examined in fetal, newborn, and 7-day-old rats. The earliest observation of cells having some, but not all, of the features of mature Merkel cells was at 16 days gestation in snout skin. These early presumptive Merkel cells resembled the neighboring keratocytes, except that they contained dense-cored vesicles scattered in the cytoplasm. Presumptive Merkel cells were seen only in the epidermis, although a careful search was made of the dermis. Developing neurons were not observed to penetrate the epidermal basal lamina when presumptive Merkel cells were first seen. The earliest observation of identifiable nerve axons in the snout epidermis was at 17-171/2 days gestation. Study of the presumptive Merkel cells through successively older gestational stages showed that the cells became innervated and progressively developed the characteristics of adult Merkel cells. We suggest that Merkel cells arise from keratocyte-like precursors in rat epidermis, at a time when skin nerves may still be several micrometers away.

Animals↗
PubMed1997

The role of radiation therapy and chemotherapy in the treatment of Merkel cell carcinoma.

BACKGROUND: Merkel cell carcinoma is a rare and highly aggressive skin tumor. The purpose of this study was to determine the role of radiation therapy and chemotherapy in the treatment of patients with Merkel cell carcinoma. METHODS: A retrospective analysis of 27 patients treated at Rabin Medical Center in Israel is presented, focusing on the treatment details. Data for 40 patients (the authors' 27 patients and an additional 13 patients from the Israeli Cancer Registry), were analyzed for prognostic factors using univariate and multivariate analyses. RESULTS: Univariate analyses revealed regional lymph node involvement and the coexistence of a second primary tumor as unfavorable prognostic factors. On multivariate analysis, only lymph node involvement showed borderline statistical significance. Radiation therapy was highly effective when given as consolidation after surgery or chemotherapy. In 11 patients irradiated effectively, only 1 (9%) in-field recurrence occurred. Radiation therapy yielded responses in 15 of 15 measurable sites (5 complete responses and 10 partial responses). Chemotherapy produced responses in 18 of 26 patients (69%), mostly complete (41%). However, in the absence of radiation therapy, the responses were short lived. CONCLUSIONS: These data support the use of combined treatment with chemotherapy followed by radiation therapy for patients with advanced locoregional Merkel cell carcinoma. In patients with metastatic disease, chemotherapy as well as radiotherapy can provide effective palliation. Further large scale investigations are warranted to confirm this approach.

Adult↗
PubMed2003

Somatostatin analogue scintigraphy in Merkel cell tumours.

BACKGROUND: Merkel cell tumours are rare neoplasms of the skin with frequent regional and distant metastases. Scintigraphy with the radiolabelled somatostatin analogue octreotide is a possible method for in vivo localization of the primary tumour and its metastases. OBJECTIVES: To estimate the diagnostic value of indium (111) -octreotide scintigraphy (Octreoscan in detecting metastases. METHODS: Scans of 11 patients with Merkel cell carcinoma were evaluated, in whom scintigraphy was performed in addition to the conventional investigations, chest X-ray, ultrasonography and computed tomography (CT). RESULTS: In four cases metastases were found both by scintigraphy and by conventional methods; two investigations showed a suspicious accumulation of radioactivity on scintigraphy that could not be confirmed by CT and clinical progression. In three cases CT-verified metastases were not found by scintigraphy. Two patients were found to be tumour free, i.e. free of metastases by scintigraphy and conventional methods, indicating true-negative results. CONCLUSION: These data confirm that scintigraphy with the radiolabelled somatostatin analogue octreotide is not clinically helpful in detecting metastases from Merkel cell carcinoma. In this relatively small sample the method generated false-positive or false-negative results in five of 11 cases.

Aged↗
PubMed1980

Merkel cell differentiation in the labial mucous epithelium of the rabbit.

To clarify the relation between the so-called 'transitional' cell and the Merkel cell, the frequency of these cells in the labial mucosal epithelium was compared between infant, juvenile and adult rabbits. The transitional cell was observed in serial ultrathin sections. Transitional cells were most numerous in the infant and juvenile, while the definitive Merkel cell showed a reciprocal increase in number. In the infant and juvenile, the transitional cells differed slightly from each other in their ultrastructure: some resembled immature keratinocytes, others resembled definitive Merkel cells. All transitional cells contained the Merkel cell granules and the intranuclear rodlet. It was interpreted that the Merkel cell in the labial mucous epithelium develops from the transitional cell. Neither definitive Merkel cells not transitional cells were identified in the lamina propria. The present circumstantial evidence favours the hypothesis that Merkel cells differentiate from precursors in the basal layer of the epithelium.

Aging↗
PubMed2003

Long-term staining of live Merkel cells with FM dyes.

Live Merkel cells in the skin and hair follicles are known to incorporate a fluorescence dye, quinacrine, which has been utilized to identify and dissect the cells for experiments. Quinacrine fluorescence of the cells is, however, quickly lost and quinacrine-stained Merkel cells soon become difficult to identify in tissue culture. To find dyes that remain in the cells for a long period of time, we tested many fluorescence dyes and found that FM dyes (such as FM1-43) are useful markers for live Merkel cells. In the rat footpad skin, FM1-43 was shown to stain 95% of live Merkel cells that were already stained with quinacrine. FM4-64 stained 98% of quinacrine-stained Merkel cells. Merkel cells in sinus hair follicles were also stained with FM dyes. The fluorescence intensity of FM dyes was stronger than that of quinacrine, and the shape of the cells was more distinct in the FM-dye-stained cells. To test how long FM dyes remain in live cells, FM-dye-stained Merkel cells in hair follicles were embedded in collagen gel and were cultured in a serum-free medium. FM-dye-stained cells were easily identified even after 7 days of culture. During the culture, Merkel cells changed their shape, moved in the preparation and tended to aggregate on the surface. We conclude that FM dyes are powerful tools for tracing live Merkel cells in in vitro experiments. Moreover, the finding that Merkel cells incorporate FM dyes suggests that vesicles in the cells are likely to have mechanisms of recycling in a manner similar to those in neurons and secretory cells.

Animals↗