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Merkel cell carcinoma is an aggressive dermal neoplasm of neuroendocrine origin with a predilection for the head-and-neck region in elderly patients. We present a case of Merkel cell carcinoma of the nasal fossa. Local wide excision was performed.
Localization of leucine aminopeptidase (LAP) in the Merkel cell-axon complex was studied immunohistochemically and cytochemically in the labial tissues of the mouse, rat, dog, and monkey. Anti-LAP was obtained in rabbits by the injection of commercially supplied swine LAP which was confirmed as electrophoretically pure. The Merkel cells of the mouse, rat, and monkey were positively stained by treatment with anti-LAP but the Merkel cells of the dog were negative. When ultrathin sections of the hair follicle from the rat whisker pad, which contain an abundance of Merkel cells, were processed by immuno-peroxidase or by the immuno-gold method, the reaction products were predominantly deposited on the Merkel cells granules. Furthermore, an immuno-blot assay revealed that an extract of the hair follicles from murine whisker pads contained a molecule of relative molecular mass Mr = 60,000 which is similar in size to a subunit of swine LAP. Thus, it appears that Merkel cell granules of rodents and the monkey contain a protein which resembles lucine aminopeptidase.
We examined the clinical and immunohistochemical features of a Merkel (neuroendocrine) cell tumor on the skin between the eyes of a 12-year-old male Yorkshire Terrier dog. The tumor was characterized by locally expansive dermal nodules composed of solid nests or clusters of epithelioid cells surrounded by fine fibrous stroma. Basal cell epithelioma, Merkel cell tumor, and extramedullary plasmacytoma were also considered as diagnoses. Because the cytoplasm of the tumor cells stained positively for cytokeratin and chromogranin A but not for immunoglobulins, the tumor was diagnosed as a Merkel cell tumor. An electron-microscopic study of a tissue specimen revealed electron-dense granules approximately 200 nm in diameter. These granules were irregularly dispersed throughout the cytoplasm of the tumor cells, which would be expected in neuroendocrine cells. Twelve months after resection, a 0.8-cm-diameter tumor recurred at the original site. However, further follow-up of 22 months revealed no evidence of additional tumor growth, invasion, or metastasis, so we concluded that this tumor was benign.
BACKGROUND: The neuroendocrine carcinoma of the skin is a rare malignant neuroendocrine tumor, which frequently metastasizes in regional lymph nodes or visceral organs. As adhesive interactions with endothelia, leukocytes, or thrombocytes enable malignant cells to penetrate the endothelium and to circulate in blood or lymphatic vessels, we here addressed the adhesion molecules CD171 (L1CAM) and CD24, which are known to be expressed by neurons, neuroblastomas, and other malignant tumors. METHODS: Thirty-one neuroendocrine carcinomas of the skin (22 primary tumors, four recurrent tumors, and five metastases) were included in the study. Immunohistochemical staining of CD171 and CD24 was performed by the streptavidin-biotin-peroxidase-complex technique and a nickel-enhanced diaminobenzidine (DAB) reaction using the monoclonal antibodies UJ 127.11 and ML-5, respectively. RESULTS: CD171 expression was detected in most neuroendocrine carcinomas of the skin, and staining was less frequent in metastases and recurrences in comparison with primary tumors which was statistically significant. The majority of neuroendocrine carcinomas of the skin was also positive for the mucin-like adhesion protein CD24. In contrast to tumor cells, cytokeratin 20-positive Merkel cells in 12 trichoblastomas and one fibroepithelioma of Pinkus were all negative for CD171 and CD24 staining. CONCLUSIONS: Expression of CD171 and CD24 is found in most neuroendocrine carcinomas of the skin, which may be used diagnostically. Further studies will assess whether this feature may contribute to metastasis of neuroendocrine carcinomas of the skin by facilitating transendothelial migration or tumor cell dissemination as has been suggested for other malignancies.
The presence of calcitonin gene-related peptide (CGRP) in the skin of pig snout and human fingertip was investigated using immunohistochemical techniques. CGRP immunoreactivity was found in Merkel cells and nerve fibres of both species. In pig snout skin, Merkel cells containing CGRP were seen forming clusters at the tips of rete ridge epidermis and in the external root sheath of sinus hair follicles (vibrissae). Human Merkel cells immunostained for CGRP were found isolated or forming small groups in the basal layer of glandular epidermal ridges. In all cases, immunoreactivity was more intense on the side of the Merkel cell facing the associated nerve terminal (which was never positive for CGRP). This part of the Merkel cell has the greatest density of dense-cored granules, suggesting that CGRP must be stored in these granules. Nerve bundles containing CGRP-immunoreactive fibres were found at dermal and hypodermal level, and blood vessels were often surrounded by CGRP nerve fibres. In pig snout skin some nerve fibres containing CGRP penetrated the epidermis and terminated as free endings, and in the human fingertip a small number of CGRP-immunoreactive nerve fibres were seen in Meissner's corpuscles.
Orexins (OXA and OXB) are peptides derived from a common precursor called prepro-orexin. They act through G-protein receptors named orexin 1 receptor (OX(1)R) and orexin 2 receptor (OX(2)R). Orexins were first demonstrated in neurons of the lateral hypothalamus and found to be related to the control of food intake. However, it has been shown that they are widely distributed in both the nervous system and peripheral tissues, including endocrine organs such as the pituitary and adrenal glands. Merkel cells are neuroendocrine cells situated in the epidermis, tactile hairs and oral mucosa, and act as mechanoreceptors. Up to the present, various neuropeptides have been detected in these cells. The aim of the present study was to detect the presence of prepro-orexin and orexin receptors (OX(1)R and OX(2)R) in porcine Merkel cells using immunohistochemistry. Prepro-orexin was expressed in the cytoplasm of Merkel cells in the skin of the pig snout. Immunoreactivity for prepro-orexin was more intense in the mature side of the cell, where the dense-cored granules are accumulated. Epidermal nerve terminals associated with Merkel cells and dermal nerve fibres showed no immunostaining. Both orexin receptors (OX(1)R and OX(2)R) were also demonstrated in the cytoplasm of Merkel cells of pig snout skin. The finding of orexins and their receptors in Merkel cells suggests that they have an autocrine function. Further studies are needed to ascertain the significance of this function.
In dog skin Merkel cells, calcitonin gene-related peptide (CGRP) immunoreactivity was consistently encountered at the subcellular dense-core granule region. The immunogold particles used as a marker for CGRP, were located specifically in and around the dense-core granules. They were also found in the surrounding cytoplasm close to the dense-core granules. Nerve terminals supplying the Merkel cell were CGRP-negative. CGRP-immunoreactive nonmyelinated nerve fibres were also found in the same specimen. These nonmyelinated nerve fibres were ensheathed by Schwann cell cytoplasm. The gold particles were only located in the dense-core granules of the axis cylinders. It is concluded that a CGRP-like substance predominantly accumulates in the dense-core granules of dog Merkel cells as well as in cutaneous nonmyelinated fibres.
The case histories of four patients with a Merkel-cell tumour of the skin are presented and the findings are compared with other reports in the literature. An association with other skin tumours is noted and ultraviolet light may be implicated in the causation of Merkel-cell tumours. The Merkel-cell tumours in this series occurred initially on the face. The difficulty of diagnosis is stressed. It is recommended that wide excision of the tumour be followed by radiotherapy to the excision site plus a large margin, in an attempt to prevent local recurrences that are brought about by lymphatic permeation.
A 54-year-old woman presented with cardiac metastasis of a Merkel cell carcinoma. Chemotherapy was not effective for the metastasis sites; therefore, radiotherapy was performed for the metastatic cardiac tumors, and it reduced the volume of the cardiac tumors. Cardiac metastasis from Merkel cell carcinoma is rare. Radiotherapy for metastatic cardiac tumors from Merkel cell carcinoma is useful as palliative treatment when the response to chemotherapy is poor.
AIMS: To report and confirm the identity of tumour cells showing leiomyosarcomatous differentiation in a regional lymph node containing metastatic Merkel cell tumour. METHODS AND RESULTS: A 79-year-old woman was found to have metastatic Merkel cell tumour within an axillary lymph node 4 months after excision of the primary tumour from the forearm. The lymph node was effaced by tumour identical to that of the primary tumour but there was an additional focus of loose spindle cells. Immunocytochemical staining showed the coexpression of cytokeratin 20, neurofilament and desmin in these sarcomatous cells. CONCLUSION: This, to the best of our knowledge, is the first report of Merkel cell carcinoma showing sarcomatous differentiation, and adds to the expanding morphological spectrum of malignant biphasic tumours.
This report describes the course of recurrent Merkel cell carcinoma and defines possible treatment strategies for recurrent disease as seen in a long-term multisite retrospective analysis. Merkel cell carcinoma is a highly aggressive neuroendocrine skin cancer. Surgery and radiation therapy have been demonstrated ability to control this disease; however, recurrence is common. Systemic chemotherapy has, as yet, no presently defined role in primary treatment, and few conclusions can be reached regarding optimal treatment of disease recurrence. Forty-six patients were identified over the last 15 years in a retrospective analysis of patient records from several hospitals in the San Antonio, TX area. Hospital charts as well as outpatient treatment records were reviewed. Almost all patients developing recurrent disease did so within the first 2 years after primary treatment. Patients presenting distant disease had a median survival of 12 months, faring worse than those who display local or nodal disease. For patients with nodal or local recurrence, the mean survival after combination therapy (chemotherapy, radiation +/- surgery) was 36.5 months as compared with 17.5 months for those treated with a single modality (surgery or radiation or chemotherapy). The overall survival rate for the 46 patients with recurrence was 37%. Multimodality therapy has shown the best results for recurrent Merkel cell carcinoma thus far, and should be used if tolerated by the patient. Aggressive salvage surgery for local or nodal recurrence is encouraged, because this disease has a tendency to become more destructive upon recurrence. Adjuvant radiation therapy should also be used, if the patient has not exceeded their dose limitations. Disseminated disease, whether primary or recurrent, warrants further investigation in terms of optimal treatment.
The identity of the mechanosensory transducing elements in the vertebrate touch receptors that contain Merkel cell-neurite complexes is unknown. The Merkel cells, however, have long been the favoured candidates. We have now selectively eliminated the Merkel cells from rat touch domes by first loading them with quinacrine, and then irradiating the domes with near-UV light. Mechanical stimulation of these domes revealed a range of mechanosensory function, evaluated qualitatively, that varied from non-responsive to normal. Since irradiation eliminated the quinacrine fluorescence, the status of the Merkel cells was evaluated by EM. In both responsive and unresponsive domes fixed for EM immediately following irradiation, the Merkel cells and associated nerve endings appeared to be normal. After 2 or more days, even in domes that continued to be normally responsive, there was a striking reduction in the normal complement of about 90 Merkel cells, and most of the remaining Merkel cells appeared to be degenerating. However, numerous 'isolated' (Merkel cell-free) nerve endings remained in the basal epidermis. A few of these nerve endings showed signs of damage, but in the non-responsive domes abnormal nerve endings were routinely observed. The EM studies did not exclude the possibility that a few surviving innervated Merkel cells, or even one such, had escaped detection and were responsible for a persisting mechanosensitivity. To resolve this issue a mechanical stimulating technique with a spatial resolution of 55 microns was used to map the mechanosensory profile of a single responsive dome irradiated 2.75 days earlier. This dome was then serially sectioned for EM study. Only seven Merkel cells had survived which appeared to be both viable and innervated, but almost all of the tested sites were normally responsive. When the correlation was made, seven of these sites were located 55-100 microns away from the nearest surviving Merkel cell, four were 110-165 microns away, and three were more than 165 microns away. Even when allowance is made for errors in the positioning of the stimulus, the responses at the last seven sites cannot be attributed to the presence of underlying Merkel cells. We conclude that mechanosensory transduction within touch domes is not a function of the Merkel cells, but must reside in the associated nerve endings.
BACKGROUND: Controversy exists regarding the optimal management of patients with Merkel cell carcinoma. The primary aim of this study was to determine whether combined treatment with surgery and radiotherapy improves outcome in a multi-institutional cohort of patients with Merkel cell carcinoma of the head and neck. The secondary aims were to determine by stage, which patients derive benefit from combined therapy and to identify predictors for survival on multivariable analysis. METHODS: A retrospective analysis of 110 patients with Merkel cell carcinoma of the head and neck was performed. Data were collected from 3 tertiary care institutions (Westmead Hospital, Sydney, Australia; Princess Margaret Hospital, Toronto, Canada; Royal Prince Alfred Hospital, Sydney). There were 78 males and 32 females, median age was 70 years, and mean follow-up of survivors was 2.3 years. Sixty-six patients underwent combined treatment, and 44 patients had either surgery or radiotherapy alone. Analysis by stage was performed using 2 staging systems. RESULTS: Local and regional control at 5 years was 84% and 69%, respectively. Combined treatment improved both local (p = .009) and regional control (p = .006). Overall and disease-specific survival at 5 years was 49% and 62%, respectively. Combined treatment was associated with significantly better disease-free survival on univariable analysis (p = .013) When analyzed by stage, patients with stage IIb (primary >1 cm, node negative) disease who underwent combined treatment had improved disease-free (p = .005) and disease-specific survival (p = .035). Predictors of survival on multivariable analysis were age >70 years (HR 6.19, p < .001), primary tumor size >1 cm (HR 7.55, p < .001), number of nodal metastases divided into none, 2 (HR 3.71 per stratum, p < .001). When analyzed with age and disease stage, treatment modality trended toward significance as a predictor of disease-specific (p = .081) and overall survival (p = .076). Disease stage was the most powerful independent predictor on Cox regression (HR 5.43 per stratum, p < .001). CONCLUSIONS: Merkel cell carcinoma is an aggressive cutaneous malignancy. Age and disease stage are the most important predictors of survival. Combined surgery and radiotherapy improves both locoregional control and disease-free survival. Patients with stage II disease appear to derive the greatest benefit from adjuvant radiotherapy, including improved disease specific survival.
OBJECTIVE: To investigate whether there is a difference in the density of Merkel cells between the gingiva of dentate and edentate subjects. METHODS: One hundred and two blocks of human mandibular (n=55) and maxillary (n=47) gingiva from 69 white skinned individuals (44 males, 25 females, mean age 70.1 years, range 42--92 years) were analysed. Twenty-six individuals had teeth remaining in at least one jaw (mean age of dentate 64.5 years, edentate 72.1 years), of which 15 were dentate in both jaws. Overall, 24/55 mandibles and 17/47 maxillae were dentate. Five micrometer sections were stained with a monoclonal antibody to cytokeratin 20 (CK 20) using standard immunoperoxidase or immunoalkaline phosphatase methods. Positive cells were counted in 20 consecutive high power fields using the x 40 objective in three sections from each biopsy, and the results analysed for differences related to age, sex, site and presence of teeth. RESULTS: CK 20-positive Merkel cells were present either singly or in clusters in the basal epithelial layers, particularly at the tips of rete ridges. Numbers of gingival Merkel cells were significantly higher (p<0.005, Mann-Whitney) in edentate (cells per field mean, median, standard deviation, respectively: 1.39, 0.64, and 1.85) when compared to dentate (0.67, 0.20, and 1.21) specimens. The differences were not statistically significant for any other variable. CONCLUSION: The data raise the possibility that reduced perception following loss of teeth may be compensated for by an increase in the local Merkel cell population.
BACKGROUND: In vitiligo, other than loss of melanocytes and melanin pigment in the lesional skin, keratinocytes are also involved. Human fetal Merkel cells are now generally considered to be derived from the epidermis. To date, no observations on Merkel cells in lesional skin of active vitiligo have been reported. METHODS: Merkel cells were identified by indirect immunofluorescence microscopy using the monoclonal antibody TROMA 1. RESULTS: No TROMA 1-positive cells were observed in the vitiliginous skin lesions in any of the specimens examined, whereas normal numbers of these cells were seen in the adjacent pigmented skin. CONCLUSIONS: This finding suggests that the processes that lead to damage of keratinocytes in vitiligo also involve other keratin-expressing cells such as the Merkel cells.
The recommended management of localised Merkel cell carcinoma has been wide surgical excision, combined with adjuvant radiotherapy in selected cases. The risk of recurrent regional disease is reported to be between 30% and 45%. A patient with a Merkel cell tumour on the cheek is presented in this paper. The patient was treated exclusively with radiotherapy to a total dose of 40 Gy. The tumour regressed rapidly during the treatment and there were no signs of local recurrence. However, the patient died of metastatic disease 31 months after initial diagnosis. A review of the literature revealed an additional eight cases of localized disease who did not undergo complete surgical excision but were primarily treated with radiotherapy alone. Regional recurrence was not found in any of the cases. One of the patients died of metastatic disease. Together with the review of the literature the present case provides evidence of the radiosensitivity of the Merkel cell carcinoma of the skin. The available data suggest that radiotherapy may be valuable as the primary treatment of localized biopsy-verified disease.
BACKGROUND: Primitive cutaneous neuroendocrine carcinoma or Merkel cell carcinoma is a rare tumor. It may be large since diagnosis is frequently delayed. The usual treatment is extensive surgical removal and radiotherapy. PATIENTS AND METHODS: A 69-year-old woman presented with a large Merkel cell carcinoma of the right leg. MRI showed a tumor invading the deep layers together with several satellite lesions. There was no regional nodal or visceral metastasis. Regional chemotherapy involving isolated limb perfusion with melphalan was performed in order to avoid amputation. Complete response was achieved a few months later and continues 5 and a half years later with minor sequelae comprising cutaneous sclerosis, pigmentation and mild ankle stiffness. DISCUSSION: Only five cases of Merkel cell carcinoma treated with isolated limb perfusion are reported in the literature: four of these involved local relapse and one was a primary tumor with regional lymph node involvement. Only one patient was still in complete remission 18 months after treatment. Isolated limb perfusion chemotherapy could thus be indicated in the treatment of advanced Merkel cell carcinoma of a limb in the absence of bone or regional lymph node involvement.
Numerous Merkel cells are situated among the epithelial cells of the hair follicle of sinus hairs. Many of them are in contact with sensitive nerve terminals and differ from the epithelial cells by the presence in the cytoplasm of specific granules concentrated in the region of contact with nerve terminals. In the connective tissue of sinus hairs of 8-9 weeks old embryos and newborn kittens there were found the cells surrounded by the basal membrane and differing from the Schwann's cells of palisade system and flesh nerve fibers. These extraepithelial cells have common structural features with the Merkel cells situated in the epithelium and are the most probable candidates for the role of their precursors.