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Postnatal loss of Merkel cells, but not of slowly adapting mechanoreceptors in mice lacking the neurotrophin receptor p75.

Merkel cells are specialized epidermal cells which are abundantly found in touch-sensitive areas and which are innervated by slowly adapting mechanosensitive afferent fibres with large myelinated (Abeta) axons. The role of Merkel cells in mechanosensation, their developmental regulation and their influence on sensory neuron function are, however, incompletely understood. Here, we used mice lacking the neurotrophin receptor p75 which is expressed on Merkel cells to investigate their postnatal development and that of their innervating sensory neurons. Using morphological studies we now show that Merkel cells develop normally in both hairy and glabrous skin in these animals until 2 weeks old, but are progressively lost thereafter and have almost completely disappeared 2 months after birth. Using standard extracellular electrophysiological recording techniques we find that despite the profound loss of Merkel cells there is no corresponding reduction in the number of myelinated slowly adapting afferent fibres. Moreover, the mean mechanical threshold of these neurons and their average stimulus response function to suprathreshold mechanical stimuli does not change during the time period when more than 99% of Merkel cells are lost. We conclude that Merkel cells require p75 during the late postnatal development. However, neither the survival nor the mechanical sensitivity of slowly adapting mechanoreceptive Abeta-fibres depends on the presence of Merkel cells.

Action Potentials↗

Merkel cell carcinoma metastatic to the head of the pancreas.

CONTEXT: Merkel cell carcinoma is an aggressive cutaneous tumor without clearly defined treatment and high propensity for metastasis. CASE REPORT: This case describes a sixty four year old presenting with obstructive jaundice approximately two years after having a Merkel cell carcinoma resected from his finger. He underwent a successful pancreaticoduodenectomy with pathology confirming metastatic Merkel cell carcinoma. This report reviews the history, presentation, and current treatment recommendations for Merkel cell carcinoma. CONCLUSIONS: We propose that resection of metastases from Merkel cell carcinoma may confer a survival advantage and should be strongly considered, particularly if isolated.

Carcinoma, Merkel Cell↗

Neuroendocrine (Merkel cell) carcinoma of the skin.

Merkel cell carcinoma was diagnosed in 10 patients (eight females and two males) with a mean age of 66 years and a range of 44-84. The most common sites of the primary tumor were the skin of the limbs, girdles, and head. Sixty percent of the cases had recurrences and 50% regional nodal metastases that appeared within 1 year. Of the patients treated variably with surgery, chemotherapy, and radiotherapy and followed for a mean period of 28 months, two were alive and free of disease, two were alive with disease after 3 and 6 years, and two have died of metastatic disease to the lungs and liver. The primary lesions showed quite distinctive clinical and gross features in terms of size, shape, and color. Histologically, the growth was usually diffuse and occasionally trabecular or pseudoglandular; infiltration was predominantly in the papillary and reticular dermis. The uniform, poorly cohesive cells contained argyrophilic granules in the cytoplasm and round to oval nuclei with frequently indented membranes. The mitotic index was high. Ultrastructurally, in two cases, two cell types were identified that probably represented the neoplastic counterpart of normal Merkel cells in different stages of maturation. Both cell types contained cytoplasmic neurosecretory granules and intermediate filaments, even though their cytoplasms were differently shaped.

Adenocarcinoma↗

Localization of serotonin-like immunoreactivity in the Merkel cells of pig snout skin.

The presence of serotonin in the Merkel cells of pig snout epidermis was investigated by the peroxidase-antiperoxidase immunohistochemical technique. Serotonin-like immunoreactive Merkel cells were found in groups located at the base of epidermal rete pegs and in the external root sheath of sinus hair follicles (vibrissae). Immunoreactivity was stronger on the basal side of the Merkel cells, where dense-cored granules are most numerous. Neither the nerve terminal associated with the Merkel cell nor the neighbouring epidermal cells were immunostained. These results are the first evidence of serotonin-like immunoreactivity in mammalian Merkel cells. The fact that immunoreactivity is strongest in those parts of the Merkel cells with the highest granule density suggests that in these cells serotonin is probably localized in the dense-cored granules.

Animals↗

Merkel cell carcinoma of the eyelid and periocular tissues.

Five patients had eyelid and periocular Merkel cell carcinoma. The tumor was located on the left lower eyelid in two patients, the left upper eyelid in one patient, the right upper eyelid in one patient, and was metastatic to the right outer canthus in one patient. The mean duration of symptoms was approximately four months. The diagnosis of Merkel cell carcinoma was not suspected clinically in any of the four primary eyelid cases, but was only established on histopathologic examination of biopsy specimens. Light microscopy disclosed carcinoma with small primitive cells in all five tumor biopsy specimens. Immunohistochemical studies showed neuron-specific enolase and keratin and transmission electron microscopy demonstrated neurosecretory granules typical for Merkel cell carcinoma. All five patients in this study were treated with wide surgical excision of the eyelid tumors with intraoperative frozen-section monitoring of the margins of resection. The left lower eyelid Merkel cell carcinoma spread to the preauricular lymph node in one patient. This patient subsequently died of metastatic Merkel cell carcinoma. One patient with metastatic right outer canthus Merkel cell carcinoma received radiotherapy (6,550 cGy). Eyelid Merkel cell carcinoma has the potential for recurrence and metastatic spread. We recommend lifetime follow-up for patients treated for eyelid Merkel cell carcinoma.

Aged↗

The appearance, density, and distribution of Merkel cells in human embryonic and fetal skin: their relation to sweat gland and hair follicle development.

The density and distribution of Merkel cells in human embryonic and fetal skin were studied using an immunolabeling technique on epidermal and dermal sheets obtained by ethylenediamine tetraacetic acid separation. Merkel cells were identified by the known cytokeratin markers CK20 and CK18. Merkel cells showed CK20 immunoreactivity as early as 56 d estimated gestational age (EGA) in the palmar epidermis (133.11 +/- 44.27 cells/mm2). The density increased rapidly, reaching a maximum of more than 1400 cells/mm2 at 80-90 d EGA. At this stage, the cells became distributed along the primary epidermal ridges. In the palmar epidermis of fetuses older than 100 d EGA, the distribution of Merkel cells showed the same pattern, but the density then decreased gradually. Merkel cells were not observed in ductal and glandular portions of eccrine sweat glands. In the epidermal sheets of hairy skin, a few cells were first seen in the fetus at 75 d EGA. At 100 d EGA, only a few Merkel cells were observed, mostly in the hair pegs and bulbous hair pegs. In the older fetus, ring-like arrangements and aggregates of Merkel cells were prominent in the infundibulum and bulge of hair follicles, respectively. Merkel cells were both globular and dendritic in shape. The ratio of dendritic to globular cells increased gradually until the period of highest Merkel cell density in both the glabrous and hairy skin. All Merkel cells located in the dermis were globular in shape. In accord with the results obtained, we postulate that Merkel cells may have some functional role in the formation and proliferation of eccrine sweat glands and hair follicle anlagen in developing skin.

Epidermal Cells↗

[The Merkel cell: morphology, developmental origin, function].

Merkel nerve endings are mechanoreceptors in the vertebrate skin. They were named after the person who first described them--F.S. Merkel (1875). They consist of large, pale cells with lobulated nuclei forming synapse-like contacts with enlarged terminal endings of myelinated nerve fibres. Inside the cell are intermediate filaments formed of simple cytokeratins and osmophilic granules containing variety of neuropeptides. In mammals, they can be found in the basal layer of the skin and in those parts of the mucosa, which is derived from ectoderm. In contrast, in birds these cells are located in the dermis. The largest accumulation of Merkel nerve endings was found in whiskers of most mammals apart from man. There has been a controversy concerning the origin of Merkel cells. Results from chick/quail chimeras and most recently also from double transgenic mice have shown that Merkel cells are derived from the neural crest. Merkel cell play a role in the mechano-transduction process. In response to mechanical stimuli calcium ions enter Merkel cell and trigger the release of neurotransmitter probably glutamate. Thus, Merkel cell appears to be essential for characteristic slowly adapting response of these receptors during maintained mechanical stimuli. Cells in the skin of a similar appearance as Merkel cells are probably part of the diffuse neuroendocrine system and they do not function as mechanoreceptors. These cells, rather than those in mechanoreceptors, are most likely the origin of the highly malignant skin cancer called Merkel cell carcinoma.

Animals↗

Merkel cells in ontogenesis of human nails.

Digital skin of human fetuses is known to contain a particularly high concentration of Merkel cells. Using antibodies against the simple epithelial cytokeratins (CK) 18 and 20, which are sensitive and specific Merkel cell markers, we studied immunohistochemically the main adnexal structure of digital skin, the nail anlage, in human fetuses (9-22 weeks of gestation) for the presence of Merkel cells. As early as week 9 some clustered Merkel cells were detected in the early matrix primordium. In specimens of week 12-15, abundant Merkel cells were found in the nail anlagen, particularly in the epithelium of the proximal nail-fold and the dorsal and ventral side of the apex region. In contrast, Merkel cells were essentially absent from the epithelium of the ventral matrix (surface-near portion), lunula and nail bed. Correspondingly, in these region, the adjacent dermis contained hardly any nerve fibres, whereas such fibres, as detected by neurofilament antibodies, were quite numerous adjacent to the proximal nail-fold epithelium. At week 22, the Merkel cell number in the nail anlage had decreased, and in adult nail matrix such cells were very rare. No Merkel cells were found in the dermal tissue surrounding the nail anlage while finger-tip skin of week 15, and particularly of week 22, exhibited single Merkel cells in the upper dermis next to clusters of such cells in the glandular ridges. We also found that Merkel cells were negative for CK 17.(ABSTRACT TRUNCATED AT 250 WORDS)

Gestational Age↗

[Cutaneous Merkel cell carcinoma: case report].

Merkel cell carcinoma is an unusual cutaneous malignancy with a propensity for spreading to regional lymph nodes, with recurrence at original site or/and in lymph node. Occurring most often on the head and neck of the elderly patients. Complete surgical resection is the mainstay of treatment of the primary tumor. A case is here described of an old patient with more than one local relapse and in regional lymph nodes too, complete surgical resected, actually in good state of health, treated with radiotherapy.

Aged↗

Metastatic Merkel cell tumor to the prostate and bladder.

Merkel cell carcinoma is an uncommon cutaneous neoplasm of neuroendocrine origin. We report the case of a 71-year-old man with Merkel cell carcinoma metastases to the prostate and bladder presenting with lower urinary tract obstruction. Efforts should be made to optimize the patient's quality of life with the finding of metastatic Merkel cell carcinoma to the bladder or prostate until better adjuvant therapies are identified.

Aged↗

Another case of spontaneous regression of Merkel cell (neuroendocrine) carcinoma.

BACKGROUND: Merkel cell (neuroendocrine) 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 this journal in 1986. Since then, other such cases have been reported. This case represents the sixth case of spontaneous regression of MCC. OBJECTIVE: To describe to clinical course in a patient with MCC who underwent spontaneous regression of metastatic disease. METHODS: Clinical records including detailed history and frequent follow-up examination made this observation possible. RESULTS: Complete clinically evident regression of metastatic MCC was observed in this case. However, the patient received no treatment known to be effective for MCC. CONCLUSIONS: Spontaneous regression of MCC has been documented. The reason for regression is unknown. Further study of these rare cases may in the future provide more answers than questions.

Aged↗

Merkel-cell carcinoma of the skin.

Merkel-cell carcinoma (MCC) is a rare form of skin cancer of neuroendocrine origin that has been described as the most aggressive cutaneous malignancy. The cell of origin is thought to be the Merkel cell or skin-pressure receptor. It has the propensity for dermal-lymphatic invasion, and nodal and haematogenous spread. Factors that have been implicated in its cause include exposure to sunlight and immunosuppression. The tumour has many similarities to small-cell carcinoma of the lung, with intrinsic sensitivity to ionising radiation and chemotherapy, and an aggressive metastatic potential. The best treatment outcomes can be achieved with early diagnosis and the integration of surgery, radiation, and chemotherapy. The treatment challenges for the clinician are often enormous because many of the patients are elderly and because lesions occur in difficult sites such as the head and neck region and the lower leg.

Carcinoma, Merkel Cell↗

Development of neuroendocrine (Merkel cell) carcinoma mixed with squamous cell carcinoma in erythema ab igne.

Squamous cell carcinoma and neuroendocrine (Merkel cell) carcinoma are cutaneous neoplasms that have only occasionally been reported to coexist. Squamous cell carcinoma, but not neuroendocrine (Merkel cell) carcinoma, is a rare complication of erythema ab igne. This report describes the development of both neoplasms arising within the same tumor mass in an area of erythema ab igne.

Aged↗

Reinnervation of the rat touch dome restores the Merkel cell population reduced after denervation.

By using the fluorescent dye quinacrine as a marker for the Merkel cells in the rat touch dome, we previously showed that a sustained denervation of the dome causes a rapid and persistent loss of about 60% of its Merkel cells [Nurse, Macintyre and Diamond (1984) Neuroscience 11, 521-533]. We now show that if the sensory nerves to the skin are crushed (or cut) in 2-week old pups and allowed to regenerate, the Merkel cell population within touch domes shows a biphasic response; there is an initial loss of Merkel cells associated with the early phase of denervation, followed by an increase, associated with the phase of reinnervation. Physiological tests revealed that many (though not all) domes within initially deafferented skin had become functionally reinnervated and had their Merkel cell numbers either wholly or partially restored some 40-100 days post operatively. In one case an adult reinnervated dome, that appeared normal physiologically and by its complement of quinacrine fluorescent (Merkel) cells, also had normal histological features in toluidine blue sections and normally innervated Merkel cells in the electron microscope. These results, based on the use of quinacrine to visualize the Merkel cell population in the touch dome, suggest that sensory nerves may induce the differentiation of new Merkel cells in domes where these cells have become reduced after denervation.

Animals↗

Biological significance of dermal Merkel cells in development of cutaneous nerves in human fetal skin.

We detected epidermal Merkel cells in 12-week fetuses with monoclonal antibodies (MAb) against simple epithelium keratin and epithelial membrane antigen. In 15-week fetuses these Merkel cells began to descend into the dermis and expressed nerve growth factor receptors (NGF-R). At approximately the same time, cutaneous nerves, as detected with an MAb against neurofilaments, extended from the subcutaneous trunk and branched to form the subepidermal nerve plexus. The expression of NGF-R on dermal Merkel cells preceded their connection with immunoreactive small nerves. Initially, most of these fine nerve endings were directed towards dermal Merkel cells. In 23-week fetuses the subepidermal nerve plexus was well developed and immunoreactive dermal Merkel cells began to disappear. At all stage of fetal development the epidermal Merkel cells did not strongly express NGF-R. We postulate that dermal Merkel cells play an inductive and a promotional role in development of the cutaneous nerve plexus in the upper dermis.

Embryonic Induction↗

An experimental study of the influence of sensory nerve fibers on Merkel cell differentiation in the labial mucosa of the rabbits.

The influence of the sensory nerve fibers on the differentiation of the Merkel cell was examined in the denervated labial mucosa of adult rabbits. Part of the lower labial mucosa was excised following mental nerve resection. Twenty-one and 50 days later, the regenerated mucosa was examined by electron microscopy with special reference to the distribution and maturation of Merkel cells, and compared with the normal and the denervated intact mucosa. A number of immature Merkel cells appeared in the denervated and regenerated epithelium by 21st day after the operation. The distribution density of the Merkel cells in a unit area of the mucosa did not change much but the percentage of the mature Merkel cells increased significantly until 50 days after the operation. The mature Merkel cells in the denervated and regenerated mucosa showed a normal ultrastructure, though their orientation and location were not uniform, shifting more superficially than the cells in the normal mucosa. In the controlateral intact epithelium of the denervated labial mucosa, no substantial decrease in the population density of Merkel cells was recognized, though the desquamation of Merkel cells was observed. It was conspicuous that the percentage of immature Merkel cells to the total number of the Merkel cells was significantly increased after the denervation in the intact labial mucosa. This study suggests that Merkel cells differentiate independently of sensory nerve fibers, but the latter are requisite to maintain the former in a uniform, basal disposition in the epithelium.

Animals↗

[Merkel cell carcinoma: a diagnostic and therapeutic challenge].

Merkel cell carcinoma (cutaneous neuroendocrine carcinoma) is a highly malignant, neuroendocrine skin tumor. It mostly occurs in elderly patients in the sun-exposed skin of the head and neck and the extremities. Merkel cell carcinomas develop as fast-growing dermal tumors. They are characterized by a high frequency of lymph-node metastases (50%) and local recurrences (25-77%). The 5-year survival rate is 30-74%. Histology reveals uniform, round cells with a small cytoplasmic rim expressing cytokeratin 20, neurofilament, synaptophysin, chromogranin, and neuron-specific enolase. Ultrastructurally, 100-200 nm electron dense granules are typical findings. Wide surgical excision, followed by radiotherapy, is the treatment of choice. Regional lymph-node metastases should be treated by radical lymph-node excision and radiotherapy. In advanced metastatic Merkel cell carcinoma, a remission can be achieved by different chemotherapy schedules or the somatostatin analogue octreotide. However, the prognosis remains poor. The current knowledge about this disease and guidelines for effective diagnosis and treatment are given.

Biomarkers, Tumor↗

Merkel cell carcinoma with bone metastasis: a case report.

A case of Merkel cell carcinoma with bone metastasis is described. The patient, who had a history of Merkel cell carcinoma of the skin in the right cheek, had spontaneous pain in the right thigh. At the initial visit, the right hip range of motion was slightly limited, but there was no gait disturbance or abnormality in the radiographs of the right hip. However, the pain gradually increased and caused gait disturbance. The patient underwent surgical treatment. A bipolar type of femoral prosthesis was implanted into the femur, and sampling of cancellous bone was performed at the time of osteotomy. Pathological examination showed the findings of Merkel cell carcinoma. Merkel cell carcinoma is a rare malignant tumor of the skin, which usually occurs on the head, neck, or extremities and metastasizes to the lymph nodes. Although osseous involvement often occurs in the adjacent facial bones through direct invasion, distant osseous metastasis appears to be extremely rare.

Aged↗