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The Merkel Cell
Carcinoma. El Carcinoma de Merkel.
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EDITORIAL ENGLISH:
These 51
bibliographical references detail us well these queries. ==================================================================== AB - BACKGROUND. Merkel cell carcinoma is an uncommon malignancy of the skin that often portends a poor prognosis. Since its first description by Toker in 1972, a plethora of case reports and articles regarding the etiopathogenesis and treatment have been published spanning multiple medical and surgical disciplines. Much confusion still exists regarding the diagnosis and treatment of this ominous tumor. OBJECT. Through extensive review of the medical, surgical, and pathological literature, to collate the observations of multiple investigators and summarize these findings. METHODS. Articles from journals of multiple subspecialties were carefully with particular emphasis placed on epidemiology, prognosis, histology, immunohistochemistry, electron microscopy, tumor origin, treatment, and work-up of Merkel cell carcinoma. RESULTS. Merkel cell carcinoma is an aggressive malignant neoplasm. Local recurrence develops in -44% of patients despite therapy. Up to three-fourths of patients eventually develop regional nodal metastases with distant metastases occurring in one-third of all patients. Reported overall 5-year survival rates range from 30% to 64%. CONCLUSION. Treatment recommendations
unfortunately are based more on anecdotal than scientific data because of
the rarity of the tumor and its recognized high risk. Most authors
recommend wide local excision of the primary lesion and regional lymph node
resection if lymph nodes are palpable followed by x-irradiation of both the
postsurgical bed and lymph node basin. The role of elective lymph node
resection in the absence of clinically positive nodes remains controversial.
AB - Since its original description in 1972, we have seen and personally
treated a group of 15 patients with Merkel cell carcinoma at the Vanderbilt
Medical Center and the Nashville VA Hospital. We will review the
demographics, management, and clinical course of this extremely lethal but
initially benign appearing cutaneous malignancy. The majority of lesions
occur on the head and neck, followed by the extremities and trunk. Location
of the primary tumor has no effect on outcome. Despite a high mortality in
our series (10 of 15), early recognition and aggressive surgical therapy
may be the only way to prolong survival. No other adjuvant therapy has
proved effective. AB - BACKGROUND. Merkel cell carcinoma (MCC) is a cutaneous neoplasm, histopathologically difficult to differentiate from other small blue cell neoplasms. Immunohistochemical and ultrastructural analyses are usually helpful in differentiating these neoplasms. Recently, cytogenetic analysis has emerged as a potential tool in the diagnosis of solid neoplasms, including MCC. OBJECTIVE. To describe the immunohistochemical and cytogenetic features of a case of primary MCC and to review the cytogenetics literature on MCC. METHODS. Formalin-fixed tissue was processed routinely and labeled with a battery of antibodies. Metaphase cells from fresh tissue were prepared by Giemsa banding. RESULTS. Histopathologically, there were irregular aggregates of pyknotic cells with little cytoplasm. Immunohistochemically, the neoplastic cells stained positive for neurofilament, cytokeratin, neuron-specific enolase, and epithelial membrane antigen. Leucocyte common antigen, S-100, 013, and chromogranin were negative. Karyotyping of neoplastic cells showed loss of chromosome Y (-Y). CONCLUSIONS. Coexpression of cytokeratin and
neurofilament is characteristic of MCC and allows it to be differentiated
from similar neoplasms. The significance of Y chromosome loss is unclear.
Further cytogenetic analyses are warranted to identify genetic mutations
significant to the pathogenesis of MCC. AB - BACKGROUND. Merkel's cell carcinoma rarely arises in the vulva. It is unclear whether those cases arising in the vulva behave differently from the usual Merkel's cell carcinomas. METHODS. A Merkel's cell carcinoma of the vulva was studied by light microscopy, immunohistochemistry, and electron microscopy. The clinical data of this case and of other reported cases are summarized and compared with those of Merkel's cell carcinoma in general. RESULTS. This tumor showed the characteristic trabecular pattern of Merkel's cell carcinoma. The tumor cells were immunoreactive to low-molecular-weight cytokeratin and neuron-specific enolase. This patient was treated initially with local excision. She died 17 months later with progressive metastatic disease unresponsive to chemotherapy. This case study and the review of six other cases indicate that Merkel's cell carcinoma of the vulva is universally metastatic, both to the regional lymph nodes and distant sites, and that it invariably follows a rapidly fatal course. CONCLUSION. Merkel's cell carcinoma of the vulva appears to have a biologic behavior more aggressive than that of Merkel's cell carcinoma in general. An initial modality combining chemotherapy, with or without irradiation, with aggressive surgery should be tried in future cases. ======================================================================= AB - We retrospectively studied 25 cases of cutaneous primary, locally
recurrent or metastatic Merkel cell carcinoma to see if expression of the
cell surface marker CD44 correlated with metastatic potential. In 3 of 6
cases in which metastasis was documented, CD44 was found on membranes of
tumor cells. Three cutaneous lesions associated with local metastasis did
not express CD44. Three primary tumors expressed CD44 but had not
disseminated at the time of this report; follow-up after excision of the
primary lesion in these cases was less than 6 months. None of the primary
or locally recurrent Merkel cell carcinomas followed longer than 6 months
(14 of 19 cases) expressed CD44. We conclude that expression of CD44 in
Merkel cell carcinoma may eventually be of some value in the assessment of
prognosis of cutaneous Merkel cell carcinoma. AB - We present 11 cases of primary neuroendocrine (Merkel cell) carcinoma of the skin with an intraepidermal component that were identified in a larger review of Merkel cell carcinomas. Among these is a case with a follow-up of over 11 years in which the primary lesion appeared as bowenoid dysplasia, with subsequent recurrences as intraepidermal Merkel cell carcinoma with focal tubular differentiation, and then with dermal invasion and lymph node metastasis. In addition to immunohistochemical markers commonly used in the identification of Merkel cell carcinomas (neuron-specific enolase and cytokeratin), these tumors stained with Ber-EP4, an immunohistochemical marker used to identify carcinomas. We believe that these histopathologic and immunohistochemical features further confirm that Merkel cell carcinomas represent an epithelial tumor with the potential for neuroendocrine and adnexal differentiation. ======================================================================= AB - BACKGROUND. The optimal management of Merkel cell carcinoma has not been clearly defined. OBJECTIVE. To describe the treatment of eight patients who presented with Merkel cell carcinoma. METHODS. Eight patients with advanced locoregional Merkel cell carcinoma were seen in our institute over a 7-year period. Four patients were successfully treated by induction chemotherapy after excisional biopsy, followed by radiotherapy. Three patients died from widespread metastases and one from neutropenic sepsis induced by chemotherapy. RESULTS. These cases demonstrate the potential lethality and aggressive nature of this rare skin tumor despite its chemosensitive and radioresponsive character. In all four patients who are alive and disease-free, chemotherapy was given first and radiotherapy was given as consolidation. CONCLUSION. We suggest that a multimodality
treatment approach--chemotherapy followed by radiotherapy--is indicated in
patients with advanced Merkel cell carcinoma.
AB - Merkel cell carcinoma (MCC) of the skin is an uncommon, but highly
aggressive neoplasm with a marked propensity for local and distant
metastasis. Despite the fact that more than half of the 600 cases of MCC
reported in the literature involved primary sites in the head and neck, MCC
has rarely been discussed in otolaryngology publications. We present five
new cases of MCC of the head and neck and summarize 89 additional cases
from the literature in which detailed treatment and survival data were
given. Our findings again emphasize the difficulty in making the initial
histopathologic diagnosis of MCC and demonstrate the necessity of early
diagnosis and multimodality treatment. AB - We report a cytogenetic study of six Merkel cell carcinomas (MCC) in which rearrangement of chromosome 1 was noted in four cases: two cases were trisomic, in one case there was a reciprocal translocation between chromosomes 1 and 5 [t(1; 5)(p36; p13)], and in the fourth case all cells had a normal chromosome 1 and three derivatives, a del(1)(p22) and del(1)(q21), and a translocation involving material of unknown origin to the long arm, t(1; ?)(q21; ?). Four cases demonstrated loss of chromosome 13; in two of these, both copies were lost, and the survival for these two patients was much longer than is common for MCC patients. Partial trisomy
of chromosome 11 was noted in two cases, and two patients demonstrated loss
of chromosome 22 in all cells examined. Although no consistent chromosome
change was noted in our cases, our data and those of previously published
reports, show that abnormalities of chromosomes 1, 11, and 13 occur in
30-47% of cytogenetic reports of this rare malignancy. AB - Merkel cell carcinoma is a rare cutaneous neuroendocrine tumor that occurs predominantly in the head and neck region of older patients. An 88-year-old white man had an erythematous, umbilicated tumor on his lower lip, which on histopathologic examination showed solid sheets of infiltrating basaloid round cells with a high mitotic index. Globular, paranuclear immunostaining for low-molecular-weight cytokeratins (Nos. 8, 18, and 19) and neurofilament was observed. On ultrastructural examination, the tumor cells demonstrated paranuclear whorls of intermediate filament aggregates and occasional electron-dense granules. This unique cytokeratin- and neurofilament-staining pattern with coexpression enabled the Merkel cell carcinoma to be differentiated from other small cell malignant tumors that included metastatic neuroendocrine carcinomas from other regions. The follow-up 1 year after surgery and radiation showed that the patient remained disease free. Review of the literature revealed 11 cases of oral Merkel cell carcinomas with a predilection for the labial mucosa of older men. The mode of treatment and the clinical course of these cases are also presented, with an update on therapeutic management of Merkel cell carcinomas. ====================================================================== AB - We report eight cases of neuroendocrine carcinomas found within
inguinal (five cases), axillary (two cases), and submandibular (one case)
lymph nodes. The patients underwent extensive investigations, but no
primary tumor was found in any case. Although the existence of an occult or
regressed primary cannot be ruled out, the possibility of a lymph node
origin should be considered on the basis of epithelial inclusions or
anomalous carcinomatous differentiation of stem cells of the
lymphoreticular system. AB - Pagetoid intraepidermal spread of neoplastic cells was noted in six cases of Merkel (primary neuroendocrine) cell carcinoma of the skin. In two cases, the volume of the intraepidermal portion of the neoplasm was either equal to or more extensive than the dermal component. The intraepidermal component in all six cases was remarkable because of the following findings: the presence of cells with scant cytoplasm arranged both individually and as nests, sometimes along the dermoepidermal junction; splaying of the apical portions of basal keratinocytes by solitary neoplastic cells; incomplete rims of compressed basal keratinocytes at the peripheries of some junctional nests; and occasional contiguity of neuroendocrine carcinoma cells with those of Bowen's disease or solar keratosis. These features can be used to distinguish these Merkel cell carcinomas from other lesions that have a pagetoid pattern, even in superficial biopsies, and immunohistochemistry can confirm the diagnosis or resolve problematic cases. The occurrence of cutaneous neuroendocrine carcinoma situated largely in the epidermis raises the possibility that some of these tumors may arise from intraepidermal Merkel cells. ====================================================================== AB - A case of multiple hamartoma syndrome (Cowden's disease) associated with renal cell adenocarcinoma and primary neuroendocrine carcinoma of the skin is described. Neither of these neoplasms has been documented previously in association with this genodermatosis. A search for epidermal growth factor receptor (c-erb-B protooncogene) gene abnormalities in the kidney, liver, and thyroid, as well as in tissue of the primary neuroendocrine carcinoma, was negative. Serum obtained from the patient before his death contained elevated levels of both chromogranin A (2641 ng/mL; normal level, less than 20 ng/mL) and calcitonin (517 pg/mL; normal level, less than 200 pg/mL), suggesting that the patient's principal tumor was neuroendocrine in origin. ====================================================================== AB - Seventy patients with Merkel cell carcinoma were treated at Memorial Sloan-kettering Cancer Center between 1969 and 1989. The overall estimated 5-year survival rate was 64%. Factors predictive of improved survival included head and neck site and negative lymph nodes at presentation. Local recurrence was seen in 18 patients (26%) and did not correlate with patient-, tumor-, or treatment-related variables. Nine patients with local recurrence (50%) were free of disease following aggressive reoperation. Regional nodes were involved at some point during the course of the disease
in forty-six patients (66%). Regional lymph node involvement was apparent
within 2 years of diagnosis in 40 (87%) of 46 patients in whom it occurred.
Systemic disease was nearly uniformly preceded by the appearance of nodal
metastases and was uniformly fatal regardless of subsequent therapy. This
suggests an orderly "cascade" pattern of spread for this tumor, in which
elective regional lymph node dissection may be justified. Our
recommendations for treatment include a wide excision of the primary tumor
and either elective or early therapeutic regional node dissection. The role
of adjuvant radiotherapy or chemotherapy remains unproven.
These patients represent the first reported use of hyperthermia in the
management of MCT. The encouraging local responses described suggest a
potential role for the use of hyperthermia and concomitant radiation
therapy in the treatment of recurrent MCT. AB - Between April 1981 and May 1990, 11 patients with Merkel cell carcinoma were treated with radiation therapy in Tucson, Arizona. The length of follow-up time from the time of irradiation ranged from 6 to 64 months. Locoregional control was maintained in seven of eight patients treated with surgery and postoperative radiation therapy for primary or recurrent cancer. The other three patients had bulky metastatic disease at the time of referral. Palliation was achieved in all three patients with radiation therapy. Hyperthermia also appeared to be beneficial in the one
patient in which it was used, and chemotherapy achieved responses in two of
four patients. These results, combined with a review of the literature,
suggest that the administration of radiation therapy postoperatively to
both the surgical bed and the draining lymph nodes improves locoregional
control and may result in long-term disease-free survival when administered
after the initial surgical resection. AB - An 82-year-old woman had a dark red to purple tumor on the left
buttock that had gradually enlarged during the last 5 years. Although
routine histologic examination was not sufficient for diagnosis,
neuroendocrine carcinoma was diagnosed by immunohistochemical and
ultrastructural studies. Immunohistochemical-positive reactions to
neurofilament, cytokeratin, neuron-specific enolase, and epithelial
membrane antigen were noted. Electron microscopically, membrane-bound,
dense core granules that yielded a positive uranaffin reaction and
intermediate filaments in the perinuclear area were observed in the
cytoplasm of most tumor cells. Desmosome-like structure between them was
also found. Approximately 6 months after local excision, metastatic lesions
developed in the regional lymph nodes and liver. AB - A first course of combination chemotherapy for large volume metastatic disease in a patient with Merkel cell carcinoma resulted in a tumor lysis syndrome. After this course a nearly complete response was documented. This case report extends further the chemosensitivity of Merkel cell carcinoma and demonstrates the need for tumor lysis syndrome prophylaxis in patients with bulky disease or fast-growing tumors.
====================================================================== AB - In two Japanese women, 68 and 88 years old, Merkel cell
(neuroendocrine) carcinoma of the face developed. Their tumors regressed
after biopsy was performed, a rare occurrence. Histological and electron
microscopic examination showed apoptosis, cellular necrosis, and an
infiltration composed mainly of lymphocytes in the tumors. These changes
may have been related to the mechanism of regression. It is interesting
that our two patients were women, as was another patient described with
Merkel cell carcinoma regression, in light of the fact that the prognosis
of this tumor is sex dependent. AB - Tumor metastases to the testes are rare and are usually found
incidentally at autopsy or after orchiectomy for prostatic carcinoma. It is
even more unusual for testicular metastases to be clinically detected or
symptomatic. The authors report two cases of clinically detected testicular
metastases from Merkel cell carcinoma of the skin. Merkel cell carcinoma
metastatic to the testes has not been reported previously. The two tumors,
to some degree, resembled testicular lymphomas and the interstitial type of
seminoma. AB - A 70-year-old male with regionally recurrent Merkel cell cancer
obtained a complete remission with three cycles of VP16 and cisplatin. His
response was consolidated with local radiation therapy. Two additional
patients have been reported to have responded to the same combination.
Chemotherapy consisting of either cyclophosphamide, vincristine, and
doxorubicin or VP16 and cisplatin should be considered in locally recurrent
Merkel cell cancer. AB - Four patients with a diagnosis of Merkel cell carcinoma initially
underwent surgery followed by radiotherapy. Recurrent disease prompted use
of radiation in three cases. The three cases of recurrent disease
illustrate the aggressiveness of Merkel cell carcinoma and also provide
further documentation of the radiosensitivity of this tumor. Additionally,
these cases suggest that surgery alone frequently is inadequate to achieve
local control of disease. AB - The clinico-morphological features in 13 patients (nine female) with neuroendocrine carcinoma of the skin are presented. The mean age was 64.9 years. The limbs were the most common site of primary tumour, followed by the face. The clinical course was characterized by a high incidence of regional lymph node metastases (69%) and recurrences (46%). Seven of the patients died of tumour, with a mean survival time of 13 months. Histologically, a solid pattern of tumour growth was most common. The cells were usually small and uniform. Squamous cell differentiation was found in one tumour. The cell of all tumours reacted positively for cytokeratins and
neuron-specific enolase. The positive reaction frequently had a ball-like
globular pattern, corresponding to inclusion-like bodies seen on light
microscopy and to paranuclear whorls of intermediate filaments observed on
electron microscopy. Neurosecretory granules were seen on electron
microscopy in the 11 cases examined and in one case a 'Luse body' was found
in the intercellular space. AB - Merkel cell carcinoma is an unusual primary cutaneous tumor with an aggressive biologic nature. Following surgical treatment, 40% of patients have local recurrences develop, 55% have regional lymph node metastases develop, and 49% have distant metastases develop. We have treated four patients with Merkel cell carcinoma; only one of the four patients was alive and well after 2 years. Two patients died of metastatic disease, one at 11 months following initial treatment and one at 39 months. The fourth
patient had a rapid recurrence following initial treatment and is currently
in remission following chemotherapy for regional metastases. Recent reports
indicate that chemotherapy may be helpful in treating patients with
recurrent or metastatic Merkel cell carcinoma. AB - A Merkel cell carcinoma of the mandibular area in a 78-year-old woman was treated successfully by direct intratumoral administration of recombinant human tumor necrosis factor. The patient received 2.5 x 10(5) U/d of recombinant human tumor necrosis factor every other day. A total of six injections (total dose, 1.5 x 10(6) U, 0.52 mg of protein) were administered over a period of 12 days. Soon after the therapy ended, the lesion softened and decreased in size. After 1 month, only erythema was visible. The lesion had completely disappeared clinically and
histologically 5 months after the local injection of recombinant human
tumor necrosis factor. Neither recurrence nor metastasis has been observed
for at least 12 months following the treatment. Recombinant human tumor
necrosis factor is suggested to be effective for the treatment of Merkel
cell carcinoma. AB - The relatively simple cytogenetic findings in an aggressive metastatic Merkel cell carcinoma are reported. Deletion 2p was found in 100% of the cells. Nevertheless, this was considered a secondary (metastatic?) change because the same aberration has been found in several other kinds of malignancy. The involvement of chromosome 22 [del(22q) and -22] in 85% of the cells seemed more intriguing, considering the fact that the Merkel cell carcinoma followed a previous meningioma. ====================================================================== AB - A study of 50 consecutive cases (22 men, 28 women; age range, 39 to 84 years; mean age, 65 years) of cutaneous neuroendocrine Merkel cell carcinoma (CNC), 39 of whom had a mean follow-up of 34 months, revealed that the prognostic significance of the histopathologic subtyping in trabecular, solid, and diffuse variants of CNC was not as important as the pathologic postsurgical staging in localized, regional, and extraregional disease. The overall mortality was 23.5%. None of the 19 patients with localized disease died of CNC, while 11% of the 24 patients with regional disease and all seven patients with extraregional disease at presentation died of CNC. A second primary malignancy was found to be associated with the CNC in 15% of the cases. The clinical course in patients with localized disease was favorable in spite of the high number of local recurrences. Also, the presence of regional metastases was not related to an unfavorable
prognosis. In 68% of the cases the disease involved the lower limbs or
girdle. In ten cases the overt exophytic presentation of primary CNC was
replaced by the presence of tumor masses infiltrating the inguinal soft
tissues with or without nodal involvement. AB - Thirteen patients with regional or distant metastases from Merkel cell carcinoma were treated with combination chemotherapy. Three patients had a complete response to therapy. In two patients with nodal disease the duration of response was 10+ and 4+ years. In addition, three patients had a partial response, and six patients had minor responses. Chemotherapy
using a combination of drugs that are active against small cell carcinoma
of the lung is recommended in the treatment of unresectable disease in
patients with Merkel cell carcinoma; it may produce prolonged responses.
While tumor regressions as a result of chemotherapy were often dramatic,
once the disease progressed, the course of the disease often moved rapidly
downhill and proved to be fatal. AB - Over 400 cases of neuroendocrine (Merkel cell) carcinoma of the skin (NCS) have been reported. This tumor continues to pose problems in diagnosis and effective treatment for physicians unfamiliar with its biological characteristics. Reported here are five additional cases of NCS and the literature for this rare neoplasm is comprehensively reviewed. An early and accurate diagnosis is made possible by combining clinical presentation with results of histologic study, immunoperoxidase staining for neuron-specific enolase (NSE), epithelial membrane antigen (EMA), cytokeratins, and electron microscopy. NCS is an aggressive tumor. Depending on the length of follow-up, up to 40% of tumors locally recur, 55% develop regional nodal metastases, and 36% undergo distant metastasis. Survival is sex, but not age, dependent, with an overall 2-year survival rate of 72% (males 58% vs. females 79%). No standard procedure for initial and/or follow-up treatment for NCS exists. The authors recommend that NCS
be treated, whenever possible, using the same rationale as applied for the
treatment of squamous cell carcinoma of the skin. AB - An elderly man presented with bright red-to-purple confluent nodules and plaques of the scalp that appeared clinically consistent with angiosarcoma. He had undergone surgical removal of a similar lesion from his left temple seven months before this presentation. Although routine histologic examination was not sufficient for diagnosis, Merkel cell carcinoma was diagnosed by immunohistochemical studies and electron microscopy. In addition, oat cell carcinoma of the lung was excluded with a computed tomographic scan of his chest. With chemotherapy, the recurrent and metastatic lesions of Merkel cell carcinoma completely resolved, rapidly recurred, and resolved a second time with chemotherapy. Eight
months following the fourth course of chemotherapy, the patient again
developed widespread cutaneous lesions. He committed suicide within one
month of this last recurrence. An autopsy revealed no primary tumor other
than of the skin. AB - Four new patients with trabecular (Merkel cell) carcinoma of the skin
are described, and an additional 76 patients from the literature are
reviewed. The mean age of the combined group of patients was 68; 84% were
60 years or older. Primary tumors appeared most frequently on the head and
neck (44%), leg (28%), arm (16%), or buttock (9%). No primary tumor
appeared on the trunk. The rate of local recurrence was 36%, regional
metastatic disease, 53%; distant metastases, 28%; and death due to
metastatic tumor (minimally), 25%. It appears that trabecular carcinoma of
the skin is more aggressive and lethal than previously thought. The authors
recommend that patients with this tumor undergo wide resection of the
primary site and, in healthy patients, prophylactic regional node
dissection. Both radiation therapy and chemotherapy are effective in
palliating unresectable disease. AB - Merkel cell carcinomas (also known as trabecular carcinomas) are primary cutaneous small cell neuroendocrine neoplasms with the potential to metastasize. Control of disseminated disease is therefore important. A case of metastatic Merkel cell carcinoma with an excellent response to chemotherapy is presented. The regimen chosen for this case is similar to that used for bronchogenic small cell anaplastic carcinoma. The reason for selecting this regimen was the common neuroendocrine differentiation and the similar histopathologic features of these two tumors. Only a few reports have described chemotherapy for Merkel cell carcinoma and similar agents were used. These cases are reviewed and critically analyzed. ====================================================================== AB - Merkel cell carcinomas have characteristic, but not pathognomonic, histomorphologic features. The diagnosis can be confirmed by immunohistochemistry studies and electron microscopy. However, differential diagnostic problems often occur only after all tumor material has been fixed in formalin and embedded in paraffin, which gives poor tissue preservation for electron microscopy. Therefore, in addition to histologic and immunohistochemical studies, parallel ultrastructural investigations were performed on tumor specimens fixed in glutaraldehyde and routinely processed, for electron microscopy, on formalin-fixed tissue and on formalin-fixed paraffin blocks. Formalin fixation led to an almost complete loss of neurosecretory granules and cell membranes; however, the characteristic paranuclear whorls of intermediate filaments were retained in all tumors. Merkel cell carcinomas are immunoreactive for
neuron-specific enolase (NSE), but NSE-antisera have only recently become
commercially available. Cytokeratin is demonstrable as a paranuclear clump,
and this feature was found in four out of six tumors. Thus histologic,
immunohistochemical, and electron microscopy studies of formalin-fixed
tissue are able to confirm the diagnosis of neuroendocrine Merkel cell
carcinoma. AB - The clinical and pathologic features of 43 cases of primary neuroendocrine carcinoma of the skin are reported. These tumors arise in the dermis and subcutaneous tissues of elderly individuals. The head and neck are the most common primary sites followed by the lower and upper extremities and trunk. Characteristic histologic features include round cells with scanty amphophilic cytoplasm and vesicular nuclei with multiple small nucleoli. The cells are arranged in sheets, solid nests, or anastomosing trabeculae. Collections of perinuclear intermediate filaments, cytoplasmic dense-core membrane-bound secretory granules, complex intercellular junctions, and cytoplasmic spinous processes are the principal fine structural features. These ultrastructural findings are similar to those of the normal cutaneous Merkel cell. The natural history of this neoplasm is characterized by local recurrence in 30% of cases, regional lymph node metastases in 65% of cases, and distant metastases in 40%. One-third of the patients were dead because of their tumors. Treatment of extensive local or distant metastatic disease with chemotherapy or radiotherapy resulted in only short-term palliative response. ====================================================================== AB - A series of 15 Merkel cell tumours of skin is reported. They occur dominantly on the head and neck and on the extremities of elderly women, frequently presenting as a reddish nodule. Three cases were associated with squamous carcinoma at the same site, an association deserving further study. There are two main patterns: the commoner one takes the form of a trabecular carcinoma in the dermis mimicking metastatic carcinoma, including oat-cell carcinoma and neuroblastoma: a dissociated-cell form mimicks malignant lymphoma. The triad of vesicular nuclei with very small nucleoli, abundant mitotic activity and apoptosis is so characteristic as to be virtually pathognomonic in conjunction with structural features. Argyrophilia is common, but Bouin fixation is necessary to demonstrate it regularly. Small round secretory granules (89 +/- 18 nm) with narrow haloes, and an abundance of intermediate size filaments are among the ultrastructural hallmarks. There is a close similarity between better differentiated tumour cells and normal Merkel cells. The neural crest origin of MC is in doubt both on the basis of studies of the development and regeneration of MC and from the study of Merkel cell tumours. ====================================================================== AB - An elderly woman presented with an ulcerating skin carcinoma located over the right parietal area. It healed after local radiotherapy but recurred locally and metastasized to the subcutaneous tissue and one regional lymph node. Neurosecretory granules were demonstrated ultrastructurally, and blood levels of calcitonin were repeatedly elevated. A metastasizing medullary carcinoma of the thyroid was suspected, and a total thyroidectomy was performed; however, no medullary carcinoma or C cell hyperplasia could be identified. Furthermore, the calcitonin levels
remained unchanged following thyroidectomy, whereas they decreased twice
after the skin tumor or its metastases were ablated. Clinical follow-up for
over seven years revealed no other lesion that could have been responsible
for the overproduction of calcitonin. The ultrastructural features of this
skin carcinoma and its metastases, particularly the neurosecretory
granules, were reminiscent of those of the so-called Merkel cell. We
conclude that this skin carcinoma might indeed produce calcitonin, that
this tumor may be derived from Merkel cells, and that Merkel cells may
belong within the APUD system. AB - Merkel cells are difficult to identify in tissue sections. Previous studies have used cytokeratins (CK) 8, 18, and 19 as histologic markers of Merkel cells. However, these CKs are also expressed in some outer root sheath keratinocytes and some early fetal epidermal cells and thus are not truly specific of Merkel cells in general. Using selective antibodies against a newly described CK, number 20--originally found in intestinal epithelium and Merkel cell carcinomas--in comparison to a key protein of neuroendocrine cells, chromogranin A, we established CK 20 as a specific Merkel cell marker in skin of humans, pigs, and mice. CK 20 seems to be an even more general and sensitive Merkel cell marker as compared to CgA. In double-labeling experiments with stratified-squamous epithelial CK (numbers 5 and 13-17) and simple epithelial CK (numbers 8, 18, and 20) antibodies evaluated by confocal laser scanning microscopy, no cell expressing CKs of both types (i.e., no cell of so-called "transitional" character between Merkel cells and keratinocytes) was identified in human skin. In addition,
various neuronal markers present in Merkel cell carcinomas including
neurofilaments, peripherin, nerve growth factor receptor, and neuronal cell
adhesion molecule appear to be absent in normal Merkel cells. Thus, Merkel
cells exhibit a distinct and unique marker profile, with CK 20 being of
particularly high value in various species. AB - BACKGROUND--Trabecular carcinomas of the skin, or Merkel cell tumors, are aggressive neoplasms that tend to occur in sun-exposed skin. These tumors frequently metastasize and, despite therapy, the number of disease-related deaths is high. Ultrastructurally and immunocytochemically, the majority of these tumors have neuroendocrine characteristics. Recently, we described the in vivo visualization of various neuroendocrine tumors after injection of a radiolabeled somatostatin analogue (octreotide). In this study, we report the results of scintigraphy with radioactive-labeled somatostatin analogues in five patients with Merkel cell tumors. OBSERVATIONS--In all four patients in whom tumor was detected using computed tomographic scanning and ultrasound, the tumor sites were also demonstrated on octreotide scintigrams. In one patient, a tumor with a diameter that was smaller than 0.5 cm could not be detected with octreotide scintigraphy, computed tomography, or ultrasound. Using octreotide scintigraphy we found presumed tumor spots in two patients that were not evident when other techniques were used. CONCLUSIONS--Octreotide
scintigraphy has an equal or even greater sensitivity than computed
tomography and ultrasound for detecting Merkel cell tumors and their
metastases. Establishing the spread of the disease in this way may ensure
an optimal choice of treatment in patients with this type of tumor. AB - The authors have recently identified a new cytokeratin (CK) polypeptide, CK 20, whose expression is almost entirely confined to the gastric and intestinal epithelium, urothelium, and Merkel cells. Seven monoclonal antibodies (MAbs) specific for CK 20 were raised and characterized by applying immunoblotting and immunocytochemical screening. All of them reacted on frozen tissue sections. A further MAb, IT-Ks20.8, recognized CK 20 in sections of formalin-fixed, paraffin-embedded tissue samples. A total of 711 cases of primary and metastatic cancer, mostly carcinomas, were analyzed immunohistochemically for CK-20 expression, using CK-20 specific guinea-pig antibodies and MAbs. The expression spectrum of CK 20 in carcinomas resembled that seen in the corresponding normal epithelia of origin. CK-20 positivity was seen in the vast majority of adenocarcinomas of the colon (89/93 cases), mucinous ovarian tumors, transitional-cell and Merkel-cell carcinomas and frequently also in adenocarcinomas of the stomach, bile system, and pancreas. Most squamous
cell carcinomas in general and most adenocarcinomas from other sites
(breast, lung, endometrium), nonmucinous tumors of the ovary, and
small-cell lung carcinomas were essentially or completely negative. The
authors propose to use CK 20 as a diagnostic marker valuable in
distinguishing different types of carcinomas, notably when presenting as
metastases. AB - Merkel cell tumor is an unusual, aggressive malignancy of skin that has been considered to be derived from cutaneous Merkel cells. We are reporting a case of Merkel cell tumor overlying the left scapula with metastases to the thoracic spine and pleura. The tumor was found incidentally in a 23-year-old pregnant black woman. The tumor recurred locally 5 months after initial wide excision. Subsequently, a second wide excision of the recurrent tumor with ipsilateral axillary dissection was performed. The course of the disease was complicated by local recurrence and formation of distant metastases to pleura and spine. At the end-stage of the disease, the patient was found to have a cardiac murmur, and echocardiography revealed a mass in the anterior wall of the right ventricle that was suspicious for a metastatic lesion. The patient expired from extensive distant metastases 23 months after diagnosis. ====================================================================== AB - We investigated a variety of endocrine tumors for the presence of chromogranins A and B and secretogranin II. These antigens were identified by one- and two-dimensional immunoblotting and in some cases by immunohistochemistry. An antigen corresponding in electrophoretic behavior to adrenal chromogranin A was present in all types of tumors, including insulinomas, oat cell carcinomas, and Merkel cell tumors of the skin. Chromogranin B had a much more limited distribution. This antigen could not
be detected in parathyroid adenomas, oat cell carcinomas, or Merkel cell
tumors, either by immunoblotting and immunohistochemistry. The occurrence
of secretogranin II was similar to that of chromogranin B, with the
exception of a positive reaction in Merkel cell tumors. In benign
pheochromocytomas, all three antigens were found consistently; whereas in
two of three malignant pheochromocytomas, chromogranin B was absent. Our
study establishes that in most cases chromogranins and secretogranin in
tumors are identical to the adrenal antigens, but that these antigens are
not always stored together. Chromogranin A is the most widely distributed
marker for endocrine tumors. Abstract The Authors report a case of Merkel cell carcinoma of the cervicofacial district, particular due to its clinical and evolutive characteristics. The Merkel cell carcinoma was first identified by Toker in 1972 and is also known as a primary neuroendocrine the or trabecular carcinoma of the skin. The Merkel cell carcinoma is a rare aggressive skin cancer most frequently localized in the cervicofacial district. Although in earlier reports on the clinical history of these tumors primary emphasis was placed on their local aggressive behaviour, it has recently become evident that these neoplasms have a marked propensity for early dissemination. Distant metastases are often responsible for disease-related mortality. Merkel cell carcinoma have
classically been managed with surgery alone or surgery followed by
radiation therapy. Treatment of Merkel cell carcinoma with radiation
therapy alone has usually been reserved for advanced unresectable tumors. Abstract The aim of the present study was to assess a possible role of the tumour suppressor gene p53 in neuroendocrine (Merkel cell) carcinoma of the skin with regard to tumour development and tumour progression. p53 was investigated in a series of routinely processed Merkel cell carcinomas, with application of four different p53 antibodies (CM-1, PAb1801, DO7, and PAb240) to 25 carcinomas and screening for p53 mutations of exons 4-8 by single-strand conformation polymorphism (SSCP) analysis in 9 cases. All 25 tumours in the present series showed the characteristic microscopic and immunohistochemical features of Merkel cell carcinoma of the skin. In 5 of the 25 Merkel cell carcinomas investigated 5-10% of tumour cell nuclei showed a positive p53 reaction with at least one anti-p53 antibody. A few scattered p53 positive nuclei were found in an additional 9 cases. The remaining 11 cases completely lacked p53 immunostaining. SSCP analysis of exons 4-8 revealed no significant alterations in the mobility shift of the single strand DNAs in the five cases with 5-10% p53-immunoreactive tumour nuclei or in five cases lacking p53 accumulation significant. Our results suggest that alterations of the p53 gene play only a minor part in the development or progression of Merkel cell carcinoma of the skin. ====================================================================== Abstract BACKGROUND. Merkel cell carcinoma is a relatively rare neuroendocrine carcinoma of the skin. It arises in the head and neck region in approximately 50% of cases. Its aggressive behavior predisposes patients to local-regional recurrence and distant metastases after surgical excision alone. In this article, we describe our experience with Merkel cell carcinoma of the head and neck. METHODS. Of 18 patients with Merkel cell carcinoma treated in the Department of Radiation Oncology at the University of Florida, 12 patients who had primary tumors in the head and neck region are reported. Eight patients were treated at initial diagnosis (group A), and four were treated at the time of local-regional recurrence (group B). RESULTS. Local-regional control was achieved in seven of eight patients in group A and all four patients in group B. One patient in group A and all patients in group B developed distant metastases and eventually died of their disease. Bone exposure developed in one patient, requiring surgical debridement and hyperbaric oxygen treatment. CONCLUSION. Patients with
Merkel cell carcinoma of the head and neck should be treated aggressively.
Our data suggest that local-regional recurrence is a harbinger of distant
metastases. We recommend that these patients receive treatment to both the
primary site and draining lymphatics at initial presentation. The role of
chemotherapy remains unclear. Abstract We report two cases of Merkel cell carcinoma within inguinal and axillary lymph nodes, respectively, showing no clinico-pathologic evidence of a primary (extranodal) tumor; one of our patients was alive with no evidence of disease five years and ten months after the surgical excision of the neoplasm with no postoperative chemotherapy. The diagnosis of nodal Merkel cell carcinoma needs to be supported by a careful immunohistochemical study: in fact, cytokeratin- and neurofilament-positive paranuclear "dots", as well as epithelial antigens and neuroendocrine markers may be variably expressed in tumor cells, thus requiring the application of a complete antibody panel. In the presence of a nodal Merkel cell tumor, an exhaustive clinico-radiologic search for a primary tumor must be carried out. After
the exclusion of any reasonable starting point of the neoplasm, a
provisional diagnosis of "primary" nodal Merkel cell carcinoma may be
acceptable; since a primary extracutaneous tumor is expected to follow a
less aggressive course than a metastatic one, follow-up data may provide
indications as to the truly extracutaneous origin of Merkel cell carcinoma. Ann Ophthalmol, 22(5):187-90 1990 May Abstract Merkel cell carcinoma is a rare skin tumor of neural crest origin and is part of the amine precursor uptake and decarboxylase system. It typically occurs on the face of elderly people. Distant metastasis is almost uniformly fatal. Choroidal metastasis, to our knowledge, has not been described. We report a patient with Merkel cell carcinoma who had a synchronous solid choroidal tumor and a biopsy-proven brain metastasis. Our 56-year-old patient presented with a rapidly growing, violaceous preauricular skin tumor. Computed tomography of the head disclosed
incidental brain and choroidal tumors. Light and electron microscopy of
biopsy specimens of both the skin and the brain lesions showed Merkel cell
carcinoma. Ophthalmoscopy, fluorescein angiography, and A and B echography
revealed a solid choroidal mass. The brain and skin tumors responded well
to irradiation. A radioactive episcleral plaque was applied subsequently to
the choroidal tumor. All tumors regressed, and the patient was doing well
28 months later. To our knowledge this is the first case of presumed
choroidal metastasis of Merkel cell carcinoma. Abstract Merkel cell carcinoma is a rare malignant tumor of the skin. We treated three patients with Merkel call carcinoma with the combination of carboplatin and etoposide, which have been mostly used in the treatment of small cell lung carcinoma. Two patients experienced partial remission of short duration. The third patient received the combination on an adjuvant basis but relapse occurred briefly. Two of these patients failed to respond to second-line chemotherapy with cisplatin, ifosfamide, and epirubicin. T
he
patient who had the first-line treatment on an adjuvant basis, responded
completely with the second-line chemotherapy plus radiotherapy and remains
disease-free for 5+months. Merkel cell carcinoma appears to be a sensitive
tumor to chemotherapeutic regimens used for small cell lung carcinoma, but
the responses are often brief. Abstract The alpha subunit of guanine nucleotide-binding protein Go (Go alpha), which was initially isolated from bovine brain, interacts with muscarinic cholinergic receptors and regulates neuronal calcium channels. Go alpha is known to be localized in neural tissues, some endocrine cells, and neuroendocrine tumors. We have immunohistochemically investigated the expression of Go alpha in 4 cases of Merkel cell carcinoma using the method of microwave treatment. In all cases of Merkel cell carcinoma, Go alpha was consistently detected on the plasma membrane and cytoplasm of the tumor cells. Nerve fibers in the skin were also positive for Go alpha, but other epidermal or dermal components such as keratinocytes, melanocytes, fibroblasts, or lymphoid cells were negative. Tumor cells of squamous cell carcinoma, cutaneous lymphoma, sweat gland carcinoma, and malignant melanoma were negative for Go alpha. The present study indicates that Go
alpha may be a useful immunohistochemical marker of Merkel cell carcinoma. Abstract
A case of neuroendocrine skin carcinoma (Merkel cell carcinoma) with a
deletion of the short arm of chromosome 1 (1p) as the sole chromosomal
abnormality was examined. The tumor originated in the skin of the left knee
of a 67-year-old man. Histopathologic study showed an undifferentiated
small cell tumor which expressed neuron-specific enolase, chromogranin, and
cytokeratin (CAM 5.2). Cytogenetic analysis of a lymph node metastasis from
the groin showed a pseudodiploid cell population with a deletion of the
short arm of chromosome 1 as the only abnormality: 46,XY,del(1)(p36.1). In
situ hybridization with the D1Z2 probe specific for the terminal band of 1p
confirmed the terminal deletion. This is the first case of Merkel cell
carcinoma in which only one chromosomal abnormality has been observed. Loss
of the terminal portion of 1p suggests that a tumor suppressor gene on 1p
plays a role in the pathogenesis of Merkel cell carcinoma. Abstract 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. ===================================================================== |
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Produced by Dr. José Lapenta R.
Dermatologist
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