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Background
This cancer is also known as trabecular cell carcinoma and neuroendocrine carcinoma of the skin. Of all the names, the last probably best represents the nature and identity of this tumor, but Merkel cell has remained ingrained in the minds of physicians. This tumor usually arises on sun-exposed surfaces of elderly patients though rare childhood cases have been reported. They are usually 2 cm in diameter and have a red nodular appearance. Histologically, these tumors are composed of small, round to oval cells with vesicular nuclei and small nucleoli. There are numerous mitotic figures and large areas of necrosis are common. Characteristically, these tumor cells show strong immunopositivity for neuroendocrine immunoperoxidase markers such as chromogranin, neuron specific enolase, and synaptophysin. The tumor cells are also strongly positive for cytokeratin with occasional paranuclear dot-like globular positivity noted.
The origin from Merkel cells is not uniformly agreed upon. Neuroendocrine differentiation is confirmed. Rarely these tumors, like other neuroendocrine tumors, may produce hormones such as calcitonin, but usually not in high enough levels to be symptomatic.
OUTLINE
DISEASE ASSOCIATIONS CHARACTERIZATION Diseases Squamous cell and basal cell carcinoma of the skin
Breast, endometrium, colon, and prostate cancersChronic lymphocytic leukemia
Ovarian clear cell carcinoma
Bladder transitional cell carcinoma
Squamous cell carcinoma of the larynxAIDS-HIV1
Merkel cell carcinoma and HIV infection.Engels EA, Frisch M, Goedert JJ, Biggar RJ, Miller RW.
Lancet 2002 Feb 9;359(9305):497-8 Abstract quote Merkel cell carcinoma (MCC) is a rare skin cancer that occurs more frequently after organ transplantation or B-cell malignancy, conditions of suppressed or disordered immunity.
To assess further whether immune suppression increases MCC risk, we studied its occurrence in a cohort of 309365 individuals with acquired immunodeficiency syndrome (AIDS) by using linked AIDS and cancer registries.
We identified six cases of MCC, corresponding to a relative risk of 13.4 (95% CI 4.9-29.1) compared with the general population. These results suggest that immune suppression induced by the human immunodeficiency virus increases MCC risk.
Merkel cell carcinoma in the setting of HIV infection
Kathy P. An, BS Désirée Ratner, MD
New York, New York
J Am Acad Dermatol 2001;45:309-12 Abstract quote
Merkel cell carcinoma has been found to have an increased incidence among immunosuppressed patients, specifically organ transplant recipients receiving immunosuppressive therapy. HIV similarly depresses the immune response of infected persons.
We report a case of Merkel cell carcinoma (MCC) in an HIV-infected patient who died from liver metastases 2 years after his tumor was diagnosed. The purpose of this report is to describe the possible relationship between HIV and MCC and to emphasize the importance of early diagnosis and aggressive management of MCC.
BOWEN'S DISEASE Merkel cell carcinoma, Bowen's disease and chronic occupational arsenic poisoning.
Tsuruta D, Hamada T, Mochida K, Nakagawa K, Kobayashi H, Ishii M.
Department of Dermatology, Osaka City University Medical School, 1-5-7 Asahimachi, Abeno-ku, Osaka 545, Japan.
Br J Dermatol 1998 Aug;139(2):291-4 Abstract quote
We diagnosed a unique case of Merkel cell carcinoma (MCC) coexisting with Bowen's disease on the sole of the foot of a 72-year-old man who had worked for about 4 years in a factory handling inorganic arsenic.
He had a past history of arsenical keratosis and multiple Bowen's disease. The tumour first appeared as a reddish macule and then showed marked growth over the next month. The tumour was excised and the specimen was examined histopathologically. The tumour consisted of two components: a group of atypical cells representing Bowen's disease in the epidermis and another group of atypical cells with a trabecular pattern characteristic of MCC in the dermis. Neither group of cells showed transitional findings, and the tumour elements were divided by a clear basement membrane. The tumour cells in the dermis were positive for neurone-specific enolase, and on electron microscopy had dense core granules in the cytoplasm.
Inorganic arsenic can cause various cutaneous neoplasms, but to our knowledge, this is the first report of a case of MCC associated with Bowen's disease.
Merkel cell carcinoma and multiple Bowen's disease: incidental association or possible relationship to inorganic arsenic exposure?
Ohnishi Y, Murakami S, Ohtsuka H, Miyauchi S, Shinmori H, Hashimoto K.
Department of Dermatology, University of Ehime School of Medicine, Japan.
J Dermatol 1997 May;24(5):310-6 Abstract quote
An 81-year-old Japanese male was referred to our clinic in 1991 with multiple Bowen's disease.
The associated hyperpigmentation of the trunk and extremities and palmoplantar keratotic nodules indicated that he had suffered from chronic arsenic poisoning. Interestingly, he was a native of Namikata in Ehime, Japan, where many residents have suffered from multiple Bowen's disease with internal malignancy. Arsenic exposure was strongly suspected. Two years later, Merkel cell carcinoma developed on the dorsum of his right hand, where Bowen's disease lesions were absent. Metastasis of this Merkel cell carcinoma led to his eventual death one year later.
To our knowledge, this is the first report of Merkel cell carcinoma associated with multiple Bowen's disease. Chronic arsenic poisoning may be responsible for the association of these two rare skin neoplasms.
TRANSPLANTION, ORGAN
Department of Dermatology/EA 37-32, University Cl. Bernard, France.
Background: Non-melanoma skin cancers are the commonest malignancies after organ transplantation and are often associated with human papillomavirus (HPV). Merkel cell carcinoma is an uncommon neuroendocrine skin tumor, of which 67 cases have been reported up till now, usually briefly, in organ transplant patients.
Methods: Among a cohort of 2340 organ-transplant recipients, two patients (one renal, one heart) developed cutaneous Merkel cell carcinomas 5 and 12 years of post graft, respectively. These were studied histologically and immunohistochemically, as well as virologically for the presence of HPV. A thorough literature review of all reported cases of Merkel cell carcinoma following solid organ transplantation was performed.
Results: Despite a typical immunophenotype, the tumors showed unusual histological features: both were epidermotropic, and one was intermingled with a bowenoid squamous cell carcinoma. Search for HPV by immunohistochemistry and PCR proved negative in both cases.
Conclusion: In the setting of organ transplantation, Merkel cell carcinoma is much rarer than other non melanoma skin cancers but may show unusual histologic features. HPV do not seem to be involved in its pathogenesis.
PATHOGENESIS CHARACTERIZATION APOPTOSIS Am J Dermatopathol 2001;23:16-23
Nine cases studies studied with TUNEL and immunostaining using antibody directed against Fas(Apo1/CD95)
Fas positive in 2/8 cases but positive cells were not numerous
TUNEL and electron microscopy demonstrated more DNA fragmentation
bcl-2 negative in all casesBIF-1
Department of Pathology, University of South Florida, College of Medicine, Tampa, FL 33612, USA.
BACKGROUND: Bax-interacting factor-1 (Bif-1) binds to Bax, which in turn activates this proapoptotic protein. In the absence of Bif-1, the ability to induce apoptosis through the intrinsic pathway is greatly reduced. Merkel cell carcinoma (MCC) classically shows an aggressive behavior and lack of response to chemotherapy, which remains unexplained. Previous studies have documented the presence of Bax in MCC, but Bif-1 expression has not been evaluated. Herein, the expression of Bif-1 and Bax in cutaneous MCC is examined.
MATERIALS AND METHODS: The immunohistochemical expression of Bif-1 and Bax protein was examined in nine cases of MCC. Both positive and negative controls were conducted. All the cases were reviewed by a single dermatopathologist.
RESULTS: Bif-1 was detected in nine cases (100%), and Bax was expressed in six cases (66%). The percent positive cells for Bif-1 in MCC ranged from 85% to 98% positive (mean 93.9%). At the same time, decreased Bax expression was shown with 0-8% positive cells (mean 3.45%).
CONCLUSION: The increased expression of Bif-1 in MCC is associated with low levels of Bax staining. These findings suggest that the upregulation of Bif-1 could in part be responsible for tumorigenesis in cutaneous MCC. As shown, Bax and Bif-1 expression are not exclusively antithetical; therefore, future studies evaluating the expression of both proteins should be conducted.CHEMORESISTANCE GENE ABCG2 (MXR/BCRP1/ABCP1)
- The chemoresistance gene ABCG2 (MXR/BCRP1/ABCP1) is not expressed in melanomas but in single neuroendocrine carcinomas of the skin.
Deichmann M, Thome M, Egner U, Hartschuh W, Kurzen H.
Department of Dermatology, Heidelberg University Clinics, Heidelberg, Germany.
J Cutan Pathol. 2005 Aug;32(7):467-73. Abstract quote
Background: As the molecular mechanisms in melanoma chemoresistance remain unknown to date, we hypothesized these tumors to express the ATP-binding cassette (ABC) transporter G2 (ABCG2/MXR/BCRP1/ABCP1), a recently detected membrane transporter and putative stem-cell marker.
Besides melanoma, we addressed the neuroendocrine carcinoma of the skin (Merkel cell carcinoma), another cutaneous cancer supposed to originate from neuroectoderm and usually chemoresistant.
Methods and Results: Upon semiquantitative reverse transcription polymerase chain reaction, ABCG2 mRNA expression was not upregulated in 18 melanoma resection specimens when compared with 19 acquired melanocytic nevi from which melanomas are known to often arise (Mantel-Haenszel test, p = 0.3). At protein level, immunohistochemistry was negative in all 66 investigated melanoma resection specimens (50 primary melanomas and 16 cutaneous/subcutaneous metastases) and in 19 acquired melanocytic nevi. Among 29 neuroendocrine carcinomas of the skin, ABCG2 protein was detected in single clusters of cells in three tumors. As a positive control, three dermatofibrosarcomas were also stained and showed ABCG2 protein expression of the endothelial cells of the blood vessels.
Conclusion: Altogether, chemoresistance of melanomas and neuroendocrine carcinomas of the skin cannot be explained by expression of the ABCG2-chemoresistance gene. Most of these tumors do not exhibit this potential stem-cell feature.CHROMOSOMAL ABNORMALITIES Abnormalities of chromosomes 1, 11, and 12 have been reported in one third of cases
Recurrent DNA copy number changes revealed by comparative genomic hybridization in primary Merkel cell carcinomas.
Larramendy ML, Koljonen V, Bohling T, Tukiainen E, Knuutila S.
Department of Medical Genetics, Haartman Institute, University of Helsinki and Helsinki University Central Hospital Laboratory Diagnostics, Helsinki, Finland.
Mod Pathol. 2004 May;17(5):561-7. Abstract quote
Comparative genomic hybridization (CGH) was used to search for gains, high-level amplifications and losses of DNA sequences along all chromosome arms in 19 primary Merkel cell carcinomas (MCC). Extensive genetic aberrations, with a mean value of 5.5+/-1.1 changes per tumor were detected in 13 out of the 19 samples analyzed.
Our CGH results reveal several new and other previously known chromosomal regions that are involved in the pathogenesis of MCC. The majority of the alterations were gains of whole chromosomes or whole chromosome arms. Compared to losses, the frequency of DNA copy number gains was two-fold. DNA sequence copy number gains were most common in chromosomes 6 (42%), 1 (37%), and 5 (32%).
The most frequent minimal common regions of gains were 6pterqter (42%), 1q11q31 (32%), and 5p (32%). No recurrent high-level amplifications were observed. High-level amplifications of small chromosomal regions were found in four samples out of the 19 tumors analyzed (21%). Amplifications affected 1q22q24 (5%), 4p (5%), and 5p (5%). Losses most frequently affected chromosomes 13 (21%) and 4 (16%). Minimal common regions with the most frequent losses were 13q13q31 (21%), 4q (16%), and 16q (11%). No significant statistical correlation between genomic aberrations and clinicopathological factors was revealed, despite the fact that there was an obvious tendency towards it.
Primary MCC expressing DNA alterations were predominantly distinguished in large tumors, and risk of metastatic dissemination was three-fold compared to tumors with no DNA alterations.MATRIX METALLO-PROTEINASES
Expression and prognostic significance of matrix metalloproteinases and their tissue inhibitors in primary neuroendocrine carcinoma of the skin.Massi D, Franchi A, Ketabchi S, Paglierani M, Pimpinelli N, Santucci M.
Department of Human Pathology and Oncology and Department of Dermatological Sciences, University of Florence, Florence, Italy.
Hum Pathol 2003 Jan;34(1):80-8 Abstract quote Matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) have been implicated in the development and progression of many tumors, but data for primary neuroendocrine carcinoma (PNC) of the skin are lacking.
The aim of the study was to assess the expression of MMPs and TIMPs in PNC and to evaluate their prognostic significance. Expression of MMP-1, MMP-2, MMP-3, MMP-9, MMP-11, MMP-13, and MMP-14 and TIMP-1, TIMP-2, and TIMP-3 was evaluated by immunohistochemistry on 23 samples of PNC of the skin. The results were matched with clinical features and patient survival. In the 23 specimens of PNC, high (>20% of positive neoplastic cells) MMP-1 expression was found in 13 (56.5%) cases. MMP-2 was evidenced in 12 (52.1%) cases, 8 (34.7%) of which showed high expression in neoplastic cells. MMP-3 was detected in 11 cases (47.8%), with high expression in 9 (39.1%) of them. High MMP-9 expression was observed in 3 (13%) cases, whereas high MMP-14 expression was detected in 11 (47.8%) specimens. Expression of TIMP-1 by neoplastic cells was found in 8 (34.7%) cases, with high expression in 3 cases, whereas high TIMP-3 expression was detected in 21 (91.3%) cases. No immunoreactivity for MMP-11, MMP-13, or TIMP-2 was found. Statistical analysis failed to identify a significant correlation between MMP/TIMP expression and clinical parameters. By univariate analysis, stage >I (P = 0.01), high expression of MMP-1 (P = 0.04) and MMP-3 (P = 0.01) resulted significant negative prognostic factors, whereas by multivariate analysis, stage was the only factor that affected survival (P = 0.02).
Our results suggest that MMP-1 and MMP-3 may influence the invasive and metastatic potential of PNCs. It is conceivable that future attempts to specifically block MMP-1 and MMP-3 activity may provide a novel means to inhibit invasiveness and distant spread in selected patients with PNC.
POLYOMA VIRUS (MERKEL CELL POLYOMA VIRUS MCC) Prevalence of MCPyV in Merkel cell carcinoma and non-MCC tumors.
Andres C, Belloni B, Puchta U, Sander CA, Flaig MJ.Department of Dermatology and Allergy, Ludwig-Maximilians-Universität München, Munich, Germany.
J Cutan Pathol. 2009 Jul 14. Abstract quote
Background: Merkel cell polyomavirus (MCPyV) is the likely causative agent of Merkel cell carcinoma (MCC). However, the prevalence of MCPyV in non-MCC population and its possible role in the pathogenesis of other skin cancers are not known yet.
Methods: A molecular pathology study was performed in 33 MCC samples and 33 age- and sex-matched samples of sun exposed non-MCC tumors [12 seborrheic keratoses (SK), 11 basal cell carcinomas (BCC) and 10 lentigo maligna melanomas (LMM)]. All tumors were analyzed for presence of MCPyV-DNA by polymerase chain reaction (PCR) and Southern-Blot hybridization of PCR products.
Results: MCPyV sequences were detected in 21 MCC samples (64%) and in 2 non-MCC tumors of sun exposed skin (6%; both SK-patients). Neither the tissue samples from BCC nor LMM proved positive for MCPyV sequences.
Conclusion: We were able to confirm prior data on prevalence of MCPyV-DNA in MCC. Furthermore, a female predominance of MCPyV-positive MCC-patients was detected. There was no relevant association of MCPyV with SK, BCC and LMM. Speculative, prevalence of MCPyV in an age- and sex-matched non-MCC population could average up to 6%.
Division of Anatomic and Molecular Pathology, Department of Pathology and Immunology, Washington University Medical Center, St Louis, MO 63110-1093, USA.
It has recently been shown that Merkel cell carcinoma, a rare and often lethal cutaneous malignancy, frequently harbors a novel clonally integrated polyomavirus aptly named Merkel cell polyomavirus.
We aimed to study the prevalence of Merkel cell polyomavirus in cases of Merkel cell carcinoma, using specimens from formalin-fixed, paraffin-embedded tissue blocks. In our archives we identified 41 cases of Merkel cell carcinoma (from 29 different patients). Of these, 20 cases were primary cutaneous tumors, 4 were local recurrences, and 17 were metastases. PCR using two previously published primer sets, LT1 (440 bp amplicon) and LT3 (308 bp amplicon), as well as a novel primer set MCVPS1 (109 bp amplicon), was performed on all cases. Selected PCR products were sequenced to confirm amplicon identity. In addition, the MCVPS1 products were digested with BamH1, yielding an 83 bp product. Amplifiable DNA was recovered in all 41 study cases. The detection rate of Merkel cell polyomavirus for each of the three primer sets was 22 of 29 patients (76%) for MCVPS1, 12 of 29 (41%) for LT3, and 8 of 29 (28%) for LT1. The variation between primer set detection rates was largely due to poor DNA quality, as supported by poor amplification of the higher molecular weight markers in size control ladder products and the fact that all cases that were positive by LT1 and LT3 were positive by MCVPS1.
Our findings provide further evidence to link Merkel cell polyomavirus with a possible role in the oncogenesis of Merkel cell carcinoma. On a more practical level, our paraffin-optimized primer set may be used as an ancillary test to confirm the diagnosis of Merkel cell carcinoma in the clinical setting or for screening other rare tumor types for the causative virus, especially those tumor types that are underrepresented in frozen tissue repositories.
Laboratory of Cellular Oncology, National Cancer Institute, Bethesda, Maryland 20892-4263, USA.
Merkel cell carcinoma (MCC) is an aggressive skin cancer that develops in individuals who are over the age of 50 or immunosuppressed. DNA from a new polyomavirus, MCPyV, was recently shown to be clonally integrated in several MCC cases.
In this issue, Becker et al. demonstrate that MCPyV DNA can be isolated from 85% of primary European MCC specimens and their metastases, and Garneski et al. present data indicating that the percentage of Australian MCC cases containing MCPyV may be lower than that of North American cases.
These reports support the possibility that MCPyV is etiologically involved in at least some cases of MCC.
Molecular Virology Program, University of Pittsburgh Cancer Institute, University of Pittsburgh, 5117 Centre Avenue, Suite 1.8, Pittsburgh, PA 15213, USA.
Merkel cell carcinoma (MCC) is a rare but aggressive human skin cancer that typically affects elderly and immunosuppressed individuals, a feature suggestive of an infectious origin.
We studied MCC samples by digital transcriptome subtraction and detected a fusion transcript between a previously undescribed virus T antigen and a human receptor tyrosine phosphatase. Further investigation led to identification and sequence analysis of the 5387-base-pair genome of a previously unknown polyomavirus that we call Merkel cell polyomavirus (MCV or MCPyV). MCV sequences were detected in 8 of 10 (80%) MCC tumors but only 5 of 59 (8%) control tissues from various body sites and 4 of 25 (16%) control skin tissues.
In six of eight MCV-positive MCCs, viral DNA was integrated within the tumor genome in a clonal pattern, suggesting that MCV infection and integration preceded clonal expansion of the tumor cells. Thus, MCV may be a contributing factor in the pathogenesis of MCC.WNT PATHWAY
First Department of Pathology, Faculty of Medicine, Oita University, Oita, Japan.
Background: The Wnt-signaling pathway, involving beta-catenin, apc, and axin, plays a critical role in numerous developmental events. Alterations in the Wnt-signaling pathway have been detected in a wide variety of neoplasms. However, similar aberrations have not been described in Merkel cell carcinoma (MCC). The aim of this study was to determine the status of the Wnt-signaling pathway in MCC.
Methods: Twelve cases of MCC were tested for the expression of beta-catenin and mutational status of CTNNB1 (gene for beta-catenin), APC, AXIN1, and AXIN2. Genomic DNA extracted from paraffin blocks was subjected to a polymerase chain reaction/single-strand conformation polymorphism analysis and sequencing.
Results: Nuclear accumulation of beta-catenin was observed in only one case (8.3%), as determined by immunochemistry. No mutations were found in CTNNB1, APC, and AXIN2 in all cases, although silent mutations in AXIN1 were detected in three cases.
Conclusions: We conclude that the Wnt-signaling pathway does not play an important role in tumorigenesis in MCC.
GROSS APPEARANCE/
CLINICAL VARIANTSCHARACTERIZATION SITES Head and neck 47% Extremities, 40% Trunk, 8% Unknown primary site, 5%
University of Washington, Division of Dermatology, Seattle, Washington 98109, USA.
BACKGROUND: Merkel cell carcinoma (MCC) is an aggressive skin cancer with a mortality of 33%. Advanced disease at diagnosis is a poor prognostic factor, suggesting that earlier detection may improve outcome. No systematic analysis has been published to define the clinical features that are characteristic of MCC.
OBJECTIVE: We sought to define the clinical characteristics present at diagnosis to identify features that may aid clinicians in recognizing MCC.
METHODS: We conducted a cohort study of 195 patients given the diagnosis of MCC between 1980 and 2007. Data were collected prospectively in the majority of cases, and medical records were reviewed.
RESULTS: An important finding was that 88% of MCCs were asymptomatic (nontender) despite rapid growth in the prior 3 months (63% of lesions) and being red or pink (56%). A majority of MCC lesions (56%) were presumed at biopsy to be benign, with a cyst/acneiform lesion being the single most common diagnosis (32%) given. The median delay from lesion appearance to biopsy was 3 months (range 1-54 months), and median tumor diameter was 1.8 cm. Similar to earlier studies, 81% of primary MCCs occurred on ultraviolet-exposed sites, and our cohort was elderly (90% >50 years), predominantly white (98%), and often profoundly immune suppressed (7.8%). An additional novel finding was that chronic lymphocytic leukemia was more than 30-fold overrepresented among patients with MCC.
LIMITATIONS: The study was limited to patients seen at a tertiary care center. Complete clinical data could not be obtained on all patients. This study could not assess the specificity of the clinical characteristics of MCC.
CONCLUSIONS: To our knowledge, this study is the first to define clinical features that may serve as clues in the diagnosis of MCC. The most significant features can be summarized in an acronym: AEIOU (asymptomatic/lack of tenderness, expanding rapidly, immune suppression, older than 50 years, and ultraviolet-exposed site on a person with fair skin). In our series, 89% of primary MCCs had 3 or more of these findings. Although MCC is uncommon, when present in combination, these features may indicate a concerning process that would warrant biopsy. In particular, a lesion that is red and expanding rapidly yet asymptomatic should be of concern.VAGINA
- Primary Neuroendocrine Carcinoma of the Vagina With Merkel Cell Carcinoma Phenotype.
Coleman NM, Smith-Zagone MJ, Tanyi J, Anderson ML, Coleman RL, Dyson SW, Reed JA.
*Departments of Pathology daggerDermatology double daggerObstetrics and Gynecology, Baylor College of Medicine, Houston, TX section signDepartments of Gynecologic Oncology perpendicularPathology and Dermatology, University of Texas M.D. Anderson Cancer Center, Houston, TX.
Am J Surg Pathol. 2006 Mar;30(3):405-410. Abstract quote
We describe a case of primary neuroendocrine carcinoma arising from the anterior vaginal wall of a 67-year-old woman. Primary neuroendocrine carcinoma of the vagina is a rare entity with only 25 previously reported cases in the literature.
In previous reports, these tumors have not been distinguished from primary neuroendocrine carcinoma of the skin (Merkel cell carcinoma). The tumor was composed of cells that showed neuroendocrine-type nuclear features with hyperchromasia, nuclear molding, occasional small nucleoli, and a chromatin pattern that was finely granular. The tumor cells were positive for cytokeratin 20 (CK20), neuron specific enolase, pancytokeratin, epithelial membrane antigen, and chromogranin A expression. Ki-67, a marker of proliferation, was also positive in>90% of cells. The tumor cells showed intense expression of Bcl-2 oncoprotein and mild to moderate expression of c-KIT. Synaptophysin, neurofilament, CD45, CD56, CD10, S-100, HMB-45, cytokeratin 7, and thyroid transcription factor 1 were negative. This pattern of staining is consistent with a Merkel cell carcinoma.
This is the first report of a primary neuroendocrine carcinoma of the vagina with a Merkel cell phenotype. Previous studies have not distinguished primary neuroendocrine carcinoma of the vagina from Merkel cell carcinoma of the skin. Positive expression of CK20 in primary small cell carcinoma of the vagina might represent a Merkel cell carcinoma subtype of this tumor.
HISTOLOGICAL TYPES CHARACTERIZATION GENERAL VARIANTS CYST
Department of Dermatology, Fundación Jiménez Díaz, Universidad Autónoma, Madrid, Spain.
Merkel cell carcinoma is a rare cutaneous neoplasm of unknown histogenesis. Several reports have described the association of Merkel cell carcinoma of the skin with other cutaneous neoplasms within the same lesion, and there are also reports describing three examples of Merkel cell carcinoma within follicular cysts.
We describe two examples of Merkel cell carcinoma developed within epithelial cysts. Neoplastic cells of Merkel cell tumor expressed immunoreactivity for chromogranin, synaptophysin, neuron-specific enolase, CAM 5.2 and cytokeratin 20, the last two markers showing the characteristic paranuclear dot-like pattern. In contrast, the epithelial wall lining the cyst and surrounding Merkel cell tumor only expressed immunoreactivity for cytokeratin MNF116.
The description of five cases of Merkel cell carcinoma within follicular cysts, including the two cases of this report, support some relationship between Merkel cell tumor and the hair follicle.Combined neuroendocrine carcinoma of the skin (Merkel cell tumor) and trichilemmal cyst.
Collina G, Bagni A, Fano RA.
Sezione di Anatomia Patologica, Dipartimento di Scienze Morfologiche e Medico Legali, Universita di Modena, Italy.
Am J Dermatopathol 1997 Oct;19(5):545-8 Abstract quote
We report a case of neuroendocrine (Merkel cell) carcinoma (NC) of the skin, associated with a trichilemmal cyst, showing pagetoid spread into the trichilemmal epithelium. The association of the two lesions may strengthen the hypothesis that NC originates from pluripotent stem cells of adnexal epithelium.
ECCRINE
Department of Pathology, Instituto Nacional de Ciencias Medicas y Nutrición Salvador Zubirán of Mexico City, Tlalpan, CP 14000, Mexico.
We described 7 examples of Merkel cell carcinoma of the skin with eccrine and squamous differentiation. Five patients were men, and 2 were women; and their ages ranged from 63 to 81 years (mean age, 73 years). Six tumors arose in the head and neck; and one, on the sole of the right foot. Three tumors recurred locally, and 2 metastasized to the regional lymph nodes. No patient developed distant metastasis. Two patients died of unrelated causes. Five Merkel cell carcinomas showed classic cytology, and 2 were similar to small cell carcinomas of the lung. All 7 tumors showed small eccrine ducts, and 2 exhibited foci of squamous differentiation. The eccrine ducts label with cytokeratin 7 and carcinoembryonic antigen, whereas the predominant endocrine component displayed the characteristic paranuclear dot-like reactivity with cytokeratin 20 and was synaptophysin and chromogranin positive. The lymph node metastasis contained both eccrine ducts and squamous elements, suggesting that they are an integral component of the tumors.
Eccrine differentiation in Merkel cell carcinomas similar to small cell carcinomas of the lung and extrapulmonary sites is an important feature in the differential diagnosis because eccrine differentiation has not been described in primary or metastatic small cell carcinomas.
The prognosis of these Merkel cell carcinomas with divergent differentiation appears to be less aggressive than that of pure Merkel cell carcinomas. However, larger series of patients with longer follow-ups are needed to confirm this observation.REGRESSION Regressing Merkel cell carcinoma-a case showing replacement of tumour cells by foamy cells.
Maruo K, Kayashima KI, Ono T.
Department of Dermatology, Kumamoto University School of Medicine, Kumamoto 860-0811, Japan.
Br J Dermatol 2000 Jun;142(6):1184-9 Abstract quote
Merkel cell carcinoma (MCC) is a malignant neuroendocrine tumour with a high rate of recurrence and metastasis. However, some cases of spontaneous regression have recently been reported.
We describe the clinical course of an 80-year-old Japanese woman with regressing MCC. We also report histological findings of the regressing tumour for the first time.
After the patient's first visit to our hospital, the lesion was a rapidly progressive tumour, but suddenly began decreasing in size, and rapidly regressed. The surface of the tumour flattened, the colour changed from red to dark red, and finally the lesion appeared as a small yellowish plaque. Histopathological analysis of the completely regressed tumour revealed that the tumour cells were completely replaced by numerous foamy cells.
This is the first report demonstrating the histopathological features of regressing MCC.
PAGETOID (INTRAEPIDERMAL)
- Merkel cell carcinoma in situ.
Ferringer T, Rogers HC, Metcalf JS.
MUSC Pathology and Lab Medicine, Charleston, SC, USA
J Cutan Pathol. 2005 Feb;32(2):162-5. Abstract quote
Background: Merkel cell carcinoma (MCC) is a dermal small blue-cell tumor that occurs in the elderly on the sun damaged head and neck. Epidermal involvement is unusual and MCC limited to the epidermis is very rare.
Case report: A slightly tender pink hyperkeratotic papule was noted on the dorsal right hand of a 76-year-old man with a history of multiple skin cancers. An intraepidermal proliferation of small blue cells distributed in nests and single units at all levels of the epidermis was found within a solar keratosis and adjacent to an area of squamous cell carcinoma in situ. Cytokeratin 20 and neuron specific enolase highlighted these cells and failed to reveal dermal involvement. There was no residue on re-excision.
Conclusion: We report the third case of MCC in situ. These lesions have only been reported in association with squamous neoplasms on the extremities.A case of intraepidermal Merkel cell carcinoma within squamous cell carcinoma in-situ: Merkel cell carcinoma in-situ?
Al-Ahmadie HA, Mutasim DF, Mutema GK.
Department of Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA
Am J Dermatopathol. 2004 Jun;26(3):230-3. Abstract quote
We report a case of a 79-year-old Caucasian male who presented with a wrist lesion of combined intraepidermal Merkel cell carcinoma and squamous cell carcinoma in-situ.
The two tumors were tightly admixed and distinct, and both were without any dermal or invasive components. No features of transition between the two tumors were seen.
We suggest the term Merkel cell carcinoma in situ for tumors that demonstrate exclusive intraepidermal proliferation of neuroendocrine cells.
Pagetoid intraepidermal spread in Merkel cell (primary neuroendocrine) carcinoma of the skin.
LeBoit PE, Crutcher WA, Shapiro PE.
Department of Pathology, University of California, San Francisco 94143-0506.
Am J Surg Pathol 1992 Jun;16(6):584-92 Abstract quote
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.
Pagetoid Merkel cell carcinoma: epidermal origin of the tumor.
Hashimoto K, Lee MW, D'Annunzio DR, Balle MR, Narisawa Y.
Department of Dermatology and Syphilology, Wayne State University School of Medicine, Detroit, MI, USA.
J Cutan Pathol 1998 Nov;25(10):572-9 Abstract quote
We report a case of intraepidermal Merkel cell carcinoma which occurred on the face of a 76-year-old white male.
This slow-growing tumor was mostly confined in the epidermis and pilosebaceous apparatus where tumor cells spread in a pagetoid fashion forming tumor cell nests. Histologically it resembled a superficial spreading melanoma. A heavy lymphocytic infiltration was seen beneath the epidermal lesion as is often seen in pagetoid melanomas. Histochemical and ultrastructural features such as the presence of cytokeratin 20, synaptophysin, neuron specific enolase, desmosomes, and dense cored granules confirmed the diagnosis of Merkel cell carcinoma. Occasional mitotic cells and many apoptotic cells were found in the tumor. Dylon positive, amyloid depositions were seen in the lower epidermis and papillary dermis; they were probably derived from apoptotic tumor cells. It was thought that apoptosis limited the speed of growth of this tumor.
We believe that this is probably the most convincing case of intraepidermal Merkel cell carcinoma originating from epidermal Merkel cells or its precursors (stem cells).
Intraepidermal Merkel cell carcinoma with no dermal involvement.
Brown HA, Sawyer DM, Woo T.
Department of Pathology and Laboratory Medicine/Faculty of Medicine, University of Calgary, Alberta, Canada.
Am J Dermatopathol 2000 Feb;22(1):65-9 Abstract quote
Cutaneous Merkel cell carcinoma (MCC) typically involves the dermis. Less than 10% of MCC have epidermal involvement. Only one MCC confined exclusively to the epidermis has been previously reported but was not recognized until the lesion recurred with typical MCC in the dermis.
We present a case of a wholly intraepidermal pagetoid MCC without dermal involvement in a 74-year-old man with a 2.0-cm solitary verrucous papule on the left index finger. The initial biopsy and complete excision specimens showed marked epidermal hyperplasia, focal prominent squamous cell atypia, and MCC with florid pagetoid spread through the epidermis. There was no evidence of tumor within the dermis. The pagetoid MCC tumor cells showed diffuse cytoplasmic staining with antibodies to cytokeratin 20, and negative staining for chromogranin, neurofilament, S-100, vimentin, HMB45, leukocyte common antigen, and CD3. The cell of origin of MCC is still debated.
The existence of an entirely intraepidermal variant of MCC would lend support to the view that MCC is a neoplastic expression of Merkel cells in at least some cases. Dermal-based MCC is a high-grade primary cutaneous neoplasm, but MCC confined exclusively to the epidermis may have a better prognosis.
RHABDOMYOSARCOMA Merkel cell (primary neuroendocrine) carcinoma of the skin with nodal metastasis showing rhabdomyosarcomatous differentiation.
Fernandez-Figueras MT, Puig L, Gilaberte M, Del Carmen Gomez-Plaza M, Rex J, Ferrandiz C, Ariza A.
Department of Pathology, Hospital Universitari Germans Trias i Pujol, Badalona; Department of Dermatology, Hospital de la Santa Creu i Sant Pau, Barcelona; and Department of Dermatology, Hospital Universitari Germans Trias i Pujol, Badalona, Spain.
J Cutan Pathol 2002 Nov;29(10):619-22 Abstract qutoe BACKGROUND: We describe a unique case of Merkel cell (primary neuroendocrine) carcinoma of the skin with a lymph node metastasis showing rhabdomyosarcomatous differentiation. Skeletal muscle differentiation has occasionally been described in primary small cell neuroendocrine carcinomas and considered a form of dual differentiation rather than a collision tumor. In the present case, capacity for divergent differentiation appeared late in the course of the tumor, which suggests a clonal origin for both components of the neoplasm.
CONCLUSIONS: The coexistence of neural and rhabdomyoblastic types of differentiation, best epitomized by the Triton tumor, has been construed as the product of dual differentiation of cells originated from neural crest-derived ectomesenchyme. Since Merkel cells seem to originate from a pluripotential primitive keratinocyte and not from the neural crest, rhabdomyoblastic differentiation in a metastasis of primary neuroendocrine carcinoma of the skin probably reflects the close proximity between the programs of neural and skeletal muscle differentiation, which would have been sequentially activated in the case we are reporting.
SQUAMOUS Squamous and atypical fibroxanthoma-like differentiation in successive local tumor recurrences Am J Dermatopathol 2001;23:46-49
Local recurrence 3 years later with large cell squamous changes
Recurrence 2 years later after radiation therapy with AFX areas
VASCULAR CHANGES
Academy of Postgraduate Education of Belarus, Minsk, Republic of Belarus.
Although prominent vascular proliferation is a known feature of various neuroendocrine tumors, it has not been systematically studied in Merkel cell carcinoma (MCC) of the skin.
The purpose of this study was to fully characterize the light microscopic, immunohistochemical, and ultrastructural features of vascular changes associated with MCC and to determine their frequency and differential diagnostic implications. Additionally, the presence of human herpesvirus 8 DNA in the lesional tissue was investigated. Of 92 studied cases of MCC, 18 cases (20%) were found to exhibit foci of prominent vascular changes which were classified into the following 6 patterns: pericyte hyperplasia, pyogenic granuloma-like, hemangioendothelioma-like, epithelioid hemangioma-like, peliosis-like, and follicular dendritic cell tumor-like pattern. In addition, Azzopardi phenomenon was observed. These changes occurred singly or in combination. Human herpesvirus 8 DNA was identified by polymerase chain reaction in none of the 18 cases. It is concluded that prominent vascular proliferations may be seen in 20% of MCC, and thereby, MCC resembles neuroendocrine tumors in other organs.
When unduly prominent and encountered in a limited biopsy specimen, vascular alterations may represent a potential diagnostic pitfall, but, on the other hand, they themselves may serve as a clue to the correct diagnosis. Human herpesvirus 8 does not play a role in angiogenesis in MCC.
SPECIAL STAINS/
IMMUNOPEROXIDASE/
OTHERCHARACTERIZATION Special stains Immunoperoxidase Cytokeratins, epithelial membrane antigen
Neuron-specific enolase, chromogranin, synaptophysinCytokeratin 20 (presence of dotlike perinuclear positivity)
CD56
J Cutan Pathol. 2005 Sep;32(8):541-5. Abstract quote
Background: Antibodies to CD56 label natural killer (NK) cell lymphomas and neuroendocrine tumors such as Merkel cell carcinoma (MCC). In MCC altered by crush artifact or obscured by lymphocytes, the histologic features coupled with CD56 positivity can lead to an erroneous impression of NK-cell lymphoma.
Methods: Eighteen cases of MCC were stained for CD56, CK20, MNF116, and pankeratin. The results were compared to histologic features and CD56 staining pattern of three NK-cell lymphomas.
Results: Three of 18 cases of MCC histologically resembled lymphoma, and CD56 positivity with CD3 and CD20 negativity initially raised the possibility of NK-cell lymphoma. Two additional cases were obscured by dense inflammation, again suggesting the diagnosis of lymphoma. Seventeen of 18 MCC labeled for CD56 and an equal number stained for CK20. All MCC tested were positive for CAM5.2 (14/14) and MNF116 (17/17). Antibodies to pankeratin labeled only one of 18 MCC. Staining for CD56 was stronger in MCC than NK-cell lymphomas.
Conclusions: CD56 is a sensitive marker for MCC as well as for NK-cell lymphoma, but is not specific. Importantly, CD56 positivity in crushed or inflamed biopsies of MCC may lead to an erroneous impression of NK lymphoma. Awareness of this potential pitfall will prevent misdiagnosis.CD99 CD99 and cytokeratin-20 in small-cell and basaloid tumors of the skin.
Nicholson SA, McDermott MB, Swanson PE, Wick MR.
Division of Surgical Pathology, Washington University Medical Center, St. Louis, Missouri, USA.
Appl Immunohistochem Molecul Morphol 2000 Mar;8(1):37-41 Abstract quote
Although it is classically a deep soft-tissue tumor of childhood, primitive neuroectodermal tumor (PNET) can occur at any age and may occasionally involve cutaneous sites. Merkel cell carcinoma (MCC) and basaloid neoplasms of cutaneous adnexa are the principal diagnostic alternatives to that tumor. The common expression of CD99 in PNET and cytokeratin-20 (CK20) in MCC suggests that these markers may be of value in this diagnostic setting, but they have not been rigorously examined in other small-cell and basaloid lesions of the skin.
Accordingly, we evaluated CD99 and CK20 reactivity in formalin-fixed, paraffin-embedded sections of 30 MCC, five cutaneous metastases of pulmonary small-cell neuroendocrine carcinomas, 10 primary cutaneous adnexal carcinomas with basaloid features, 18 benign basaloid adnexal neoplasms of the skin (nine spiradenomas and nine cylindromas), and two cutaneous PNETs, using a standard immunohistologic technique and microwave-mediated epitope retrieval. Of the 30 MCC, 12 showed crisp membrane staining for CD99. Among the remaining tumors, only the two PNETs were positive for that marker. Although the majority of MCCs did not label for CD99, the pattern of reactivity in positive cases was indistinguishable from that observed in PNETs. Eighteen of 27 MCCs that were stained for CK20 were reactive for that protein, in contrast to metastatic small cell carcinomas, cutaneous PNETs, and appendageal skin tumors, which were uniformly negative for this marker. However, a subset of nine tumors, which were most consistent with MCC on clinical grounds, was CD99 positive and CK20 negative.
Hence, reliance on CD99 alone as a diagnostic marker for PNET in this context cannot be recommended. Rather, careful assessment of the clinical presentation, together with extended immunophenotyping that includes other lineage markers and, when possible, cytogenetic analysis for characteristic chromosomal aberrations, remains the best means of separating MCC from PNET. Finally, the lack of CD99 reactivity in basaloid adnexal neoplasms of the skin suggests a utility in their differential diagnosis from cutaneous tumors with neuroendocrine or neuroectodermal differentiation.
CD117
- c-kit expression in primary and metastatic merkel cell carcinoma.
Feinmesser M, Halpern M, Kaganovsky E, Brenner B, Fenig E, Hodak E, Sulkes J, Okon E.
Department of Pathology, Rabin Medical Center, Beilinson and Golda Campuses, Petah Tiqva, and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
Am J Dermatopathol. 2004 Dec;26(6):458-62. Abstract quote
Merkel cell carcinoma (MCC) is an aggressive neuroendocrine tumor of the skin that is associated with a high incidence of recurrence and metastasis. The therapeutic arsenal for this malignancy is limited and once it spreads, there is no effective treatment. c-kit expression has been demonstrated previously in primary MCCs thus raising the possibility of treating MCCs with imatinib mesylate, the tyrosine kinase inhibitor that has shown promise in the management of c-kit expressing tumors.
In this study we examine 25 additional primary MCCs and also 6 of their lymph node metastases. Formalin-fixed, paraffin-embedded tissues were stained immunohistochemically with an antibody directed against the KIT receptor. Percentage and intensity of staining were analyzed semiquantitatively using a three-tiered system. Twenty-one of the 25 (84%) primary tumors stained positively for KIT, of which 14 (67%) showed widespread positivity. Five of the 6 lymph nodes (83%) were similarly positive. High mitotic rate and vascular invasion in the primary tumors tended to be associated with prominent staining in the lymph node metastases. No association was found between c-kit expression and outcome.
We confirm that the majority of primary MCCs express c-kit and further find that metastases are positive for the KIT receptor as well. Thus, c-kit expression may be an early event in the transformation of MCC, but not a marker for tumor progression.
CD117, CK20, TTF-1, and DNA topoisomerase II- antigen expression in small cell tumors
David T. Yang, Joseph A. Holden1 and Scott R. Florell
Journal of Cutaneous Pathology
Volume 31 Issue 3 Page 254 - March 2004 Abstract quote
Background: Distinguishing merkel cell carcinoma (MCC), small cell lung carcinoma (SCLC) metastatic to the skin, and atypical basal cell carcinoma (BCC) can be problematic in some cases. Significant differences in the biology of these tumors necessitate that they need to be distinguished from one another.Methods: We evaluated the immunophenotypic characteristics of 22 MCCs, nine SCLCs, and 19 BCCs using antibodies to cytokeratin 20 (CK20), thyroid transcription factor-1 (TTF-1), CD117, and DNA topoisomerase II- (topo II).
Results: Nineteen of 22 MCCs stained with the antibody to CK20, none stained with anti-TTF-1, and 13 stained with anti-CD117. No SCLC stained with anti-CK20, all stained with anti-TTF-1, and eight stained with anti-CD117. No BCC stained with any of the three markers. The proliferative index (PI), determined by the expression of topo II, was similar for SLCLs (mean 58.5 ± 9.0%) and MCCs (mean 45.2 ± 12.4%) and was lowest in BCCs (mean 25.0 ± 8.7%).
Conclusions: CK20 and TTF-1 appear to be reliable in distinguishing MCC from SCLC. CD117 is expressed in both MCC and SCLC, limiting its diagnostic utility. CK20, TTF-1, and CD117 are not expressed in BCC. The high PI seen in MCCs suggests a role for topoisomerase II inhibitors in their treatment.
CD117 (KIT Receptor) Expression in Merkel Cell Carcinoma.
Su LD, Fullen DR, Lowe L, Uherova P, Schnitzer B, Valdez R.
Department of Pathology (L.D.S., D.R.F., L.L., P.U., B.S., R.V.) and Dermatology (L.D.S., D.R.F., L.L.), University of Michigan Medical Center, Ann Arbor, Michigan, U.S.A.
Am J Dermatopathol 2002 Aug;24(4):289-93 Abstract quote The KIT receptor tyrosine kinase (CD117 antigen) is found in a variety of normal tissue cell types and in several malignant tumors, including acute myeloid leukemia. We recently encountered two tumors initially suspected as acute myeloid leukemia cutis and expressing CD117 that showed punctate positivity for cytokeratin 20 diagnostic for Merkel cell carcinoma.
We evaluated 20 additional cases of MCC and found that 21 of 22 tumors (95%) expressed CD117. Intensity of CD117 expression did not appear to correlate with aggressive behavior. While the function of the KIT receptor in MCC is not known, its pathogenic role in other malignant neoplasms suggests the possibility of a similar role in MCC.
CD171
Adhesion molecules CD171 (L1CAM) and CD24 are expressed by primary neuroendocrine carcinomas of the skin (Merkel cell carcinomas).Deichmann M, Kurzen H, Egner U, Altevogt P, Hartschuh W.
Department of Dermatology, Heidelberg University Clinics, and Tumor immunology programme, German Cancer Research Centre, Heidelberg, Germany.
J Cutan Pathol. 2003 Jul;30(6):363-8 Abstract quote 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.
CK 20
A case series and immunophenotypic analysis of CK20-/CK7+ primary neuroendocrine carcinoma of the skin.University of South FLorida College of Meidcine Department of Pathology, Tampa, FL, USA.
Background: The diagnosis of Merkel cell carcinoma (MCC) can be rather challenging; therefore, the immunohistochemical profile is important in confirming the microscopic diagnosis. Characteristic of the neuroendocrine and epithelial differentiation of MCC, antibodies to cytokeratin (CK) 20, CK7, epithelial membrane antigen, and neuron-specific enolase among others, are used in confirming the diagnosis. As reported in the literature, the majority of MCC express CK20 and are CK7 negative. Herein, we present a case series of seven patients with CK20-/CK7+ primary cutaneous neuroendocrine carcinoma. Methods: All cases of MCC with specific CK20-/CK7+ staining on file at a large Veterans' hospital and tertiary referral dermatopathology service were reviewed. All seven cases were analyzed for clinical, pathologic and immunophenotypic attributes. All specimens were submitted for immunohistochemical staining and interpreted by a single dermatopathologist.
Results: All the cases showed diffuse cytoplasmic staining for CK7 and positive staining for synaptophysin. CK20 and thyroid transcription factor-1 staining was negative.
Conclusions: Herein we have presented a hitherto unreported group of patients with CK20-/CK7+ primary neuroendocrine carcinoma of the skin. The purpose of this case series is to describe a new immunophenotypic variant of MCC, while further expanding the differential diagnosis of tumors included in the subset of neoplasms showing CK20-/CK7+ staining.
Immunostaining for cytokeratin 20 improves detection of micrometastatic Merkel cell carcinoma in sentinel lymph nodes.Su LD, Lowe L, Bradford CR, Yahanda AI, Johnson TM, Sondak VK.
Departments of Pathology, Dermatology, Otorhinolaryngology, and Surgery (Division of Surgical Oncology and Division of Plastic Surgery), the University of Michigan Comprehensive Cancer Center, and the University of Michigan Health System.
J Am Acad Dermatol 2002 May;46(5 Pt 1):661-6 Abstract quote BACKGROUND: Sentinel lymph node biopsy (SLNBx) can identify Merkel cell carcinoma (MCC) micrometastasis.
OBJECTIVE: We attempted to examine the effectiveness of immunostaining and identify antibodies most appropriate for evaluation of SLNBxs for MCC.
METHODS: Histopathologic material from 10 patients with MCC who had SLNBx was reviewed.
RESULTS: Twenty-three SLNBxs from 10 patients appeared tumor-free in routine hematoxylin-eosin (H&E)-stained sections. However, tumor cells were detected in immunostained sections from 5 (22%) of 23 SLNBxs in 4 (40%) of 10 patients. Immunostains with pancytokeratin (panCK), cytokeratin-20 (CK-20), neurofilament protein, and chromogranin A were used for all primary and SLNBx specimens. All 5 (100%) micrometastatic foci stained strongly for CK-20 and panCK. Background normal lymph node tissue also stained for panCK but not for CK-20.
CONCLUSION: Examination of H&E sections alone is insufficient for excluding micrometastatic MCC in sentinel lymph nodes. We observed the greatest sensitivity and specificity with anti-CK-20 antibody in identifying micrometastatic MCC in sentinel lymph nodes.
COX-2
- Cyclooxygenase-2 expression in primary Merkel cell carcinoma.
Koljonen V, Lassus P, Tukiainen E, Ristimaki A, Haglund C, Bohling T.
Department of Plastic Surgery, Helsinki University Hospital, Helsinki University, Helsinki, Finland.
J Cutan Pathol. 2005 Jan;32(1):55-8. Abstract quote
Background: Merkel cell carcinoma (MCC) is a highly malignant neuroendocrine skin tumor. The typical course of MCC is rapid progression of the primary tumor and metastatic dissemination to the regional lymph nodes. Thus far, no biological, prognostic marker has been established for this aggressive neoplasm. Cyclooxygenase-2 (Cox-2) is undetectable in most normal tissues, but it is induced in various cell types by inflammation and carcinogenesis. Although the expression and function of Cox-2 have been studied extensively in several carcinomas, little is known about Cox-2 expression in neuroendocrine carcinomas. The aim of the present report was to study Cox-2 expression in MCC and find out whether this expression correlates with outcome.
Methods: Immunohistochemical analysis for Cox-2 was performed on 22 primary MCC samples.
Results: Almost 70% of the samples showed positive staining. Protein expression of Cox-2 was sparse and low in intensity. We found a tendency for enhanced Cox-2 expression in tumors located in sun-exposed areas. Cox-2 expression had no significant statistical correlation with clinical parameters.
Conclusions: MCC expresses Cox-2 in low levels, and the expression did not prove to be a prognostic factor. Furthermore, the low expression suggests that the primary treatment option for MCC is not therapeutic inhibition of Cox-2.PAX-5
- B-Cell Specific Activation Protein Encoded by the PAX-5 Gene Is Commonly Expressed in Merkel Cell Carcinoma and Small Cell Carcinomas.
Dong HY, Liu W, Cohen P, Mahle CE, Zhang W.
From Genzyme Genetics/IMPATH, New York, NY.
Am J Surg Pathol. 2005 May;29(5):687-92. Abstract quote
PAX-5 is a B cell specific transcription factor crucial for B cell ontogeny and has been detected in most of human B-cell lymphomas. In mouse, PAX-5 is also highly expressed in the central nervous system under tight temporal and spatial controls during embryogenesis. In humans, however, detection of PAX-5 in cells other than B lymphocytes has rarely been reported.
We have encountered cases of Merkel cell carcinoma expressing PAX-5 during our routine evaluation of lymphoma. Because Merkel cell carcinoma is a small blue round cell tumor constantly in the differential diagnosis of lymphoma, we expanded our study in an effort to determine if PAX-5 is significantly expressed in neuroendocrine tumors. Based on our immunohistochemistry results using a monoclonal anti-PAX5 antibody with paraffin-embedded tissue sections, we report herein that PAX-5 was detected in 29 of 31 (93.5%) of Merkel cell carcinoma and 22 of 30 (73.3%) of small cell carcinoma, but in none of 17 cases of carcinoid tumor. Furthermore, the staining intensity of PAX-5 in Merkel cell carcinoma was frequently comparable with that in most B-cell lymphomas.
We conclude that expression of PAX-5 is not confined to the B cell lineage and is frequently associated with neuroendocrine carcinomas.TdT
1Division of Anatomical Pathology, Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada.
Merkel cell carcinoma is an uncommon aggressive primary cutaneous neuroendocrine carcinoma. Histologically, the differential diagnosis includes the 'small round cell' tumor group, particularly metastatic small cell carcinoma and blastic hematological malignancies involving skin/soft tissues. Terminal deoxynucleotidyl transferase (TdT) is a DNA polymerase, which is a sensitive and specific antibody for acute lymphoblastic lymphoma with a small proportion of acute myeloid leukemia showing positivity.
This study investigates the expression of TdT in 20 cases with initial diagnosis of Merkel cell carcinoma. Archival blocks and slides were retrieved and reviewed and clinical information obtained from patient charts. Immunohistochemistry was performed and graded as: 0, no staining; 1+, less than 50% staining in the cells; 2+, 50% or more staining in the cells. After review, 15 cases were confirmed as Merkel cell carcinoma.
Immunohistochemical positivity was as follows: 8/15 cases were positive for TdT with strong nuclear staining, morphologically resembling 'blasts', AE1AE3, CAM5.2 (15/15) (both membrane and paranuclear dot positivity), CD56 and BCL-2 (15/15), Synaptophysin (13/15), Chromogranin A (11/15), NSE (15/15), CK20 (14/15), CK7 (3/15), both CK7 and CK20 (3/15), CD117 (8/15), CD99 (2/15), CD10 (1/15). One case was negative for CK7/CK20. All 15 cases were negative for thyroid transcription factor-1, LCA, CD20, CD3 and CD34. Expanded immunohistochemical panel with positive staining for epithelial/neuroendocrine markers, CK20, negative staining for hematolymphoid markers and awareness of TdT expression and other markers that show overlap with blastic hematological malignancies avoids misinterpretation in the diagnosis of Merkel cell carcinoma.
This aids in further diagnosis of Merkel cell carcinoma, avoiding the potential diagnostic pitfall with other small round cell tumors and hematological malignancies primary or metastatic to the skin.TTF-1 (THYROID TRANSCRIPTION FACTOR1-)
St. Andrew's Centre for Plastic Surgery, Broomfield Hospital, Chelmsford, Essex, United Kingdom.
We report on a case of metastatic Merkel cell carcinoma in a 74-year-old patient with positive staining for thyroid transcription factor-1.
This represents a new immunohistochemical staining pattern for Merkel cell carcinoma and has implications regarding the accurate diagnosis of this tumor type.Electron microscopy (EM) Cytoplasmic, peripherally placed, dense-core granules (80-120 nm) and paranuclear fibrous bodies (aggregates of intermediate filament)
DIFFERENTIAL DIAGNOSIS KEY DIFFERENTIATING CHARACTERISTICS BASAL CELL CARCINOMA
Departments of Pathology and Dermatology, The University of British Columbia and Vancouver General Hospital, Vancouver, British Columbia, Canada.
Background: Merkel cell carcinoma (MCC) is a basaloid cutaneous neoplasm that may be mistaken for basal cell carcinoma (BCC).
Methods: Thirty MCCs were examined for areas that histologically resembled BCC.
Results: One of the histologic features of BCC (either a mucinous stroma or stromal artifactual retraction) was identified in all MCCs. A mucinous stroma was found in 28 MCCs (93%), stromal artifactual retraction in 27 (90%), mucin-containing gland-like spaces within tumor nests in 8 (27%), focal peripheral palisading in 8 (27%), epidermal involvement in 3 (10%) and dystrophic calcification in 1 MCC (3%). The cytologic features and absence of widespread peripheral palisading were the most reliable discriminators between MCC and BCC on routine sections. Squamous cell carcinoma was identified in four cases (13%). Two cases (7%) contained pagetoid intraepidermal spread (IES) of MCC. In one case, there was IES over the entire epidermal surface associated with intranuclear clearing, resembling the intranuclear cytoplasmic inclusions (INI) common in melanocytic tumors. INI were identified in six MCCs (20%).
Conclusions: MCCs frequently contain areas that histologically resemble BCC and other more common cutaneous malignancies. This can lead to diagnostic errors, particularly in small fragmented curettage specimens or frozen sections.LUNG, SMALL CELL CARCINOMA
- Immunohistochemical distinction between merkel cell carcinoma and small cell carcinoma of the lung.
Bobos M, Hytiroglou P, Kostopoulos I, Karkavelas G, Papadimitriou CS.
Department of Pathology, Aristotle University Medical School, Thessaloniki, Greece.
Am J Dermatopathol. 2006 Apr;28(2):99-104. Abstract quote
We assessed the usefulness of several immunohistochemical stains in distinguishing these two neoplasms, including cytokeratin 7, cytokeratin 20 (CK20), neuron-specific enolase, chromogranin, synaptophysin, neurofilaments (NF), thyroid-transcription factor-1 (TTF-1), CD56 antigen, S-100 protein, vimentin, c-erbB-2 oncoprotein, and CD117 antigen. All 13 cases of Merkel cell carcinoma evaluated were positive for CK20, and negative for TTF-1. Twelve of 13
Merkel cell carcinoma cases were positive for NF. Eleven of 13 cases of small cell lung carcinoma were positive for TTF-1. All small cell lung carcinoma cases were negative for NF, and all but one were negative for CK20. In terms of the remaining antigens, there were no differences of significance between the two neoplasms.
These findings suggest that a set of three immunohistochemical stains, including CK20, NF, and TTF-1, is useful in affording a distinction between Merkel cell carcinoma and small cell lung carcinoma.
PROGNOSIS AND TREATMENT CHARACTERIZATION Negative Prognostic Factors Large Cell size
Mitotic rate (>10/high-power field)
T umor size (>2 cm)
Nodal and systemic metastases are significant prognostic factorsQuestionable Prognostic Factors Bcl-2 (a proto-oncogene that inhibits programmed cell death) and p53 (tumor-suppressor gene) expression appears unrelated to survival
Cutaneous Pathology, Nedlands, Western Australia, Australia.
We examined the role of mast cell infiltrates and other clinical and histological factors in the prognosis of Merkel cell carcinoma. Mast cells were stained immunohistochemically in 36 Merkel cell carcinomas with an antibody to tryptase. The number of stainable cells was quantified within the tumors and surrounding stroma. Other clinical and histological parameters were examined, statistically analyzed, and compared to subsequent clinical course and prognosis. Patient prognosis was worse with higher tumor mast cell numbers (P < 0.002).
Prognosis was also found to be adversely affected by the presence of lymphovascular invasion (P = 0.03) and increased tumor size (P = 0.05). Increased mast cells counts, tumor size, and lymphovascular invasion are associated with an adverse prognosis in Merkel cell carcinomas.
Evaluation of mast cell infiltrates may provide useful prognostic data and ultimately could assist in selecting patients that require adjuvant treatment in this aggressive form of skin cancer.
- Merkel cell carcinoma: does tumor size or depth of invasion correlate with recurrence, metastasis, or patient survival?
Sandel HD 4th, Day T, Richardson MS, Scarlett M, Gutman KA.
Department of Otolaryngology, Head and Neck Surgery, Georgetown University Hospital, Washington, DC 20007, USA.
Laryngoscope. 2006 May;116(5):791-5. Abstract quote
OBJECTIVE: The objective of this retrospective study and literature review was to compare the clinical and histologic criteria including tumor size and depth of invasion with outcomes in patients with Merkel cell carcinoma.
METHODS: The state cancer registry provided patients (n = 46) diagnosed with Merkel cell carcinoma from 1992 through 2002. Pathology slides were reviewed by the author for tumor size, depth of invasion, Clark level, and margin status. Further clinical information and survival data were gathered from patient records. Statistical analysis was performed using t tests and Kaplan-Meier survival curves. Patients were excluded from specific analysis based on misdiagnosis, unavailability of pathology slides, absent medical records, or those lost to follow up.
RESULTS: Disease-free survival rates were 52%, 39%, and 9% at 1, 2, and 5 years, respectively. The average disease-free interval was 18.4 months (range, 1-80 months). No correlation was found between tumor size (P = .49), depth (P = .41), or Clark level (P = .82) to overall survival. A trend was found comparing tumor size or depth of invasion with local recurrence (P = .07) but with no correlation to regional recurrence (P = .93 and P = .60) or distant metastasis (P = .16 and P = .24). Overall recurrence was found in 60.7% of patients with local recurrence occurring in 18.1%, regional recurrence 40.9%, and distant recurrence 47.8%. Comparing patients with positive versus negative margins at initial excision, local recurrence was found in 33.3% versus 9.09% (P = .19), regional recurrence 66.6% versus 27.2% (P = .08), and distant metastasis 66.6% versus 45.4% (P = .36), respectively.
CONCLUSIONS: No correlation was found between tumor size or depth of invasion to patient survival or metastasis. However, there was a trend toward increased local and regional recurrence rates when comparing size and depth and in specimens with positive tumor margins. These outcomes are consistent with those reported in recent literature and further characterize the unpredictable nature of this disease. An aggressive approach should be taken, including wide local excision with negative tumor margins and lymph node dissection; however, larger multistate reviews are needed for additional support.
Merkel cell carcinoma: a clinicopathologic study with prognostic implications
Ryan T. Mott, Bruce R. Smoller and Michael B. Morgan.
Journal of Cutaneous Pathology Volume 31 Issue 3 Page 217 - March 2004 Abstract quote
Background: Merkel cell carcinoma (MCC) is a frequently aggressive neuroendocrine malignancy of the skin that presents in sun-exposed areas on elderly patients. Although originally described over 30 years ago, many aspects of MCC remain to be defined. Of particular importance is the need to identify prognostic factors capable of predicting the biological behavior of these tumors. Knowledge of these factors may help in determining which patients require more aggressive treatment regimens. In this study, we examined 25 cases of MCC with an attempt to identify clinical, histopathological, or immunohistochemical features capable of predicting disease outcome.Methods: Features that we evaluated in each case included age, gender, race, tumor location, tumor size, depth of invasion, growth pattern, lymphocytic infiltration, mitotic activity, ulceration, necrosis, vascular invasion, and perineural invasion. In addition, we examined neural cell adhesion molecule and cytokeratin-20 expression using immunohistochemical methods.
Results: We found that most patients were males (84%) with an average age of 74 years. The tumors were located on the head and neck (68%) and upper extremities (32%). Overall, 64% of the patients developed metastatic disease to regional lymph nodes or distant sites (average follow-up time of 21 months). Local recurrence was also common, occurring in 29% of the patients. The overall 1- and 2-year survival rates were 80 and 53%, respectively. Histopathological examination revealed tumors with an average size of 7.2 mm. Common features included invasion into the subcutaneous adipose tissue, solid growth pattern, tumor necrosis, and vascular and perineural invasion. Findings that had a statistically significant correlation with poor outcome included tumor size 5 mm (p = 0.047), invasion into the subcutaneous adipose tissue (p = 0.005), diffuse growth pattern (p = 0.040), and heavy lymphocytic infiltration (p = 0.017). The remaining findings, including the immunohistochemical results, did not correlate with disease outcome. Using logistic regression models, we show that depth of invasion and degree of lymphocytic infiltration are strong predictors of disease outcome.
Conclusions: The current controversies regarding the treatment of early-stage MCC (i.e., localized disease) underscore the importance of identifying clinicopathological features capable of predicting tumor behavior. In this study, we have identified several prognostic features in MCC. Perhaps, these features may prove useful in identifying patients who require more aggressive treatment regimens.
Primary neuroendocrine (Merkel cell) carcinoma of the skin: Morphologic diversity and implications thereof
Noreen M.G. Walsh, MD
Hum Pathol 2001;32:680-689. Abstract quote
A significant proportion of primary neuroendocrine cell carcinomas of the skin (Merkel cell carcinomas [MCCs]) have been reported to occur in intimate association with malignant epithelial neoplasms, mainly squamous cell carcinomas. In addition, divergent differentiation within these tumors, particularly of squamous and eccrine types, is not infrequent. This expanded morphologic spectrum of MCC calls for evaluation of potential biologic implications of the phenotypic diversity and begs reconsideration of the histogenesis of the lesion. The current retrospective review of 29 cases of primary cutaneous neuroendocrine cell carcinoma aims to address these issues by integrating new information with that which is extant. Eleven tumors were associated with evolving or established cutaneous carcinomas: 2 actinic keratoses, 5 Bowen's disease, 3 superficial squamous cell carcinomas, and 1 basal cell carcinoma. Two combined squamous-neuroendocrine tumors occurred in recipients of solid organ transplants, and another developed in a Marjolin's ulcer at the site of a previous burn. Squamous and/or adnexal differentiation within the dermal component of the tumor was observed in 4 instances and was significantly associated with MCCs in intimate association with another cutaneous carcinoma. The outcome of the group as a whole is similar to that recorded in previous series of MCC, with local recurrence in 32% of cases and death caused by the neoplasm in 28%. Only 52% of the patients were alive with no history of metastasis at follow-up. No significant difference in outcome was observed between the patients with pure MCCs and those with MCCs in combination with another cutaneous carcinoma.
Survival Distant metastasis and death occurs in one-third or more of cases Recurrence Local recurrences seen in up to one-third of cases Am J Dermatopathol 1997;19:614-618
Arch Dermatol 1991;127:550-553
J Dermatol 1998;25:45-50
Spontaneous regression reported in rare cases
METASTASIS Metastasis to regional lymph nodes may occur in up to 75% of cases Merkel cell carcinoma: a report of gastrointestinal metastasis and review of the literature.
Idowu MO, Contos M, Gill S, Powers C.
Department of Pathology, Medical College of Virginia Hospitals, Virginia Commonwealth University, Richmond 23298, USA.
Arch Pathol Lab Med 2003 Mar;127(3):367-9 Abstract quote Merkel cell carcinoma (MCC) is an uncommon, highly aggressive cutaneous neoplasm of neuroendocrine differentiation with a poor prognosis. MCC most often presents as a painless, firm, raised lesion in sun-exposed sites of the head and neck region of the elderly.
We report a case of a metastatic MCC to the stomach presenting as upper gastrointestinal bleeding.
To our knowledge, this is the second reported case of MCC presenting as upper gastrointestinal bleeding and the first case confirmed by the newer immunohistochemical techniques. The literature is reviewed.
TREATMENT GENERAL
University of Washington, Department of Dermatology, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
Merkel cell carcinoma (MCC) is a skin cancer with 30% mortality and an incidence that has tripled in the past 15 years. There is agreement that surgical excision with negative margins is an appropriate therapeutic first step and that sentinel lymph node biopsy is a powerful prognostic indicator. After excision of detectable cancer, optimal adjuvant therapy is not well established.
A role for adjuvant radiotherapy is increasingly supported by observational data. These data suggest that a regimen of surgery plus adjuvant radiotherapy is associated with both a lower loco-regional recurrence rate and longer overall survival when compared with surgery alone.
In contrast, a role for adjuvant chemotherapy is not well supported. The rationale for chemotherapy in this disease is based on small-cell lung cancer, a more common neuroendocrine tumor for which chemotherapy is the primary treatment modality. Several issues call into question the routine use of adjuvant chemotherapy in MCC: lack of evidence for improved survival; the associated morbidity and mortality; important differences between small-cell lung cancer and MCC; and rapid development of resistance to chemotherapy. Importantly, chemotherapy suppresses immune function that plays an unusually large role in defending the host from the development and progression of MCC.
Taken together, these arguments suggest that adjuvant radiation may be indicated for many MCC patients while adjuvant chemotherapy should largely be restricted to clinical trials.ALOE The effect of aloe emodin on the proliferation of a new merkel carcinoma cell line.
Wasserman L, Avigad S, Beery E, Nordenberg J, Fenig E.
Felsenstein Medical Research Center (L.W., S.A., E.B., J.N.) and Institute of Oncology (E.F.), Sackler Faculty of Medicine, Tel Aviv University, Rabin Medical Center Beilinson Campus, Petah Tikva 49100, Israel.
Am J Dermatopathol 2002 Feb;24(1):17-22 Abstract quote A free-floating cell line has been established from a metastatic lesion of a Merkel cell carcinoma (MCC) patient. The cell line was characterized by immunocytochemical reactions with antibodies against the epithelial and neuroendocrine antigens: cytokeratin 20, neuron-specific enolase, chromogranin A, neurofilament protein, synaptophysin, and calcitonin.
Karyotype analysis of the MCC cells showed deletion in chromosomes 3 and 7, loss of chromosome 10, and several translocations in other chromosomes. No mutation was detected in the TP53 gene, after analyzing the complete coding region. Growth factors such as basic fibroblast growth factor, transforming growth factor-beta, and nerve and epidermal growth factors had no effect on the proliferation of the cells. The differentiation-inducing agents sodium butyrate and dimethyl sulfoxide, especially the former, markedly inhibited the proliferation of the MCC cells.
Aloe emodin, a natural constituent of aloe vera leaves, significantly inhibited the growth of MCC cells. Aloe emodin has been reported to be nontoxic for normal cells but to possess specific toxicity for neuroectodermal tumor cells. Differentiation-inducing agents, and aloe emodin, merit further investigation as potential agents for treating MCC.
RADIATION
Radiotherapy alone for primary Merkel cell carcinoma.
Mortier L, Mirabel X, Fournier C, Piette F, Lartigau E.
Clinique de Dermatologie, Hopital Huriez, Centre Hospitalier Regional Universitaire de Lille, France.
Arch Dermatol. 2003 Dec;139(12):1587-90. Abstract quote
BACKGROUND: Merkel cell carcinoma is a rare and potentially aggressive cancer of the skin. Cumulative data from small retrospective series have supported treatment by wide excision and adjuvant radiotherapy. However, wide excision may be difficult to perform in patients with tumors of the head and neck or in older populations with comorbidities that may be incompatible with general anesthesia.
OBSERVATIONS: Nine patients (group 1) with stage I (without lymph node involvement) Merkel cell carcinoma primary tumors were treated in our center by radiotherapy alone. The rate of recurrence was compared between this group and 17 additional patients (group 2) with stage I Merkel cell carcinoma who received conventional treatment (surgery followed by radiotherapy).
RESULTS: The median follow-up was 3.0 years (range, 8 months to 7 years) for group 1 and 4.6 years (range, 5 months to 11 years) for group 2. During this period, we observed 1 relapse and 1 progression of disease in group 2. No statistical difference was found in overall and disease-free survival between the 2 groups of patients.
CONCLUSION: This study demonstrates the possibility of treating inoperable Merkel cell carcinoma by radiotherapy alone, with outcomes similar to those of classic treatment.
Local control of primary Merkel cell carcinoma: Review of 45 cases treated with Mohs micrographic surgery with and without adjuvant radiation.Boyer JD, Zitelli JA, Brodland DG, D'Angelo G.
National Naval Medical Center, Bethesda; Shadyside Hospital, Pittsburgh; and Pittsburgh Cancer Institute.
J Am Acad Dermatol 2002 Dec;47(6):885-92 Abstract quote BACKGROUND: Optimal treatment of primary Merkel cell carcinoma (MCC) is unknown. High local recurrence rates after excision alone compel some physicians to advocate postoperative radiation therapy to improve local control.
OBJECTIVE: We wondered whether marginal recurrence and survival rates differed between patients with primary MCC treated with Mohs surgery alone and those treated with Mohs surgery and adjuvant postoperative radiation.
METHODS: A collaborative retrospective study was performed; the study group consisted of 45 patients with stage I MCC who were histologically and clinically free of disease after Mohs excision. Twenty patients subsequently received elective postoperative radiation to the primary site, and 25 patients had no adjuvant radiation therapy.
RESULTS: One marginal recurrence (4%) and 3 in-transit metastases were observed in the Mohs surgery alone group, whereas none were observed in the Mohs surgery and radiation group. The proportion of patients with these events was not significantly different between treatment groups. Overall survival, relapse-free survival, and disease-free survival were not significantly different between treatment groups.
CONCLUSION: Adjuvant radiation appears unessential to secure local control of primary MCC lesions completely excised with Mohs micrographic surgery. Adjuvant radiation is recommended for patients unable to have complete excision or if complete histologic margin control is unavailable and should be considered for patients with large or recurrent tumors.
SENTINEL LYMPH NODE MAPPING Early experience with sentinel lymph node mapping for Merkel cell carcinoma
Lori K. E. Rodrigues, MD etal.
San Francisco, California, and Honolulu, Hawaii
J Am Acad Dermatol 2001;45:303-8 Abstract quote
Merkel cell or cutaneous neuroendocrine carcinoma is a malignant tumor with a propensity toward local and systemic recurrence. A new surgical technique, intraoperative lymphatic mapping and selective sentinel lymph node dissection (SSLND), has been demonstrated to have a high predictive value for the detection of metastatic disease in the regional lymphatic basin in cutaneous melanoma.
The use of this technology may be particularly useful to accurately stage patients with Merkel cell carcinoma (MCC) because this tumor has a frequent propensity toward regional nodal metastases. Intraoperative lymphatic mapping and SSLND were performed on 6 patients with biopsy-proven MCC. Three patients with MCC had positive disease in the sentinel lymph node(s).
SSLND is a feasible technique with minimal procedural morbidity to detect clinically occult disease in patients with MCC.
A Meta-analysis of the Prognostic Significance of Sentinel Lymph Node Status in Merkel Cell Carcinoma.Mehrany K, Otley CC, Weenig RH, Phillips PK, Roenigk RK, Nguyen TH.
Department of Dermatology, Mayo Clinic, Rochester, Minnesota.
Dermatol Surg 2002 Feb;28(2):113-7Abstract quote BACKGROUND: Merkel cell carcinoma is an aggressive cutaneous neoplasm with a high propensity to metastasize to lymph nodes.
OBJECTIVE: The objective of this study was to determine the prognostic significance of sentinel lymph node status in patients with Merkel cell carcinoma.
METHODS: A meta-analysis of case series of patients with Merkel cell carcinoma managed with sentinel lymph node biopsy was performed.
RESULTS: Forty of 60 patients (67%) had a biopsy-negative sentinel lymph node; 97% of this group had no recurrence at 7.3 months median follow-up. Twenty patients (33%) had a biopsy-positive sentinel lymph node; 33% of this group experienced local, regional, or systemic recurrence at 12 months median follow-up. Risk of recurrence or metastasis was 19-fold greater in biopsy-positive patients (odds ratio, 18.9; p = 0.005). None of 15 biopsy-positive patients who underwent therapeutic lymph node dissection experienced a regional recurrence; 3 of 4 who did not receive therapeutic lymphadenectomy experienced regional recurrence.
CONCLUSION: Sentinel lymph node positivity is strongly predictive of a high short-term risk of recurrence or metastasis in patients with Merkel cell carcinoma. Therapeutic lymph node dissection appears effective in preventing short-term regional nodal recurrence. Aggressive adjuvant treatment should be considered for patients with positive sentinel lymph nodes.
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Neurosecretory Granules -These are cytoplasmic ultrastructural organelles best viewed with an electron microscope. Their presence indicates neurosecretory differentiation and are one of the hallmarks of this cancer.
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