Recurrent primary cutaneous mucinous carcinoma with neuroendocrine differentiation: case report and review of the literature

We report the case of a 60‐year‐old woman presenting with primary cutaneous mucinous carcinoma (PCMC) with neuroendocrine differentiation, revealed by neuroendocrine tumor lymph node metastasis 7 years before identification of the skin tumor. Only five cases of PCMC with neuroendocrine differentiation have been reported to date. The frequency of this neuroendocrine component may be underestimated, as it can require immunohistochemistry for identification, rather than being obvious on initial histopathologic examination. In the case presented here, the prominent neuroendocrine component displayed the morphological features of a well‐differentiated neuroendocrine tumor with expression of common neuroendocrine markers, strong expression of estrogen and progesterone receptors and low Ki67 proliferation index (5%). This case shows that not all primary cutaneous neuroendocrine carcinomas are Merkel cell carcinomas (MCCs). In addition to rare primary cutaneous carcinoid tumors, the diagnosis of PCMC with neuroendocrine differentiation must be considered, particularly when confronted by a mucinous tumor or lymph node metastases of neuroendocrine carcinoma of unknown origin. On the basis of this case, identification of a neuroendocrine component in a PCMC might be an adverse prognostic indicator of recurrence or of lymph node metastasis and should support wider excision margins of the tumor.     

CD56: a useful marker for diagnosing Merkel cell carcinoma

BACKGROUND: Merkel cell carcinoma (MCC) of the skin is an aggressive but rare malignant neuroendocrine tumor. For its pathological diagnosis, we use a panel of immunohistochemical markers, such as cytokeratin 20 (CK 20), epithelial membrane antigen (EMA), chromogranin A, neuron specific enolase (NSE), synaptophysin, and Leu7 (CD57) to demonstrate its epithelial and neuroendocrine features. CD56, or neural cell adhesion molecule (NCAM), has been demonstrated recently as the tumor marker of the pulmonary neuroendocrine cell system. Its expression in MCC, however, has still rarely been investigated. Furthermore, in such very few previous studies on NCAM expression in MCC, all the tumor cells were not necessarily demonstrated to express NCAM. OBJECTIVES: To study the immunoreactivity of CD56 in MCC, especially using a monoclonal antibody of a clone 1B6, different from those adopted in the previous reports. METHODS: We reexamined CD56 expression immunohistochemically in five MCC cases, along with the conventional panel of markers described above, using paraffin-embedded tissue sections. RESULTS: CD56 revealed the most diffuse and intense positive staining, which was noted along the cell borders, in all specimens compared with other neuroendocrine tumor markers. CONCLUSIONS: The results of our study indicate that CD56, especially a new monoclonal antibody (clone 1B6), is a useful immunohistochemical marker for MCC.     

Cutaneous undifferentiated small (Merkel) cell carcinoma,that developed synchronously with multiple actinic keratoses,squamous cell carcinomas and basal cell carcinoma

Merkel Cell Carcinoma (MCC) is an uncommon undifferentiated neuroendocrine tumor, arising in skin mainly on sun-exposed areas. We present an unusual case of primary cutaneous undifferentiated small cell carcinoma that co-existed with six other lesions; 2 actinic keratoses, 3 squamous-cell carcinomas and a basal-cell carcinoma. HE stained sections revealed MCC located in the mid-dermis, co-existing with severe actinic keratosis. Immunohistochemically, the tumor cells reacted to cytokeratin 20, epithelial membrane antigen, chromogranin and neuron specific enolase. This is an unusual case of cutaneous MCC co-existing with six other different lesions. The concurrent development of MCC, squamous-cell and basal-cell carcinoma in the same patient indicates the pluripotent epidermal stem cell origin of these tumors. Further research is needed to enlighten the factors inducing this divergent differentiation.     

Expression of MUC 1 and Ep-CAM in Merkel cell carcinomas: implications for immunotherapy

The Merkel cell carcinoma (MCC) is a highly malignant carcinoma of the skin that is characterized by granules containing neuroendocrine peptides and by the expression of simple epithelial type cytokeratins. The glycoprotein Ep-CAM is a homophilic cell-cell adhesion molecule, present in most simple, pseudostratified and transitional epithelia and the tumors derived therefrom. MUC 1 is a well-established marker for squamous cell carcinomas and is generally secreted by glandular epithelial cells. We compared the expression of Ep-CAM and MUC 1 in Merkel cells and 33 cases of MCC and 12 MCC metastases using immunohistochemistry on paraffin-embedded sections. In addition, we examined the glycosylation status of MUC 1 with specific monoclonal antibodies. MUC 1 and Ep-CAM were expressed in Merkel cells and in about 82% and 70% of all MCC irrespective of clinical outcome. Both antigens were expressed in 66% of metastases. Similar to breast cancer, the presence of MUC 1 was not correlated with clinical outcome, but the staining intensity of monoclonal antibodies against glycosylation-independent and hypoglycosylated epitopes was. In MCC we found an altered glycosylation pattern in the immunodominant APDTR region of MUC 1 as compared to normal Merkel cells. Hyperglycosylated MUC 1 epitopes were not present in either MCC or normal Merkel cells. There was no correlation between glycosylation pattern and clinical outcome. Ep-CAM expression seemed to be stronger in primary MCC that metastasized than in those that did not. In conclusion, Merkel cells and the majority of MCC express Ep-CAM and MUC 1. This opens the door for treatments based on monoclonal antibodies or vaccination strategies against these antigens, already established for other tumor entities.     

Adhesion molecules CD171 (L1CAM) and CD24 are expressed by primary neuroendocrine carcinomas of the skin (Merkel cell carcinomas)

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.     

Merkel Cell Polyomavirus Is Frequently Detected in Korean Patients with Merkel Cell Carcinoma

Background

Merkel cell carcinoma (MCC) is an increasingly common neuroendocrine cancer of the skin. Merkel cell polyomavirus (MCPyV) is one of the causative agents of MCC. The prevalence of MCPyV in primary MCC and sun-exposed non-MCC tumors has been known to have different results depending on where it was investigated.

Objective

This study assesses the prevalence of MCPyV from primary MCC and sun-exposed non-MCC tumors in Korea.

Methods

A molecular pathology study was performed on 7 tissue specimens of MCC, 1 tissue specimen of metastatic small cell carcinoma of the lung, and 32 tissue specimens of non-MCC tumors occurring from sun-exposed areas [8 basal cell carcinomas (BCCs), 8 squamous cell carcinomas (SCCs), 8 actinic keratoses (AKs), and 8 seborrheic keratoses (SKs)]. All specimens were analyzed to determine the presence of MCPyV-DNA using both polymerase chain reaction (PCR) and real-time quantitative PCR. Immunohistochemistry with monoclonal antibody of MCPyV large T antigen (CM2B4) was also conducted.

Results

Using both PCR, MCPyV sequences were detected in six of seven MCC tissue specimens (85.7%). Five (71%) of seven MCC tumors were immunoreactive for CM2B4. All five immunoreactive cases were positive for MCPyV. However, there was no association of MCPyV with BCC, SCC, AK, and SK.

Conclusion

Our results implicate that MCPyV may contribute to the pathogenesis of primary MCC, not of non-MCC skin tumors in Korea, and the persons with MCPyV infection are unusual in Korea compared to other areas.     

Merkel cell carcinoma update: the case for two tumours

Merkel cell carcinoma (MCC) is an aggressive tumour with neuroendocrine differentiation. Clinically significant differences within the entity we know as MCC are apparent. This review aims to evaluate the evidence for differences in tumours within Merkel cell carcinoma and to stratify these. A literature search of research pertaining to various characteristics MCC was undertaken from 1972, when Merkel cell carcinoma was first described, to 2018, using PubMed and similar search engines. A total of 41 papers were analysed, including clinical trials, laboratory-based research and reviews. A proportion of MCC has Merkel cell polyomavirus genome integrated (MCPyV+) while others do not (MCPyV−). Both types have a different mutation burden. MCPyV+ tumours are likely true neuroendocrine carcinomas, with a dermal origin, probably from fibroblasts which have been transformed by integration of the viral genome. MCPyV−tumours are likely derived from either keratinocytes or epidermal stem cells, are probably squamous cell carcinomas with neuroendocrine differentiation, and are related to sun damage. Prognostic factors (apart from tumour stage) include the MCPyV status, with MCPyV+ tumours having a better prognosis. P63 expression confers a worse prognosis in most studies. CD8+ lymphocytes play an important role, providing a possible target for PD1/PD-L1 blockade treatment. The incidence of MCC varies from country to country. Countries such as Australia have a high rate and a far greater proportion of MCPyV− tumours than places such as the United Kingdom. MCC doubtlessly encompasses two tumours. The two tumours have demonstrated differences in prognosis and management. One is a neuroendocrine carcinoma related to MCPyV integration likely derived from fibroblasts, and the other is a UV-related squamous cell carcinoma with neuroendocrine differentiation, presumptively derived from either keratinocytes or epidermal stem cells. We propose naming the former Merkel type sarcoma and the latter squamous cell carcinoma, Merkel type.     

Spontaneous regression of merkel cell carcinoma: a comparative study of TUNEL index and tumor-infiltrating lymphocytes between spontaneous regression and non-regression group

Some Merkel cell carcinomas (MCC) have been reported to regress spontaneously. To clarify the mechanisms of spontaneous regression (SR) of MCC, we analyzed the TUNEL index, the labeling index of proliferating cell nuclear antigen (PCNA), the labeling index of bcl-2 protein, and the expression of p53 of the tumor cells. We also evaluated the number of infiltrating lymphocytes surrounding the tumor in the tissue specimens. Among seven patients with MCC (SR: n=4; non-regression (NR): n=3), the TUNEL index in the SR group was significantly higher than that in NR group (5.2 and 2.0%, respectively). In addition, the number of lymphocytes around the tumor nests was also significantly increased in the SR group compared to NR group (1576 and 663 cells/mm(2), respectively). Most of the infiltrating lymphocytes were UCHL-1 positive T-cells. There were no significant differences of the PCNA labeling index, the bcl-2 protein labeling index, and the expression p53 between SR and NR group. These results indicate that apoptosis and local T-cell mediated immune response might be involved in spontaneous regression of MCC.     

Proliferation markers and prognosis in Merkel cell carcinoma

Merkel cell carcinotna (MCC) is a frequently aggressive primary cutaneous neuroendocrine malignancy. We investigated 3 cell proliferation markers which may be useful in predicting the aggressiveness of MCC: 1) p53, a tumor suppressor protein, 2) Ki-67, a marker of cell cycling, and 3) proliferating cell nuclear antigen (PCNA). Twenty patients with MCC were studied. The 3 cell proliferation markers were studied by immunoperoxidase. Clinical and immunoperoxidase results were tabulated according to recurrence or death from disease. Of the 20 patients, 10 experienced recurrence, and 10 did not. Seven tumors were positive for p53. We found correlations between recurrence and death in MCC patients, between p53 positivity and recurrence/death, and between p53 positivity and head/neck primary sites. We found no correlation with recurrence by gender or primary site. PCNA was positive in only 1 patient, while Ki-67 was positive in all patients, making these 2 markers unsuitable for predicting recurrence. Further clinical studies will be helpful to confirm and refine the application of this test. Prognostic information from such studies may be useful in planning observation and treatment for patients in the future.     

Merkel cell carcinoma: squamous and atypical fibroxanthoma-like differentiation in successive local tumor recurrences

Merkel cell carcinoma (MCC) is a rare, frequently lethal, primary neuroendocrine carcinoma of the skin. Histopathologically, it appears as a dermal nodule of small, undifferentiated malignant cells. Historically, MCC was considered to be an eccrine carcinoma. Recognition of its neuroendocrine features later led to the hypothesis that it arose from Merkel cells in the skin, although recent evidence revisits the question of an epithelial origin. We present a case of MCC arising on the temple of a 78-year-old male, in association with an actinic keratosis. Three years later, a local tumor recurrence showed a mixed malignancy comprising small cell neuroendocrine and large cell squamoid components. A further recurrence at the site two years later, after local radiotherapy, revealed a bizarre pleomorphic large cell morphology with retention of immunohistochemical features of a neuroendocrine carcinoma. Evolution to a bizarre pleomorphic large cell neoplasm has been recorded in malignant tumors treated by radiotherapy, but is unique for MCC. The association of this MCC with an actinic keratosis and the development of squamoid differentiation in a local recurrence support the link between MCC and epithelial neoplasia. In addition, its evolution to an atypical fibroxanthoma-like morphology is of interest, because some view atypical fibroxanthomas as bizarre variants of squamous cell carcinoma.     

Merkel细胞癌3例临床与病理分析

目的探讨Merkel细胞癌的临床与病理特点、病因学、诊断及鉴别诊断。方法观察3例Merkel细胞癌的组织病理特点和免疫组化染色结果,并复习相关文献。结果 3例均为老年患者,女2例,男1例。镜下见肿瘤主要位于真皮,呈巢索状和弥漫片状分布,癌细胞圆形、卵圆形或梭形,大小及形态较一致,胞质较少,核染色质细颗粒状,病理性核分裂像多见。免疫组化见CK20和神经内分泌标记阳性,HMB45,TTF-1,LCA和CD99等阴性。结论 Merkel细胞癌是一种发生于皮肤的少见的高度恶性神经内分泌肿瘤,易局部复发或转移。近年来发现的Merkel细胞多瘤病毒可能是其重要的致病因子。其临床病理及特征性的免疫组化表达有助于诊断及鉴别诊断。目前的治疗方法主要有手术切除和辅助放疗及化疗。     

Diagnostic Pitfalls of Merkel Cell Carcinoma and Dramatic Response to Chemotherapy

Merkel cell carcinoma (MCC) is an unusual malignant tumor that arises from neuroendocrine cells with features of epithelial differentiation. We describe a MCC patient with unusual clinical, histopathological, and immunohistochemical features. Although the microscopic, immunohistochemical, and ultrastructural characteristics of MCC have been well defined, diagnostic difficulties remain, particularly in distinguishing it from lymphoma involving the skin, as suggested by our case. This is an unusual case in which dense lymphoid infiltration masked the true tumor. All the immunohistochemical markers of MCC except neuron-specific enolase (NSE) were negative. The dramatic response to primary chemotherapy was also very noteworthy.     

Merkel cell carcinoma: is this a true carcinoma?

Recent years have brought an enhanced understanding of Merkel cell carcinoma (MCC) biology, especially with regard to the Merkel cell polyoma virus as a causative agent. Differences between Merkel cell polyomavirus‐positive and Merkel cell polyomavirus‐negative MCC in morphology,^, gene expression, miRNA profiles and prognosis have been reported. Origin of MCC is controversial. Presence of neurosecretory granules has suggested that these carcinomas originate from one of the neurocrest derivatives, most probably Merkel cells; the name Merkel cell carcinoma is now widely accepted. Expression of PGP 9.5, chromogranin A and several neuropeptides, initially regarded as specific markers for neural and neuroendocrine cells, has recently been shown in a subset of lymphomas. MCC commonly expresses terminal deoxynucleotidyl transferase and PAX5. Their co‐expression under physiologic circumstances is restricted to pro/pre‐B cells and pre‐B cells. These findings lead to the hypothesis by zur Hausen et al. that MCC originates from early B cells. This review was intended to critically appraise zur Hausen's hypothesis and discuss the possibility that MCC is a heterogenous entity with distinct subtypes.     

c-kit expression in primary and metastatic merkel cell carcinoma

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

Merkel-Zell-Karzinom des Handrückens

A 67-year old patient developed multiple flesh-colored nodules on the back of his left hand. Histological examination led to the diagnosis of a Merkel cell carcinoma (MCC). This highly aggressive primary cutaneous tumor is classified as a neuroendocrine carcinoma. It affects mostly elderly and immunosuppressed patients. Recently, a new polyomavirus (MCPyV) has been detected in about 75–85% of MCC and seems to play an important role in their pathogenesis. This new finding may help to develop new therapeutic options for MCC.     

Combined intraepidermal neuroendocrine (Merkel cell) and squamous cell carcinoma in situ with CM2B4 negativity and p53 overexpression(*)

Primary cutaneous neuroendocrine carcinoma, also known as Merkel cell carcinoma (MCC), usually presents as a dermal and/or subcutaneous tumor. Rarely, it is confined to the epidermis or adnexal epithelium [MCC in situ (MCCIS)]. Little is known about the spectrum of features and biology of MCCIS. Herein, we report a case of MCCIS arising on the cheek of a 77-year-old Caucasian male, which was associated with squamous cell carcinoma in situ. The tumor cells of both the neuroendocrine and squamous components prominently involved adnexal structures but did not invade the dermis. The tumor cells with neuroendocrine features were immunoreactive for cytokeratin-20, chromogranin and synaptophysin. They also expressed p53 but were non-reactive with the monoclonal antibody CM2B4. Lack of labeling for CM2B4 is in keeping with prior observations of combined squamous and MCC. Our findings support the concept of a distinct subtype of virus-independent cutaneous neuroendocrine carcinoma that differs from conventional MCC. The observed overexpression of p53 suggests that the development of this tumor type may be related to chronic ultraviolet damage.     

Acetylcholine receptor expression in Merkel cell carcinoma

Neurocrest-derived tissues express muscarinic and nicotinic acetylcholine receptors (mAChR and nAChR respectively). These receptors are critical for migration of neurocrest-derived cells to their corresponding tissues during development. Recent reports demonstrate neurocrest-derived melanoma and numerous non-Merkel cell neuroendocrine tumors express both muscarinic and nicotinic receptors. In light of the controversy surrounding the origin and pathogenesis of Merkel cell carcinoma (MCC), we investigated the immunohistochemical expression of both mAChR and nAChR in MCC. Fifteen cases of primary non-metastatic cutaneous MCC archived at a large veterans' hospital and tertiary referral dermatopathology service were retrieved by computer-assisted search. Immunohistochemistry was utilized to evaluate the presence of M3, M5 and beta 2 nAChR expression. All the cases were confirmed prior to study by a single board certified dermatopathologist (MBM). Fifteen cases of primary cutaneous MCC were diffusely positive for M3 and M5 mAChR staining. All cases lacked immunohistochemical staining for the beta 2 nAChR. Despite the limited number of cases, MCC appears to uniformly express M3 and M5 receptors. These receptors have been linked to cell proliferation and migration which may confer a potential therapeutic target.     

Spontaneous regression of recurrent and metastatic Merkel cell carcinoma

Merkel cell carcinoma (MCC) is a malignant neuroendocrine tumor with a high rate of recurrence and metastasis. Despite its high degree of malignancy, spontaneous regression has been documented. We report an 87-year-old woman who presented with recurrent MCC on her left cheek and regional lymph node metastasis. Although she received no treatment due to her poor condition, the recurrent metastatic lesion regressed spontaneously within 2 months.     

Intraepidermal and dermal Merkel cell carcinoma with squamous cell carcinoma in situ: a case report with review of literature

Merkel cell carcinoma (MCC), a rare aggressive primary cutaneous neuroendocrine carcinoma, occurs on sun‐damaged skin, especially in the elderly. Its unique co‐expression of cytokeratin 20 (CK20) and neuroendocrine markers, including neuron‐specific enolase (NSE), is diagnostic. Most MCCs are located in the dermis, rarely has an intraepidermal component been reported. We report a case of MCC with an intraepidermal component admixed with squamous cell carcinoma in situ (SCCIS). We were able to identify the differences in the immunohistochemical expression pattern between that of the intraepidermal and the dermal components. Most intraepidermal neoplastic cells of MCC in this case showed a less intense immunoreactivity to CK20 and NSE compared to that of dermal neoplastic cells. This case reports an unusual occurrence of combined SCC and MCC that shows both intraepidermal and dermal components. Sirikanjanapong S, Melamed J, Patel R. Intraepidermal and dermal Merkel cell carcinoma with squamous cell carcinoma in situ: a case report and review of literature.