A machine-learning modified CART algorithm informs Merkel cell carcinoma prognosis.

BACKGROUND: Merkel cell carcinoma (MCC) is a rare neuroendocrine skin cancer with a high mortality rate. MCC staging is currently based on tumour primary size, clinical detectability of lymph node metastases, performance of a lymph node biopsy, and presence of distant metastases. OBJECTIVE: We aimed to use a modified classification and regression tree (CART) algorithm using available data points in the National Cancer Database (NCDB) to elucidate novel prognostic factors for MCC. METHODS: Retrospective cohort study of the NCDB and Surveillance, Epidemiology, and End Results (SEER) registries. Cases from the NCDB were randomly assigned to either the training or validation cohorts. A modified CART algorithm was created with data from the training cohort and used to identify prognostic groups that were validated in the NCDB validation and SEER cohorts. RESULTS: A modified CART algorithm using tumour variables available in the NCDB identified prognostic strata as follows: I: local disease, II: ≤3 positive nodes, III: ≥4 positive nodes, and IV: presence of distant metastases. Three-year survival for these groups in the NCDB validation cohort were 81.2% (SE: 1.7), 59.6% (SE: 3.0), 38.0% (SE: 6.0), and 20.2% (SE: 7.0), respectively. These strata were exhibited greater within-group homogeneity than AJCC groups and were more predictive of survival. CONCLUSIONS: Risk-stratified grouping of MCC patients incorporating positive lymph node count were strongly predictive of survival and demonstrated a high degree of within-group homogeneity and survival prediction. Incorporation of positive lymph node count within overall staging or sub-staging may help to improve future MCC staging criteria.

UV Signature Mutations Reclassify Salivary High-grade Neuroendocrine Carcinomas as Occult Metastatic Cutaneous Merkel Cell Carcinomas.

Salivary high-grade neuroendocrine carcinomas (NECs) are rare, occur predominantly in the parotid gland, and are difficult to differentiate from metastatic cutaneous Merkel cell carcinomas (MCCs), which have overlapping morphologic, immunophenotypic, and molecular profiles. Oncogenic Merkel cell polyomavirus (MCPyV), found in 70% to 80% of MCCs, has also been reported in a few salivary NECs, but this is controversial. A promising biomarker to distinguish the 2 tumor types are UV signature mutations. UV signature mutations indicate a sun damage-induced mechanism of pathogenesis and recently have been found to be highly prevalent in MCPyV-negative MCCs but would be inconsistent with salivary origin. Here, we examine UV signature mutations as a molecular marker to distinguish primary salivary high-grade NEC from MCC. Whole exome DNA sequencing was performed on matched tumor-normal tissue from 4 MCPyV-negative high-grade salivary NECs with no other primary source identified, as well as 3 melanomas and 3 lung NECs as positive and negative controls, respectively. UV signature mutations were found in all salivary NECs, when defined as ≥60% of total mutations being C-to-T transitions at dipyrimidine sites, and when compared with known human cancer-related mutational signatures. The presence of UV signature mutations in salivary high-grade NECs strongly favors these to be occult metastatic MCCs. True salivary primary NECs are likely exceedingly rare. When a high-grade NEC is encountered in the salivary gland, the presence of UV signature mutations or MCPyV may be useful to exclude occult unknown primary MCC.

Update on eighth edition American Joint Committee on Cancer classification for Merkel cell carcinoma and histopathological parameters that determine prognosis.

Merkel cell carcinoma (MCC) is a rare primary cutaneous neuroendocrine carcinoma. The annual incidence of MCC is increasing in the USA. Timely diagnosis and proper staging of this tumour are crucial as MCC has high rates of regional recurrence and lymph node and distant metastasis. In this review, we outline the key differences between the tumor node metastasis (TNM) staging criteria for MCC in the seventh and eighth editions of the AJCC Cancer Staging Manual We also discuss histopathological parameters that are not included in the eighth edition of the manual but have been shown in other studies to predict a worse prognosis in patients with MCC. Correct assessment and reporting of these clinically relevant histopathological parameters is of utmost importance for practising pathologists as management differs according to the stage of the tumour. This review aims to increase awareness of all these parameters, and proper recognition would guide the treating clinicians towards the most appropriate treatment options that can be given to patients.

Los nuevos sistemas de estadificación del AJCC incorporan novedades en el cáncer cutáneo / Novel Additions to the AJCC's New Staging Systems for Skin Cancer

Cuarenta años después de la publicación de la primera edición de la estadificación del American Joint Committee on Cancer, la octava edición se publica con cambios relevantes en el cáncer de piel. En el cáncer cutáneo no melanoma el American Joint Committee on Cancer mantiene un enfoque específico para el carcinoma de células de Merkel y tiene en cuenta algunos trabajos publicados recientemente sobre el pronóstico del carcinoma epidermoide cutáneo en la definición de una categoría T completamente nueva para este tumor. Por otra parte, la estadificación se contempla para el carcinoma epidermoide cutáneo de cabeza y cuello (excluyendo el párpado) y en otras localizaciones; únicamente ofrece soluciones para la estratificación de tumores de vulva, pene y región perineal. En relación con el melanoma, el valor del índice mitótico desaparece y el pronóstico del tumor primario se define basándose en el espesor de Breslow y la ulceración. Además, el espesor pasa a registrarse con una precisión de 0,1mm y aparece el concepto de T0 para los melanomas metastásicos en los que el primario ha regresado completamente. Existen diferencias en la categoría N de todos los sistemas de estadificación de cáncer cutáneo en esta nueva edición, y en relación con la categoría M, en el melanoma aparece la categoría M1d para hacer referencia a la afectación metastásica del SNC, que hasta el momento se incluía dentro de la categoría M1c. Será necesario validar este nuevo sistema con series de pacientes para valorar si efectivamente cumple con el objetivo de estratificar por riesgo los tumores de una manera adecuada (AU)

The eighth edition of the staging manual of the American Joint Committee on Cancer incorporates important changes in the classification of skin cancers. Coming 40 years after the first edition, the latest manual preserves its specific system for Merkel cell carcinoma and takes into account recent publications on the prognosis of squamous cell carcinoma by defining a completely new T category for this neoplasm. Staging for squamous cell carcinoma considers head and neck tumors (excluding the eyelid) and does not offer solutions for other sites except the vulva, penis, and perianal region. Regarding melanoma, use of the mitotic index has been eliminated and the prognosis of the primary tumor is based on Breslow thickness and ulceration. In addition, thickness is now recorded to an accuracy of 0.1mm, and the T0 concept has been introduced to define those metastatic melanomas in which the primary tumor has regressed completely. In this new edition, changes have also been made to the N category of all the skin cancer staging systems, and M1d has been added to the M category for melanoma to refer to metastatic involvement of the central nervous system, which, up to now, had been included in the M1c category. This new system will need to be validated with patient series to determine if it adequately satisfies the objective of tumor risk stratification (AU)

Actualización en el carcinoma de células de Merkel: Epidemiología, etiopatogenia, clínica, diagnóstico y estadificación / Update on Merkel cell carcinoma: epidemiology, etiopathogenesis, clinical features, diagnosis, and staging

El carcinoma de células de Merkel (CCM) es un tumor poco frecuente, con un curso evolutivo muy agresivo, que con frecuencia origina recidivas locorregionales y metástasis. Asienta predominantemente en zonas fotoexpuestas en pacientes ancianos. Su incidencia se ha cuadriplicado en las últimas décadas debido al envejecimiento de la población y a un mayor diagnóstico gracias al uso de técnicas inmunohistoquímicas. La patogénesis del CCM no está clara, pero la radiación ultravioleta, la inmunosupresión y la presencia del poliomavirus MCPyV en el genoma del tumor parecen desempeñar un papel fundamental en el desarrollo de esta neoplasia. El objetivo de este artículo es realizar una revisión actualizada sobre los diferentes aspectos de la epidemiología, la etiopatogenia y la clínica del CCM. A su vez, detallamos los aspectos histológicos e inmunohistoquímicos necesarios para su diagnóstico y revisamos la estadificación por su importante trascendencia en el pronóstico de estos pacientes

Merkel cell carcinoma (MCC) is a rare, highly aggressive tumor, and local or regional disease recurrence is common, as is metastasis. MCC usually develops in sun-exposed skin in patients of advanced age. Its incidence has risen 4-fold in recent decades as the population has aged and immunohistochemical techniques have led to more diagnoses. The pathogenesis of MCC remains unclear but UV radiation, immunosuppression, and the presence of Merkel cell polyomavirus in the tumor genome seem to play key roles. This review seeks to update our understanding of the epidemiology, etiology, pathogenesis, and clinical features of MCC. We also review histologic and immunohistochemical features required for diagnosis. MCC staging is discussed, given its great importance in establishing a prognosis for these patients

[Merkel cell carcinoma]. / Merkel-Zell-Karzinom.

Merkel cell carcinoma (MCC, cutaneous neuroendocrine carcinoma) is a rare form of tumor of unclear histogenesis which predominantly occurs in elderly patients on areas exposed to the sun. A higher incidence and occurrence in younger people is predominantly found in immunosuppressed persons which is why a pathogenetic role is also attributed to immunosuppression in addition to ultraviolet (UV) radiation. Additionally, in 80% of cases clonally integrated polyomavirus (Merkel cell polyomavirus, MCPyV) could be detected. Clinically MCC represents an uncharacteristic tumor. Histopathologically, monomorphic dermal and/or subcutaneous nodes are found consisting of round or oval medium sized cells with a vesicular nucleus and sparse cytoplasm. The neoplastic cells of MCC express cytokeratin (CK) 20 with a dot-like perinuclear accentuation. In addition, pan-CK, neuroendocrine markers (e.g. chromogranin A and synaptophysin), neurofilament proteins, CD56, CD57, Bcl-2, TdT and PAX-5 are immunohistochemically positive. In most cases CM2B4, an antibody against MCPyV is also positive. Expression of p63 has been observed in some of the cases and in some studies was associated with a favorable prognosis. The markers thyroid transcription factor 1, mammalian achaete scute complex like 1, vimentin, S-100 and CK7 are not normally expressed by MCC. The prognosis is primarily dependent on tumor size and the lymph node status. The presence of intralymphatic tumor complexes is associated with a higher rate of local recurrence and lymph node metastasis. A larger number of intratumoral cytotoxic T-lymphocytes is accompanied by a favorable prognosis and the presence of > 50% of K-67+ neoplastic cells with an unfavorable prognosis. Further morphological, phenotypical and genetic factors have not yet been validated in larger cohorts with respect to the prognostic relevance.

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.

Correlation of American Joint Committee on Cancer T category for eyelid carcinoma with outcomes in patients with periocular Merkel cell carcinoma.

PURPOSE: Merkel cell carcinoma is a rare but potentially deadly cancer of the eyelid. To date, no studies have reported on clinical parameters at initial presentation of the eyelid tumor that may correlate with disease-free survival (DFS). The purpose of this study was to determine whether the American Joint Committee on Cancer (AJCC) T category for eyelid carcinoma correlates with metastasis and DFS in patients with Merkel cell carcinoma of the periocular region. METHODS: This is a retrospective cohort study from a tertiary referral cancer center. All consecutive patients treated for eyelid or periocular Merkel cell carcinoma between November 1, 1998, and November 1, 2012, were reviewed. The main outcome measures included AJCC T category for eyelid carcinoma and Merkel cell carcinoma at presentation, nodal metastasis at presentation, metastasis during follow up, and DFS. RESULTS: The study included 18 patients, 7 men and 11 women, with median age of 68.5 years. The AJCC T categories for both eyelid carcinoma and Merkel cell carcinoma were significantly correlated with DFS. Using the T categories for eyelid carcinoma, when TX and T2a were grouped into a single category and T2b and T3a into another category, the estimated DFS rate at 3 years was 100% for patients with TX or T2a lesions and 57% for patients with T2b or T3a lesions (p=0.0298). Four patients (22%) had lymph node metastasis at presentation. Presence of lymph node metastasis at presentation was the strongest single predictor of shorter DFS and an increased risk of metastasis during follow up (p=0.0222). CONCLUSIONS: The AJCC eyelid carcinoma T at presentation correlates with DFS in patients with Merkel cell carcinoma of the periocular region. The DFS rate at 3 years was significantly worse for patients with T2b or more extensive tumors by eyelid carcinoma T category. Presence of lymph node metastasis at presentation was predictive of shorter DFS and an increased risk of metastasis during follow up.

Feasibility of using American Joint Committee on Cancer Classification criteria for staging eyelid carcinomas.

PURPOSE: To evaluate the feasibility of staging eyelid carcinomas using the American Joint Committee on Cancer (AJCC) criteria, and to compare the 6(th) and 7(th) editions. METHODS: The records of 27 consecutive patients who underwent excision of eyelid carcinoma between April 2007 and April 2008 were reviewed. Patients with melanoma, lymphoid tumors, nonmeasurable disease, or medial or lateral canthal tumors were excluded. Each patient was staged using the AJCC 6(th) and 7(th) edition criteria based on clinical, pathologic, and radiographic data. RESULTS: The study included 13 men and 14 women aged 32 to 93 years (median, 65 years). Seventeen patients had basal cell carcinoma; 3, squamous cell carcinoma; 6, sebaceous carcinoma; and 1, Merkel cell carcinoma. Tumor location was lower eyelid in 20 patients and upper eyelid in 7. TNM designations were reliably determined for all 27 patients and were: A) using the 6(th) edition: T1N0M0, 6 patients; T2N0M0, 6; T2N1M0, 1; T3N0M0, 4; T4N0M0, 9; and T4N1M0, 1. B) using the 7(th) edition: T1N0M0, 6 patients; T2aN0M0, 8; T2aN1M0, 1; T2bN0M0, 2; T3aN0M0, 6; T3aN1M0, 1; T3bN0M0, 2; and T4N0M0, 1. Pathologic tumor size and nodal status, and systemic work-up were recorded for all patients. CONCLUSIONS: Eyelid carcinomas can be reliably staged using the AJCC criteria. There are notable differences between the 6(th) and 7(th) editions of AJCC TNM designation. We recommend AJCC staging using the latest published edition during the initial work-up for all patients with eyelid carcinoma to make reporting of outcomes more reliable and reproducible.

[Changes in the TNM classification of head and neck tumors]. / Neuerungen der TNM-Klassifikation der Kopf-Hals-Tumoren.

Only minor modifications were introduced in the classification of squamous cell carcinomas of the oro- and hypopharynx, namely in the definition of some T and N categories. A new TNM classification has been introduced for mucosal melanoma of the head and neck. Some proposals for ramification of the T1 categories of thyroid tumours have been adopted from the TNM Supplement, unfortunately not those proposed for the T3 categories. The new TNM classification of Merkel cell carcinomas, which frequently occur in the head and neck region, is also discussed.

[TNM 2010. What's new?]. / TNM 2010. Was ist neu?

In the seventh edition of the TNM Classification of Malignant Tumours there are several entirely new classifications: upper aerodigestive mucosal melanoma, gastrointestinal stromal tumour, gastrointestinal carcinoid (neuroendocrine tumour), intrahepatic cholangiocarcinoma, Merkel cell carcinoma, uterine sarcomas, and adrenal cortical carcinoma. Significant modifications concern carcinomas of the oesophagus, oesophagogastric junction, stomach, appendix, biliary tract, lung, skin, prostate and ophthalmic tumours, which will be not addressed in this article. For several tumour entities only minor changes were introduced which might be of importance in daily practice. The new classifications and changes will be commented on without going into details.

Detection of Merkel cell polyomavirus (MCPyV) in Merkel cell carcinoma cell lines: cell morphology and growth phenotype do not reflect presence of the virus.

The recently discovered human polyomavirus (MCPyV) is frequently found in Merkel cell carcinoma (MCC) tissue and is believed to be causally linked to MCC pathogenesis. While cell lines established from MCC represent a valuable tool to study the contribution of MCPyV to MCC pathogenesis, hitherto only 1 MCPyV-positive line has been described. We have analyzed 7 MCC cell lines for the presence, integration pattern and copy number of MCPyV. In 5 cell lines, MCPyV specific sequences were detected. In 3 of these lines, multiple copies of viral genomes per cell were detected, and sequencing of PCR amplificates identified distinct mutations predicted to lead to the expression of a truncated large T-Antigen (LT-Ag). In 1 cell line, clonal integration of concatamerized viral genomes was confirmed by Southern Blotting. MCC cell lines are conventionally categorized as "classic" or "variant" and further divided into 4 subtypes, based on expression of neuroendocrine markers and morphology. While it has been suggested that the presence of MCPyV might promote a classic phenotype, such a notion is not supported by our data. Instead, we find MCPyV-positive as well as -negative lines of the classic variety, indicating that the distinguishing features are either inherently independent of viral infection or have become so in the course of tumorigenesis and/or cell line establishment. We therefore suggest a novel classification scheme based on MCPyV presence, integration patterns and T-Ag mutations. The cell lines described here extend the repertoire of available MCPyV-positive MCC-lines and should aid in the elucidation of the role of MCPyV in the pathogenesis of MCC.

Merkel cell carcinoma subgroups by Merkel cell polyomavirus DNA relative abundance and oncogene expression.

Merkel cell polyomavirus (MCPyV) was recently discovered in Merkel cell carcinoma (MCC), a clinically and pathologically heterogeneous malignancy of dermal neuroendocrine cells. To investigate this heterogeneity, we developed a tissue microarray (TMA) to characterize immunohistochemical staining of candidate tumor cell proteins and a quantitative PCR assay to detect MCPyV and measure viral loads. MCPyV was detected in 19 of 23 (74%) primary MCC tumors, but 8 of these had less than 1 viral copy per 300 cells. Viral abundance of 0.06-1.2 viral copies/cell was directly related to presence of retinoblastoma gene product (pRb) and terminal deoxyribonucleotidyl transferase (TdT) by immunohistochemical staining (p < or = 0.003). Higher viral abundance tumors tended to be associated with less p53 expression, younger age at diagnosis and longer survival (p < or = 0.08). These data suggest that MCC may arise through different oncogenic pathways, including ones independent of pRb and MCPyV.

Merkel cell carcinoma metastasizing to the kidney mimicking primary neuroendocrine renal cancer.

A 56-year-old male with a history of cutaneous neuroendocrine (Merkel cell) carcinoma presented with a solid mass of the left kidney, measuring 10 cm in largest diameter. On histology, the tumour was composed of loosely packed uniform cells with round-to-oval nuclei and scant cytoplasm. Immunohistochemically, the tumour cells diffusely expressed pancytokeratin and neuroendocrine markers, such as chromogranin A, synaptophysin and CD56 (NCAM). Distinct paranuclear dot-like expression of cytokeratin 20 showed the lesion to be metastatic Merkel cell carcinoma. This is the first reported case of Merkel cell carcinoma metastatic to the kidney mimicking primary neuroendocrine renal cancer. We discuss the differential diagnosis of the tumour and perform a systematic literature review, including potential indications for renal tumour biopsy in patients with a history of nonrenal malignancy.

Primary neuroendocrine carcinoma of the vagina with Merkel cell carcinoma phenotype.

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.

[Cutaneous neuroendocrine carcinoma. Apropos of a case]. / Le carcinome neuroendocrine cutané. A propos d'une observation.

Cutaneous neuroendocrine carcinoma (CNEC) is a rare tumour. We report the case of a 75-year old woman affected with a rapidly progressive CNEC of the right cheek which kept recurring despite surgical excision followed by radiotherapy. The clinical features of CNEC are not specific. The tumour is located in the dermis, and the tumoral cells (Merkel cells) have a monotonous appearance. Gould's classification of these carcinomas into three types has a prognostic value. Immunohistochemistry is a mandatory complement to light microscope examination. It is very difficult to distinguish between CNEC and metastasis from a visceral small cell carcinoma. Treatment consists of surgery combined with radiotherapy. Chemotherapy was very successful in our patient and should be considered in other cases.