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Cowman AW, Lourdault K, Hanes D, Nassoiy S, Shin P, Aguilar T, Goldfarb M, Essner R. Importance of Surgical Margins in Patients with Early-Stage Merkel Cell Carcinoma. Dermatol Ther (Heidelb) 2025:10.1007/s13555-025-01345-x. [PMID: 39988692 DOI: 10.1007/s13555-025-01345-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2024] [Accepted: 01/17/2025] [Indexed: 02/25/2025] Open
Abstract
INTRODUCTION The National Comprehensive Cancer Network (NCCN) recommends excision of the primary tumor using 1-2-cm surgical margins and sentinel lymph node biopsy (SLNB) as the initial management of early-stage Merkel cell carcinoma (MCC). However, there is no clear consensus on the appropriate size of the surgical margins and/or the use of Mohs micrographic surgery (MMS). Our aim was to demonstrate that, independent of the type of surgery, obtaining negative surgical margins is associated with enhanced overall survival (OS). METHODS A retrospective study was performed using early-stage MCC patients from the National Cancer Database (NCDB) who were diagnosed between 2004 and 2020 and underwent surgical excision (SE) of their primary tumor. Patients were stratified into three groups based on the surgical treatment they received: < 1 cm excision margin, ≥ 1 cm excision margin, or MMS. OS was assessed with Kaplan-Meier curves, log-rank tests, and multivariable risk-adjusted Cox proportional-hazards regression. RESULTS Of the 4,607 patients included in this study; 53% underwent SE of ≥ 1 cm (n = 2,474), 41% had SE < 1 cm (n = 1,905), and the remainder had MMS (n = 228). 75% of patients had an SLNB, and 56% received adjuvant radiation to the primary site and/or nodal basin. While no difference in OS was observed between the three surgical treatments, negative surgical margins (hazard ratio (HR) 0.78; 95% confidence interval (CI) 0.65-0.94) and receipt of radiation to the primary site (HR 0.82; 95% CI 0.73-0.92) were both independently associated with improved OS. CONCLUSION Achieving negative surgical margins is associated with improved OS in MCC, suggesting that MMS and conventional excision are both suitable approaches for the treatment of primary MCC.
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Affiliation(s)
- Arthur W Cowman
- Providence Saint John's Cancer Institute, 2200 Santa Monica Blvd., Santa Monica, CA, 90404, USA
| | - Kristel Lourdault
- Providence Saint John's Cancer Institute, 2200 Santa Monica Blvd., Santa Monica, CA, 90404, USA
| | - Douglas Hanes
- Department of Biostatistics, Providence St. Joseph Health, Portland, OR, USA
| | - Sean Nassoiy
- Providence Saint John's Cancer Institute, 2200 Santa Monica Blvd., Santa Monica, CA, 90404, USA
| | - Paul Shin
- Providence Saint John's Cancer Institute, 2200 Santa Monica Blvd., Santa Monica, CA, 90404, USA
| | - Tyler Aguilar
- Providence Saint John's Cancer Institute, 2200 Santa Monica Blvd., Santa Monica, CA, 90404, USA
| | - Melanie Goldfarb
- Providence Saint John's Cancer Institute, 2200 Santa Monica Blvd., Santa Monica, CA, 90404, USA
| | - Richard Essner
- Providence Saint John's Cancer Institute, 2200 Santa Monica Blvd., Santa Monica, CA, 90404, USA.
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Zahid A, Sheikh A. Rare but Still There: An Interesting Case of Cytokeratin 20-Negative Merkel Cell Carcinoma. Cureus 2024; 16:e55612. [PMID: 38586649 PMCID: PMC10995648 DOI: 10.7759/cureus.55612] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/05/2024] [Indexed: 04/09/2024] Open
Abstract
Merkel cell carcinoma (MCC) of the skin is a rare and aggressive primary neuroendocrine tumor that mainly involves sun-exposed areas and can metastasize to other parts of the body. Due to varied clinical features and the sharing of similar histological features with other neuroendocrine tumors, diagnosis can be challenging. Therefore, immunohistochemistry plays an important role in diagnosis, and the characteristic perinuclear staining with cytokeratin 20 (CK 20) helps to differentiate it from other morphologically similar tumors, especially metastatic small cell carcinoma of the lung. We describe an interesting case of a 78-year-old female who was referred by a general practitioner (GP) with a few months' history of asymptomatic, rapidly enlarging, erythematous, nodular lesion on her left upper arm. Due to clinical findings and the location of the lesion on the sun-exposed area, wide differential diagnoses were considered. The lesion was excised for histological diagnosis. Surprisingly, morphological features favour the diagnosis of a neuroendocrine tumor. However, histological features including immunohistochemistry rendered it difficult to differentiate between primary cutaneous neuroendocrine carcinoma (Merkel cell CA) and metastatic small cell carcinoma of the lung due to the lack of specific and sensitive marker of CK 20 on immunohistochemistry. Subsequently, the patient had computer tomography of the chest/abdomen and pelvis (CTTAP) and positron emission tomography (PET) scans to rule out underlying primary malignancy. The case was also discussed at local and specialist skin multidisciplinary team meetings (MDT) including neuroendocrine MDT and a consensus diagnosis of Merkel cell carcinoma of the skin with negative CK 20 was established.
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Affiliation(s)
- Amna Zahid
- Dermatology, Ormskirk District General Hospital (Mersey and West Lancashire Teaching Hospitals), Ormskirk, GBR
| | - Arsalan Sheikh
- Dermatology, Ormskirk District General Hospital (Mersey and West Lancashire Teaching Hospitals), Ormskirk, GBR
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SUMI A, CHAMBERS JK, ITO S, KOJIMA K, OMACHI T, DOI M, UCHIDA K. Different expression patterns of p63 and p73 in Felis catus papillomavirus type 2-associated feline Merkel cell carcinomas and other epidermal carcinomas. J Vet Med Sci 2024; 86:39-48. [PMID: 38030281 PMCID: PMC10849848 DOI: 10.1292/jvms.23-0293] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2023] [Accepted: 11/16/2023] [Indexed: 12/01/2023] Open
Abstract
Merkel cell carcinoma (MCC) is a cutaneous neuroendocrine tumor, and more than 90% of feline MCC cases test positive for Felis catus papillomavirus type 2 (FcaPV2). In the present study, basal cell markers p40, p63, and p73 and the stem cell marker SOX2 and cytokeratin 14 (CK14) were immunohistochemically examined in normal fetal, infant, and adult feline skin tissues. The expression of these proteins was examined in tumors positive for FcaPV2, including MCC, basal cell carcinoma (BCC), Bowenoid in situ carcinoma (BISC), and squamous cell carcinoma (SCC). Infant and adult feline skin tissues had mature Merkel cells, which were CK14-, CK18+, CK20+, SOX2+, synaptophysin+ and CD56+, while fetal skin tissue had no mature Merkel cells. MCC was immunopositive for p73, CK18, and SOX2 in 32/32 cases, and immunonegative for CK14 in 31/32 cases and for p40 and p63 in 32/32 cases. These results indicate that MCC exhibits different immunophenotypes from Merkel cells (p73-) and basal cells (p40+, p63+, and SOX2-). In contrast, all 3 BCCs, 1 BISC, and 2 SCCs were immunopositive for the basal cell markers p40, p63, and p73. The life cycle of papillomavirus is closely associated with the differentiation of infected basal cells, which requires the transcription factor p63. Changes in p63 expression in FcaPV2-positive MCC may be associated with unique cytokeratin expression patterns (CK14-, CK18+, and CK20+). Furthermore, SOX2 appears to be involved in Merkel cell differentiation in cats, similar to humans and mice.
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Affiliation(s)
- Ayumi SUMI
- Laboratory of Veterinary Pathology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan
| | - James K CHAMBERS
- Laboratory of Veterinary Pathology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan
| | - Soma ITO
- Nippon Institute for Biological Science, Tokyo, Japan
| | - Kazuhiro KOJIMA
- Laboratory of Veterinary Pathology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan
| | | | - Masaki DOI
- Diagnostic Laboratory, Patho-Labo, Shizuoka, Japan
| | - Kazuyuki UCHIDA
- Laboratory of Veterinary Pathology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan
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Zoccarato M, Grisold W. Paraneoplastic neurologic manifestations of neuroendocrine tumors. HANDBOOK OF CLINICAL NEUROLOGY 2024; 200:397-407. [PMID: 38494292 DOI: 10.1016/b978-0-12-823912-4.00023-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/19/2024]
Abstract
Neuroendocrine neoplasms (NENs) are a heterogeneous group of tumors arising from the transformation of neuroendocrine cells in several organs, most notably the gastro-entero-pancreatic system and respiratory tract. The classification was recently revised in the 5th Edition of the WHO Classification of Endocrine and Neuroendocrine Tumors. NENs can rarely spread to the central or peripheral nervous systems. Neurologic involvement is determined by the rare development of paraneoplastic syndromes, which are remote effects of cancer. Mechanisms depend on immunologic response to a tumor, leading to the immune attack on the nervous system or the production of biologically active ("functioning") substances, which can determine humoral (endocrine) effects with neurologic manifestations. Paraneoplastic neurologic syndromes (PNS) are immunologically mediated and frequently detected in small cell lung cancer but rarely seen in other forms of NEN. PNS and Merkel cell carcinoma is increasingly reported, especially with Lambert Eaton myasthenic syndrome. Endocrine manifestations are found in a wide spectrum of NENs. They can develop at any stage of the diseases and determine neurologic manifestations. Patient outcomes are influenced by tumor prognosis, neurologic complications, and the severity of endocrine effects.
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Affiliation(s)
- Marco Zoccarato
- Neurology Unit O.S.A., Azienda Ospedale-Università di Padova, Padova, Italy
| | - Wolfgang Grisold
- Ludwig Boltzmann Institute for Experimental and Clinical Traumatology, Vienna, Austria.
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5
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Juan HY, Khachemoune A. A review of Merkel cell carcinoma. JAAPA 2023; 36:11-16. [PMID: 37820270 DOI: 10.1097/01.jaa.0000979460.69305.b7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/13/2023]
Abstract
ABSTRACT Merkel cell carcinoma (MCC) is a rare and aggressive type of metastatic, nonmelanoma skin cancer derived from Merkel cells in the epidermis. MCC can be induced by sun exposure or via Merkel cell polyomavirus (MCV) gene expression. MCV is found in most patients with MCC and is associated with a lower recurrence rate of MCC. MCC has a wide range of clinical presentations that make diagnosis challenging. Histologic examination is performed using unique markers to differentiate it from other diagnoses. This article reviews the pathogenesis, clinical presentation, histopathology, differential diagnosis, and treatment of MCC.
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Affiliation(s)
- Hui Yu Juan
- At the time this article was written, Hui Yu Juan was a student in the Virginia Commonwealth University School of Medicine in Richmond, Va. Amor Khachemoune practices at the Brooklyn (N.Y.) VA Medical Center and SUNY Downstate's Department of Dermatology, also in Brooklyn, N.Y. The authors have disclosed no potential conflicts of interest, financial or otherwise
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Colef R, Kiran N, Mescallado L, Kong F, Khan S. Merkel Cell Carcinoma in an Elderly Male With Extensive Local Disease. Cureus 2023; 15:e48001. [PMID: 38034209 PMCID: PMC10686785 DOI: 10.7759/cureus.48001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/29/2023] [Indexed: 12/02/2023] Open
Abstract
Merkel cell carcinoma (MCC) is a rare, highly aggressive neuroendocrine carcinoma of the skin. It is often found in the sun-exposed skin areas of elderly individuals of Caucasian descent. MCC has a tendency for local recurrence and the potential to invade nearby lymph nodes and spread to distant sites in the body. Here, we present the case of an 83-year-old male with a history of multiple comorbidities, including congestive heart failure, obesity, hypertension, benign prostatic hyperplasia, and sarcoidosis, who presented with a slow-growing, fungating lesion on his left lower leg. Histopathological examination revealed MCC with extensive necrosis and involved resection margins. Additional skin lesions on the left knee were confirmed to be MCC. Follow-up CT scans showed lymphadenopathy and a femoral lesion. The patient was deemed a poor candidate for resection and placed on immunotherapy treatment. The low incidence rate and indistinct clinical manifestations of MCC make a conclusive diagnosis dependent on examining histological features and immunohistochemical markers through a lesioned biopsy or resection. Due to the aggressive nature of MCC and the tendency for asymptomatic and painless lesions to escape notice, it is important to raise awareness about this condition. This will lead to earlier detection and intervention, potentially enhancing patient survival rates.
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Affiliation(s)
- Robert Colef
- Pathology and Laboratory Medicine, Staten Island University Hospital, Northwell Health, New York, USA
| | - Nfn Kiran
- Pathology and Laboratory Medicine, Staten Island University Hospital, Northwell Health, New York, USA
| | - Leslie Mescallado
- Pathology and Laboratory Medicine, Staten Island University Hospital, Northwell Health, New York, USA
| | - Fanyi Kong
- Pathology and Laboratory Medicine, Staten Island University Hospital, Northwell Health, New York, USA
| | - Shahbaz Khan
- Gastrointestinal, Hepatobiliary and Transplant Pathology, Indiana University School of Medicine, Indianapolis, USA
- Hematopathology, Northwell Health, New York, USA
- Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, USA
- Pathology and Laboratory Medicine, Staten Island University Hospital, Northwell Health, New York, USA
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7
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Wong AS, du Plessis JJ, Jackett LA. Merkel cell carcinoma: an unusual case with SOX10 nuclear staining. Pathology 2023; 55:718-721. [PMID: 36925343 DOI: 10.1016/j.pathol.2022.12.352] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Revised: 11/22/2022] [Accepted: 12/08/2022] [Indexed: 02/24/2023]
Affiliation(s)
- Anders S Wong
- Department of Anatomical Pathology, Austin Hospital, Heidelberg Vic, Australia.
| | - Justin J du Plessis
- Department of Anatomical Pathology, Austin Hospital, Heidelberg Vic, Australia
| | - Louise A Jackett
- Department of Anatomical Pathology, Austin Hospital, Heidelberg Vic, Australia
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Brazel D, Kumar P, Doan H, Pan T, Shen W, Gao L, Moyers JT. Genomic Alterations and Tumor Mutation Burden in Merkel Cell Carcinoma. JAMA Netw Open 2023; 6:e2249674. [PMID: 36602798 PMCID: PMC9856969 DOI: 10.1001/jamanetworkopen.2022.49674] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Accepted: 11/15/2022] [Indexed: 01/06/2023] Open
Abstract
Importance Merkel cell carcinoma (MCC) is a rare and highly aggressive cutaneous neuroendocrine carcinoma with increasing incidence. Cytotoxic chemotherapy and checkpoint inhibitors provide treatment options in the metastatic setting; however, there are no approved or standard of care targeted therapy treatment options. Objective To identify actionable alterations annotated by the OncoKB database therapeutic evidence level in association with tumor mutation burden (TMB). Design, Setting, and Participants This is a retrospective, cross-sectional study using data from the American Association for Cancer Research Genomics Evidence Neoplasia Information Exchange, a multicenter international cancer consortium database. Patients with MCC were enrolled in participating institutions between 2017 and 2022. Data from version 11.0 of the database were released in January 2022 and analyzed from April to June 2022. Main Outcomes and Measures The main outcome was the percentage of patients with high TMB and OncoKB level 3B and 4 alterations. Results A total of 324 tumor samples from 313 patients with MCC (107 women [34.2%]; 287 White patients [91.7%]; 7 Black patients [2.2%]) were cataloged in the database. The median (range) number of alterations was 4.0 (0.0-178.0), with a mean (SD) of 13.6 (21.2) alterations. Oncogenic alterations represented 20.2% of all alterations (862 of 4259 alterations). Tissue originated from primary tumor in 55.0% of patients (172 patients) vs metastasis in 39.6% (124 patients). TMB-high (≥10 mutations per megabase) was present in 26.2% of cases (82 patients). Next-generation sequencing identified 55 patients (17.6%) with a level 3B variation for a Food and Drug Administration-approved drug for use in a biomarker-approved indication or approved drug in another indication. An additional 8.6% of patients (27 patients) had a level 4 variation. Actionable alterations were more common among high TMB cases, with 37 of 82 patients (45.1%) harboring level 3 alterations compared with only 18 of 231 patients (7.8%) with low TMB. The most common level 3B gene variants included PIK3CA (12 patients [3.8%]), BRCA1/2 (13 patients [4.2%]), ATM (7 patients [2.2%]), HRAS (5 patients [1.6%]), and TSC1/2 (6 patients [1.9%]). The most common level 4 variants include PTEN (13 patients [4.1%]), ARID1A (9 patients [2.9%]), NF1 (7 patients [2.2%]), and CDKN2A (7 patients [2.2%]). Copy number alterations and fusions were infrequent. In 61.0% of cases (191 cases), a PanCancer pathway was altered, and 39.9% (125 cases) had alterations in multiple pathways. Commonly altered pathways were RTK-RAS (119 patients [38.0%]), TP53 (103 patients [32.9%]), cell cycle (104 patients [33.2%]), PI3K (99 patients [31.6%]), and NOTCH (93 patients [29.7%]). In addition, oncogenic DNA mismatch repair gene alterations were present in 8.0% of cases (25 patients). Conclusions and Relevance In this cross-sectional retrospective study of alterations and TMB in MCC, a minority of patients had potentially actionable alterations. These findings support the investigation of targeted therapies as single agent or in combination with immunotherapy or cytotoxic chemotherapy in selected MCC populations.
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Affiliation(s)
- Danielle Brazel
- Department of Medicine, University of California, Irvine, Orange
| | - Priyanka Kumar
- Department of Medicine, University of California, Irvine, Orange
| | - Hung Doan
- Unafilliliated Independent Contractor
| | - Tianyu Pan
- Department of Statistics, University of California, Irvine
| | - Weining Shen
- Department of Statistics, University of California, Irvine
| | - Ling Gao
- Department of Dermatology, Long Beach Veterans Health Administration, Long Beach, California
| | - Justin T. Moyers
- Division of Hematology and Oncology, Department of Medicine, University of California, Irvine School of Medicine, Chao Family Comprehensive Cancer Center, Orange
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Vanderbeck K, Cho WC, Aung PP, Ivan D, Rothrock AT, Torres-Cabala CA, Prieto VG, Curry JL, Nagarajan P. Ductal differentiation: A rare phenomenon in Merkel cell carcinoma. J Cutan Pathol 2022; 50:511-519. [PMID: 36454019 DOI: 10.1111/cup.14372] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2022] [Revised: 11/20/2022] [Accepted: 11/27/2022] [Indexed: 12/03/2022]
Abstract
Merkel cell carcinoma (MCC) is an aggressive cutaneous neuroendocrine carcinoma that may occasionally present divergent histopathologic features. We present two cases of MCC demonstrating ductal differentiation, one on the lower lip of an 81-year-old man and another on the right forearm of a 67-year-old man. The histopathologic features included TTF1-negative, infiltrative, high-grade basaloid tumor with paranuclear punctate positivity for cytokeratin (CK) 20 and synaptophysin. Rare luminal structures lined by atypical epithelioid cells positive for CEA and CK19 were noted, confirming the presence of ductal differentiation. Although the ductal differentiation is unusual, other histopathologic features and the immunohistochemical profile supported the diagnosis of MCC. Like most divergent features, ductal differentiation is rare in MCC and typically constitutes a very small proportion of the tumor, and is therefore under-recognized. Although the clinical significance of this feature is unclear, recognition and documentation of ductal differentiation and distinguishing it from other mimics such as acantholysis within squamous nests and entrapped eccrine ducts is essential to determine its clinical significance. We also discuss the differential diagnoses of cutaneous basaloid neoplasms with ductal differentiation.
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Affiliation(s)
- Kaitlin Vanderbeck
- Department of Pathology, University of Texas, MD Anderson Cancer Center, Houston, Texas, USA
| | - Woo Cheal Cho
- Department of Pathology, University of Texas, MD Anderson Cancer Center, Houston, Texas, USA
| | - Phyu P Aung
- Department of Pathology, University of Texas, MD Anderson Cancer Center, Houston, Texas, USA
| | - Doina Ivan
- Department of Pathology, University of Texas, MD Anderson Cancer Center, Houston, Texas, USA
| | - Aimi T Rothrock
- Department of Pathology, University of Texas, MD Anderson Cancer Center, Houston, Texas, USA
| | - Carlos A Torres-Cabala
- Department of Pathology, University of Texas, MD Anderson Cancer Center, Houston, Texas, USA
| | - Victor G Prieto
- Department of Pathology, University of Texas, MD Anderson Cancer Center, Houston, Texas, USA
| | - Jonathan L Curry
- Department of Pathology, University of Texas, MD Anderson Cancer Center, Houston, Texas, USA
| | - Priyadharsini Nagarajan
- Department of Pathology, University of Texas, MD Anderson Cancer Center, Houston, Texas, USA
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Gonzalez MR, Bryce-Alberti M, Portmann-Baracco A, Castillo-Flores S, Pretell-Mazzini J. Treatment and survival outcomes in metastatic Merkel cell carcinoma: Analysis of 2010 patients from the SEER database. Cancer Treat Res Commun 2022; 33:100665. [PMID: 36446191 DOI: 10.1016/j.ctarc.2022.100665] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Revised: 10/03/2022] [Accepted: 11/18/2022] [Indexed: 11/25/2022]
Abstract
INTRODUCTION Merkel cell carcinoma (MCC) is an aggressive cutaneous cancer that frequently compromises the lymph nodes (LN) and distal organs. We sought to describe clinical and demographic characteristics of affected patients, analyze risk factors for LN compromise, metastasis, and death, and evaluate their impact on survival. MATERIALS AND METHODS Patients with MCC were retrieved from the SEER database. Demographic, clinical and treatment data were analyzed. Logistic and Cox proportional hazard regression were used to analyze risk factors. Survival analysis was done with the Kaplan-Meier method. RESULTS A total of 2010 patients were included, among which 288 (14.33%) had distant metastases at diagnosis. LN involvement occurred in 45.8% and 20.1% of patients with and without distant metastasis, respectively. Males were more likely to present LN compromise (OR = 1.33, p<0.001). Tumors >10 mm showed a significantly higher risk for LN involvement and distant metastasis, with those >20 mm showing the highest risk (OR = 2.76 p<0.001 and OR = 8.88 p<0.001 respectively). Location of the tumor in the trunk was a protective factor for overall death (OR = 0.27), while LN compromise was a risk factor (OR = 3.12). Only history of previous malignancy significantly affected disease-specific death (OR = 0.32, p = 0.01). One-year survival was 79.7% and 38.2% for patients with regional LN disease and distant metastasis, respectively. CONCLUSION MCC is an aggressive cancer with high rates of LN involvement and distant metastases. Male gender and tumor size were risk factors for regional LN and metastatic disease. Tumor location in the trunk decrease the risk of overall death, while LN involvement increased it.
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Affiliation(s)
- Marcos R Gonzalez
- Facultad de Medicina Alberto Hurtado, Universidad Peruana Cayetano Heredia, Lima, Peru
| | - Mayte Bryce-Alberti
- Facultad de Medicina Alberto Hurtado, Universidad Peruana Cayetano Heredia, Lima, Peru
| | | | - Samy Castillo-Flores
- Facultad de Medicina Alberto Hurtado, Universidad Peruana Cayetano Heredia, Lima, Peru
| | - Juan Pretell-Mazzini
- Miami Cancer Institute, Division of Orthopedic Oncology, Baptist Health System South Florida. Plantation, Florida, United States.
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Lewis DJ, Sobanko JF, Etzkorn JR, Shin TM, Giordano CN, McMurray SL, Walker JL, Zhang J, Miller CJ, Higgins HW. Merkel Cell Carcinoma. Dermatol Clin 2022; 41:101-115. [DOI: 10.1016/j.det.2022.07.015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
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12
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Merkel Cell Carcinoma of the Left Eyelid with Metastasis to the Left Submandibular Lymph Nodes: A Case Report and Brief Review. Case Rep Ophthalmol Med 2022; 2022:4712301. [PMID: 35251726 PMCID: PMC8894019 DOI: 10.1155/2022/4712301] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2021] [Accepted: 02/01/2022] [Indexed: 11/18/2022] Open
Abstract
Merkel cell carcinoma (MCC) is a cutaneous cancer often found on sun-exposed areas. MCC is rare but very often lethal making early diagnosis challenging although critical. There are only a few cases that have reported MCC of the eyelid making it often hard to identify in clinic. A 52-year-old woman with a firm nodule on the left eyelid was diagnosed with MCC that had also metastasized to a left submandibular lymph node. She underwent surgical excision of the mass and lymph node as well as parotid gland and neck dissection to rule out other metastases and then underwent radiation therapy. The aim of this study is to report a case of eyelid MCC with metastasis to a local lymph node to provide another example of the rare cancer in hopes that diagnosis and treatment options for MCC are more thoroughly studied and understood.
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Lanceta J, Toprak M, Rosca OC. Merkel cell carcinoma presenting as a malignant pleural effusion post-COVID-19 hospitalization: A case report and literature review. Diagn Cytopathol 2022; 50:E37-E41. [PMID: 34609068 PMCID: PMC8652838 DOI: 10.1002/dc.24882] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2021] [Revised: 09/19/2021] [Accepted: 09/21/2021] [Indexed: 12/15/2022]
Abstract
Merkel cell carcinoma (MCC) is a rare, highly aggressive neuroendocrine carcinoma of the skin, associated with immunosuppression, UV light exposure, and the Merkel cell polyomavirus (MCPyV). Cases of metastatic MCC diagnosed in body fluid cytology are extremely rare; only five cases have been reported previously in the English literature. We present a case of a 65-year-old male with acute respiratory failure and an enlarged right pleural effusion. He had two hospitalizations for COVID-19 pneumonia 2 months prior, for which he received steroid treatment and tocilizumab. Emergent thoracentesis was done, with pleural fluid sent for cytologic evaluation. Both the Papanicolaou stained ThinPrep slide and cell block demonstrated clusters of predominantly small to medium sized blue round cells with hyperchromatic nuclei, scant cytoplasm and fine chromatin, in a background of rare mesothelial cells, macrophages and numerous lymphocytes. Tumor cells were positive for CD56, chromogranin, synaptophysin, SAT2B, MCPyV, and CK20 in perinuclear dot like pattern, while negative for TTF-1 and CD45 immunostains. Ki67 proliferative index was approximately 40%. The patient had a history of MCC of the right ulnar forearm 4 years before the current presentation, which was unknown to us at the time of cytologic evaluation. To the best of our knowledge, this is the sixth case of metastatic MCC diagnosed by fluid cytology and the first reported in a patient receiving immunosuppressive treatment for COVID-19. Further reporting of such cases may increase awareness, especially when prior history is not readily available, such as in our case.
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Affiliation(s)
- Joel Lanceta
- Department of Pathology and Laboratory MedicineNorthwell Health‐Staten Island University HospitalNew York CityNew YorkUSA
| | - Mesut Toprak
- Department of Pathology and Laboratory MedicineNorthwell Health‐Staten Island University HospitalNew York CityNew YorkUSA
| | - Oana C. Rosca
- Department of Pathology and Laboratory MedicineNorthwell Health‐Staten Island University HospitalNew York CityNew YorkUSA
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Soler-Sempere MJ, Alvárez-Fernández MO, Padilla-Navas I, Cabezas-Macián M, Sánchez-Hernández JF, García-Pachón E. Merkel cell carcinoma with pleural effusion. Arch Bronconeumol 2021; 57:715-717. [PMID: 35699019 DOI: 10.1016/j.arbr.2021.09.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2021] [Accepted: 02/22/2021] [Indexed: 06/15/2023]
Affiliation(s)
- María J Soler-Sempere
- Sección de Neumología, Hospital General Universitario de Elche, Elche, Alicante, Spain.
| | | | - Isabel Padilla-Navas
- Sección de Neumología, Hospital General Universitario de Elche, Elche, Alicante, Spain
| | - María Cabezas-Macián
- Sección de Anatomía Patológica, Hospital General Universitario de Elche, Elche, Alicante, Spain
| | | | - Eduardo García-Pachón
- Sección de Neumología, Hospital General Universitario de Elche, Elche, Alicante, Spain
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15
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Merkel Cell Carcinoma of the Head and Neck: Epidemiology, Pathogenesis, Current State of Treatment and Future Directions. Cancers (Basel) 2021; 13:cancers13143506. [PMID: 34298720 PMCID: PMC8305628 DOI: 10.3390/cancers13143506] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2021] [Revised: 07/07/2021] [Accepted: 07/07/2021] [Indexed: 12/12/2022] Open
Abstract
Merkel cell carcinoma (MCC) is a rare, cutaneous neuroendocrine malignancy with increasing incidence. The skin of the head and neck is a common subsite for MCC with distinctions in management from other anatomic areas. Given the rapid pace of developments regarding MCC pathogenesis (Merkel cell polyoma virus (MCPyV)-positive or virus-negative, cell of origin), diagnosis, staging and treatment, and up to date recommendations are critical for optimizing outcomes. This review aims to summarize currently available literature for MCC of the head and neck. The authors reviewed current literature, including international guidelines regarding MCC pathogenesis, epidemiology, diagnosis, staging, and treatment. Subsequently recommendations were derived including the importance of baseline imaging, MCPyV serology testing, primary site surgery, nodal evaluation, radiotherapy, and the increasing role of immune modulating agents in MCC. MCPyV serology testing is increasingly important with potential distinctions in treatment response and surveillance between virus-positive and virus-negative MCC. Surgical management continues to balance optimizing local control with minimal morbidity. Similarly, radiotherapy continues to have importance in the adjuvant, definitive, and palliative setting for MCC of the head and neck. Immunotherapy has changed the paradigm for advanced MCC, with increasing work focusing on optimizing outcomes for non-responders and high-risk patients, including those with immunosuppression.
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Leão I, Marinho J, Costa T. Long-term response to avelumab and management of oligoprogression in Merkel cell carcinoma: A case report. World J Clin Cases 2021; 9:4829-4836. [PMID: 34222455 PMCID: PMC8223835 DOI: 10.12998/wjcc.v9.i18.4829] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Revised: 05/04/2021] [Accepted: 05/08/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Merkel cell carcinoma (MCC) is a rare and aggressive cutaneous neuroendocrine neoplasia, with high risk of recurrence and metastasis and poor survival. Immune checkpoint inhibitors, like the anti-programmed death-ligand 1 agent avelumab, were recently approved for the treatment of advanced MCC. We, herein, report the first case of advanced MCC with oligoprogression managed with avelumab and local radical treatment.
CASE SUMMARY A 61-year-old man was presented to the hospital with sporadic fever and an exudative malodorous mass (10 cm of diameter), located on the right gluteal region. The final diagnosis was MCC, cT4N3M1c (AJCC, TNM staging 8th edition, 2017), with invasion of adjacent muscle, in-transit metastasis, and bone lesions. Patient started chemotherapy (cisplatin and etoposide), and after six cycles, the main tumor increased, evidencing disease progression. Two months later, the patient started second line treatment with avelumab (under an early access program). After two cycles of treatment, the lesion started to decrease, achieving a major response. Local progression was documented after 16 cycles. However, as the tumor became resectable, salvage surgery was performed, while keeping the systemic treatment with avelumab. Since the patient developed bilateral pneumonia, immunotherapy was suspended. More than 2.5 years after surgery (last 19 mo without systemic therapy), the patient maintains complete local response and stable bone lesions.
CONCLUSION This report highlights the efficacy and long-term response of avelumab on the management of a chemotherapy resistant advanced MCC, with evidence of oligoprogression, in combination with local radical treatment.
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Affiliation(s)
- Inês Leão
- Department of Oncology, Centro Hospitalar Vila Nova de Gaia/Espinho, Vila Nova de Gaia 4434-502, Portugal
| | - Joana Marinho
- Department of Oncology, Centro Hospitalar Vila Nova de Gaia/Espinho, Vila Nova de Gaia 4434-502, Portugal
| | - Telma Costa
- Department of Oncology, Centro Hospitalar Vila Nova de Gaia/Espinho, Vila Nova de Gaia 4434-502, Portugal
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17
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Soler-Sempere MJ, Alvárez-Fernández MO, Padilla-Navas I, Cabezas-Macián M, Sánchez-Hernández JF, García-Pachón E. Merkel Cell Carcinoma with Pleural Effusion. Arch Bronconeumol 2021; 57:S0300-2896(21)00074-0. [PMID: 33773839 DOI: 10.1016/j.arbres.2021.02.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2021] [Revised: 02/21/2021] [Accepted: 02/22/2021] [Indexed: 11/18/2022]
Affiliation(s)
- María J Soler-Sempere
- Sección de Neumología, Hospital General Universitario de Elche, Elche, Alicante, España.
| | | | - Isabel Padilla-Navas
- Sección de Neumología, Hospital General Universitario de Elche, Elche, Alicante, España
| | - María Cabezas-Macián
- Sección de Anatomía Patológica, Hospital General Universitario de Elche, Elche, Alicante, España
| | | | - Eduardo García-Pachón
- Sección de Neumología, Hospital General Universitario de Elche, Elche, Alicante, España
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18
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Abstract
Approximately, 1.4 million virus-induced cancers occur annually, representing roughly 10% of the worldwide cancer burden, with the majority (> 85%) occurring in the lower- and middle-income countries. The viruses associated with the greatest number of cancer cases are human papillomaviruses (HPVs), which cause cervical cancer and several other epithelial malignancies, and hepatitis viruses HBV and HCV, which are responsible for the majority of hepatocellular cancer. Other oncoviruses include Epstein-Barr virus (EBV), Kaposi's sarcoma herpesvirus (KSHV), human T-cell leukemia virus (HTLV-I), and Merkel cell polyoma virus (MCPyV). These oncoviruses include various classes of DNA and RNA viruses and induce cancer by a variety of mechanisms. However, cancers develop in a minority of infected individuals and almost always after chronic infection of many year's duration. Identification of the oncoviruses has provided critical insights in human carcinogenesis and led to several interventions that may reduce the risk of developing the tumors they induce. These interventions include preventive vaccines against HBV and HPV, screening for persistent HPV and HCV infections, antivirals for the treatment of chronic HBV and HCV infection, and screening the blood supply for the presence of HBV and HCV. Further efforts to identify additional oncogenic viruses in human cancers and new insights into etiology and pathogenesis of virally induced cancers would likely lead to new approaches for prophylactic and therapeutic interventions.
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Affiliation(s)
- John T Schiller
- Laboratory of Cellular Oncology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
| | - Douglas R Lowy
- Laboratory of Cellular Oncology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
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19
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Kaspi E, Fritz S, Colle J, Amatore F, Frankel D, Roll P. A rare case of pleural localisation of both metastatic Merkel cell carcinoma and chronic lymphocytic leukaemia. Cytopathology 2020; 32:367-370. [PMID: 33289204 DOI: 10.1111/cyt.12947] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2020] [Revised: 11/09/2020] [Accepted: 11/25/2020] [Indexed: 01/21/2023]
Affiliation(s)
- Elise Kaspi
- Aix Marseille Univ, APHM, INSERM, MMG, Hôpital la Timone, Service de Biologie Cellulaire, Marseille, France
| | - Shirley Fritz
- AP-HM, CHU La Conception, Hematology and Vascular Biology Laboratory, Marseille, France
| | - Julien Colle
- Aix Marseille Univ, APHM, INSERM, TAGC, La Conception, Hematology and Cellular Therapy Department, Marseille, France
| | - Florent Amatore
- Aix Marseille Univ, APHM, Timone Hospital, Dermatology and Oncodermatology Department, Marseille, France
| | - Diane Frankel
- Aix Marseille Univ, APHM, INSERM, MMG, Hôpital la Timone, Service de Biologie Cellulaire, Marseille, France
| | - Patrice Roll
- Aix Marseille Univ, APHM, INSERM, MMG, Hôpital la Timone, Service de Biologie Cellulaire, Marseille, France
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20
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Farah M, Reuben A, Spassova I, Yang RK, Kubat L, Nagarajan P, Ning J, Li W, Aung PP, Curry JL, Torres-Cabala CA, Hudgens CW, Ugurel S, Schadendorf D, Gumbs C, Little LD, Futreal A, Wistuba II, Prieto VG, Wang L, Wong MK, Wargo JA, Becker JC, Tetzlaff MT. T-Cell Repertoire in Combination with T-Cell Density Predicts Clinical Outcomes in Patients with Merkel Cell Carcinoma. J Invest Dermatol 2020; 140:2146-2156.e4. [PMID: 32304704 DOI: 10.1016/j.jid.2020.02.031] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2019] [Revised: 02/09/2020] [Accepted: 02/12/2020] [Indexed: 02/03/2023]
Abstract
The integrity of the immune system represents a pivotal risk factor and prognostic biomarker for Merkel cell carcinoma. A higher density of tumor-associated T cells correlates with improved Merkel cell carcinoma-specific survival, but the prognostic importance of the T-cell infiltrate reactivity is unknown. We evaluated the T-cell receptor repertoire associated with 72 primary Merkel cell carcinomas and correlated metrics of the T-cell receptor repertoire with clinicopathologic characteristics and patient outcomes. We showed that a high Simpson's Dominance index (SDom) was significantly associated with fewer metastases (P = 0.01), lower stage at presentation (P = 0.02), lower final stage at last follow-up (P = 0.05), and longer time to first lymph node metastasis (P = 0.04). These correlations were mostly preserved in the Merkel cell polyomavirus-negative subgroup. Combining SDom with CD3+ or CD8+ T-cell density revealed three distinct prognostic groups with respect to disease-specific survival. Patients with both high SDom and high CD3+ or CD8+ T-cell density had markedly improved disease-specific survival compared with patients with low SDom and low CD3+ or CD8+ T-cell density (P = 0.002 and P = 0.03, respectively). Patients with either high SDom or high CD3+ or CD8+ had intermediate disease-specific survival. Our findings demonstrate that the quality of the tumor-associated T-cell infiltrate informs patient prognosis in primary Merkel cell carcinoma beyond the T-cell density.
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Affiliation(s)
- Maya Farah
- Department of Pathology and Laboratory Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Alexandre Reuben
- Department of Thoracic/Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Ivelina Spassova
- Translational Skin Cancer Research, University Clinic Essen, Essen, Germany
| | - Richard K Yang
- Department of Pathology and Laboratory Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Linda Kubat
- Translational Skin Cancer Research, University Clinic Essen, Essen, Germany
| | - Priyadharsini Nagarajan
- Department of Pathology and Laboratory Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Jing Ning
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Wen Li
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Phyu P Aung
- Department of Pathology and Laboratory Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Jonathan L Curry
- Department of Pathology and Laboratory Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA; Department of Dermatology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA; Department of Translational and Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Carlos A Torres-Cabala
- Department of Pathology and Laboratory Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA; Department of Dermatology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Courtney W Hudgens
- Department of Translational and Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Selma Ugurel
- Department of Dermatology, University Clinic Essen, Essen, Germany
| | - Dirk Schadendorf
- Department of Dermatology, University Clinic Essen, Essen, Germany
| | - Curtis Gumbs
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Latasha D Little
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Andrew Futreal
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Ignacio I Wistuba
- Department of Translational and Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Victor G Prieto
- Department of Pathology and Laboratory Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA; Department of Dermatology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Linghua Wang
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Michael K Wong
- Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Jennifer A Wargo
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA; Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Jürgen C Becker
- Translational Skin Cancer Research, University Clinic Essen, Essen, Germany; Department of Dermatology, University Clinic Essen, Essen, Germany; German Cancer Consortium, German Cancer Center, Heidelberg, Germany
| | - Michael T Tetzlaff
- Department of Pathology and Laboratory Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA; Department of Translational and Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
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21
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Primary Merkel Cell Carcinoma: A Retrospective Analysis of 31 Cases in Poland. Dermatol Ther (Heidelb) 2020; 10:1003-1012. [PMID: 32654000 PMCID: PMC7477030 DOI: 10.1007/s13555-020-00424-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2020] [Indexed: 11/08/2022] Open
Abstract
Introduction Merkel cell carcinoma (MCC) is a rare, aggressive cutaneous neuroendocrine cancer that typically arises in sun-exposed areas of the skin, especially in the elderly. Significant advances have recently been made regarding skin cancers, but data on cases of MCC are rather limited as these patients are frequently grouped together with other non-melanoma skin cancers (NMSC). Here, we performed an analysis of the clinical profile of patients with MCC in Poland to identify major factors influencing the prognosis. Methods Approximately 13,000 pathology and medical records were examined to identify patients with MCC diagnosed between 2010 and 2019. The management and outcomes of patients with histologically confirmed MCC were retrospectively evaluated. Results Thirty-one patients diagnosed with MCC were identified. The tumor occurred predominantly in women (61.3%) and in the elderly (mean 75.6 years). Twenty-nine patients had locoregional MCC and two had metastatic MCC at the time of diagnosis. Patients in stage I disease had excellent prognosis. In stages II and III, respectively 22.2% and 50.0% of patients developed metastases. Among patients who received chemotherapy with cisplatin and etoposide, 17% achieved partial remission with progression-free survival (PFS) of 8.0 months, and a further 50% achieved stable disease with PFS of 4.0, 4.5, and 4.5 months respectively. In 6 (19.4%) patients MCC coexisted with chronic lymphocytic leukemia (CLL). In all six cases CLL preceded MCC development. Conclusions Female gender, tumor-free resection margins, and local disease were found to be independent prognostic factors in MCC progression. Patients with hematological malignancies, immunosuppression, and those with immune deficiencies should be closely followed up as they are predisposed to develop MCC. Electronic supplementary material The online version of this article (10.1007/s13555-020-00424-5) contains supplementary material, which is available to authorized users.
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22
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Kwiatkowska D, Reich A. Landscape of current and future therapies of Merkel cell carcinoma. Dermatol Ther 2020; 33:e13281. [PMID: 32083780 DOI: 10.1111/dth.13281] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2020] [Accepted: 02/14/2020] [Indexed: 12/30/2022]
Abstract
Merkel cell carcinoma is rare and aggressive skin cancer, which occurrence is linked to exposure to ultraviolet light and the Merkel-cell polyomavirus. In recent years, significant progress in understanding the mechanism of Merkel cell carcinoma pathogenesis has been observed. This neoplasm often expresses PD-L1, and MCPyV-specific T cells can express PD-1 thus PD-1/PD-L1 checkpoint therapies seem to be remarkably interesting treatment options. Many clinical trials are currently being conducted to confirm their effectiveness and safety for this group of patients. However, only about half of advanced Merkel cell carcinoma patients could achieve remission or disease stabilization through PD-1/PD-L1 checkpoint therapies thus innovative treatments are still needed. In this article, we have presented current and future directions in the development of Merkel cell carcinoma therapy.
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Affiliation(s)
| | - Adam Reich
- Department of Dermatology, University of Rzeszow, Rzeszów, Poland
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23
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Danger is only skin deep: aggressive epidermal carcinomas. An overview of the diagnosis, demographics, molecular-genetics, staging, prognostic biomarkers, and therapeutic advances in Merkel cell carcinoma. Mod Pathol 2020; 33:42-55. [PMID: 31676786 DOI: 10.1038/s41379-019-0394-6] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2019] [Revised: 09/27/2019] [Accepted: 10/14/2019] [Indexed: 12/19/2022]
Abstract
Merkel cell carcinoma (MCC) is a high grade primary cutaneous neuroendocrine carcinoma and is among the most aggressive cutaneous malignancies. The rising incidence of MCC, together with its often rapidly aggressive course, underscore a critical need to recognize the histopathologic and the immunohistochemical features that inform its accurate diagnosis. In the current review, we summarize the current state of knowledge regarding the accurate diagnosis of MCC and the exclusion of other entities in the differential diagnosis. We provide a comprehensive review of genomic studies that identified the molecular-genetic drivers of MCC as well as a summary of studies identifying prognostic biomarkers that can facilitate risk stratification. Importantly, Merkel cell polyomavirus (MCPyV) appears to be causative in most cases of MCC and represents both a diagnostic and prognostic marker. Finally, as staging of MCC has undergone critical refinements with the introduction of the 8th Edition of the American Joint Committee on Cancer staging system, we provide an update on MCC staging. In particular, the prognostic significance of the sentinel lymph node (SLN) in MCC necessitates a systematic approach to its evaluation and diagnosis to ensure accurate and consistent risk stratification for patients, and we therefore provide a comprehensive overview of SLN evaluation in MCC. Finally, the intimate relationship between MCC and the integrity of the host immune system has led to paradigm-shifting therapeutic advances with the successful application of immune checkpoint blockade to treat patients with advanced disease, and we therefore summarize those studies and the correlative studies in which predictive biomarkers have been identified.
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24
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Garcia GA, Kossler AL. Avelumab as an Emerging Therapy for Eyelid and Periocular Merkel Cell Carcinoma. Int Ophthalmol Clin 2020; 60:91-102. [PMID: 32205656 PMCID: PMC7101017 DOI: 10.1097/iio.0000000000000306] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
Merkel cell carcinoma (MCC) is a highly aggressive cutaneous malignancy, with a high metastasis rate and a significant proportion of cases affecting the eyelid or periocular region. Current treatments for periocular MCC include wide local excision (WLE) with or without adjuvant radiotherapy and can result in profound morbidity and visual deficit. Metastatic disease has been traditionally treated with chemotherapy, though durable responses are typically poor and toxicity is high. Avelumab (Bavencio®, Merck KgaA, Darmstadt, Germany and Pfizer Inc., New York, NY, USA), the first FDA-approved human anti-programmed death-ligand 1 (PD-L1) antibody for the treatment of metastatic MCC (mMCC), has demonstrated safety and efficacy as first-line treatment and in chemotherapy-refractory cases. This review summarizes pivotal clinical trial data for avelumab in the treatment of mMCC, including efficacy, safety and tolerability, and describes the efficacy of two other immune checkpoint inhibitors, pembrolizumab (Keytruda®, Merck & Co., Inc., Kenilworth, NJ, USA) and nivolumab (Opdivo®, Bristol‐Myers Squibb, New York, NY, USA and Ono Pharmaceuticals, Trenton, NJ, USA) for the treatment of advanced MCC. Our purpose is to provide the rationale to further investigate avelumab as a potential therapy for advanced or metastatic eyelid and periocular MCC.
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Affiliation(s)
- Giancarlo A. Garcia
- Department of Ophthalmology, Byers Eye Institute at Stanford University, Palo Alto, California
| | - Andrea Lora Kossler
- Department of Ophthalmology, Byers Eye Institute at Stanford University, Palo Alto, California
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25
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Abdallah N, Nagasaka M, Chowdhury T, Raval K, Hotaling J, Sukari A. Complete response with neoadjuvant avelumab in Merkel cell carcinoma - A case report. Oral Oncol 2019; 99:104350. [PMID: 31277904 DOI: 10.1016/j.oraloncology.2019.06.031] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2019] [Accepted: 06/28/2019] [Indexed: 01/30/2023]
Abstract
Merkel cell carcinoma (MCC) is a rare but aggressive neuroendocrine skin malignancy. We report here a case of localized MCC achieving pathologic complete response upon treatment with avelumab in the neoadjuvant setting. Preclinical and clinical studies have revealed a close relationship between MCC and the immune system, thus supporting a role for PD-1/PD-L1 inhibitors in MCC. This neoadjuvant use of PD-1/PD-L1 inhibitors can avoid potentially disfiguring surgery in MCC. As the incidence of MCC is rising, clinical trials are needed to evaluate the efficacy and safety of immunotherapy in resectable disease.
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Affiliation(s)
- Nadine Abdallah
- Department of Internal Medicine, Wayne State University, Detroit, MI, USA
| | - Misako Nagasaka
- Department of Oncology, Karmanos Cancer Institute/Wayne State University, Detroit, MI, USA; Department of Advanced Medical Innovation, St. Marianna University Graduate School of Medicine, Kawasaki, Japan
| | - Tahmida Chowdhury
- Department of Oncology, Karmanos Cancer Institute/Wayne State University, Detroit, MI, USA
| | - Kunil Raval
- Department of Pathology, Wayne State University, Detroit, MI, USA
| | - Jeffrey Hotaling
- Department of Otolaryngology Head and Neck Surgery, Wayne State University, Detroit, MI, USA
| | - Ammar Sukari
- Department of Oncology, Karmanos Cancer Institute/Wayne State University, Detroit, MI, USA.
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26
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Abstract
Merkel cell carcinoma is an aggressive neuroendocrine carcinoma with increasing incidence over the past few decades. The TNM Staging System used for Merkel cell carcinoma was updated by the American Joint Committee on Cancer in 2017. Clinical practice guidelines were updated by the National Comprehensive Cancer Network on August 31, 2018. This article reviews the most recent evidence-based updates on staging and management.
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Affiliation(s)
- Christine Cornejo
- Department of Dermatology, University of Pennsylvania, 2 Maloney Building, 3600 Spruce Street, Philadelphia, PA 19104, USA
| | - Christopher J Miller
- Department of Dermatology, Perelman Center for Advanced Medicine, University of Pennsylvania, 1st Floor South Pavilion, 3400 Civic Center Boulevard, Suite 1-330S, Philadelphia, PA 19104, USA.
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27
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Abstract
This article reviews the most common nonmelanoma skin cancers affecting the head and neck region. Although the most common of these malignancies rarely result in mortality, local morbidity caused by the tumors and their extirpation cannot be underestimated. Complete tumor extirpation with pathologically confirmed negative margins is the gold standard. Regional and distant metastases are rare, but must be treated appropriately should they occur. Although reconstructive surgery can be life changing for the patients and rewarding for the clinicians, it behooves the treating surgeons to remain true to oncologic principles above all else.
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Affiliation(s)
- Michael G Brandt
- Division of Facial Plastic and Reconstructive Surgery, Department of Otolaryngology-Head and Neck Surgery, Faculty of Medicine, University of Toronto, 190 Elizabeth Street, Room 3S-438, TGH RFE Building, Toronto, Ontario M5G 2C4, Canada.
| | - Corey C Moore
- Division of Facial Plastic and Reconstructive Surgery, Department of Otolaryngology-Head and Neck Surgery, Schulich School of Medicine, Western University, St Joseph's Hospital, 268 Grosvenor Street 2nd Floor, London, Ontario N6A 4V2, Canada
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28
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Aung PP, Parra ER, Barua S, Sui D, Ning J, Mino B, Ledesma DA, Curry JL, Nagarajan P, Torres-Cabala CA, Efstathiou E, Hoang AG, Wong MK, Wargo JA, Lazar AJ, Rao A, Prieto VG, Wistuba I, Tetzlaff MT. B7-H3 Expression in Merkel Cell Carcinoma-Associated Endothelial Cells Correlates with Locally Aggressive Primary Tumor Features and Increased Vascular Density. Clin Cancer Res 2019; 25:3455-3467. [PMID: 30808776 DOI: 10.1158/1078-0432.ccr-18-2355] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2018] [Revised: 12/04/2018] [Accepted: 02/22/2019] [Indexed: 12/19/2022]
Abstract
PURPOSE Merkel cell carcinoma (MCC) is an aggressive cutaneous malignancy whose pathogenesis and prognosis are related to the integrity of the host immune system. Despite promising clinical responses to immune-checkpoint blockade, response and resistance remain unpredictable, underscoring a critical need to delineate novel prognostic biomarkers and/or therapeutic targets for this disease.Experimental Design: Expression of immune-regulatory markers (PD-L2, B7-H3, B7-H4, IDO-1, ICOS, TIM3, LAG3, VISTA, and OX-40) was assessed using singlet chromogenic IHC in 10 primary MCCs. Multiplex immunofluorescence quantified CD31 and B7-H3 expression in 52 primary and 25 metastatic MCCs. B7-H3 and CD31 expressions were tabulated as a series of independent (X,Y) cell centroids. A spatial G-function, calculated based on the distribution of distances of B7-H3+ (X,Y) cell centroids around the CD31+ (X,Y) cell centroids, was used to estimate a colocalization index equivalent to the percentage of CD31-positive cell centroids that overlap with a B7-H3-positive cell centroid. RESULTS Primary and metastatic MCCs exhibit a dynamic range of colocalized CD31 and B7-H3 expression. Increasing colocalized expression of B7-H3 with CD31 significantly associated with increased tumor size (P = 0.0060), greater depth of invasion (P = 0.0110), presence of lymphovascular invasion (P = 0.0453), and invasion beyond skin (P = 0.0428) in primary MCC. Consistent with these findings, increasing colocalized expression of B7-H3 and CD31 correlated with increasing vascular density in primary MCC, but not metastatic MCC. CONCLUSIONS Our results demonstrate that colocalized expression of B7-H3/CD31 is a poor prognostic indicator and suggest therapies targeting B7-H3 may represent an effective approach to augmenting immune-activating therapies for MCC.
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Affiliation(s)
- Phyu P Aung
- Department of Pathology, the University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Edwin Roger Parra
- Department of Translational Molecular Pathology, the University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Souptik Barua
- Department of Electrical and Computer Engineering, Rice University, Houston, Texas
| | - Dawen Sui
- Department of Bioinformatics and Computational Biology, the University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Jing Ning
- Department of Bioinformatics and Computational Biology, the University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Barbara Mino
- Department of Translational Molecular Pathology, the University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Debora Alejandra Ledesma
- Department of Translational Molecular Pathology, the University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Jonathan L Curry
- Department of Pathology, the University of Texas MD Anderson Cancer Center, Houston, Texas
| | | | - Carlos A Torres-Cabala
- Department of Pathology, the University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Eleni Efstathiou
- Department of Genitourinary Medical Oncology, the University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Anh G Hoang
- Department of Genitourinary Medical Oncology, the University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Michael K Wong
- Department of Melanoma Medical Oncology, the University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Jennifer A Wargo
- Department of Surgical Oncology, the University of Texas MD Anderson Cancer Center, Houston, Texas.,Department of Genomic Medicine, the University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Alexander J Lazar
- Department of Pathology, the University of Texas MD Anderson Cancer Center, Houston, Texas.,Department of Translational Molecular Pathology, the University of Texas MD Anderson Cancer Center, Houston, Texas.,Department of Genomic Medicine, the University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Arvind Rao
- Department of Electrical and Computer Engineering, Rice University, Houston, Texas.,Department of Bioinformatics and Computational Biology, the University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Victor G Prieto
- Department of Pathology, the University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Ignacio Wistuba
- Department of Translational Molecular Pathology, the University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Michael T Tetzlaff
- Department of Pathology, the University of Texas MD Anderson Cancer Center, Houston, Texas. .,Department of Translational Molecular Pathology, the University of Texas MD Anderson Cancer Center, Houston, Texas
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Trinidad CM, Torres-Cabala CA, Prieto VG, Aung PP. Update on eighth edition American Joint Committee on Cancer classification for Merkel cell carcinoma and histopathological parameters that determine prognosis. J Clin Pathol 2019; 72:337-340. [PMID: 30636696 DOI: 10.1136/jclinpath-2018-205504] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2018] [Revised: 12/07/2018] [Accepted: 12/22/2018] [Indexed: 11/03/2022]
Abstract
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.
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Affiliation(s)
- Celestine M Trinidad
- Department of Pathology, Dermatopathology Section, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.,University of Santo Tomas Hospital Benavides Cancer Institute, Manila, Philippines
| | - Carlos A Torres-Cabala
- Department of Pathology, Dermatopathology Section, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Victor G Prieto
- Department of Pathology, Dermatopathology Section, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Phyu P Aung
- Department of Pathology, Dermatopathology Section, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
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