Merkel cell polyomavirus and trichodysplasia spinulosa-associated polyomavirus DNAs and antibodies in blood among the elderly

Merkel cell polyomavirus and trichodysplasia spinulosa-associated polyomavirus DNAs and antibodies in blood among the elderly

Merkel cell polyomavirus (MCPyV) and trichodysplasia spinulosa-associated polyomavirus (TSPyV) are recently found pathogens causing two rare skin disorders, Merkel cell carcinoma (MCC) and trichodysplasia spinulosa (TS). MCC is proportionally common in the elderly and most often is associated with immunosuppression.

TS is a folliculocentric infection seen in patients in an immunocompromised state. Little or no baseline information exists, however, on the prevalences of these two viruses among the elderly.

Epidemiologic data on this population could help in understanding their natural biology. We wished to determine the occurrences and blood levels of MCPyV and TSPyV DNAs among the elderly and any association between the prevalences of their corresponding antiviral IgG antibodies. 

Methods: From 394 hospitalized elderly individuals (age >=65 years) with respiratory symptoms, cardiovascular, and other diseases, we studied 621 serum samples by four different real-time quantitative (q) PCRs, two for the DNAs of MCPyV and two for TSPyV.

The IgG antibodies for both viruses among 481 serum samples of 326 subjects were measured with enzyme immunoassays (EIAs), using as antigen recombinant virus-like particles (VLPs). 

Results: Of the 394 patients, 39 (9.9%) were positive at least once for MCPyV DNA by the LT PCR, and 33 (8.4%) by the VP1 PCR, while 6 (1.5%) were positive by both PCR assays. In general, the viral DNA copy numbers were low.

In sharp contrast, no TSPyV DNA was detectable with qPCRs for the corresponding genomic regions. The IgG seroprevalence of MCPyV was 59.6% and of TSPyV, 67.3%. 

Conclusions: MCPyV DNA, unlike TSPyV DNA, occurs in low copy number in serum samples from a notable proportion of aging individuals.

Whether this reflects enhanced viral replication possibly due to waning immune surveillance, and is associated with increased MCC risk, deserves exploration.

Author: Mohammadreza SadeghiMatti AronenTingting ChenLaura JarttiTuomas JarttiOlli RuuskanenMaria Söderlund-VenermoKlaus Hedman
Credits/Source: BMC Infectious Diseases 2012, 12:383

7th Space

Merkel cell carcinoma arising in a patient with a history of multiple malignancies.

Oct 2012

Stevenson ML, Saggar S, Amin B, Mann RE.

Source

Department of Dermatology, Columbia University School of Physicians and Surgeons, New York, New York, USA. marylstevenson@gmail.com

Abstract

Merkel cell carcinoma (MCC) is a rare and highly aggressive neuroendocrine carcinoma of the skin. Although the association between MCC and other primary malignancies has been documented, the mechanism of this association has not been elucidated. We report a case of MCC in a man with a history of multiple primary malignancies and treatment with immunomodulators. This case highlights the increased incidence of other malignancies in patients with MCC and is unique given the number and diversity of primary malignancies found in this patient.

PubMed

Metastatic Merkel cell carcinoma of the oral cavity in a human immunodeficiency virus-positive patient and the detection of Merkel cell polyomavirus

Dec 2011

Li M, Saghafi N, Freymiller E, Basile JR, Lin YL.

Source

Division of Diagnostic and Surgical Sciences, School of Dentistry, University of California, Los Angeles, California.

Abstract

The etiology of Merkel cell carcinoma (MCC) was recently linked to a newly identified human virus, the Merkel cellpolyomavirus (MCPyV). The discovery that MCPyV plays an important role in the tumorigenesis of >80% of MCCs provides an explanation for the increased incidence of this rare malignancy in human immunodeficiency virus (HIV)-positive and immunocompromised patients. We report an unusual metastasis of MCC to the mandibular gingiva of an HIV-positive patient. In addition to routine hematoxylin-eosin and immunohistochemical studies, we also performed a molecular biologic analysis to look for the presence of MCPyV in this case. We detected evidence of the MCPyV genome in this lesion similar to what has been observed for MCCs reported in other immunocompromised patients. These results stress the importance of combining morphologic and molecular biologic analyses in the evaluation of MCC, because confirmation of viral etiology would likely affect the choice of treatment and prognosis when specific antiviral therapy becomes available for this aggressive tumor

Science Direct.

Sarcoid reaction associated with Merkel cell carcinoma revealed by fluorodeoxyglucose positron emission tomography: a case report

2011

Yuko Higashi,¹ Kentaro Mera,¹ Mitsuyoshi Shimokawa,¹ Mitsuhiro Hisadome,¹ Atsunori Baba,¹Shigeto Matsushita,¹ Masakazu Yanagi,² and Takuro Kanekura¹

^Abstract

Introduction

Although the association between cancer and sarcoidosis  or sarcoid reaction is known, sarcoid reaction associated with Merkel cell carcinoma is rare.

Case presentation

We report the case of a 57-year-old Japanese woman with Merkel cell carcinoma in the inguinal area associated with sarcoid reaction. Fluorodeoxyglucose positron emission tomography demonstrated elevated fluorodeoxyglucose uptake by mediastinal lymph nodes and at the carcinoma site. Histopathologically, the mediastinal lymph nodes contained no Merkel cell carcinoma components. Sarcoid lesions were identified. Systemic examinations returned no sarcoidosis-specific findings.

Conclusion

Fluorodeoxyglucose positron emission tomographic scans can be used to assess neoplastic lesions and depict sarcoidosis. Sarcoid reactions must be considered in the interpretation of fluorodeoxyglucose positron emission tomographic scans.

NCBI-NIH

A review of radiotherapy for merkel cell carcinoma of the head and neck.

2012

Lee J, Poon I, Balogh J, Tsao M, Barnes E.

Source

Odette Cancer Centre, Sunnybrook Health Sciences Centre, Department of Radiation Oncology, University of Toronto, Toronto, ON, Canada.

Abstract

Merkel cell carcinoma of the head and neck (MCCHN) presents a clinical challenge due to its aggressive natural history, unpredictable lymphatic drainage, and high degree of treatment related morbidity. Histological examination of the regional lymph nodes is very important in determining the optimal treatment and is usually achieved by sentinel lymph node biopsy. Radiotherapy plays a critical role in the treatment of most patients with MCCHN. Surgery with adjuvant radiotherapy to the primary tumour site is associated with high local control rates. If lymph nodes are clinically or microscopically positive, adjuvant radiotherapy is indicated to decrease the risk of regional recurrence. The majority of locoregional recurrences occur at the edge or just outside of the radiation field, reflecting both the inherent radiosensitivity of MCC and the importance of relatively large volumes to include "in-transit" dermal lymphatic pathways. When surgical excision of the primary or nodal disease is not feasible, primary radiotherapy alone should be considered as a potentially curative modality and confers good loco-regional control. Concurrent chemoradiotherapy is well tolerated and may further improve outcomes. 

Full text article

PubMed - Journal of Skin Cancer

Merkel cell polyomavirus: A newly discovered human virus with oncogenic potential.

Jan 2013

Spurgeon ME, Lambert PF.

Source

Department of Oncology, McArdle Laboratory for Cancer Research, University of Wisconsin School of Medicine and Public Health, 1400 University Ave. Madison, WI 53706, USA.

Abstract

Keywords:

• DNA tumor virus; 
• Merkel; 
• Tumor antigen; 
• Merkel cell polyomavirus; 
• MCV; 
• MCPyV; 
• Polyomavirus; 
• Merkel cell carcinoma

A marked escalation in the rate of discovery of new types of human polyomavirus has occurred over the last five years largely owing to recent technological advances in their detection. Among the newly discovered viruses, Merkel Cell Polyomavirus (MCPyV or MCV) has gained the most attention due to its link with a rare human cancer. Infection with MCPyV is common in the human population, and the virus is detected in several anatomical locations, but most frequently in skin. Study of MCPyV molecular virology has been complicated by the lack of straightforward cell culture models, but recent in vitro studies are making strides towards understanding the virus life cycle, its cellular tropism, and mode of transmission. While MCPyV shares several traditional traits with other human polyomaviruses, the burst of research since its discovery reveals insight into a virus with many unique genetic and mechanistic features. The evidence for a causal link between MCPyV and the rare neuroendocrine cancer, Merkel Cell Carcinoma (MCC), is compelling. A majority of MCCs contain clonally integrated viral DNA, express viral T antigen transcripts and protein, and exhibit an addiction to the viral large T and small t antigen oncoproteins. The MCPyV large T antigen contains MCC tumor-specific mutations that ablate its replication capacity but preserve its oncogenic functions, and the small t antigen promotes an environment favorable for cap-dependent translation. The mechanisms of MCPyV-induced transformation have not been fully elucidated, but the likely etiological role of this new polyomavirus in human cancer provides a strong opportunity to expand knowledge of virus-host interactions and viral oncology.

Elsevier - Scielo

Tumor-infiltrating lymphocytes and outcome in Merkel cell carcinoma, a virus-associated cancer.

Nov 2012 

Sihto H, Joensuu H.

Source

Laboratory of Molecular Oncology and Molecular Cancer Biology Program; University of Helsinki; Helsinki, Finland.

Abstract

Keywords: Merkel cell carcinoma, Merkel cell polyomavirus, cytotoxic T cells, survival, tumor-infiltrating lymphocytes

An intense immune infiltrate, enriched in T cells, is associated with the presence of Merkel cell polyomavirus (MCPyV) DNA in Merkel cell carcinoma (MCC), a rare skin cancer. High tumor-infiltrating T-cell counts are associated with favorable survival regardless of the tumor MCPyV status. Hence, boosting host immune functions might constitute a new approach for the treatment of MCC.

Full text article with images:

NCBI-NLM

The Merkel cell carcinoma challenge: A review from the fine needle aspiration service.

Dec 2012

Bechert CJ, Schnadig V, Nawgiri R.

Source

Division of Cytopathology, University of Texas Medical Branch, Galveston, Texas.

Abstract

Merkel cell carcinoma (MCC) is a highly aggressive neuroendocrine carcinoma of the skin that occurs primarily in elderly or immunocompromised patients. For this report, the authors reviewed the diagnostic challenges associated with MCC encountered on their fine-needle aspiration (FNA) service and also conducted an in-depth review of the literature on MCC. A computer search for patients who were diagnosed with MCC by FNA at the authors' institution from 2006 to 2010 was conducted, and 5 patients were selected for cytologic and immunochemical analyses based on their varied and diagnostically challenging clinical presentations. The 5 selected patients had clinical findings commonly associated with MCC, including advanced age (4 of the 5 patients were ages 75-85 years) and a history of previous malignancies (3 of the 5 patients had a history of previous malignancy), and 1 patient was diagnosed with a concomitant low-grade lymphoma. The patients and their disease illustrated the protean clinical presentation of MCC and the clinical and cytologic challenges associated with this neoplasm. The current findings indicate the need for cytopathologists to be aware of the deceptive presentation of this neoplasm and its cytologic and immunochemical features to correctly diagnose this insidious neoplasm.

Wiley Online

Additional Information:

Small Needle Biopsy (fine needle aspiration)

Merkel cell carcinoma with lymph node metastasis in the absence of a primary site: Case report and literature review.

Dec 2012

Zhao M, Meng MB.

Source

Tianjin University of Traditional Chinese Medicine; ; Tianjin Tasly Co. Ltd.;

Abstract 

Merkel cell carcinoma (MCC) is a rare malignant skin neoplasm with the potential for local recurrence, spreading to regional lymph nodes (LNs) and distant metastases. Although it has been identified in various anatomical sites, LN metastatic MCC in the absence of a primary site is extremely rare. The present case reports a 54-year-old male who initially underwent histological examination of a biopsy specimen from the right inguinal LNs. A diagnosis of metastatic small cell carcinoma was made. Nine months later, this diagnosis was changed to MCC with multiple metastases following observation of a tumour mass in the right dorsal thigh. Additionally, in the present study a summary is provided of 23 published cases of MCC with initial LN metastasis in the absence of a primary site, with details of clinical characteristics, natural history and pertinent therapy of this uncommon tumour. The present patient with LN metastatic MCC in the absence of a primary site and the other reported cases demonstrate that although multimodal treatment with surgery, radiotherapy (RT) and chemotherapy provides excellent local control, local recurrence and distant metastases commonly develop in this uncommon tumour. LN metastatic MCC in the absence of a primary site is a highly malignant disease and the role of adjuvant postoperative RT and/or chemotherapy remains to be fully determined.

PubMed

Merkel cell carcinoma: a systematic review of ENT presentations.

Nov 2012

Gioacchini FM, Postacchini V, Simonetti O, Offidani A, Magliulo G, Re M.

Source

Otolaryngology Department, University Hospital of Modena, Via del Pozzo 71, 41100, Modena, Italy, giox83@hotmail.com.

Abstract

The aim of this study was to perform a systematic literature review of Merkel cell carcinomas (MCCs) originating exclusively in the ear, nose and throat (ENT) district. An appropriate string was run on PubMed to retrieve articles dealing with ENT presentations of MCC. A double cross-check was performed on citations and full-text articles found using the selected inclusion and exclusion criteria. In total, 43 articles were finally included in the study, describing 51 cases of MCC involving the ENT region: 22/51 (43 %) cases involving the ear; 20/51 (39 %) cases involving the mucosal sites; 9/51 (18 %) cases involving other ENT regions. Patients with mucosal site involvement showed a higher mortality rate from the disease (45 %) in comparison with the other two groups, especially when compared with those patients having primary involvement of the ear (22 %). The ENT specialist should suspect and consider MCC, especially in elderly patients presenting with a suspicious lesion of the auricular pavilion, so as to avoid misdiagnosis and delayed treatments.

PubMed

Positron emission tomography/computed tomography imaging in Merkel cell carcinoma: A study of 270 scans in 97 patients at the Dana-Farber/Brigham and Women's Cancer Center.

2012

Hawryluk EB, O'Regan KN, Sheehy N, Guo Y, Dorosario A, Sakellis CG, Jacene HA, Wang LC.

Source

Department of Dermatology, Harvard Medical School, Boston.

Abstract

BACKGROUND:

 Merkel cell carcinoma (MCC) is a rare and lethal cutaneous neuroendocrine carcinoma. Imaging is crucial for accurate staging, which remains a strong predictor of survival, as well as earlier detection of recurrence and progression, which are common despite aggressive management. There is no consensus on the role of initial and subsequent imaging for MCC.

OBJECTIVE:

 We sought to evaluate the use of 2-fluoro-[(18)F]-deoxy-2-D-glucose (FDG)-positron emission tomography (PET)/computed tomography (CT) in the management of MCC.

METHODS:

In all, 270 FDG-PET/CT studies were performed in 97 patients with pathology-proven MCC at the Dana-Farber/Brigham and Women's Cancer Center, Boston, Mass, from August 2003 to December 2010.

RESULTS:

 FDG-PET/CT scans were obtained as part of the initial (61 scans in 61 patients) and subsequent (209 scans in 79 patients) treatment strategies. MCCs were FDG-avid with a mean maximum standardized uptake value of primary lesions of 6.5 (range 1.3-12.9) and a mean maximum standardized uptake value of regional and distant metastases of 7.2 (range 1.5-9.9). FDG-PET/CT upstaged 16% of patients who underwent baseline scans. FDG-PET/CT studies showed that bone and bone-marrow metastases were more common than previously reported, and were often undetected by CT.

LIMITATIONS:

Our study is limited by its retrospective design, and potential referral bias associated with a tertiary care center.

CONCLUSIONS:

 FDG-PET/CT performed as part of the initial management strategy tended to upstage patients with more advanced disease. FDG-PET/CT performed as part of the subsequent treatment strategy identified metastatic disease, particularly in bone/bone marrow, which was not seen on CT. FDG-PET/CT imaging is a valuable staging and restaging tool in MCC management.

J A A D

PET Scans Clear Hurdle for Merkel Cell Dx

By Ed Susman, Contributing Writer, MedPage Today

Published: November 01, 2012

Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco and Dorothy Caputo, MA, BSN, RN, Nurse Planner

BOSTON – Use of fluorodeoxyglucose positron emission tomography (FDG-PET) imaging has an impact on how Merkel cell carcinoma patients are diagnosed or treated in about a third of cases, researchers said here.

In fact, 64 of 194 scans (33%) performed on 123 consecutive patients with Merkel cell carcinoma had a 'high' impact -- defined as a change in treatment or treatment plans -- on care, Michael MacManus, MD, of the Peter MacCallum Cancer Centre in Melbourne, Australia, reported at the American Society of Radiation Oncology meeting.

That result broke down as follows, according to McManus:

• In 102 scans performed for staging, 23 (23%) had 'high' impact and 15 (15%) had 'medium' impact
• In 39 scans performed to assess response to disease, 17 (44%) had high impact and none had 'medium' impact
• In 53 scans performed for re-staging at the time of suspected relapse, 24 (45%) had 'high' impact and 6 (11%) had medium impact

"Merkel cell carcinoma is a rare cutaneous neuroendocrine carcinoma," MacManus said. The disease arises in hair follicles and appears to be related to ultraviolet light and Merkel cell polyoma virus. The disease is easily pinpointed with PET imaging, and yet the largest study to date included a mere 12 patients, he said.

The primary endpoint of the study was to show that PET would have at least a 10% high impact or a 25% high or medium impact. MacManus said his finding met those criteria (P<0 .001=".001" b="b">

Among the other findings in the study, the researchers found that of the 23 staging PET scans with 'high impact,' 14 resulted in a change in treatment, 5 caused a change in treatment intent, and 4 resulted in changes in both treatment modality and radiotherapy techniques.

MacManus also noted that 22% of patients had incongruent staging between conventional and PET staging. The use of PET scans upstaged 17 patients -- four because of occult distant disease and 13 because of occult nodal disease.

On the other hand, PET imaging downstaged five patients – two of whom were suspected of having Stage 4 disease and 3 who were thought to have had Stage 3 disease, MacManus said.

Med Page Today

Merkel Cell Carcinoma Prognosis Linked to Vitamin D

Merkel Cell Carcinoma Prognosis Linked to Vitamin D

By: BRUCE JANCIN, Clinical Endocrinology News Digital Network

PRAGUE – Add Merkel cell carcinoma to the seemingly ever-growing list of malignancies linked to vitamin D deficiency.

A multicenter French study involving 89 patients with histologically confirmed Merkel cell carcinoma indicates that individuals with this rare and often aggressive neuroendocrine skin malignancy have an increased prevalence of vitamin D deficiency. Moreover, the vitamin D–deficient subgroup had a greater mean tumor size at diagnosis and sharply worse outcomes, Dr. Mahtab Samimi reported at the annual caongress of the European Academy of Dermatology and Venereology.

Fifty-eight of the 89 (65%) Merkel cell carcinoma patients were vitamin D deficient as defined by a serum level below 50 nmol/L. During follow-up, 33 patients developed nodal and/or distant metastases and 19 died of Merkel cell carcinoma. The 4-year Merkel cell carcinoma–free survival rate was 40% in the vitamin D deficient group and more than 90% in patients with normal-range vitamin D. The metastasis-free survival rate at 4 years was 20% in vitamin D–deficient patients and 70% in those without serum vitamin D deficiency.

In a multivariate regression analysis, low vitamin D was independently associated with an adjusted 2.89-fold increased risk of developing nodal and/or distant metastases and a 5.28-fold increased risk for death from their malignancy, reported Dr. Samimi of Francois Rabelais University in Tours, France.

The multivariate analysis was adjusted for age, gender, immune status, tumor location, time of year of the serum vitamin D measurement, and Merkel cell polyomavirus DNA levels.

It’s biologically plausible that a patient’s vitamin D status influences Merkel cell carcinoma behavior, according to Dr. Samimi. She and her coworkers analyzed 19 primary tumor specimens and 9 nodal metastases and found every single one strongly expressed the vitamin D receptor.

"The active metabolites of vitamin D bind to the vitamin D receptor, which is able to regulate genes involved in cell cycle control and others that have anti-inflammatory effects," the dermatologist explained.

Other investigators have shown that melanoma, too, is affected by a patient’s vitamin D status. Vitamin D deficiency is associated with thicker melanomas at diagnosis and reduced survival, she noted.

Dr. Samimi stressed that the newly shown association that she and her coworkers have found between vitamin D deficiency and worse-prognosis Merkel cell carcinoma must be considered hypothesis-generating rather than proof of causality. Serum vitamin D wasn’t measured until an average of 3 months after cancer diagnosis.

Asked by the audience if she screens her patients with Merkel cell carcinoma or melanoma for vitamin D deficiency, Dr. Samimi replied affirmatively. And if they’re deficient, as is so often the case, she puts them on vitamin D supplementation.

"The protective role of doing this in terms of cancer prognosis is not proven, but at the very least the supplementation has beneficial effects on skeletal and muscle health, so it’s a good thing," she said.

In a separate study, Dr. Nicolas Kluger of the University of Helsinki presented national Finnish data showing a predisposition of Merkel cell carcinoma for the left side of affected patients.

The  comprehensive Finnish Cancer Registry is thought to have captured all 177 Finns diagnosed with Merkel cell carcinoma in a recent 20-year period. Fifty-six percent of the tumors were on the left, 37% on the right, and 7% occurred on the midline.

Tumors located on the trunk were equally likely to be left or right sided, but tumors on the head and neck were 3.2-fold more likely to be on the left side. Merkel cell carcinomas arising on the forearm or hand were fourfold more likely to occur on the left than the right side. On the leg and foot, the left-sided excess was 2.4-fold. Tumors located on the face were 1.5-fold more likely to occur on the left side.

These Finnish data confirm an earlier U.S. study involving a much larger patient population: 2,384 individuals with Merkel cell carcinoma included the National Cancer Institute’s Surveillance, Epidemiology and End Results (SEER) database, Dr. Kluger noted. In the U.S. study, 52.7% of the cancers occurred on the left side. On the arm it was 55%, while on the face it was 52%, but there was no difference in lateral distribution of the tumors on the legs (J. Am. Acad. Dermatol. 2011;65:35-9).

The same large U.S. study also showed an excess of left-sidedness in the distribution of melanomas among 82,587 affected patients in the SEER registry.

Since ultraviolet light exposure figures in the pathogenesis of both of these serious skin cancers, one leading theory regarding the explanation for the left-sided predominance of Merkel cell carcinoma and melanoma involves increased driver-side UV exposure while operating motor vehicles. Dr. Kluger finds this explanation unlikely. Although steering wheels are placed on the left side of vehicles in Finland, as in the United States, left-side predominance of these skin cancers also has been reported in countries such as Scotland, where drivers stick to the left side of the road and the steering wheel is on the right, he noted.

In Finland, there was a significant excess of Merkel cell carcinomas on the left side in nearly every year of the 20-year study. That means if the skewed lateral distribution of the tumors is due to some as-yet-unidentified environmental factor, it’s a factor that hasn’t changed in 20 years, Dr. Kluger observed.

"For now it’s an interesting curiosity," he commented.

Both Dr. Kluger and Dr. Samimi reported having no financial conflicts.

Clinical Endocrinology News

Metastatic merkel cell carcinoma in the bone marrow of a patient with plasma cell myeloma and therapy-related myelodysplastic syndrome.

2012

Kressin MK, Kim AS.

Source

Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center Nashville, TN, USA ; Department of Pathology & Laboratory Medicine, Tennessee Valley Healthcare System Veterans Affairs Nashville, TN, USA ; Current address: Austin Pathology Associates 901 W. Ben White Blvd., Austin, TX, USA.

Abstract

Merkel cell carcinoma is an aggressive neoplasm of the skin that shows frequent lymph node metastases, but has only rarely been reported in the bone marrow. Herein we report a case of a 64-year-old male with a history of plasma cell myeloma and recent skin diagnosis of Merkel cell carcinoma who presented for a routine follow-up bone marrow to assess his myeloma. The biopsy showed persistent plasma cell myeloma, trilineage dysplasia, and clusters of neuroendocrine cells consistent with metastatic Merkel cell carcinoma. Discussion of this case, a review of metastatic Merkel cell carcinoma, and identification of clinical settings in which staging bone marrow biopsy may be warranted are presented.

PubMed