Bianca D. Lemos

Clinical characteristics of Merkel cell carcinoma at diagnosis in 195 patients: the “AEIOU” features

BACKGROUND Merkel cell carcinoma (MCC) is an aggressive skin cancer with a mortality of 33%. Advanced disease at diagnosis is a poor prognostic factor, suggesting that earlier detection may improve outcome. No systematic analysis has been published to define the clinical features that are characteristic of MCC. OBJECTIVE We sought to define the clinical characteristics present at diagnosis to identify features that may aid clinicians in recognizing MCC. METHODS We conducted a cohort study of 195 patients given the diagnosis of MCC between 1980 and 2007. Data were collected prospectively in the majority of cases, and medical records were reviewed. RESULTS An important finding was that 88% of MCCs were asymptomatic (nontender) despite rapid growth in the prior 3 months (63% of lesions) and being red or pink (56%). A majority of MCC lesions (56%) were presumed at biopsy to be benign, with a cyst/acneiform lesion being the single most common diagnosis (32%) given. The median delay from lesion appearance to biopsy was 3 months (range 1-54 months), and median tumor diameter was 1.8 cm. Similar to earlier studies, 81% of primary MCCs occurred on ultraviolet-exposed sites, and our cohort was elderly (90% >50 years), predominantly white (98%), and often profoundly immune suppressed (7.8%). An additional novel finding was that chronic lymphocytic leukemia was more than 30-fold overrepresented among patients with MCC. LIMITATIONS The study was limited to patients seen at a tertiary care center. Complete clinical data could not be obtained on all patients. This study could not assess the specificity of the clinical characteristics of MCC. CONCLUSIONS To our knowledge, this study is the first to define clinical features that may serve as clues in the diagnosis of MCC. The most significant features can be summarized in an acronym: AEIOU (asymptomatic/lack of tenderness, expanding rapidly, immune suppression, older than 50 years, and ultraviolet-exposed site on a person with fair skin). In our series, 89% of primary MCCs had 3 or more of these findings. Although MCC is uncommon, when present in combination, these features may indicate a concerning process that would warrant biopsy. In particular, a lesion that is red and expanding rapidly yet asymptomatic should be of concern.

Association of Merkel Cell Polyomavirus–Specific Antibodies With Merkel Cell Carcinoma

Background Merkel cell polyomavirus (MCPyV) has been detected in approximately 75% of patients with the rare skin cancer Merkel cell carcinoma. We investigated the prevalence of antibodies against MCPyV in the general population and the association between these antibodies and Merkel cell carcinoma. Methods Multiplex antibody-binding assays were used to assess levels of antibodies against polyomaviruses in plasma. MCPyV VP1 antibody levels were determined in plasma from 41 patients with Merkel cell carcinoma and 76 matched control subjects. MCPyV DNA was detected in tumor tissue specimens by quantitative polymerase chain reaction. Seroprevalence of polyomavirus-specific antibodies was determined in 451 control subjects. MCPyV strain–specific antibody recognition was investigated by replacing coding sequences from MCPyV strain 350 with those from MCPyV strain w162. Results We found that 36 (88%) of 41 patients with Merkel cell carcinoma carried antibodies against VP1 from MCPyV w162 compared with 40 (53%) of the 76 control subjects (odds ratio adjusted for age and sex = 6.6, 95% confidence interval [CI] = 2.3 to 18.8). MCPyV DNA was detectable in 24 (77%) of the 31 Merkel cell carcinoma tumors available, with 22 (92%) of these 24 patients also carrying antibodies against MCPyV. Among 451 control subjects from the general population, prevalence of antibodies against human polyomaviruses was 92% (95% CI = 89% to 94%) for BK virus, 45% (95% CI = 40% to 50%) for JC virus, 98% (95% CI = 96% to 99%) for WU polyomavirus, 90% (95% CI = 87% to 93%) for KI polyomavirus, and 59% (95% CI = 55% to 64%) for MCPyV. Few case patients had reactivity against MCPyV strain 350; however, indistinguishable reactivities were found with VP1 from strain 350 carrying a double mutation (residues 288 and 316) and VP1 from strain w162. Conclusion Infection with MCPyV is common in the general population. MCPyV, but not other human polyomaviruses, appears to be associated with Merkel cell carcinoma.

Array-CGH Reveals Recurrent Genomic Changes in Merkel Cell Carcinoma Including Amplification of L-Myc

Merkel cell carcinoma (MCC) is an aggressive neuroendocrine skin cancer with poorly characterized genetics. We performed high resolution comparative genomic hybridization on 25 MCC specimens using a high-density oligonucleotide microarray. Tumors frequently carried extra copies of chromosomes 1, 3q, 5p, and 6 and lost chromosomes 3p, 4, 5q, 7, 10, and 13. MCC tumors with less genomic aberration were associated with improved survival (P=0.04). Tumors from 13 of 22 MCC patients had detectable Merkel cell polyomavirus DNA, and these tumors had fewer genomic deletions. Three regions of genomic alteration were of particular interest: a deletion of 5q12-21 occurred in 26% of tumors, a deletion of 13q14-21 was recurrent in 26% of tumors and contains the well-characterized tumor suppressor RB1, and a previously unreported focal amplification at 1p34 was present in 39% of tumors and centers on L-Myc (MYCL1). L-Myc is related to the c-Myc proto-oncogene, has transforming activity, and is amplified in the closely related small cell lung cancer. Normal skin showed no L-Myc expression, whereas 4/4 MCC specimens tested expressed L-Myc RNA in relative proportion to the DNA copy number gain. These findings suggest several genes that may contribute to MCC pathogenesis, most notably L-Myc.

Relationships among primary tumor size, number of involved nodes, and survival for 8044 cases of Merkel cell carcinoma

BACKGROUND The effects of primary tumor size on nodal involvement and of number of involved nodes on survival have not, to our knowledge, been examined in a national database of Merkel cell carcinoma (MCC). OBJECTIVE We sought to analyze a retrospective cohort of patients with MCC from the largest US national database to assess the relationships between these clinical parameters and survival. METHODS A total of 8044 MCC cases in the National Cancer Data Base were analyzed. RESULTS There was a 14% risk of regional nodal involvement for 0.5-cm tumors that increased to 25% for 1.7-cm (median-sized) tumors and to more than 36% for tumors 6 cm or larger. The number of involved nodes was strongly predictive of survival (0 nodes, 76% 5-year relative survival; 1 node, 50%; 2 nodes, 47%; 3-5 nodes, 42%; and ≥6 nodes, 24%; P < .0001 for trend). Younger and/or male patients were more likely to undergo pathological nodal evaluation. LIMITATIONS The National Cancer Data Base does not capture disease-specific survival. Hence, relative survival was calculated by comparing overall survival with age- and sex-matched US population data. CONCLUSION Pathologic nodal evaluation should be considered even for patients with small primary MCC tumors. The number of involved nodes is strongly predictive of survival and may help improve prognostic accuracy and management.

Duration of Voriconazole Exposure: An Independent Risk Factor for Skin Cancer After Lung Transplantation

Objective To determine whether there is an association between duration of voriconazole therapy and number of nonmelanoma skin cancers (NMSC) after lung transplantation. Design A telephone‐based survey and chart review were performed for all living patients who received a lung transplant at Emory University from 1993 to 2009. Setting Academic medical center. Participants Lung transplant recipients. Main Outcome Measured Number of NMSC after lung transplantation. Results Sixty of 91 (65.9%) subjects were exposed to voriconazole for at least 3 months (11.2 ± 8.7 months, range 3–58 months) after lung transplantation, of whom 16 developed NMSC, with a mean of 38 months to first NMSC. Of 31 patients not exposed to voriconazole, 12 developed NMSC, with a mean of 52 months to first NMSC . By univariate analysis, time since transplant (correlation coefficient (r) = 0.514), age (r = 0.101), and high lifetime sun exposure (r = 0.211) were correlated with number of skin cancers after transplantation. Skin types V and VI were protective (r = −0.353). In multivariate regression, time since transplantation (0.061 per month), age (0.151 per year), skin type I or II (4.939), and months of exposure to voriconazole (0.149) were found to be independent risk factors for number of skin cancers after lung transplantation. Conclusion Duration of voriconazole exposure correlates with number of NMSC after lung transplantation. All patients exposed to voriconazole should be educated about their increased risk of skin cancer and should have regular dermatologic follow‐up for skin cancer screening. Physicians caring for lung‐transplant recipients should consider alternatives to voriconazole in patients at risk for skin cancer.

Protection from UV-induced skin carcinogenesis by genetic inhibition of the ataxia telangiectasia and Rad3-related (ATR) kinase

Multiple human epidemiologic studies link caffeinated (but not decaffeinated) beverage intake with significant decreases in several types of cancer, including highly prevalent UV-associated skin carcinomas. The mechanism by which caffeine protects against skin cancer is unknown. Ataxia telangiectasia and Rad3-related (ATR) is a replication checkpoint kinase activated by DNA stresses and is one of several targets of caffeine. Suppression of ATR, or its downstream target checkpoint kinase 1 (Chk1), selectively sensitizes DNA-damaged and malignant cells to apoptosis. Agents that target this pathway are currently in clinical trials. Conversely, inhibition of other DNA damage response pathways, such as ataxia telangiectasia mutated (ATM) and BRCA1, promotes cancer. To determine the effect of replication checkpoint inhibition on carcinogenesis, we generated transgenic mice with diminished ATR function in skin and crossed them into a UV-sensitive background, Xpc−/−. Unlike caffeine, this genetic approach was selective and had no effect on ATM activation. These transgenic mice were viable and showed no histological abnormalities in skin. Primary keratinocytes from these mice had diminished UV-induced Chk1 phosphorylation and twofold augmentation of apoptosis after UV exposure (P = 0.006). With chronic UV treatment, transgenic mice remained tumor-free for significantly longer (P = 0.003) and had 69% fewer tumors at the end of observation of the full cohort (P = 0.019), compared with littermate controls with the same genetic background. This study suggests that inhibition of replication checkpoint function can suppress skin carcinogenesis and supports ATR inhibition as the relevant mechanism for the protective effect of caffeinated beverage intake in human epidemiologic studies.

Protocol for the Examination of Specimens From Patients With Merkel Cell Carcinoma of the Skin

The College of American Pathologists offers these protocols to assist pathologists in providing clinically useful and relevant information when reporting results of surgical specimen examinations. The College regards the reporting elements in the ‘‘Surgical Pathology Cancer Case Summary (Checklist)’’ portion of the protocols as essential elements of the pathology report. However, the manner in which these elements are reported is at the discretion of each specific pathologist, taking into account clinician preferences, institutional policies, and individual practice. The College developed these protocols as an educational tool to assist pathologists in the useful reporting of relevant information. It did not issue the protocols for use in litigation, reimbursement, or other contexts. Nevertheless, the College recognizes that the protocols might be used by hospitals, attorneys, payers, and others. Indeed, effective January 1, 2004, the Commission on Cancer of the American College of Surgeons mandated the use of the checklist elements of the protocols as part of its Cancer Program Standards for Approved Cancer Programs. Therefore, it becomes even more important for pathologists to familiarize themselves with these documents. At the same time, the College cautions that use of the protocols other than for their intended educational purpose may involve additional considerations that are beyond the scope of these documents. PROTOCOL FOR THE EXAMINATION OF SPECIMENS FROM PATIENTS WITH MERKEL CELL CARCINOMA OF THE SKIN This protocol applies to Merkel cell carcinoma of cutaneous surfaces only. The seventh edition TNM staging system for Merkel cell carcinoma of the American Joint Committee on Cancer (AJCC) and the International Union Against Cancer (UICC) is recommended.

Case 19-2008: Merkel-cell carcinoma.

n engl j med 359;15 www.nejm.org october 9, 2008 1629 The study findings, taken in conjunction with the known myocardial abnormalities of fibrosis and conduction-system degeneration, make it probable that acute unstable arrhythmias were responsible for the majority of sudden deaths. The study was a multicenter investigation, and the ability to request autopsies was limited. We agree that progressive skeletal-muscle weakness leading to respiratory failure is a significant issue in the care of patients with myotonic dystrophy. Respiratory failure was the most common cause of death in our study. Whether respiratory status had a role in the initiation of the event leading to sudden death is not clear. As detailed in our article, the presence of severe muscular weakness did affect the patients’ and caregivers’ decisions regarding the treatment of unstable arrhythmias. On the basis of our study findings, we agree that a yearly noninvasive evaluation, including assessment for atrial tachyarrhythmias and severe conduction abnormalities on the ECG, will aid in determining the risk of sudden death. We do not agree that nonmortality outcomes from nonrandomized observations in a referred population have proved the diagnostic usefulness of invasive electrophysiological studies or the therapeutic benefit of prophylactic pacemakers in the management of sudden death in patients with myotonic dystrophy.1-3 The cohort analysis by Hermans and colleagues provides support for our finding that sudden death is a common cause of death among patients with myotonic dystrophy type 1 and that pacemakers may not prevent sudden death. We understand the rationale behind their recommendation for prophylactic ICDs. However, we believe that the population of patients with myotonic dystrophy type 1 is of sufficient size and clinical complexity that a prospective mortality assessment of the benefit of ICDs is indicated. With the worldwide interest in evaluating methods to prevent sudden death in patients with myotonic dystrophy type 1, a multinational trial would be optimal. We encourage investigators providing care for patients with myotonic dystrophy type 1 to design and implement such a necessary trial. Vrtovec and Haddad question whether QT prolongation detected on ECG predicts sudden death in patients with myotonic dystrophy type 1. We found no independent association between markers of prolonged repolarization and sudden death. Sovari and Dudley hypothesize that TGF-β1 could serve as a biomarker for sudden death in patients with myotonic dystrophy type 1. We did not evaluate TGF-β1 and have seen no published data.