Background The management of Merkel cell carcinoma (MCC) has been complicated by a lack of detailed prognostic data and by the presence of conflicting staging systems. Objective We sought to ...determine the prognostic significance of tumor size, clinical versus pathologic nodal evaluation, and extent of disease at presentation and thereby derive the first consensus staging/prognostic system for MCC. Methods A total of 5823 prospectively enrolled MCC cases from the National Cancer Data Base had follow-up data (median 64 months) and were used for prognostic analyses. Results At 5 years, overall survival was 40% and relative survival (compared with age- and sex-matched population data) was 54%. Among all MCC cases, 66% presented with local, 27% with nodal, and 7% with distant metastatic disease. For cases presenting with local disease only, smaller tumor size was associated with better survival (stage I, ≤2 cm, 66% relative survival at 5 years; stage II, >2 cm, 51%; P < .0001). Patients with clinically local-only disease and pathologically proven negative nodes had better outcome (76% at 5 years) than those who only underwent clinical nodal evaluation (59%, P < .0001). Limitations The National Cancer Data Base does not capture disease-specific survival. Overall survival for patients with MCC was therefore used to calculate relative survival based on matched population data. Conclusion Although the majority (68%) of patients with MCC in this nationwide cohort did not undergo pathologic nodal evaluation, this procedure may be indicated in many cases as it improves prognostic accuracy and has important treatment implications for those found to have microscopic nodal involvement.
Reactivity and titers of autoantibodies vary during the course of autoimmune hepatitis (AIH), and some autoantibodies have been associated with disease activity and adverse outcomes after treatment. ...The aim of this study was to assess the autoantibody behavior in AIH and its significance as predictors of biochemical and histological remission. A total of 117 patients with AIH (mean age 18.6 4‐69 years) were evaluated and tested for autoantibodies at disease onset and successively (mean 3.2 2‐6 times) after a mean follow‐up evaluation of 70 20‐185 months. Antismooth muscle (ASMA), antiliver kidney microsome type 1 (anti‐LKM1), antiliver cytosol type 1 (anti‐LC1), antimitochondrial, antinuclear (ANA), and antiactin antibodies (AAA) were determined at disease onset and 379 other times during the follow‐up evaluation through indirect immunofluorescence in rodent tissues, HEp‐2 cells, and human fibroblasts. Anti‐SLA/LP were assessed 45 times in the follow‐up evaluation of 19 patients using enzyme‐linked immunosorbent assay (ELISA). Upon admission, AIH types 1 and 2 were observed in 95 and 17 patients, respectively. Five subjects had AIH with anti‐SLA/LP as the sole markers. Patients initially negative for AAA did not develop these antibodies thereafter. ANA were detected de novo in six and three subjects with AIH types 1 and 2, respectively. After treatment, only ASMA (>1:80) and AAA (>1:40) were significantly associated with biochemical (76.9% and 79.8%) and histological features (100% and 100%) of disease activity (P < 0.001). Conclusion: With the exception of ANA, the autoantibody profile does not markedly vary in the course of AIH. The persistence of high titers of ASMA and/or AAA in patients with AIH is associated with disease activity. (Hepatology 2014;59:592–600)
Merkel cell carcinoma (MCC) is a polyomavirus-associated skin cancer that is frequently lethal and lacks established prognostic biomarkers. This study sought to identify biomarkers that improve ...prognostic accuracy and provide insight into MCC biology.
Gene expression profiles of 35 MCC tumors were clustered based on prognosis. The cluster of genes overexpressed in good-prognosis tumors was tested for biologic process enrichment. Relevant mRNA expression differences were confirmed by quantitative polymerase chain reaction and immunohistochemistry. An independent set of 146 nonoverlapping MCC tumors (median follow-up, 25 months among 116 living patients) was employed for biomarker validation. Univariate and multivariate Cox regression analyses were performed.
Immune response gene signatures were prominent in patients with good prognoses. In particular, genes associated with cytotoxic CD8+ lymphocytes were overexpressed in tumors from patients with favorable prognoses. In the independent validation set, cases with robust intratumoral CD8+ lymphocyte infiltration had improved outcomes (100% MCC-specific survival, n = 26) compared with instances characterized by sparse infiltration (60% survival, n = 120). Only stage and intratumoral CD8 infiltration (but not age, sex, or CD8+ lymphocytes localized to the tumor-stroma interface) were significant in both univariate and multivariate Cox regression analyses. Notably, traditional histologic identification of tumor-infiltrating lymphocytes was not a significant independent predictor of survival.
Intratumoral CD8+ lymphocyte infiltration can be readily assessed on paraffin-embedded tissue, is independently associated with improved MCC-specific survival, and therefore, may provide prognostic information that enhances established MCC staging protocols.
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.
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.
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.
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 ( a symptomatic/lack of tenderness, e xpanding rapidly, i mmune suppression, o lder than 50 years, and u ltraviolet-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.
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.
Case 19-2008: Merkel-cell carcinoma Lemos, Bianca D; Yu, Siegrid S; Nghiem, Paul
The New England journal of medicine,
2008-Oct-09, Letnik:
359, Številka:
15
Journal Article
PDF
