Patterns of Human Leukocyte Antigen Class I and Class II Associations and Cancer.

Human leukocyte antigen (HLA) gene variation is associated with risk of cancers, particularly those with infectious etiology or hematopoietic origin, given its role in immune presentation. Previous studies focused primarily on HLA allele/haplotype-specific associations. To answer whether associations are driven by HLA class I (essential for T-cell cytotoxicity) or class II (important for T-cell helper responses) genes, we analyzed GWAS from 24 case-control studies and consortia comprising 27 cancers (totaling >71,000 individuals). Associations for most cancers with infectious etiology or of hematopoietic origin were driven by multiple HLA regions, suggesting that both cytotoxic and helper T-cell responses are important. Notable exceptions were observed for nasopharyngeal carcinoma, an EBV-associated cancer, and CLL/SLL forms of non-Hodgkin lymphomas; these cancers were associated with HLA class I region only and HLA class II region only, implying the importance of cytotoxic T-cell responses for the former and CD4+ T-cell helper responses for the latter. Our findings suggest that increased understanding of the pattern of HLA associations for individual cancers could lead to better insights into specific mechanisms involved in cancer pathogenesis. SIGNIFICANCE: GWAS of >71,000 individuals across 27 cancer types suggest that patterns of HLA Class I and Class II associations may provide etiologic insights for cancer.

A Multicenter Application of the 2018 Banff Classification for BK Polyomavirus-associated Nephropathy in Renal Transplantation.

BACKGROUND: With current immunosuppressive regimens, BK polyomavirus-associated nephropathy (BKPyVAN) is still a matter of concern. Stratification of patients at risk for allograft loss is of uttermost importance to guide treatment choice and assess prognosis. In 2018, the Banff working group proposed a classification scheme for the prognosis of BKPyVAN, but external application on independent cohorts is yet to be performed. We investigated how the 2018 Banff classification would perform in a multicenter cohort comprising 50 cases of biopsy-proven BKPyVAN compared to previously published classification systems. METHODS: We analyzed consecutive BKPyVAN cases from two Dutch university hospitals between 2002 and 2013, retrieved clinical data, and scored all biopsies according to the Banff 2018 classification, and as a comparison, 4 previously proposed BKPyVAN classification systems. We used estimated glomerular filtration rate trajectories and death-censored graft survival as primary endpoints. RESULTS: The 2018 Banff classification did not associate with estimated glomerular filtration rate decline or graft failure and performed only slightly better than the 4 previously proposed classifiers. Anti-human leukocyte antigen donor-specific antibodies (DSAs), especially in combination with ongoing biopsy-proven BKPyVAN on follow-up, did correlate with graft function and survival. Patients who were DSA+/BKPyVAN+ on follow-up had more inflammation at the baseline biopsy, which by itself was not associated with graft outcomes. CONCLUSIONS: Neither the 2018 Banff BKPyVAN classification nor previously published stratification systems could be applied to our multicenter patient cohort. Our data suggest that there might be a prognostic value for follow-up biopsies and DSA measurements to improve risk stratification after BKPyVAN, although prospective multicenter efforts with protocol measurements are needed to confirm this.

Immunologic evidence of a strong association between non-Hodgkin lymphoma and simian virus 40.

BACKGROUND: Non-Hodgkin lymphoma (NHL), the most common cancer of the lymphatic system, is of unknown etiology. The identification of etiologic factors in the onset of NHL is a key event that could facilitate the prevention and cure of this malignancy. Simian virus 40 (SV40) has been considered an oncogenic agent in the onset/progression of NHL. METHODS: In this study, an indirect enzyme-linked immunosorbent assay with 2 synthetic peptides that mimic SV40 antigens of viral capsid proteins 1 to 3 was employed to detect specific antibodies against SV40. Serum samples were taken from 2 distinct cohorts of NHL-affected patients (NHL1 [n = 89] and NHL2 [n = 61]) along with controls represented by oncologic patients affected by breast cancer (BC; n = 78) and undifferentiated nasopharyngeal carcinoma (UNPC; n = 64) and 3 different cohorts of healthy subjects (HSs; HS1 [n = 130], HS2 [n = 83], and HS3 [n = 87]). RESULTS: Immunologic data indicated that in serum samples from NHL patients, antibodies against SV40 mimotopes were detectable with a prevalence of 40% in NHL1 patients and with a prevalence of 43% in NHL2 patients. In HSs of the same median age as NHL patients, the prevalence was 16% for the HS1 group (57 years) and 14% for the HS2 group (65 years). The difference was statistically significant (P < .0001 and P < .001). Interestingly, the difference between NHL1/NHL2 patients and BC patients (40%/43% vs 15%, P < .001) and between NHL1/NHL2 patients and UNPC patients (40%/43% vs 25%, P < .05) was significant. CONCLUSIONS: Our data indicate a strong association between NHL and SV40 and thus a need for innovative therapeutic approaches for this hematologic malignancy.

Interobserver agreement for Polyomavirus nephropathy grading in renal allografts using the working proposal from the 10th Banff Conference on Allograft Pathology.

A classification schema for grading Polyomavirus nephropathy was proposed at the 2009 Banff allograft meeting. The schema included 3 stages of Polyomavirus nephropathy: early (stage A), florid (stage B), and late sclerosing (stage C). Grading categories for histologic viral load levels were also proposed. To examine the applicability and the interobserver agreement of the proposed Polyomavirus nephropathy grading schema, we evaluated 24 renal allograft biopsies with confirmed Polyomavirus nephropathy by histology and SV40. Four renal pathologists independently scored the Polyomavirus nephropathy stage (A, B, or C), without knowledge of the clinical history. Viral load was scored as a percent of tubules exhibiting viral replication, using either a 3-tier viral load score (1: ≤1%; 2: >1%-10%; 3: >10%) or a 4-tier score (1: ≤1%; 2: >1%-≤5%; 3: >5%-15%; 4: >15%). The κ score for the Polyomavirus nephropathy stage was 0.47 (95% confidence interval, 0.35-0.60; P < .001). There was a substantial agreement using both the 3-tier and the 4-tier scoring for the viral load (Kendall concordance coefficients, 0.72 and 0.76, respectively; P < .001 for both). A better complete agreement was found using the 3-tier viral load score. In this first attempt to evaluate the interobserver reproducibility of the proposed Polyomavirus nephropathy classifying schema, we demonstrated moderate κ agreement in assessing the Polyomavirus nephropathy stage and a substantial agreement in scoring the viral load level. The proposed grading schema can be applied in routine allograft biopsy practice for grading the Polyomavirus nephropathy stage and the viral load level.

Tissue-based classification of HPV infections of the uterine cervix and vagina (mucosal HPV infections).

Terminology of HPV infections of the uterine cervix and vagina is somewhat confusing, with various terms having different meanings to different authors. This prompted us to revise the current terminology and propose a "tissue-based" classification of HPV infections of the cervix and vagina (mucosal HPV infections), which is based on histological appearance of the lesions and should be clear-cut in everyday practice of managing these patients. We hope the proposed nomenclature may overcome some of the confusion and controversy that exist in the current terminologies describing these lesions.

[The role of colposcopy in Population Program of Cervical Cancer Early Detection]. / Miejsce kolposkopii w Populacyjnym Programie Profilaktyki i Wczesnego Wykrywania Raka Szyjki Macicy.

Cervical screening is the most effective method of controlling and fighting with cervical cancer. The article has presented the role and importance of cytology and colposcopy in the realization of The Population Programme of Cervical Cancer Early Detection. Furthermore, the significance of cytological examination during the first two stages of the programme, as well as the role of colposcopy in the realization of the third stage of the precise diagnosis among women with abnormal pap smears, have been presented as well. The goals and basic advice on performing colposcopy have been introduced. Methodology of colposcopy has been presented in detail.

Early vulvar squamous neoplasia: advances in classification, diagnosis, and differential diagnosis.

The recognition and classification of preinvasive vulvar neoplasia are complicated by the facts that (a) their respective carcinomas have a diverse (human papillomavirus [HPV]- and non-HPV-related) pathogenesis; (b) not all vulvar squamous carcinomas are associated with precursors with strictly defined morphologic features; (c) many carcinomas have epithelial changes that are abnormal but lack sufficient nuclear atypia to warrant classification as an intraepithelial neoplasm; and (d) even lesions associated with a common etiologic agent (HPV) present a diverse morphologic spectrum. In this review, five categories of early vulvar neoplasia are defined, based on the available literature, into (a) low-grade lesions with minimal cancer risk, (b) high-grade lesions associated with HPV, (c) high-grade lesions associated with other etiologies, (d) squamous atypias defined by abnormalities in differentiation rather than abnormalities in nuclear morphology, and (d) early carcinomas that do not exhibit conspicuous stromal invasion. The first three groups are arranged into low- and high-grade intraepithelial lesions, the fourth into intraepithelial atypias that bear careful follow-up and attention to the co-existing squamous mucosa, and the fifth into a category that, depending on the degree of cell differentiation, may warrant local excision or lymph node dissection. Recognition of these five categories is germane to proper management of women with squamous lesions of the vulva.

Human papillomavirus infection of the epididymis and ductus deferens: an evaluation by nested polymerase chain reaction.

CONTEXT: Human papillomaviruses (HPVs) play an important role in the etiology of squamous cell carcinoma of the uterine cervix. The possible role of the male urogenital tract as a reservoir of HPV infection is not fully understood. We inferred from our previous observation of HPV-31 in epididymal tissue in a case of chronic epididymitis that HPV might be commonly present in cases of epididymitis caused by sexually transmitted pathogens. OBJECTIVE: To assess the presence of HPV in the epididymis and ductus deferens in nontuberculous epididymitis. DESIGN: Epididymal samples obtained from 17 patients and epididymal and ductus deferens samples from 5 patients surgically treated for nontuberculous epididymitis were analyzed by nested polymerase chain reaction for the presence of HPV DNA. In positive samples, the HPV type was determined by DNA sequencing. SETTING: Tertiary-care academic hospital and national reference laboratory for papillomaviruses. RESULTS: Low-risk HPV type 6 and high-risk HPV types 16, 33, 35, 55, and 73 were detected in 7 patients (31%). Neither koilocytes nor dysplastic changes were found in the epididymis and ductus deferens. CONCLUSION: Low-risk and high-risk HPV types were detected in the epididymis and ductus deferens of patients with nontuberculous epididymitis. The infection was not accompanied by koilocytic atypia or dysplasia. Our findings support the hypothesis that the male urogenital tract serves as a reservoir of HPV infection.

Determinants of clearance of human papillomavirus infections in Colombian women with normal cytology: a population-based, 5-year follow-up study.

Little is known about the factors that influence clearance of human papillomavirus (HPV), the primary cause of cervical carcinoma. A total of 227 women cytologically normal and HPV positive at baseline were identified from a population-based cohort of 1,995 Bogota, Colombia, women aged 13-85 years followed between 1993 and 2000 (mean follow-up, 5.3 years). HPV DNA detection and viral load determination were based on a GP5+/GP6+ polymerase chain reaction enzyme immunoassay. Rate ratio estimates for HPV clearance were calculated by using methods for interval-censored survival time data. Analyses were based on 316 type-specific HPV infections. HPV 16 had a significantly lower clearance rate than infections with low-risk types (rate ratio (RR) = 0.47, 95% confidence interval (CI): 0.32, 0.72), HPV types related to HPV 16 (types 31, 33, 35, 52, 58) had intermediate clearance rates (RR = 0.62, 95% CI: 0.47, 0.94), and other high-risk types did not show evidence of slower clearance compared with low-risk types. Infections with single and multiple HPV types had similar clearance rates. There was no evidence of a dose-response relation between clearance and viral load. Observed was slower clearance in parous women (RR = 0.64, 95% CI: 0.47, 0.89) and faster clearance in ever users of oral contraceptives (RR = 1.38, 95% CI: 1.07, 1.77).

Human papillomavirus biology and cervical neoplasia: implications for diagnostic criteria and testing.

Human papillomaviruses are necessary for the development of cervical neoplasia. Progress in our understanding of the epithelial biology of this common pathogen has greatly influenced current concepts of cervical carcinogenesis. This understanding has provided a framework for understanding the biologic basis of many diagnostic criteria. Furthermore, classification schemes, diagnostic testing, and clinical management have been modified and clarified in light of this knowledge.

Human papillomavirus testing methods.

Testing for human papillomavirus (HPV) relies exclusively on techniques of molecular biology using nucleic acid probes. Tests for HPV using nucleic acid probes have been commercially available since the late 1980s, but early tests were cumbersome, involving the use of nucleic acid probes labeled with radioactive phosphorus (32P). These early HPV tests did not achieve widespread use because they did not detect all oncogenic HPV genotypes. The current commercial HPV detection kit, Digene's Hybrid Capture 2 kit, detects virtually all high-risk oncogenic HPV types, as well as most low-risk nononcogenic HPV genotypes. The Hybrid Capture 2 test format is a proprietary nucleic acid hybridization signal amplification system owned by Digene Corporation. Virtually all test formats for DNA sequence analysis are amenable to applications intended to detect and perhaps quantify the various HPV genotypes. These methods can involve direct hybridization with complementary DNA probes, such as Southern blotting or in situ hybridization, signal amplification, such as the Hybrid Capture 2 method or target nucleic acid amplification, most notably the polymerase chain reaction (PCR). Polymerase chain reaction has been used for HPV detection, genotyping, and viral load determination. General or consensus primer-mediated PCR assays have enabled screening for a broad spectrum of HPV types in clinical specimens using a single PCR reaction. Following amplification using consensus primers, individual HPV genotypes are identified using a variety of methods. Using consensus primers in a test format known as real-time quantitative PCR (RQ-PCR), it is possible to generate viral load (concentration) data from reaction curves generated by monitoring PCR reaction kinetics in real time.

Human papillomavirus reporting: impact on Bethesda cytology reports.

In 2001, the Bethesda Committee revised the terminology for reporting Papanicolaou tests. One of the 2001 Bethesda forum groups addressed the use of ancillary tests, and the most commonly used ancillary test is for human papillomavirus (HPV). The Bethesda Ancillary Testing Forum presented terminology related to HPV testing. The Ancillary Testing Forum recommended that the specific HPV test method be presented and the results reported as positive or negative for HPV of a certain type or class. The Papanicolaou test and the HPV test should be reported together or should refer to each other if possible. A number of reporting schema currently are used to report HPV results; these schema include probabilistic reporting, integrated reporting, reporting as a result, and reporting with clinical management recommendations. Few data currently are available to support an optimal reporting method.

Human papillomavirus reporting: minimizing patient and laboratory risk.

Risk management efforts in the cytology laboratory must address the gap between what can be achieved with medical history's most effective cancer screening test, the Papanicolaou (Pap) test, and even higher entrenched public expectations. Data from the Atypical Squamous Cells of Undetermined Significance (ASCUS)/Low-Grade Squamous Intraepithelial Lesion Triage Study (ALTS) now provide level I clinical evidence from a large, randomized, controlled, multicenter clinical trial that reflex human papillomavirus (HPV) DNA testing of ASCUS cases is generally the preferred method for initial assessment of the most prevalent category of abnormal Pap interpretation. The proposed combination of HPV DNA testing with cytologic Pap testing, the DNA Pap test, further shows the potential to nearly eliminate false-negative screening results, based on sensitivity and negative predictive values reported in available studies. Human papillomavirus DNA testing also appears to represent a significant enhancement for detection of endocervical adenocarcinomas, which are difficult to detect and prevent. Human papillomavirus DNA testing, when used in conjunction with cervical cytology, can significantly reduce risk to both the patient and the laboratory.

Human papillomavirus type 18 and rapidly progressing cervical intraepithelial neoplasia.

BACKGROUND: Human papillomavirus type 18 (HPV-18) is the second most frequent of the HPV types detected when squamous-cell cancer is diagnosed and the type most strongly associated with adenocarcinoma of the cervix. However, in cross-sectional studies, HPV-18 is rarely detected at the time of diagnosis of high-grade cervical intraepithelial neoplasia (CIN). We used a longitudinal study design to describe the occurrence of cytological abnormality after incident HPV-18 and HPV-16 infections. METHODS: The analysis was based on 1075 women aged 15-19 years, who had normal cytology and were negative for HPV at recruitment from a single family-planning clinic, and who had further follow-up. The women reattended every 6 months, and samples were taken for cytological and virological examination. FINDINGS: The relative risk of a cytological diagnosis of borderline nuclear abnormality after exposure to HPV-18 was 2.06 (95% CI 1.24-3.43) and that after exposure to HPV-16 was 1.99 (1.32-3.01). The relative risks of mild dyskaryosis were 3.11 (1.86-5.18) and 4.76 (3.15-7.18), and the relative risks of moderate or severe dyskaryosis were 0.80 (0.24-2.65) and 2.85 (1.36-5.97). Time to acquisition of cytological abnormality was unrelated to the infecting type (p=0.88). INTERPRETATION: Our findings do not support the long-held view that the reason why HPV-18 infection is under-represented at the time of diagnosis of high-grade CIN is because HPV-18-associated disease rapidly progresses through the preinvasive stages of neoplasia. We suggest that the cytological changes detected after HPV-18 infection might understate the severity of underlying disease. This feature could compromise the effectiveness of screening programmes in reducing the frequency of HPV-18-associated cancers.

Detection of polyomavirus simian virus 40 tumor antigen DNA in AIDS-related systemic non-Hodgkin lymphoma.

Systemic non-Hodgkin lymphoma (S-NHL) is a common malignancy during HIV infection, and it is hypothesized that infectious agents may be involved in the etiology. Epstein-Barr virus DNA is found in <40% of patients with AIDS-related S-NHL, suggesting that other oncogenic viruses, such as polyomaviruses, may play a role in pathogenesis. We analyzed AIDS-related S-NHL samples, NHL samples from HIV-negative patients, peripheral blood leukocytes from HIV-infected and -uninfected patients without NHL, and lymph nodes without tumors from HIV-infected patients. Specimens were examined by polymerase chain reaction analysis with use of primers specific for an N-terminal region of the oncoprotein large tumor antigen ( T-ag ) gene conserved among all three polyomaviruses (simian virus 40 [SV40], JC virus, and BK virus). Polyomavirus T-ag DNA sequences, proven to be SV40-specific, were detected more frequently in AIDS-related S-NHL samples (6 of 26) than in peripheral blood leukocytes from HIV-infected patients (6 of 26 vs. 0 of 69; p =.0001), NHL samples from HIV-negative patients (6 of 26 vs. 0 of 10; p =.09), or lymph nodes (6 of 26 vs. 0 of 7; p =.16). Sequences of C-terminal T-ag DNA from SV40 were amplified from two AIDS-related S-NHL samples. Epstein-Barr virus DNA sequences were detected in 38% (10 of 26) AIDS-related S-NHL samples, 50% (5 of 10) HIV-negative S-NHL samples, and 57% (4 of 7) lymph nodes. None of the S-NHL samples were positive for both Epstein-Barr virus DNA and SV40 DNA. Further studies of the possible role of SV40 in the pathogenesis of S-NHL are warranted.

Human papillomavirus infection in cyclosporin-induced gingival overgrowth in renal allograft recipients.

BACKGROUND: Host immunity plays an important role in the development of human papillomavirus (HPV)-associated disease. The HPV infection in oral cyclosporin-induced gingival overgrowth in renal transplant recipients has not been investigated previously. The aim of this study was to establish the HPV infection of cyclosporin-induced gingival hyperplasia in renal transplant recipients through morphological changes and use of the in situ hybridization technique. METHODS: We examined 13 renal transplant recipient biopsies with gingival overgrowth lesions and 4 healthy mucosa samples of these patients. The histopathological diagnoses were established on the basis of widely accepted criteria, and the pathologist was not aware of the HPV result. An in situ molecular hybridization was carried out under low stringent conditions to detect HPV species with mixed biotin-labeled probes of HPV 6 and HPV 11, and under high stringent conditions with HPV 6, HPV 11, HPV 16, and HPV 18 probes for HPV typing. RESULTS: The HPV prevalence among the 13 samples studied was 92.31% (12/13), of which 4 tested positive for HPV 6-11 and 1 for HPV 16. The 4 biopsies of normal mucosa from gingival overgrowth patients were also reactive for HPV DNA. In 11/12 (91.7%) HPV-positive cases, koilocytotic atypia was found. CONCLUSIONS: The suppression of T-cell function by cyclosporin therapy can result in an increase of HPV infection, adding to the proliferative activity of cyclosporin in the oral mucosa.

Correlations between nuclear/cytoplasmic area ratio and classification of cervical smears.

The aim of this study was to assess the nuclear/cytoplasmic (N/C) ratio using computerized image analysis of cervical smears with intraepithelial neoplasia (CIN) grade I to III associated or not with cellular changes of human papillomavirus (HPV) in an attempt to determine if this method is more sensitive for the estimation of the grade of CIN. One hundred and ten cervical smears from women with a mean age 35.03 years were studied. The cytological diagnosis was as follows: CIN I + HPV (11), CIN II + HPV (11), CIN II + HPV (8), CIN I (7), CIN II (6), CIN III (8), Ca (22), HPV (32), CIN I-II + HPV (2) and CIN II-III + HPV (3). All cases were histologically examined: 93 cases were in agreement and 17 were under- or overestimated cytologically. The morphometric study of cervical smears was carried out by image analysis. Data were analysed by one way analysis of variance followed by Bonferroni test of multiple comparisons. Statistically significant differences were detected between the three grades of CIN or CIN HPV or only HPV (p<0.0001). The results demonstrated that the N/C ratio measured by image analysis on precancerous lesions of cervical smears could be considered as an additional tool for the classification of cervical smears, especially in determining the discrepancies between cytological and histological diagnoses.

Histopathological characteristics of five clinical types of equine sarcoid.

The purpose of this study was to determine the characteristics of occult, verrucous, fibroblastic, nodular and mixed equine sarcoids. Ten tumours of each type were examined histologically and analysed for the presence of bovine papilloma virus (BPV)- DNA. All tumours were positive for BPV - DNA and showed an increased density of dermal fibroblasts. Epidermal hyperplasia, hyperkeratosis, rete peg and 'picket fence' formation were only found consistently in the verrucous and mixed types and were often not present in occult and nodular sarcoids. Immunohistochemical staining for Keratins 10 and 16, Ki67 and p53 showed no important differences between the clinical types. It can be concluded that the presence of BPV - DNA and the increased density of dermal fibroblasts were the only common characteristics for all sarcoids of the different clinical types. The presence of other microscopic alterations was variable but could not be used in the differentiation of the clinical types based on histology.