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Background Primary effusion lymphoma (PEL) is a very rare non-Hodgkin lymphoma caused by human herpesvirus-8 (HHV8) that grows in liquid phase within body cavities. The diagnosis of PEL is based on cytology but requires confirmatory ancillary tests. PEL occurs mainly in association with HIV infection. This study describes 9 cases of PEL in HIV-negative patients and compares their characteristics with 10 HIV-associated cases of PEL diagnosed at a single institution in Italy between 1995 and 2019. Methods Clinical records were reviewed for demographic data, comorbidities, laboratory abnormalities, and outcome. PEL samples were evaluated for cytomorphology, immunophenotype, immunoglobulin (IG)/T cell receptor (TR) rearrangements, and HHV8 and Epstein-Barr virus (EBV) viral loads in effusion supernatants. Results HIV-unrelated PEL occurred in 8 elderly patients (7 men, 1 woman) and 1 young adult with primary antibody deficiency. Cytology revealed HHV8-positive lymphoma cells lacking B/T cell antigens and exhibiting 2 cell patterns (polymorphous or monotonous). IG was clonally rearranged in all cases; aberrant TRG occurred in 2 cases. Effusion supernatants had more than 106 HHV8 DNA copies per mL and variable loads of EBV DNA. Compared with HIV-associated PEL, the HIV-negative cohort was characterized by older age, less frequent association with Kaposi sarcoma and/or multicentric Castleman disease, comparable but less abnormal laboratory parameters, and a nonsignificant survival benefit. PEL cases with low apoptosis were associated with better prognosis. Conclusion To the best of our knowledge, our case series of HIV-unrelated PEL is the largest thus far, expands the spectrum of cytological findings, and supports the need for a multidisciplinary approach in the diagnostic workup.

The classification of indeterminate cytopathology at thyroid fine-needle-aspiration (FNA) has been updated to reduce the number of unnecessary surgery; the 2014 Italian classification introduced the low-risk (TIR3A) and high-risk (TIR3B) subcategories. Aim of this study was to identify the ultrasonographic (US), clinical and cytological predictors of malignancy among TIR3B nodules from a single institution. A prospective observational study including 1844 patients who underwent thyroid FNA from June 2014 to January 2019. Ultrasonographic, clinical and cytological features were recorded. All TIR3B diagnoses were referred to surgery. According to final histology, patients were divided into thyroid cancer (TC) or benign nodules. Chi-square test, or Fisher exact test when appropriate, were used to compare groups and logistic regression analyses were used to determine independent predictors of malignancy. Of 1844 FNAs, 96 (5.2%) were TIR3B. Histology report was available in 65. Among them, 25 (38.5%) were TC. Predictors of TC were nodule size

Primary effusion lymphoma (PEL) is a large B-cell lymphoma growing within body-cavities caused by the Kaposi sarcoma-associated herpesvirus (KSHV)/human herpesvirus-8 (KSHV/HHV-8). It is mainly reported in HIV-infected patients. The uncommon occurrence in the elderly supports a form paralleling classic Kaposi sarcoma (KS), i.e. classic PEL, whose characteristics are relatively underexplored. To better understand the diagnostic modalities and clinical-epidemiological features of classic PEL, articles reporting cases of PEL were identified through MEDLINE/EMBASE databases (January 1998-July 2020) and screened according to PRISMA guidelines to extract individual-level data. A comparison was also performed between classic PEL and classic KS to evaluate similarities and differences. We identified 105 subjects (median age 77 years; 86% males), mainly from Mediterranean countries (52%, first Italy) and Eastern Europe (7%). Common comorbidities were heart failure (32%), cirrhosis (16%), and malignancy (20%) including lymphoid neoplasms. Pleural cavity was the commonest site (67%). PEL diagnosis was based on cytomorphology (89%), evidence of KSHV/HHV-8 infection (94%), EBV co-infection (28%) and clonality of IGH (59%), IGK (14%), TRG (9%) alone or in multiple combinations. Compared to KS, age (P

Mezei et al's letter (1) is an opportunity to provide more details about our study on pericardial and tunica vaginalis testis (TVT) mesothelioma (2), which is based on the Italian national mesothelioma registry (ReNaM): a surveillance system on mesothelioma, with individual asbestos exposure assessment. Incidence of pericardial mesothelioma has been estimated around 0.5 and 0.2 cases per 10 million person-years in men and women, respectively, and around 1 case for TVT mesothelioma. ReNaM collected 138 cases thanks to its long period of observation (1993-2015) and national coverage. Conducting a population-based case-control study with incidence-density sampling of controls across Italy and over a 23 year time-span should have been planned in 1993 and would have been beyond feasibility and ReNaM scope. We rather exploited two existing series of controls (3). The resulting incomplete time- and spatial matching of cases and controls is a limitation of our study and has been acknowledged in our article. The analysis of case-control studies can nevertheless be accomplished in logistic models accounting for the variables of interest, in both individually and frequency matched studies (4). Furthermore, analyses restricted to (i) regions with enrolled controls, (ii) cases with definite diagnosis, (iii) incidence period 2000-2015, and (iv) subjects born before 1950 have been provided in the manuscript, confirming the strength of the association with asbestos exposure (supplemental material tables S4-7). Following Mezei et al's suggestion, we performed further sensitivity analyses by restriction to regions with controls and fitting conditional regression models using risk-sets made of combinations of age and year of birth categories (5-year classes for both). We confirmed positive associations with occupational exposure to asbestos of pericardial mesothelioma, with odds ratios (OR) (adjusted for region) of 9.16 among women [95% confidence interval (CI) 0.56-150] and 5.63 (95% CI 1.02-31.0) among men; for TVT mesothelioma the OR was 7.70 (95% CI 2.89-20.5). Using risk sets of age categories and introducing year of birth (5-year categories) as a covariate (dummy variables) the OR were similar: OR (adjusted for region) of 9.17 among women (95% CI 0.56-150) and 5.76 (95% CI 1.07-31.0) among men; for TVT the OR was 9.86 (95% CI 3.46-28.1). Possible bias from incomplete geographical overlap between cases and controls has been addressed in the paper (table S4) and above. In spatially restricted analyses, OR were larger than in those including cases from the whole country, indicating that bias was towards the null. Mezei et al further noted that "the regional distribution of controls is different from that of person-time observed". This objection is not relevant because the above analyses were adjusted by region. Our controls were provided by a population-based study on pleural mesothelioma (called MISEM) and a hospital-based study on cholangiocarcinoma (called CARA). In MISEM, the response rate was 48.4%, a low but not unexpected rate as participation among population controls is usually lower and has been declining over time (5). It is important to underline that ReNaM applied the same questionnaire that was used for interviews and carried out the same exposure assessment as both MISEM and CARA. As repeatedly stated in ReNaM papers (6-7), each regional operating center assesses asbestos exposure based on the individual questionnaire, other available information, and knowledge of local industries. Occupational exposure to asbestos is classified as definite, probable or possible. Occupational exposure is (i) definite when the subject`s work was reported or otherwise known to have involved the use of asbestos or asbestos-containing materials (MCA); (ii) probable when subjects worked in factories where asbestos or MCA were used, but their personal exposure could not be documented; and (iii) possible when they were employed in industrial activities known to entail the use of asbestos or MCA. Hence, the definite and probable categories are closer to one another and were combined in our analyses. In any case, restricting analyses to subjects with definite occupational exposure and using each set of controls separately, as suggested by Mezei et al, yielded elevated OR for TVT and pericardial mesothelioma among men using both the above described modelling strategies; the OR could not be calculated for women. There were 70 (25 pericardial and 45 TVT) occupationally exposed mesothelioma cases. In population-based studies, analyses by occupation are limited by the low prevalence of most specific jobs. As briefly reported in our paper, for purely descriptive purposes, the industrial activity of exposure (cases may have multiple exposures), were construction (22 exposures, 7 and 15 for pericardial and TVT mesotheliomas, respectively), steel mills and other metal working industries (4 and 11), textile industries (2 and 3), and agriculture (2 and 5); other sectors had lower exposure frequencies. The absence of industries like asbestos-cement production, shipbuilding and railway carriages production/repair should not be surprising and had already been observed (7). In the Italian multicenter cohort study of asbestos workers (8), given the person-years of observation accrued by workers employed in these industries and gender- and site-specific crude incidence rates, approximately 0.1 case of pericardial and 0.2 of TVT mesothelioma would have been expected from 1970 to 2010. Even increasing ten-fold such figures to account for higher occupational risks among these workers would not change much. Asbestos exposure in agriculture has been repeatedly discussed in ReNaM reports (9: pages 70, 73, 128, 164 and 205). Exposure opportunities included the presence of asbestos in wine production, reuse of hessian bags previously containing asbestos, or construction and maintenance of rural buildings. Similarly, mesothelioma cases and agricultural workers exposed to asbestos have been noted in France (10). In conclusion, the additional analyses we performed according to Mezei et al's suggestions confirm the association between asbestos exposure and pericardial and TVT mesothelioma, supporting the causal role of asbestos for all mesotheliomas. ReNaM`s continuing surveillance system with national coverage is a precious platform for launching analytical studies on pleural and extra pleural mesothelioma. References 1. Mezei G, Chang ET, Mowat FS, Moolgavkar SH. Comments on a recent case-control study of malignant mesothelioma of the pericardium and the tunica vaginalis testis Scand J Work Environ Health. 2021;47(1):85-86. https://doi.org/10.5271/3909 2. Marinaccio A, Consonni D, Mensi C, Mirabelli D, Migliore E, Magnani C et al.; ReNaM Working Group. Association between asbestos exposure and pericardial and tunica vaginalis testis malignant mesothelioma: a case-control study and epidemiological remarks. Scand J Work Environ Health. 2020;46(6):609-617. https://doi.org/10.5271/sjweh.3895. 3. Greenland S. Control-initiated case-control studies. Int J Epidemiol 1985 Mar;14(1):130-4. https://doi.org/10.1093/ije/14.1.130. 4. Pearce N. Analysis of matched case-control studies. BMJ 2016 Feb;352:i969. https://doi.org/10.1136/bmj.i969. 5. Bigert C, Gustavsson P, Straif K, Pesch B, Bruning T, Kendzia B et al. Lung cancer risk among cooks when accounting for tobacco smoking: a pooled analysis of case-control studies from Europe, Canada, New Zealand, and China. J Occup Environ Med 2015 Feb;57(2):202-9. https://doi.org/10.1097/JOM.0000000000000337. 6. Marinaccio A, Binazzi A, Marzio DD, Scarselli A, Verardo M, Mirabelli D et al.; ReNaM Working Group. Pleural malignant mesothelioma epidemic: incidence, modalities of asbestos exposure and occupations involved from the Italian National Register. Int J Cancer 2012 May;130(9):2146-54. https://doi.org/10.1002/ijc.26229. 7. Marinaccio A, Binazzi A, Di Marzio D, Scarselli A, Verardo M, Mirabelli D et al. Incidence of extrapleural malignant mesothelioma and asbestos exposure, from the Italian national register. Occup Environ Med 2010 Nov;67(11):760-5. https://doi.org/10.1136/oem.2009.051466. 8. Ferrante D, Chellini E, Merler E, Pavone V, Silvestri S, Miligi L et al.; the working group. Italian pool of asbestos workers cohorts: mortality trends of asbestos-related neoplasms after long time since first exposure. Occup Environ Med 2017 Dec;74(12):887-98. https://doi.org/10.1136/oemed-2016-104100. 9. ReNaM VI Report. Available from: https://www.inail.it/cs/internet/docs/alg-pubbl-registro-nazionale-mesoteliomi-6-rapporto.pdf. Italian 10. Marant Micallef C, Shield KD, Vignat J, Baldi I, Charbotel B, Fervers B et al. Cancers in France in 2015 attributable to occupational exposures. Int J Hyg Environ Health 2019 Jan;222(1):22-9. https://doi.org/10.1016/j.ijheh.2018.07.015.

There is irrefutable evidence that germline BRCA1-associated protein 1 gene (BAP1) mutations contribute to malignant mesothelioma (MM) susceptibility. However, BAP1 mutations are not found in all cases with evidence of familial MM or in other high-risk cancer families affected by various cancers, including MM. The goal of this study was to use whole genome sequencing (WGS) to determine the frequency and types of germline gene variants occurring in 12 MM patients who were selected from a series of 141 asbestos-exposed MM patients with a family history of cancer but without a germline BAP1 mutation. WGS was also performed on two MM cases, a proband and sibling, from a previously reported family with multiple cases of MM without the inheritance of a predisposing BAP1 mutation. Altogether, germline DNA sequencing variants were identified in 21 cancer-related genes in 10 of the 13 probands. Germline indel, splice site and missense mutations and two large deletions were identified. Among the 13 MM index cases, 6 (46%) exhibited one or more predicted pathogenic mutations. Affected genes encode proteins involved in DNA repair (ATM, ATR, BRCA2, BRIP1, CHEK2, MLH3, MUTYH, POLE, POLE4, POLQ and XRCC1), chromatin modification (ARID1B, DNMT3A, JARID2 and SETD1B) or other cellular pathways: leucine-rich repeat kinase 2 gene (LRRK2) (two cases) and MSH4. Notably, somatic truncating mutation or deletions of LRRK2 were occasionally found in MMs in The Cancer Genome Atlas, and the expression of LRRK2 was undetectable or downregulated in a majority of primary MMs and MM cell lines we examined, implying that loss of LRRK2 expression is a newly recognized tumor suppressor alteration in MM.

Summary Rectal prolapse is a disorder in which the rectum protrudes from the anal canal. Solitary rectal ulcer may coexist. Both conditions have been associated with chronic constipation and excessive straining during defecation. Rectal prolapse has been rarely reported in women suffering from anorexia nervosa. Lack of rectal support because of loss of ischiorectal fat has been proposed as one of the possible mechanisms in this condition, together with chronic constipation and abuse of laxative. We report the case of an anorexic woman with a severe rectal prolapse and bleeding requiring urgent Altmeier’s procedure. Surgery was complicated by dehiscence of the anastomosis and volvulus, requiring ileostomy and laciniae debridement. Pathological analysis of all the surgical samples taken from different abdominal sites highlighted changes in the visceral adipose tissue consisting in nodular aggregates of small adipocytes dispersed in a myxoid matrix surrounding blood vessels within abundant fibrosis. The morphologic features resemble those observed in primordial fetal fat and are comparable to those observed in cancer associated cachexia. The diffuse myxoid degeneration of visceral adipose tissue may play a role in the pathogenesis of rectal prolapse in patients with anorexia nervosa. Besides starvation, the mechanism sustaining myxoid degeneration of the adipose tissue is not entirely clear. Whenever possible improving nutritional and clinical conditions should be ideal before any surgical approach.

The identification of somatic mutations in cancer specimens enables detection of molecular markers for personalized treatment. We recently developed a novel molecular assay and evaluated its clinical performance as an ancillary molecular method for indeterminate thyroid nodule cytology. Herein we describe the analytical validation of the novel targeted next-generation sequencing (NGS) assay in thyroid samples from different sources. We present validation data of a novel NGS-based panel on 463 thyroid samples, including 310 fine-needle aspiration (FNA) specimens from different sources (FNA collected in preservative solution, liquid-based, and stained smears), 10 fresh frozen, and 143 formalin-fixed paraffin-embedded (FFPE) thyroid tissue specimens. Sequencing performance in the different samples was evaluated along with reproducibility, repeatability, minimum nucleic acid input to detect variants, and analytical sensitivity of the assay. All thyroid samples achieved high sequencing performance, with a mean base coverage depth ranging from 2228 × (in liquid-based FNA) to 3661 × (in FNA stained smears), and coverage uniformity ranging from 86% (in FFPE) to 95% (in FNA collected in preservative solution), with all target regions covered above the minimum depth required to call a variant (500×). The minimum nucleic acid input was 1 ng. Analytic sensitivity for mutation detection was 2–5% mutant allele frequency. This validation study of a novel NGS-based assay for thyroid nodules demonstrated that the assay can be reliably used on multiple thyroid sample types, including FNA from different sources and FF and FFPE thyroid samples, thus providing a robust and reliable assay to genotype thyroid nodules, which may improve thyroid cancer diagnosis and care.

Surgical pathology units face chemical and biological risks. While chemical risks have been intensely evaluated since the formalin ban, less attention has been drown to biological risks. The actual epidemiologic situation due to the SARS-CoV-2 pandemia has raised a series of questions, which need to be addressed as soon as possible. We have to pursue two lines of action: on one side we must immediately adopt urgent measures to reduce the risk of SARS-CoV-2 infection of our laboratory personnel, and on the other side we must address crucial technical and organizational aspects of biological risk reduction, preserving as much as possible the quality of tissue and cell samples. Continue reading (Download PDF)

The new Italian cytological classification (2014) of thyroid nodules replaced the TIR3 category of the old classification (2007) with two subclasses, TIR3A and TIR3B, with the aim of reducing the rate of surgery for benign diseases. Moreover, thyroid imaging reporting and data system (TI-RADS) score appears to ameliorate the stratification of the malignancy risk. We evaluated whether the new Italian classification has improved diagnostic accuracy and whether its association with TI-RADS score could improve malignancy prediction. We retrospectively analyzed 70 nodules from 70 patients classified as TIR3 according to the old Italian classification who underwent surgery for histological diagnosis. Of these, 51 were available for cytological revision according to the new Italian cytological classification. Risk of malignancy was determined for TIR3A and TIR3B, TI-RADS score, and their combination. A different rate of malignancy (p=0.0286) between TIR3A (13.04%) and TIR3B (44.44%) was observed. Also TI-RADS score is significantly (p=0.003) associated with malignancy. By combining cytology and TI-RADS score, patients could be divided into three groups with low (8.3%), intermediate (21.4%), and high (80%) risk of malignancy. In conclusion, the new Italian cytological classification has an improved diagnostic accuracy. Interestingly, the combination of cytology and TI-RADS score offers a better stratification of the malignancy risk.

Introduction The asbestos industry began operations in Colombia in 1942, with an asbestos-cement facility located in the municipality of Sibate. In recent years residents from Sibate have been complaining about what they consider is an unusually large number of people diagnosed with asbestos-related diseases in the town. A study to analyze the situation of Sibate started in 2015, to verify if the number of asbestos related diseases being diagnosed were higher than expected, and to identify potential asbestos exposure sources in the town. Methods A health and socioeconomic survey was implemented door-to-door to identify potential asbestos-related diseases. Several self-reported mesothelioma cases were identified, and for confirmation purposes, copies of the medical record with the histopathology report were obtained. A panel of six physicians analyzed the medical records. Information of validated cases was used to estimate the male and female age-adjusted incidence rate for Sibate. Based on reports of the existence of potential asbestos-contaminated landfills, topographic maps, a digital elevation model, and current satellite images were crossed using a geographic information system to identify potential landfilled areas, and soils samples were collected in some of these areas. Results A total of 355 surveys were completed, and 29 self-reported mesothelioma cases were identified. Twenty-five of these cases have been persons who had lived at some moment of their lives in Sibate. It was possible to obtain copies of the medical diagnosis for 17 cases. Of these, the panel of physicians classified 15 cases as certain pleural mesothelioma, one as probable, and one as not mesothelioma. Based on this information, the estimated age-adjusted incidence rate of mesothelioma in Sibate was 3.1 × 105 persons-year for males and 1.6 × 105 persons-year for females. These rates are high in comparison to those reported in other cities, regions, and countries of the world. Using geographic information systems, landfilled zones in the urban area of Sibate were identified, on top of which a school and different sports facilities were built. The analysis of four soil samples collected in landfilled zones, confirmed the existence of an underground layer of friable and non-friable asbestos. Conclusion The collected evidence suggests the presence of a malignant pleural mesothelioma cluster in Sibate.

Objective The Italian reporting system for thyroid cytology classifies indeterminate lesions as TIR3A (low risk) or TIR3B (high risk) and is meant to provide practical guidance rather than a detailed consideration of morphological features. We aimed to assess which cytological features have the most diagnostic value and whether they are effective in classifying nodules as either TIR3A or TIR3B and in predicting histological outcomes. Methods Thyroid fine-needle aspirates from 111 indeterminate nodules were reviewed blinded to clinical information, TIR3A/TIR3B classification, and histology in order to assess which cytological features (pooled into artefacts, smear background, architectural and nuclear atypia, and oncocytes) differentiate TIR3A from TIR3B, and benign from malignant histological outcomes. Results Of the cytological features examined, those specific for TIR3B included high cellularity, nuclear atypia, oncocyte predominance and transgressing vessels. Features specific for TIR3A included artefacts, low cellularity and oncocyte sparseness. Other features, such as microfollicules/trabeculae, were non-specific. Due to the different distributions of these features, three TIR3B subgroups were identifiable: follicular lesions with oncocytic changes, pure follicular lesions, and follicular lesions with nuclear atypia, whereas no subgroups were identifiable in TIR3A. Nuclear atypia was a significant indicator of malignancy, whereas oncocyte predominance was not a reliable predictor of malignancy. High cellularity and microfollicules/trabeculae were not indicative of any histological outcome. Conclusions The majority of the assessed features were good predictors of histological outcomes. The TIR3A category included undefined nodules due to the absence of characterising features, whereas the TIR3B category included nodules with a greater number of distinguishing features.

Accurate pathologic diagnosis and reporting in malignant pleural mesothelioma are essential for clinical care, and cancer registration. Practical guidelines for pathologists are provided in publications and textbooks but it is unclear how these recommendations are applied in routine practice. We investigated the characteristics of pathology reports, and the extent to which they meet guideline standards. We reviewed 819 pathology reports relating to a first diagnosis of malignant pleural mesothelioma. Data sources were a regional section of the Italian network of the Mesothelioma Registry (2001-2014) and a pathology archive (1990-2000). We evaluated tumor characteristics, the diagnosis field including terminology and immunohistochemistry (IHC) workup, and report completeness (the proportion of items recorded). We investigated also two IHC panels identified by the most used markers in current practical guidelines, one best suited for epithelioid mesotheliomas (combinations of at least 2 positive and at least 2 negative mesothelioma markers) and the other best suited for sarcomatoid mesotheliomas (positive mesothelioma markers plus cytokeratins). Reports (753 histology, 66 cytology, IHC-confirmed 86%) were 74% complete and always narrative. Missing data were related to clinical history (76%), tumor laterality (61%), specimen size (38%), and histological subtype (23%). The proportion of cases with IHC was higher for epithelioid (90%) than sarcomatoid mesothelioma (87%). Compliance to IHC recommendations was higher for epithelioid (59%) than sarcomatoid mesothelioma (11%). The mean number of stains was significantly higher for sarcomatoid than epithelioid mesothelioma (p

Introduction: Sibate is a small town (38,000 inhabitants) nearby Colombia’s capital, Bogota. A water reservoir, el Muna, is located south-west of the town. Residents from Sibate rep...

Context The prevalence of thyroid nodules in the general population is increasingly high, and at least half of those biopsied prove to be benign. Sonographic risk-stratification systems are being proposed as “rule-out” tests that can identify nodules that do not require fine-needle aspiration (FNA) cytology. Objective To comparatively assess the performances of five internationally endorsed sonographic classification systems [those of the American Thyroid Association, the American Association of Clinical Endocrinologists, the American College of Radiology (ACR), the European Thyroid Association, and the Korean Society of Thyroid Radiology] in identifying nodules whose FNAs can be safely deferred and to estimate their negative predictive values (NPVs). Design Prospective study of thyroid nodules referred for FNA. Setting Single academic referral center. Patients Four hundred seventy-seven patients (358 females, 75.2%); mean (SD) age, 55.9 (13.9) years. Main Outcome Measures Number of biopsies classified as unnecessary, false-negative rate (FNR), sensitivity, specificity, predictive values, and diagnostic ORs for each system. Results Application of the systems’ FNA criteria would have reduced the number of biopsies performed by 17.1% to 53.4%. The ACR Thyroid Imaging Reporting and Data System (TIRADS) allowed the largest reduction (268 of 502) with the lowest FNR (NPV, 97.8%; 95% CI, 95.2% to 99.2%). Except for the Korean Society of Thyroid Radiology TIRADS, all other systems exhibited significant discriminatory performance but produced significantly smaller reductions in the number of procedures. Conclusions Internationally endorsed sonographic risk stratification systems vary widely in their ability to reduce the number of unnecessary thyroid nodule FNAs. The ACR TIRADS outperformed the others, classifying more than half the biopsies as unnecessary with a FNR of 2.2%.

Finkelstein1 invited physicians and researchers interested in mesothelioma to investigate on past usage of talcum powders by affected people. In Italy, asbestos contamination in talc for industrial use has been documented,2 and, as he underlines tremolite contamination at low levels of cosmetic and pharmaceutical talc has been reported in USA by Blount3 and Gordon and colleagues.4 In the Italian National Mesothelioma Register (ReNaM), the analysis of intensive exposure to talc has been evaluated with respect to occupational and environmental history. The catalogue of possible asbestos exposure circumstances (a tool for the interviewers) reports the potential presence of industrial talcs in quarries or mines working activities, in leather tanning and in rubber industries. The use of intensive cosmetic talc for personal use is evaluated by means of a structured questionnaire,5 as reported in the ReNaM guidelines (see https://www.inail.it/cs/internet/docs/all-linee-guida-renam.pdf%3Fsection=attivita, p82, p98, in Italian). In our paper regarding gender differences in mesothelioma epidemiology,6 we have presented figures referring to 21 463 MM cases detected by ReNaM with a diagnosis between 1993 and 2012. Among female case list (6087 cases), 4374 cases (71.9%) have been interviewed for defining exposure. During the interview, 30 MM female cases referred an intensive use of talc in the context of occupational or life habits. For five of them, the regional centre has identified an exposure to asbestos due to intensive talc use, classifying such modality of exposure as ‘leisure activities’ (see ReNaM guidelines5). For the remaining 25 cases, an occupational exposure to asbestos in other working (or familiar or environmental) circumstances has been identified and coded. Registry data such as those provided by ReNaM cannot provide estimates of the mesothelioma risk associated with any particular exposure circumstance. We plan to include talc exposure at work and cosmetic talc usage in the analyses of a case–control study on pleural mesothelioma currently under way. A specific survey to compare and discuss how the modalities of exposure to talc have been evaluated in patients with mesothelioma in countries where epidemiological surveillance systems are active could improve knowledge and support prevention policies.

The Italian consensus to classify thyroid cytology has provided a standardized reporting scheme, including the subdivision of indeterminate for malignancy TIR-3 category into TIR-3A (low-risk) and TIR-3B (high-risk). We aimed to present our experience on this subclassification by evaluating risks of malignancy and the validity in sorting nodules with dissimilar risks. Another aim was to compare our performance against the Bethesda system. Fine-needle aspirates of 290 TIR-3 that underwent thyroid surgery at our hospital (2008–2013) were reviewed and divided into TIR-3A or TIR-3B, and AUS/FLUS or FN/SFN. Cytological diagnoses were then correlated to histology. Results were evaluated using univariate analysis. The subclassification into TIR-3A and TIR-3B differentiated hyperplastic nodules (p = 0.000) but not adenomas (p = 0.090). Rates of malignancy were significantly different between TIR-3A (10.2%) and TIR-3B (43.8%); TIR-3B malignancies were often papillary carcinomas (83%). TIR-3A/TIR-3B accounted for high sensitivity (84.5%; CI 79.7–88.4%), accuracy (64.1%; CI 58.6–69.6%) and NPV (89.8%; CI 85.6–93.0%) as opposed to modest specificity (55.8%; CI 49.9–61.6%) and PPV (43.8%; CI 38.1–49.8%). The rate of malignancy in AUS-FLUS was higher than in TIR-3A (p = 0.007), whereas it was not different between FN/SFN and TIR-3B (p = 0.337). Sensitivity of the Bethesda system was significantly lower respect to the Italian system. The study supports the Italian consensus showing a different risk of malignancy for TIR-3A as compared to TIR-3B. TIR-3A/TIR-3B subclassification is valid to sort out benign nodules (high NPV) and malignancies (high sensitivity) but not adenomas (modest specificity, low PPV). In our experience, sensitivity is the main difference between Italian and Bethesda systems.

Incidental sonographic discovery of thyroid nodules is an increasingly common event. The vast majority is benign, and those that are malignant, are generally associated with an indolent course and low mortality. Sonographic scoring systems have been developed to help clinicians identify nodules that warrant prompt fine-needle aspiration cytology (FNAC), but they are based largely on experience with papillary thyroid cancers. We analyzed the performance of four scoring systems widely used for this purpose (American Thyroid Association Guidelines, American Association of Clinical Endocrinologists/American College of Endocrinology/Associazione Medici Endocrinologi Guidelines, European Thyroid Imaging Reporting and Data System, and Korean Thyroid Imaging Reporting and Data System) in patients whose nodules proved to be metastases from other solid cancers. Such nodules reportedly account for 0.2% to 3% of all thyroid malignancies. Each scoring system was used to assess retrospectively the malignancy risk and indications for FNAC of five patients’ thyroid nodules that were ultimately diagnosed as metastases (from renal cell carcinoma, breast cancer, and lung cancer in two cases and esophageal cancer). The primaries identified in these cases are those most commonly reported to metastasize to the thyroid. In two cases, the thyroid metastases were the first sign of undetected neoplastic disease. Although sonography alone cannot distinguish thyroid metastases from primary thyroid malignancies, all four scoring systems classified the metastatic nodules as suspicious enough to require FNAC. The five cases accounted for 0.2% of those cytologically examined in our center. In most cases, cytology provided useful guidance for the subsequent management of these lesions, which differs from that of primary thyroid cancers and requires multidisciplinary input., Sonographic systems for assessing the risk of primary thyroid cancer in thyroid nodules can also guide management decisions for the rare nodules that prove to be metastases from other solid tumors.

Introduction Peritoneal mesothelioma, a very rare and lethal malignancy, has not been investigated as extensively as pleural mesothelioma, although the role of asbestos exposure in its occurrence is well-known. Data from Italy are relevant, as it was the largest European asbestos producer, and asbestos was widely used in many economic activities. Methods A population-based mortality and incidence analysis was performed in Italy. Data sources were the National Multiple-causes-of-death Database (1995–2010) and the Italian Mesothelioma Register (1993–2008). Results We found an increasing trend of age standardized mortality rates in men, but no clear trend in women; moreover, we showed significant risks of death in several northern regions, formerly heavy asbestos users; finally, mortality/incidence ratios similar for both genders (about 0.8) were estimated. Conclusions The study, based on national data, showed a higher risk of mortality from and incidence of peritoneal mesothelioma in areas with formerly heavy exposure to asbestos. Am. J. Ind. Med. 58:1050–1058, 2015. © 2015 Wiley Periodicals, Inc.

Objective: To provide practical guidelines for the cytopathologic diagnosis of malignant mesothelioma. Data Sources: Cytopathologists with an interest in the field involved in the International Mesothelioma Interest Group (IMIG) and the International Academy of Cytology (IAC) contributed to this update. Reference material includes peer-reviewed publications and textbooks. Rationale: This article is the result of discussions during and after the IMIG 2012 conference in Boston, followed by thorough discussions during the 2013 IAC meeting in Paris. Additional contributions have been obtained from cytopathologists and scientists who could not attend these meetings, with final discussions and input during the IMIG 2014 conference in Cape Town.

To assess the accuracy and reproducibility of ultrasonography classification systems in characterizing cytologically indeterminate thyroid nodules.We retrospectively identified 49 nodules that had been surgically resected owing to features classified as indeterminate according to 2010 Italian Consensus on Thyroid Cytology criteria. Three experienced sonographers independently reviewed original sonographic images of each nodule and classified it using the 2015 American Thyroid Association (ATA) guidelines and the Thyroid Imaging Reporting and Data System (TI-RADS) classification proposed by Korean radiologists; later, images were reviewed jointly to obtain consensus classifications of each nodule. Original cytology slides were similarly reviewed by three experienced cytopathologists, who reclassified the nodule (independently, then jointly) according to revised Italian Consensus on Thyroid Cytology (ICTC-2014) criteria. Consensus ICTC-2014, ATA, and TI-RADS classifications were analyzed against surgical histology reports to estimate each system's sensitivity, specificity, positive and negative predictive values.Of the 49 indeterminate nodules examined, 30 (61.2 %) were histologically benign. Consensus ICTC-2014 classification correctly classified malignant nodules with positive predictive value of 50 % and negative predictive value of 90 %. Sonographic classification of nodules as intermediate to high suspicion by ATA or TI-RADS category 4c displayed positive predictive value of 63 and 71 %, respectively; positive predictive values dropped to 44 and 42 % when lower positivity thresholds were used (ATA low suspicion, TI-RADS category 4a). Negative predictive values for ATA and TI-RADS were 91 and 74 %, respectively, with higher positivity thresholds and 100 % for both with lower thresholds. All systems displayed appreciable inter-observer variability (Krippendorff alphas: ATA 0.36, TIRADS 0.42, ICTC-2014 0.74).With stringent negativity cut-offs, American Thyroid Association and Thyroid Imaging Reporting and Data System assessment of cytologically indeterminate thyroid nodules allows high-confidence exclusion of malignancy.

Malignant mesothelioma is a sporadic cancer linked to asbestos exposure. Its occurrence among blood relatives (familial mesothelioma) may point to genetic susceptibility or shared exposures. The burden of the familial disease is unknown. The aims of the study were to assess at population level the proportion of familial mesotheliomas among all mesotheliomas and to investigate the family history of cancer among relatives of mesothelioma cases. We actively searched familial clusters based on a mesothelioma registry from central Italy (5.5 million people, 10% of the Italian population) of the National Mesothelioma Register network (ReNaM) as well as a pathology-based archive. Among 997 incident mesotheliomas recorded in a 32-year-period (1980–2012), we detected 13 clusters and 34 familial cases, accounting for 3.4% of all mesotheliomas. The most common clusters where those with affected siblings and unaffected parents. Asbestos exposure was occupational ( n =7 clusters), household ( n =2), environmental ( n =1), or not attributable for insufficient information ( n =3). There were 25 additional cancers in nine families. Some were cancer sites for which there is sufficient evidence (lung and larynx) or limited evidence (stomach and colon) of causal association with asbestos. The results suggest potential genetic recessive effects in mesothelioma that interact with asbestos exposure, but it is not possible to estimate the specific proportion attributable to each of these components.

Introduction: In the past, asbestos was widely used in railroad industries. Railroad workers are considered a high-risk population for asbestos related diseases. Until 1980, train drivers and worke...

BAP1 germline mutations predispose to a cancer predisposition syndrome that includes mesothelioma, cutaneous melanoma, uveal melanoma and other cancers. This co-occurrence suggests that these tumors share a common carcinogenic pathway. To evaluate this hypothesis, we studied 40 Italian families with mesothelioma and/or melanoma. The probands were sequenced for BAP1 and for the most common melanoma predisposition genes (i.e. CDKN2A, CDK4, TERT, MITF and POT1) to investigate if these genes may also confer susceptibility to mesothelioma. In two out of six families with both mesothelioma and melanoma we identified either a germline nonsense mutation (c.1153C > T, p.Arg385*) in BAP1 or a recurrent pathogenic germline mutation (c.301G > T, p.Gly101Trp) in CDKN2A. Our study suggests that CDKN2A, in addition to BAP1, could be involved in the melanoma and mesothelioma susceptibility, leading to the rare familial cancer syndromes. It also suggests that these tumors share key steps that drive carcinogenesis and that other genes may be involved in inherited predisposition to malignant mesothelioma and melanoma.

Introduction Malignant pleural mesothelioma (MPM) is a highly aggressive disease with limited therapeutic options. Histological subtype remains among the most reliable prognostic factors, because the epithelioid subtype associated with the best prognosis and the sarcomatoid subtype with the worst. The biphasic subtype has an intermediate prognosis, but its definitive histological diagnosis may be challenging owing to the difficulty of assessing the neoplastic nature of the stromal component. Recent data identified BRCA1-associated protein 1 gene ( BAP1 ) as one of the most frequently mutated genes in MPM. Immunohistochemical testing for BRCA1-associated protein 1 (BAP1) has been proposed to be predictive for the detection of BAP1 mutation in neoplastic cells. The aim of the present study was to define the diagnostic usefulness of immunohistochemical determination of BAP1 in MPM, with clinicopathological correlation. Methods A series of 143 MPMs were investigated for BAP1 protein expression in correlation with clinical and pathological data, including with a newly proposed nuclear grade. A pilot series of 20 selected cases were also investigated for BAP1 mutational status. Results Negative nuclear staining for BAP1 occurred in 62% of MPMs (including 27% with a cytoplasmic pattern) and was significantly associated with the presence of BAP1 mutation, epithelioid subtype, and a better prognosis. In a subgroup of cases, the pattern of expression of BAP1 in stromal cells supported their distinction as reactive versus neoplastic, thus helping achieve the correct classification of biphasic histological subtype. Conclusions We showed that BAP1 protein determination is a diagnostic tool to correctly distinguish biphasic MPM from epithelial subtypes with an atypical/activated reactive stroma and an independent prognostic parameter in MPM.

Familial malignant mesothelioma clusters are ideal candidates to explore BAP1 genomic status as a predisposing risk factor. We report data on BAP1 analysis in four families with multiple mesothelioma cases to investigate possible BAP1 alterations associated with an inherited cancer syndrome. We also recorded family history of cancer and assessed asbestos exposure. By genomic direct sequencing, we found no evidence of a BAP1 germline mutation in tumor DNA samples (one mesothelioma per family: n = 3 epithelioid; n = 1 biphasic). On the other hand, we identified a novel BAP1 somatic alteration (c.329_335delinsTC) in exon 5 (n = 1 biphasic), and we hypothesized the occurrence of somatic inactivating events not identifiable by sequencing in the other cases (n = 3 epithelioid), as demonstrated by the loss of nuclear BAP1 immunostaining. History of other cancers was in sites not typical of the BAP1 cancer syndrome. Asbestos exposure was occupational (n = 2 clusters), household (n = 1), and unknown (n = 1). These family units without inheritance of a BAP1 predisposing mutation expand the number of unmutated germline BAP1 families with multiple mesothelioma cases. This suggests that besides the exposure to asbestos other currently unknown genetic or epigenetic factors may be responsible for the high incidence of mesothelioma in BAP1 -unmutated families.

Background Few population-based epidemiological data are available on Merkel cell carcinoma (MCC), a rare lethal non-melanoma skin cancer. We analysed multiple-cause-of-death records to describe MCC mortality and trends and the association with other primary cancers. Methods We reviewed all 6,713,059 death certificates in Italy (1995–2006) to identify those mentioning MCC. We evaluated the association with other primary cancers by calculating the ratio of observed to expected deaths, using a standardized mortality ratio (SMR)-like analysis. We also evaluated the geographic distribution of deaths. Results We identified 351 death certificates with the mention of MCC. The age-adjusted mortality was 0.031/100,000, with a significant trend of increase and a slight north–south gradient. There was a significant deficit for solid cancers (SMR = 0.15) and a non-significant excess for lymphohematopoietic malignancies (SMR = 1.62). There were significant excesses for chronic lymphocytic leukemia (SMR = 4.07) and Waldenström’s macroglobulinemia (SMR = 27.2) and a non-significant excess for chronic myeloid leukemia (SMR = 5.12). Conclusions The increase in MCC mortality reflects the incidence trend in the literature. The association with chronic lymphocytic leukemia confirms the importance of immunologic factors in MCC. Regarding Waldenström’s macroglobulinemia, an association with MCC has never been reported.

Objectives The epidemiology of extrapleural malignant mesothelioma is rarely discussed and the risk of misdiagnosis and the very low incidence complicate the picture. This study presents data on extrapleural malignant mesothelioma from the Italian National Mesothelioma Register (ReNaM). Methods ReNaM works on a regional basis, searching for cases and interviewing subjects to investigate asbestos exposure. Classification and code criteria for certainty of diagnosis and exposure modalities are set by national guidelines. Between 1993 and 2004, 681 cases were collected. Incidence measures and exposure data refer to the ReNaM database. Age-standardised rates were estimated by the direct method using the Italian resident population in 2001. Correlations between the incidence of pleural and non-pleural malignant mesothelioma for the 103 Italian provinces were analysed. Results Standardised incidence rates (Italy, 2004, per million inhabitants) were 2.1 and 1.2 cases for the peritoneal site (in men and women, respectively), 0.2 cases for the tunica vaginalis testis, and 0.1 in the pericardial site, varying widely in different parts of the country. Mean age at diagnosis for all extrapleural malignant mesothelioma cases was 64.4 years and the men/women ratio was 1.57:1. Median latency was over 40 years for all extrapleural sites combined. The correlation between pleural and peritoneal mesothelioma was 0.71 (Pearson’s r coefficient, p

The patchy geographical distributions of classic Kaposi's sarcoma (KS) and human herpesvirus type 8 (HHV-8), better known as Kaposi's sarcoma-associated herpesvirus (KSHV) remain unexplained. It has been proposed that certain species of bloodsucking insects (‘promoter arthropods') promote the reactivation of HHV-8/KSHV and facilitate both HHV-8/KSHV transmission and KS development. This hypothesis was tested by sampling the presence and density of human-biting Diptera with CDC light traps in two areas of Sardinia with contrasting incidence rates of classic KS. In total, 11 030 specimens (99.9% sandflies and 0.1% mosquitoes) belonging to 10 species were collected from 40 rural sites. Five of these species are considered to be possible promoter arthropods because of the irritation their bites cause: Phlebotomus perniciosus Newstead; Phlebotomus perfiliewi Parrot (Diptera: Psychodidae); Aedes berlandi Seguy; Culiseta annulata (Schrank) and Culex theileri Theobald (Diptera: Culicidae). Five species are probable ‘non-promoters' because their bites are not particularly irritating: Culiseta longiareolata (Macquart); Culex pipiens s.l.; Anopheles algeriensis Theobald; Anopheles maculipennis s.l., and Anopheles plumbeus Stephens. A significant correlation was found between the geographical distribution of promoter arthropods and incidence rates of KS (Spearman's r = 0.59,P < 0.01). Promoter arthropods were more likely to be caught in areas with cutaneous leishmaniasis and a past high prevalence of malaria, and in areas of limestone, acid volcanic soil and cereal cultivation. The study supports the association between promoter arthropods and classic KS, which may explain the geographic variability of KS and HHV-8/KSHV, and highlights the links with a number of variables previously associated with the incidence of KS.

Background Malignant mesothelioma is a sporadic tumor related to asbestos. Its occurrence in blood relatives raises the question of potential contribution of predisposing factors. Methods The study analyses the features of mesothelioma in blood relatives that might explain the disease clustering. Data sources of familial clusters were three population-based Mesothelioma Registries in Italy (Veneto and Apulia Regions, Brescia province; 1978–2005) and Medline, Toxline, and Oshline/Hseline databases for a review of the literature (1968–2006). Results Eleven clusters (22 cases) were identified among 1954 Italy mesothelioma cases, and 51 clusters (120 cases) were extracted from 33 studies. The proportion of Italy familial cases was 1.4 per 100 mesothelioma cases; the ratio between the number of familial clusters and the number of non-familial mesothelioma cases was 1:148. The mesothelioma profile in consanguineous is the same as in non-consanguineous subjects (male prevalence; pleural site; age at diagnosis >50 years; asbestos exposure). Most clusters occurred in asbestos workers (shipyard, asbestos-cement production/processing, and insulation) and household-exposed blood relatives. Others were related to asbestos-cement factory pollution, asbestos-in-place, and handling asbestos-contaminated textiles. Two clusters were without any known exposure. Cancer family history revealed lung cancer cases in eight clusters. Conclusions Available data support asbestos exposure as the main risk factor in mesothelioma cases among blood relatives. Our finding of a low proportion of familial cases would not suggest the influence of a large genetic component for mesothelioma in blood relatives. Am. J. Ind. Med. 50:357–369, 2007. © 2007 Wiley-Liss, Inc.

We report a family with domestic exposure to asbestos and diagnosis of multiple cancers, including eight pleural malignant mesotheliomas and several other lung or pleural tumors. DNA sequence analysis revealed no evidence for an inherited mutation of BAP1. Sequence analysis of other potentially relevant genes, including TP53, CDKN2A, and BARD1, also revealed no mutation. DNA microarray analysis of tissue from two mesotheliomas revealed multiple genomic imbalances, including consistent losses of overlapping segments in 2q, 6q, 9p, 14q, 15q, and 22q, but no losses of chromosome 3 harboring the BAP1 locus. However, the results of immunohistochemical analysis demonstrated loss of nuclear BAP1 staining in three of six mesotheliomas tested, suggesting that somatic alterations of BAP1 occurred in a subset of tumors from this family. Since mesothelioma could be confirmed in only a single generation, domestic exposure to asbestos may be the predominant cause of mesothelioma in this family. Given the existence of unspecified malignant pleural tumors and lung cancers in a prior generation, we discuss the possibility that some other tumor susceptibility or modifier gene(s) may contribute to the high incidence of mesothelioma in this family. Because the incidence of mesothelioma in this family is higher than that expected even in workers heavily exposed to asbestos, we conclude that both asbestos exposure and genetic factors have played a role in the high rate of mesothelioma and potentially other pleural or lung cancers seen in this family.

To provide practical guidelines for the cytopathologic diagnosis of malignant mesothelioma.Cytopathologists with an interest in the field involved in the International Mesothelioma Interest Group (IMIG) and the International Academy of Cytology (IAC) contributed to this update. Reference material includes peer-reviewed publications and textbooks.This article is the result of discussions during and after the IMIG 2012 conference in Boston, followed by thorough discussions during the 2013 IAC meeting in Paris. Additional contributions have been obtained from cytopathologists and scientists who could not attend these meetings, with final discussions and input during the IMIG 2014 conference in Cape Town.

To provide practical guidelines for the cytopathologic diagnosis of malignant mesothelioma (MM). Cytopathologists involved in the International Mesothelioma Interest Group (IMIG) and the International Academy of Cytology (IAC), who have an interest in the field contributed to this update. Reference material includes peer-reviewed publications and textbooks. This article is the result of discussions during and after the IMIG 2012 conference in Boston, followed by thorough discussions during the 2013 IAC meeting in Paris. Additional contributions have been obtained from cytopathologists and scientists, who could not attend these meetings, with final discussions and input during the IMIG 2014 conference in cape town. During the previous IMIG biennial meetings, thorough discussions have resulted in published guidelines for the pathologic diagnosis of MM. However, previous recommendations have stated that the diagnosis of MM should be based on histological material only.[12] Accumulating evidence now indicates that the cytological diagnosis of MM supported by ancillary techniques is as reliable as that based on histopathology, although the sensitivity with cytology may be somewhat lower.[345] Recognizing that noninvasive diagnostic modalities benefit both the patient and the health system, future recommendations should include cytology as an accepted method for the diagnosis of this malignancy.[67] The article describes the consensus of opinions of the authors on how cytology together with ancillary testing can be used to establish a reliable diagnosis of MM.

Peritoneal mesothelioma, a very rare and lethal malignancy, has not been investigated as extensively as pleural mesothelioma, although the role of asbestos exposure in its occurrence is well-known. Data from Italy are relevant, as it was the largest European asbestos producer, and asbestos was widely used in many economic activities.A population-based mortality and incidence analysis was performed in Italy. Data sources were the National Multiple-causes-of-death Database (1995-2010) and the Italian Mesothelioma Register (1993-2008).We found an increasing trend of age standardized mortality rates in men, but no clear trend in women; moreover, we showed significant risks of death in several northern regions, formerly heavy asbestos users; finally, mortality/incidence ratios similar for both genders (about 0.8) were estimated.The study, based on national data, showed a higher risk of mortality from and incidence of peritoneal mesothelioma in areas with formerly heavy exposure to asbestos.

Aims: To investigate the association between occurrence of soft tissue sarcomas (STS) in Mantua and residence near an incinerator of industrial wastes. Methods: Cases were subjects with histologically confirmed primary malignant STS diagnosed 1989–98 in the population resident in Mantua and in the three neighbouring municipalities. Controls were randomly extracted from population registries, matched for age and sex. Residential history was reconstructed for all study subjects since 1960. Main residence was geographically positioned according to GPS standards. Results: The study included 37 STS cases (17 men and 20 women) and 171 controls. The incidence of STS in the area of study was estimated as 8.8 per 100 000 in men and 5.6 per 100 000 in women. The odds ratio associated with residence within 2 km, standardised by age and sex, was 31.4 (95% CI 5.6 to 176.1), based on five exposed cases. At greater distances, risk rapidly decreased, showing a fluctuation around the null value of 1. Conclusion: The study shows a significant increase in risk of STS associated with residence within 2 km of an industrial waste incinerator; an aetiological role of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) can be hypothesised.