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Despite efforts to ban asbestos mining and manufacturing, mesothelioma deaths in the United States have remained stable at approximately 2500 cases annually. This trend is not unique to the United States but is also a global phenomenon, associated with increased aging of populations worldwide. Although geoeconomic factors such as lack of regulations and continued asbestos manufacturing in resource-poor countries play a role, it is essential to consider biological factors such as immune senescence and increased genetic instability associated with aging. Recognizing that mesothelioma shares genetic instability and immune system effects with other age-related cancers is crucial because the impact of aging on mesothelioma is frequently assessed in the context of disease latency after asbestos exposure. Nevertheless, the long latency period, often cited as a reason for mesothelioma's elderly predominance, should not overshadow the shared mechanisms. This communication focuses on the role of immune surveillance in mesothelioma, particularly exploring the impact of immune escape resulting from altered TSG function during aging, contributing to the phylogenetic development of gene mutations and mesothelioma oncogenesis. The interplay between the immune system, TSGs, and aging not only shapes the immune landscape in mesothelioma but also contributes to the development of heterogeneous tumor microenvironments, significantly influencing responses to immunotherapy approaches and survival rates. By understanding the complex interplay between aging, TSG decline, and immune senescence, health care professionals can pave the way for more effective and personalized immunotherapies, ultimately offering hope for better outcomes in the fight against mesothelioma., (Copyright © 2023 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Asbestosis, defined as diffuse pulmonary fibrosis caused by inhalation of asbestos fibers, occurs after heavy exposures to asbestos dust over several decades. Because workplace exposures have been significantly curtailed since the banning of asbestos in insulation products, we were interested in examining the clinicopathological characteristics of cases diagnosed in the 21 st century. The consultation files of one of the authors (VLR) were reviewed for cases of asbestosis diagnosed since 1/1/2001. 102 cases were identified, with a median age of 75 years (range: 45-89). There were 100 men and 2 women. The women were from Turkey and Brazil (none from the United States). Malignancies were present in 78 cases, including 38 lung cancers, 29 pleural mesotheliomas, and 8 peritoneal mesotheliomas. The grade of asbestosis was available in 88 cases (median severity of 2; scale: 1-4). Pleural plaque was present in 94% of cases. The most common exposure categories were insulators (39), shipyard workers (16), asbestos manufacturing (9), boiler workers (8) and pipefitter/welders (6). The median duration of exposure was 33 years (range: 2-49 years). Lung fiber burden analysis was performed in 34 cases, with amosite being the predominant fiber type. Results were compared with similar information for 475 cases diagnosed prior to 1/1/2001.

Background: The diagnosis of mesothelioma may be challenging. We investigated a large database of cases in order to determine the frequency with which a diagnosis of mesothelioma was made incorrectly and the most frequent causes of error., Design: A database including more than 4000 consultation cases of histologically confirmed mesothelioma was examined to identify cases in which mesothelioma was diagnosed by at least one pathologist when the available information pointed towards a different diagnosis., Results: There were 311 cases misdiagnosed as mesothelioma. The most common category was metastatic carcinoma to the pleura or peritoneum (129 cases: 73 lung carcinomas, 15 renal cell carcinomas). The next most common category was primary lung cancer (111 cases: 55 sarcomatoid carcinoma, 56 pseudomesotheliomatous carcinoma). The third most common category was primary malignancies arising from or near the serosal membranes (33 cases). The fourth most common category was fibrous pleurisy (38 cases). The most common errors were failure to consider important radiographic information regarding the gross distribution of tumor, lack of awareness or consideration of another malignancy, overreliance on certain immunohistochemical results, and failure to perform certain diagnostic histochemical, immunohistochemical, or ultrastructural studies., Conclusions: There are a number of diagnostic pitfalls that can lead to the over diagnosis of mesothelioma. Careful attention to clinical and radiographic information as well as performance of appropriate ancillary tests can help to prevent such misdiagnoses. Detailed examples will be presented to assist in the avoidance of these pitfalls with emphasis on the most commonly observed errors., Competing Interests: Declaration of competing interest Dr. Roggli has consulted with plaintiff and defense attorneys in asbestos litigation cases. Dr. Pavlisko and Dr. Carney have consulted with defense attorneys in asbestos litigation cases. Drs. Glass and Pina-Oviedo have no disclosures., (Copyright © 2024 Elsevier Inc. All rights reserved.)

This paper summarizes recent insights into causal biological mechanisms underlying the carcinogenicity of asbestos. It addresses their implications for the shapes of exposure-response curves and considers recent epidemiologic trends in malignant mesotheliomas (MMs) and lung fiber burden studies. Since the commercial amphiboles crocidolite and amosite pose the highest risk of MMs and contain high levels of iron, endogenous and exogenous pathways of iron injury and repair are discussed. Some practical implications of recent developments are that: (1) Asbestos-cancer exposure-response relationships should be expected to have non-zero background rates; (2) Evidence from inflammation biology and other sources suggests that there are exposure concentration thresholds below which exposures do not increase inflammasome-mediated inflammation or resulting inflammation-mediated cancer risks above background risk rates; and (3) The size of the suggested exposure concentration threshold depends on both the detailed time patterns of exposure on a time scale of hours to days and also on the composition of asbestos fibers in terms of their physiochemical properties. These conclusions are supported by complementary strands of evidence including biomathematical modeling, cell biology and biochemistry of asbestos-cell interactions in vitro and in vivo, lung fiber burden analyses and epidemiology showing trends in human exposures and MM rates., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: BTM has participated as an expert witness in asbestos-related litigation. S Moolgavkar has served as a consulting and testifying expert in asbestos and talc litigation. V Roggli has consulted with plaintiff and defense attorneys in asbestos litigation cases., (Copyright © 2023 Elsevier Inc. All rights reserved.)

We reviewed 354 cases of malignant diffuse mesothelioma (MM) in women from a database of 2858 histologically confirmed MM cases. There was a pleural predominance with 78% pleural MM and 22% peritoneal MM. The pleural tumors consisted of 72% epithelioid, 19% biphasic, and 9% sarcomatoid variant. The peritoneal tumors consisted of 82% epithelioid, 13% biphasic, and 5% sarcomatoid. The immunohistochemical profile was typical of what is well-accepted and previously described for MM. When examining tumor subtype and location, there was a trend toward epithelioid subtype and peritoneal location; however, this did not reach statistical significance. Age at the time of diagnosis ranged from 19 to 93 years with a mean of 60 years. The median age at time of diagnosis for pleural MM was 65 years and for peritoneal MM was 52 years. A further look at age and histologic subtype showed no statistically significant difference in age between MM subtypes. Survival was greatest for epithelioid variant, and this was magnified in the peritoneum. A majority of our cases were exposed to asbestos through a household contact. Asbestosis and parietal pleural plaque were present in 5% and 50% of cases with data, respectively. Fiber analysis data was available in 67 cases; 38 cases had elevated asbestos fiber burden, and tremolite was the most common asbestos fiber type detected. Commercial and noncommercial amphibole asbestos fibers were elevated in nearly equal numbers of cases.

Neurofibromatosis type 2 (NF2), an inherited disorder associated with multiple inherited schwannomas, meningiomas and ependymomas is caused by an autosomal dominant, likely loss of function germline mutation of the NF2 gene. Interestingly, biallelic NF2 gene inactivation is one of the most common mutations associated with the development of malignant mesothelioma (MM), a highly fatal malignancy that arises in the pleura and less frequently in the pericardium, peritoneum, and tunica vaginalis. It has been proposed that NF2 patients could potentially be at increased risk of developing MM. However, patients with inherited NF2 rarely develop MM. To date, only 2 cases describing patients diagnosed with both have been reported in the literature. Here, we describe the third case and for the first time, also provide molecular evidence that a "second hit" involving a somatic mutation is likely required to trigger the development of MM in this rare cohort. In our patient diagnosed with NF2 at age 25 who developed an aggressive peritoneal MM 15 years later, we identified a germline NF2 mutation and somatic mutations including BAP1. Of clinical relevance, our case supports a germline NF2 mutation may not necessarily be more susceptible to develop mesothelioma without a "second hit" mutation.

Malignant mesothelioma (MM) arising from the serosal membranes of the tunica vaginalis testis (TVT) is rare. Most examples in the published medical literature are individual case reports. This study presents the clinicopathological findings of mesothelioma of the TVT in one of the largest series to date. Individuals with mesothelioma of the TVT were identified from a database of more than 4000 mesothelioma cases, and their clinicopathological features were recorded. Eighteen men with MM and 2 with well-differentiated papillary mesothelioma of the TVT were identified, which represented 0.6% of males with mesothelioma in study population. The median age at diagnosis was 72 years (range, 32-85 years). A neoplasm was not suspected preoperatively in 12 of the 17 (71%) men whose clinical presentation was known, 7 of whom presented with hydrocele and 5 with inguinal hernia. The other 5 had a clinically recognized mass. Seven of the men underwent herniorrhaphy; 7, radical orchiectomy; 3, hydrocelectomy; and 3, paratesticular mass biopsy or excision as the initial diagnostic procedure. Twelve of the MM cases were epithelioid and 6 were biphasic. Among the 6 men with MM who had ≥6 months of follow-up, 1 was alive with no evidence of disease at 6 months, and 5 were known to have died of disease 8-74 months (median = 31.5 months) following diagnosis. Three men with MM had received either chemotherapy or radiation therapy. Of the 2 men initially diagnosed with well-differentiated papillary mesothelioma, 1 was alive without evidence of disease 5 years after diagnosis, while the other had findings more compatible with MM with peritoneal involvement 2 years following initial diagnosis. In 15 of the 18 cases of MM (83%), there was documented occupational or paraoccupational exposure to asbestos, the average duration of which was 33 years (range, 2-46 years). Information regarding the presence or absence of pleural plaques was available in 5 of the MM cases, and pleural plaques had been found in 4. Lung tissue was not available for fiber analysis in any of the cases. One additional case originally diagnosed at another institution as MM of the TVT was reclassified as adenocarcinoma following performance of additional immunohistochemical testing. TVT is a rare site of MM, the diagnosis of which is often unsuspected preoperatively. Like its counterparts at other serosal sites, MM of the TVT is an aggressive tumor with a poor prognosis that evidence would suggest is etiologically associated with asbestos in at least some cases., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Asbestos is well-recognized as the cause of a variety of disorders of the respiratory tract, including neoplastic as well as non-neoplastic conditions. Fiber dimensions and biopersistence are important determinants of the pathologic response, and analytical electron microscopy is a powerful technique for determining the fiber content of lung tissue samples. For decades our laboratory has examined lung tissue samples counting fibers measuring 5 µm or greater in length. More recent observations have indicated that fibers 10 µm or greater in length are pathogenic, and that a length of 10 µm and diameter less than 1.0 µm are useful features for distinguishing asbestiform fibers from cleavage fragments. We examined more than 570 fibers from more than 90 cases to determine the dimensions of fibers that might be classified as asbestos. The vast majority of fibers classified as amosite or crocidolite met the criteria for length greater than 10 µm and diameter less than 1.0 µm. However, a significant proportion of fibers classified as tremolite, actinolite, or anthophyllite did not meet these criteria. These findings have important implications for the identification and classification of elongated mineral particles, both in terms of pathogenicity as well as classification as asbestiform vs. cleavage fragments.

Aims: Florid mesothelial hyperplasia is known to result from endometriosis. Well-differentiated papillary mesothelioma and multiloculated peritoneal inclusion cysts have also been described in women with endometriosis. To our knowledge, peritoneal diffuse malignant mesothelioma (MM) arising in the setting of endometriosis has not been reported. The purpose of this study is to report the clinicopathological characteristics of women with MM and endometriosis., Methods: The surgical pathology files of a tertiary academic medical centre and the consultation files of one of the study authors were reviewed for cases of MM in females with and without endometriosis., Results: Six women with MM and endometriosis ranging in age from 29 to 55 years (median=45 years) were identified. All had peritoneal MM and endometriosis involving the peritoneum and/or adnexa. Five had epithelioid MM and one had biphasic MM. Two had paraoccupational exposure to asbestos. The median age of women with MM and endometriosis (44.5 years) was significantly less than the median age of cases without endometriosis (58.0 years) (p value=0.01)., Conclusions: To our knowledge, this is the first report of MM in women with endometriosis. Interestingly, MM in the setting of endometriosis has only been observed in the peritoneum and not in other serosal cavities. The findings in the present study suggest that chronic serosal inflammation secondary to endometriosis may be an inducing factor in rare cases of MM of the peritoneum., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Asbestos exposure is the main etiology of malignant mesothelioma, but there are conflicting data on whether the intensity of exposure modulates the development of this disease. This study considered 594 patients with malignant mesothelioma for whom count data on asbestos bodies and fibers (per gram of wet lung tissue) were available. The relationships between age at diagnosis (a time-to-event outcome variable) and these two measures of internal asbestos exposure, along with other possible modulating factors (sex, tumor location, histological subtype and childhood exposure), were assessed on multivariable Cox proportional hazard models, stratifying by decade of birth year. For both measures of asbestos in lung tissue, younger age at diagnosis was associated with higher internal measures of exposure to asbestos. Stratified Cox analyses showed that for each doubling in asbestos body count patients were 1.07 times more likely to be diagnosed at a younger age [hazard ratio (HR) = 1.07; 95% confidence interval (CI), 1.04-1.09; P = 2.2 × 10-7] and for each doubling in asbestos fiber count patients were 1.13 times more likely to be diagnosed at a younger age (HR = 1.13; 95% CI, 1.09-1.17; P = 8.6 × 10-11). None of the other variables considered were associated with age at diagnosis. Our finding that tumors become clinically apparent at a younger age in heavily exposed subjects suggests that asbestos is involved not only in the malignant mesothelioma tumor initiation but, somehow, also in the progression of the disease.

Introduction: The 2015 WHO classification of tumors categorized malignant mesothelioma into epithelioid, biphasic (BMM), and sarcomatoid (SMM) for prognostic relevance and treatment decisions. The survival of BMM is suspected to correlate with the amount of the sarcomatoid component. The criteria for a sarcomatoid component and the interobserver variability between pathologists for identifying this component are not well described. In ambiguous cases, a "transitional" (TMM) subtype has been proposed but was not accepted as a specific subtype in the 2015 WHO classification. The aims of this study were to evaluate the interobserver agreement in the diagnosis of BMM, to determine the nature and the significance of TMM subtype, and to relate the percentage of sarcomatoid component with survival. The value of staining for BRCA-1-associated protein (BAP1) and CDKN2A(p16) fluorescence in situ hybridization (FISH) were also assessed with respect to each of the tumoral components., Methods: The study was conducted by the International Mesothelioma Panel supported by the French National Cancer Institute, the network of rare cancer (EURACAN) and in collaboration with the International Association for the Study of Lung Cancer (IASLC). The patient cases include a random group of 42 surgical biopsy samples diagnosed as BMM with evaluation of SMM component by the French Panel of MESOPATH experts was selected from the total series of 971 BMM cases collected from 1998 to 2016. Fourteen international pathologists with expertise in mesothelioma reviewed digitally scanned slides (hematoxylin and eosin - stained and pan-cytokeratin) without knowledge of prior diagnosis or outcome. Cases with at least 7 of 14 pathologists recognizing TMM features were selected as a TMM group. Demographic, clinical, histopathologic, treatment, and follow-up data were retrieved from the MESOBANK database. BAP1 (clone C-4) loss and CDKN2A(p16) homozygous deletion (HD) were assessed by immunohistochemistry (IHC) and FISH, respectively. Kappa statistics were applied for interobserver agreement and multivariate analysis with Cox regression adjusted for age and gender was performed for survival analysis., Results: The 14 panelists recorded a total of 544 diagnoses. The interobserver correlation was moderate (weighted Kappa = 0.45). Of the cases originally classified as BMM by MESOPATH, the reviewers agreed in 71% of cases (385 of 544 opinions), with cases classified as pure epithelioid in 17% (93 of 544), and pure sarcomatoid in 12% (66 of 544 opinions). Diagnosis of BMM was made on morphology or IHC alone in 23% of the cases and with additional assessment of IHC in 77% (402 of 544). The median overall survival (OS) of the 42 BMM cases was 8 months. The OS for BMM was significantly different from SMM and epithelioid malignant mesothelioma (p < 0.0001). In BMM, a sarcomatoid component of less than 80% correlated with a better survival (p = 0.02). There was a significant difference in survival between BMM with TMM showing a median survival at 6 months compared to 12 months for those without TMM (p < 0.0001). BAP1 loss was observed in 50% (21 of 42) of the total cases and in both components in 26%. We also compared the TMM group to that of more aggressive patterns of epithelioid subtypes of mesothelioma (solid and pleomorphic of our large MESOPATH cohort). The curve of transitional type was persistently close to the OS curve of the sarcomatoid component. The group of sarcomatoid, transitional, and pleomorphic mesothelioma were very close to each other. We then considered the contribution of BAP1 immunostaining and loss of CDKN2A(p16) by FISH. BAP1 loss was observed in 50% (21 of 41) of the total cases and in both component in 27% of the cases (11 of 41). There was no significant difference in BAP1 loss between the TMM and non-TMM groups. HD CDKN2A(p16) was detected in 74% of the total cases with no significant difference between the TMM and non-TMM groups. In multivariate analysis, TMM morphology was an indicator of poor prognosis with a hazard ratio = 3.2; 95% confidence interval: 1.6 - 8.0; and p = 0.003 even when compared to the presence of HD CDKN2A(p16) on sarcomatoid component (hazard ratio = 4.5; 95% confidence interval: 1.2 - 16.3, p = 0.02)., Conclusions: The interobserver concordance among the international mesothelioma and French mesothelioma panel suggests clinical utility for an updated definition of biphasic mesothelioma that allows better stratification of patients into risk groups for treatment decisions, systemic anticancer therapy, or selection for surgery or palliation. We also have shown the usefulness of FISH detection of CDKN2A(p16) HD compared to BAP1 loss on the spindle cell component for the separation in ambiguous cases between benign florid stromal reaction from true sarcomatoid component of biphasic mesothelioma. Taken together our results further validate the concept of transitional pattern as a poor prognostic indicator., (Copyright © 2018 International Association for the Study of Lung Cancer. All rights reserved.)

Context: - Malignant mesothelioma (MM) is a component of the BAP1 tumor predisposition syndrome. Other than in BAP1 familial studies, nonmesothelial neoplasms in individuals with MM has not been comprehensively assessed., Objective: - To assess the spectrum and prevalence of nonmesothelial neoplasms in individuals with MM., Design: - Individuals with MM and second neoplasms were identified from a database of 3900 MM cases. The expected prevalence of each type of neoplasm was calculated and compared with the actual prevalence in the study population using available Surveillance, Epidemiology, and End Results data and other published data., Results: - Two hundred seventy nonmesothelial neoplasms were identified in 241 individuals (6% of the study population) with MM. Prostate adenocarcinoma was most common. Non-Hodgkin lymphoma, Hodgkin lymphoma, lung carcinoma, urothelial carcinoma, breast carcinoma, chronic lymphocytic leukemia, clear cell renal cell carcinoma, head and neck squamous cell carcinoma, papillary renal cell carcinoma, multiple myeloma/plasmacytoma, meningioma, pleomorphic undifferentiated sarcoma, chronic myelogenous leukemia, ocular melanoma, hepatocellular carcinoma, liposarcoma, and Wilms tumor all were more prevalent than expected., Conclusions: - Nonmesothelial neoplasms are uncommon in individuals with MM, but certain tumor types are increased in prevalence. In an unselected study population with respect to BAP1 status, the prevalence of several tumor types described in BAP1 mutation carriers, including lung carcinoma, clear cell renal cell carcinoma, breast carcinoma, meningioma, pleomorphic undifferentiated sarcoma, and ocular melanoma, was increased.

Context: - Although many mesotheliomas are related to asbestos exposure, not all are, and there is increasing information on other causes of mesothelioma., Objective: - To provide a review of non-asbestos causes for malignant mesothelioma., Data Sources: - Review of relevant published literature via PubMed and other search engines., Conclusions: - Currently, most pleural mesotheliomas (70% to 90%) in men in Europe and North America are attributable to asbestos exposure; for peritoneal mesothelioma the proportion is lower. In North America few mesotheliomas in women at any site are attributable to asbestos exposure, but in Europe the proportion is higher and varies considerably by locale. In certain geographic locations other types of mineral fibers (erionite, fluoro-edenite, and probably balangeroite) can induce mesothelioma. Therapeutic radiation for other malignancies is a well-established cause of mesothelioma, with relative risks as high as 30. Carbon nanotubes can also induce mesotheliomas in animals but there are no human epidemiologic data that shed light on this issue. Chronic pleural inflammation may be a cause of mesothelioma but the data are scanty. Although SV40 can induce mesotheliomas in animals, in humans the epidemiologic data are against a causative role. A small number of mesotheliomas (probably in the order of 1%) are caused by germline mutations/deletions of BRCA1-associated protein-1 ( BAP1) in kindreds that also develop a variety of other cancers. All of these alternative etiologies account for a small proportion of tumors, and most mesotheliomas not clearly attributable to asbestos exposure are spontaneous (idiopathic).

A recently described nuclear grading system predicted survival in patients with epithelioid malignant pleural mesothelioma. The current study was undertaken to validate the grading system and to identify additional prognostic factors. We analyzed cases of epithelioid malignant pleural mesothelioma from 17 institutions across the globe from 1998 to 2014. Nuclear grade was computed combining nuclear atypia and mitotic count into a grade of I-III using the published system. Nuclear grade was assessed by one pathologist for three institutions, the remaining were scored independently. The presence or absence of necrosis and predominant growth pattern were also evaluated. Two additional scoring systems were evaluated, one combining nuclear grade and necrosis and the other mitotic count and necrosis. Median overall survival was the primary endpoint. A total of 776 cases were identified including 301 (39%) nuclear grade I tumors, 354 (45%) grade II tumors and 121 (16%) grade III tumors. The overall survival was 16 months, and correlated independently with age (P=0.006), sex (0.015), necrosis (0.030), mitotic count (0.001), nuclear atypia (0.009), nuclear grade (<0.0001), and mitosis and necrosis score (<0.0001). The addition of necrosis to nuclear grade further stratified overall survival, allowing classification of epithelioid malignant pleural mesothelioma into four distinct prognostic groups: nuclear grade I tumors without necrosis (29 months), nuclear grade I tumors with necrosis and grade II tumors without necrosis (16 months), nuclear grade II tumors with necrosis (10 months) and nuclear grade III tumors (8 months). The mitosis-necrosis score stratified patients by survival, but not as well as the combination of necrosis and nuclear grade. This study confirms that nuclear grade predicts survival in epithelioid malignant pleural mesothelioma, identifies necrosis as factor that further stratifies overall survival, and validates the grading system across multiple institutions and among both biopsy and resection specimens. An alternative scoring system, the mitosis-necrosis score is also proposed.

Context: - Malignant mesothelioma (MM) is an uncommon tumor that can be difficult to diagnose., Objective: - To provide updated, practical guidelines for the pathologic diagnosis of MM., Data Sources: - Pathologists involved in the International Mesothelioma Interest Group and others with an interest and expertise in the field contributed to this update. Reference material included up-to-date, peer-reviewed publications and textbooks., Conclusions: - There was discussion and consensus opinion regarding guidelines for (1) distinguishing benign from malignant mesothelial proliferations (both epithelioid and spindle cell lesions), (2) cytologic diagnosis of MM, (3) recognition of the key histologic features of pleural and peritoneal MM, (4) use of histochemical and immunohistochemical stains in the diagnosis and differential diagnosis of MM, (5) differentiating epithelioid MM from various carcinomas (lung, breast, ovarian, and colonic adenocarcinomas, and squamous cell and renal cell carcinomas), (6) diagnosis of sarcomatoid MM, (7) use of molecular markers in the diagnosis of MM, (8) electron microscopy in the diagnosis of MM, and (9) some caveats and pitfalls in the diagnosis of MM. Immunohistochemical panels are integral to the diagnosis of MM, but the exact makeup of panels employed is dependent on the differential diagnosis and on the antibodies available in a given laboratory. Depending on the morphology, immunohistochemical panels should contain both positive and negative markers for mesothelial differentiation and for lesions considered in the differential diagnosis. Immunohistochemical markers should have either sensitivity or specificity greater than 80% for the lesions in question. Interpretation of positivity generally should take into account the localization of the stain (eg, nuclear versus cytoplasmic) and the percentage of cells staining (>10% is suggested for cytoplasmic and membranous markers). Selected molecular markers are now being used to distinguish benign from malignant mesothelial proliferations. These guidelines are meant to be a practical diagnostic reference for the pathologist; however, some new pathologic predictors of prognosis and response to therapy are also included.

Aims: Mesothelial reaction simulating peritoneal diffuse malignant mesothelioma (MM) has been reported in the setting of Crohn ileitis. To our knowledge, peritoneal MM arising in patients with inflammatory bowel disease (IBD) has not been reported. The purpose of this study is to report the clinicopathological characteristics of patients with peritoneal MM and IBD., Methods: A database of approximately 3800 MM was reviewed for cases of MM in patients with IBD., Results: Three patients (0.08%) with peritoneal MM and Crohn disease (CD) were identified, including two women and one man ranging in age from 56 to 65 years. All had a long-standing history of diarrhoea and an established diagnosis of CD of 3 years or greater duration. Two had epithelial MM and one had biphasic MM. Only one had documented asbestos exposure., Conclusions: Peritoneal MM occurs rarely in patients with IBD, but interestingly, has only been observed in the setting of CD and not in patients with ulcerative colitis. Chronic inflammation has been associated with the development of MM in rare instances and these three cases suggest that CD with transmural inflammation may also be a precursor. The precise role of CD-related transmural inflammation in the carcinogenesis of peritoneal MM remains to be determined., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Asbestos is universally recognized as a carcinogen for the lower respiratory tract. However, asbestos is a contributory factor in a small fraction of lung cancers, the vast majority of which are related to cigarette smoking. The challenge for the pathologist is to determine when a lung cancer may be attributed to past asbestos exposure. The finding of asbestosis either clinically or pathologically is a useful marker for such a determination. However, in the absence of asbestosis, it has been suggested that a fiber burden as determined by analytical electron microscopy within the range of asbestosis is sufficient for determination of a causal contribution. We report here an example of a case of lung cancer in which fiber burden studies showed an asbestos concentration within the range of asbestosis as determined by scanning electron microscopy (SEM).

Objectives: To examine the clinicopathologic characteristics of individuals with diffuse malignant mesothelioma (DMM) occurring concurrently with lung cancer (LC)., Materials and Methods: A database of approximately 3800 patients with DMM was reviewed, from which 18 patients (0.5%) who had synchronous LC were identified. The clinicopathologic features, as well as the occupational exposure history and fiber burden analysis data were examined., Results: The patient median age was 68 years (range 58-84 years). Of the 18 patients (14 male, 4 female), 11 (61%) had epithelial, 5 (28%) had biphasic, and 2 (11%) had sarcomatoid DMM, with the majority (16 cases; 89%) originating in the pleura and only 2 were peritoneal. Among the histologic types of LC, adenocarcinoma was most frequent (12 cases; 67%), while 5 cases of squamous cell carcinoma, and 1 case of small cell carcinoma were observed. Three patients also had a history of prior malignancy (1 with testicular seminoma and bladder carcinoma and 2 with prostate carcinoma). Fifteen patients had a positive smoking history. All but 3 had documented asbestos exposure. Three had histologic features of asbestosis. Mineral analysis performed in 8 showed an elevated asbestos fiber burden in 4 (22%). Amosite was detected in 4 patients, crocidolite in 3, and non-commercial amphiboles in 5., Conclusion: The finding of simultaneous carcinoma of the lung and DMM is distinctly unusual. The majority of patients are male smokers with pleural epithelial DMM and lung adenocarcinoma. This study represents the largest cohort of patients reported to date with synchronous malignant mesothelioma and lung cancer, and we propose guidelines for making a diagnosis of synchronous malignant mesothelioma and primary lung cancer., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Lung tissue from 42 peritoneal mesothelioma cases was analyzed by light microscopy and scanning electron microscopy/energy dispersive spectrometry. There were 34 men and 8 women with a mean age of 61 ± 10 years. Also, 17% of cases had histologically confirmed asbestosis, and 26% had only parietal pleural plaques. The asbestos body count exceeded our normal range in 22 of 42 cases (52%). Cases with asbestos-related pulmonary disease had higher fiber burdens than those without. The vast majority of fibers were commercial amphiboles (amosite with lesser amounts of crocidolite). These findings concur with previously published epidemiological observations.

Peritoneal mesothelioma is rare, and the sarcomatoid variant is more infrequent, with <30 cases reported to date in the literature. Several case series have described the morphologic features of sarcomatoid peritoneal mesothelioma (SPe); however, the clinicopathologic features are not well characterized. To our knowledge, this is the first large series reporting the clinicopathologic features of SPe. We reviewed our database of 3106 malignant mesothelioma cases. Of 248 peritoneal mesotheliomas, 15 (4%) were sarcomatoid variant (0.5% of all mesotheliomas). Only cases with 100% sarcomatoid morphology diagnosed by open surgical biopsy and/or autopsy were included. Thus, 4 cases were excluded leaving 11 cases of SPe. Two additional cases of SPe previously published by 1 of the authors (V.L.R.), not included in the database, are added yielding 13 cases total. The median age at diagnosis was 66 years (range=48 to 85 y), and there was a male predominance (M:F=3.25:1). Survival from date of diagnosis to date of death was 5 months (range=0 to 12 mo). The most common presenting symptom was abdominal pain, and 3 of 4 women were suspected to have cholecystitis/cholelithiasis. All cases stained positive for cytokeratins, and 2 contained heterologous elements. Seven cases had objective markers of asbestos exposure, and 2 additional cases had occupations strongly associated with mesothelioma. Two cases with alleged household contact exposures could not be confirmed to be asbestos related by lung fiber analysis. SPe is a rare variant of mesothelioma attributed to asbestos exposure in 69% of our cases.

Context: Ionizing radiation has a role in the development of malignant mesothelioma, in several epidemiologic studies, including patients with hematologic malignancies., Objective: To study the clinicopathologic characteristics of patients with malignant mesothelioma and hematologic malignancies with and without a history of radiotherapy., Design: From a database of approximately 3600 patients with malignant mesothelioma, we identified 45 patients (1%) who also had hematologic malignancies. We examined clinicopathologic features and noted whether the patient had received radiotherapy for malignancy, comparing those with and those without such exposure., Results: Among the 45 cases, 18 (40%) had Hodgkin lymphoma, 15 (33%) had non-Hodgkin lymphoma, 10 (4%) had chronic lymphocytic leukemia, and 2 (22%) had chronic myelogenous leukemia; 20 patients (44%) had a history of radiotherapy, and 23 (51%) did not. Most patients with Hodgkin lymphoma (16 of 18; 90.0%) received radiation, whereas none of the patients with leukemia (0 of 12) and only 20% (3 of 15) of the patients with non-Hodgkin lymphoma did so. Patients without radiation were older than patients who received radiotherapy (median, 73 versus 54 years, respectively; P < .001), had a shorter interval from diagnosis of hematologic malignancy to that of mesothelioma (median, 2 versus 24 years, respectively; P < .001), and had a shorter survival period (median, 6.0 versus 14.0 months, respectively; P = .02). Epithelial mesotheliomas were proportionately more common in patients with a history of radiotherapy., Conclusions: Patients with mesothelioma and hematologic malignancies with a history of radiation tended to be younger, had a longer interval from diagnosis of hematologic malignancy to that of mesothelioma, had a longer survival period, and were more likely to have the epithelial variant compared with patients without radiotherapy.

Context: Numerous articles in the scientific literature indicate that pathogenic fibers with respect to asbestos-related diseases are those that exceed 5 μm in length. Nonetheless, some authors have expressed concerns regarding pathogenicity of shorter fibers., Objective: To review the scientific evidence regarding pathogenicity (or lack thereof) of fibers less than or equal to 5 μm in length, with particular attention to publications indicating that such fibers might be hazardous., Data Sources: The scientific literature was reviewed for experimental animal studies and human studies that address the role of fiber size in causation of disease. Sources included original studies, as well as review articles related to the topic., Conclusions: Experimental animal studies involving inhalation of fibers have demonstrated that fibers greater than 5 μm in length are associated with both pulmonary fibrosis (ie, asbestosis) and malignancies (carcinoma of the lung and mesothelioma). There is no convincing evidence for a pathogenic effect for fibers that are 5 μm or less in length. Fiber analyses of human lung tissue samples provide further support for pathogenicity of long fibers, particularly the more biopersistent amphibole fibers. Similar observations have been reported for nonasbestos mineral fibers. Concerns expressed by some authors (eg, the greater abundance of short fibers) do not alter these conclusions. Similarly, in vitro studies demonstrating biological activity of short fibers do not override inhalational studies of whole animals or the epidemiological findings in humans.

Immunohistochemical stains have become invaluable for the diagnosis of pulmonary malignancies (both primary and metastatic), particularly given the small size of transbronchial and endobronchial biopsies and the increasing need to conserve tissue for molecular studies. There are many panels of immunostains currently available to help differentiate between common types of pulmonary malignancies. It is the purpose of this review to summarize some of the most commonly used immunostains for the distinction of primary pulmonary malignancies from one another in areas with histological overlap and for distinguishing primary pulmonary malignancies from other cancers with which they may be confused. These include differentiating between poorly differentiated adenocarcinoma and poorly differentiated squamous cell carcinoma, small cell/large cell neuroendocrine carcinoma and basaloid carcinoma, and primary and metastatic adenocarcinoma involving the lung. In addition, we address the distinction between mesothelioma and pulmonary adenocarcinoma. Pitfalls in the use of these markers are also addressed. Although not aiming to be comprehensive, this review aims to guide and influence common practice by furthering the clinician's knowledge on using immunohistochemical stains for characterization of pulmonary neoplasms. This summary of frequently used immunohistochemical stains can provide usefulness by allowing accurate characterization of pulmonary tumors, thereby allowing for conservation of tissue for additional molecular testing.

The presence of individual neuroendocrine cells in rare peripancreatic lymph nodes (LNs) suggests that neuroendocrine tumor or nested neuroendocrine cell proliferation can arise in situ from neuroendocrine cells native to any LN. However, it is very difficult to ascertain whether any neuroendocrine lesion in LNs is a primary tumor or a metastasis from adjacent organs. We encountered 4 cases of neuroendocrine proliferation in intrathoracic LNs (ILNs) of patients with primary lung adenocarcinoma. All patients had a single lung mass without mediastinal lymphadenopathy based on computed tomography and positron emission tomography imaging. Mediastinal staging was done by either mediastinoscopy or thoracotomy and none of them had metastasis from adenocarcinoma in any LN. One patient had three ILNs positive for neuroendocrine proliferation measuring 1.7, 1.8, and 4.0 mm, respectively and a minute tumorlet less than 1.0 mm in the lung. Three other patients had small areas of neuroendocrine proliferation no more than 1 mm in single ILN without any lung neuroendocrine lesion. Neuroendocrine cells in ILNs often formed nests of varying size with similar morphology to carcinoid tumorlet in the lung. Small clusters of neuroendocrine cells without any particular pattern were often seen together with these nests. These cells were positive for neuroendocrine markers: synaptophysin, chromogranin, and CD56. They were also positive for CK7 and TTF-1. It is interesting to note, single cells positive for neuroendocrine markers and TTF-1 were identified near or away from these neuroendocrine nests or clusters. These findings suggest that neuroendocrine lesion can be incidentally identified in ILNs. Close clinical follow-up is warranted as metastasis from or synchronous lesions in adjacent organs cannot be excluded.

Context: The development of successful chemotherapeutic agents directed against the Kit receptor tyrosine kinase protein has generated intense interest in the Kit (CD117) immunoreactivity of various neoplasms. Immunoreactivity for Kit in small cell lung carcinoma (SCLC) has been well established. However, data on Kit immunostaining in other lung tumors is limited. Likewise, while solitary fibrous tumors of the gastrointestinal tract have been examined for Kit expression, the Kit staining characteristics of their counterpart in the pleura, namely, localized fibrous tumor, are not well known., Objective: To characterize the Kit immunohistochemical profiles of major types of lung and pleural tumors., Design: We stained 60 lung carcinomas, including 11 SCLCs, 4 large cell neuroendocrine carcinomas, 22 squamous cell carcinomas, 23 adenocarcinomas, 11 pulmonary carcinoid tumors, 19 pleural malignant mesotheliomas, and 6 localized pleural fibrous tumors with a commonly used polyclonal Kit antibody., Results: Small cell lung carcinomas demonstrated Kit staining in 82% of cases, nearly all of which demonstrated moderate to intense immunoreactivity. Immunostaining was observed in 25% of large cell neuroendocrine carcinomas. Focal staining was observed in 9% of squamous cell carcinomas and 17% of adenocarcinomas. None of the pulmonary carcinoid tumors were immunoreactive. Moderately intense immunostaining was present in 50% of localized fibrous tumors. Malignant mesotheliomas were nonimmunoreactive for Kit in 95% of cases., Conclusion: Non-small cell lung carcinomas showed very limited expression of Kit. Lung tumors with neuroendocrine differentiation exhibited a wide spectrum of Kit immunoreactivity, ranging from rare in pulmonary carcinoid tumors to frequent in SCLC. The high frequency of Kit immunostaining in SCLC has important potential therapeutic implications. Demonstration of Kit positivity in some localized fibrous tumors in this study contrasts with absent immunoreactivity in solitary fibrous tumors of the gastrointestinal tract. The paucity of Kit staining in malignant mesothelioma suggests these tumors are unlikely to respond to currently available tyrosine kinase inhibitors.

Malignant mesothelioma is a highly aggressive tumor of the serous membranes, which in humans results from exposure to asbestos and asbestiform fibers. Although occupational malignant mesothelioma is still the most common form of this lesion, naturally contaminated soil can play an important role in the development of environmental malignant mesothelioma in some parts of the world. Fifty cases of malignant mesothelioma (MM) from southern Turkey with no occupational history of asbestos exposure were reviewed regarding pathologic and clinical features. A case of hyaline fibrous plaque of the pleura was also included in this series. Histologically the cases were classified as epithelial (36 cases); sarcomatous (7 cases); and biphasic (7 cases). One of the sarcomatous cases was desmoplastic. Ultrastructural examination of the tumor tissue in three cases revealed long-surface microvilli in epithelial cells. Interstitial cells of the lung in one case showed electron-dense asbestos fibers in the cytoplasm. Mineralogical analyses of the lung tissue in three cases of MM and the case of pleural plaque showed high amounts of asbestos fibers most consistent with tremolite and actinolite. The clinical and pathologic features of our cases support that the environmental inhalation of asbestos is still a major health problem in some parts of Turkey.

The aim of this study was to investigate the asbestos content of lung tissue in a series of patients with lung cancer and some history of asbestos exposure. This information was then correlated with demographic information, occupational and smoking history, presence or absence of pathologic asbestosis or pleural plaques, and pathologic features of the cancer. The pulmonary concentration of asbestos fibers in 234 cases of primary carcinoma of the lung was determined by means of a tissue digestion technique. Asbestos body counts were performed in 229 cases and fiber analysis by scanning electron microscopy in 221 cases. Asbestos content was recorded as total asbestos fibers, commercial amphibole fibers, noncommercial amphibole fibers, and chrysotile fibers 5 microm or greater in length per gram of wet lung tissue. The study group included 70 patients with asbestosis (Group I), 44 patients with parietal pleural plaques but without asbestosis (Group II), and 120 patients with neither (Group III). The median asbestos body content of Group I was more than 35 times greater than Group II and more than 300 times greater than Group III. The total asbestos fiber count for Group I was nearly 20 times greater than Group II and more than 50 times greater than Group III. The difference was due almost entirely to commercial amphiboles. In a series of primary lung cancer cases with some history of asbestos exposure, a markedly elevated asbestos content was identified among those with pathologic asbestosis as compared with patients with pleural plaques alone or with neither plaques nor asbestosis.

Pulmonary blastomas (PBs) are rare primary malignancies that include adult types: biphasic pulmonary blastoma (BPB) and well-differentiated fetal adenocarcinoma (WDFA); and childhood type: pleuropulmonary blastoma (PPB). Their pathogenesis and relationship to bronchogenic carcinoma (BCA) are controversial. To determine whether or not PB share molecular pathological features with BCA, the authors immunostained three BPB, three WDFA, three PPB, and 80 standard BCA for p53 protein and MDM2 protein, gene products believed to be significant in the pathogenesis of BCA. Paraffin-embedded tissue sections were immunostained with monoclonal antibody to p53 and MDM2 proteins. Strong intranuclear staining in greater than 10% of cells was considered positive. Three (50%) BPB and WDFA stained for p53 and five (83%) for MDM2. None of the PPB stained for p53, and one PPB did not stain for either p53 or MDM2. Five of six adult type PB occurred in smokers, whereas none of the PPB was associated with smoking. Seventy-five (94%) of the BCA stained for MDM2 and 46 (61%) for p53. Immunostaining patterns for p53 and MDM2 in adult types of PB, and not PPB, appear similar to those for BCA. This may suggest that adult type PB, but not childhood PB, have a similar pathogenesis to BCA.

Most malignant mesothelioma cases are associated with pulmonary asbestos body (AB) counts significantly greater than those of the general population. However, the question remains whether malignant mesothelioma cases associated with "normal" AB counts (i.e., indistinguishable from the general population) represent background incidence levels or are, actually, asbestos related. We performed AB counts (by light microscopy) and mineral fiber analysis (by scanning electron microscopy) in 18 mesothelioma cases with AB counts within our normal range (0 to 20 AB/G wet lung) and in 19 "control" cases. Our study demonstrated that approximately one-third (6 of 18) of the mesothelioma cases have asbestos fiber burdens greater than 95% of the control levels. These results suggest that these six mesothelioma cases may be asbestos related despite AB counts similar to those of the general population. An asbestos etiology was suggested in three additional cases, but too few amphibole fibers were identified in these cases to be certain of a value above background. The remaining nine cases showed no evidence of an asbestos etiology. Electron microscopic analysis of pulmonary mineral fibers may be required to differentiate asbestos-related mesotheliomas from non-asbestos-related cases when AB counts are within the range of background values.

Tremolite is nearly ubiquitous and represents the most common amphibole fiber in the lungs of urbanites. Tremolite asbestos is not mined or used commercially but is a frequent contaminant of chrysotile asbestos, vermiculite, and talc. Therefore, individuals exposed to these materials or to end-products containing these materials may be exposed to tremolite. We have had the opportunity to do asbestos body counts and mineral fiber analysis on pulmonary tissue from five mesothelioma cases and two asbestosis cases with pulmonary tremolite burdens greater than background levels. There were no uncoated amosite or crocidolite fibers detected in any of these cases. Three patients were occupationally exposed to chrysotile asbestos; two patients had environmental exposures (one to vermiculite and one to chrysotile and talc) and one was a household contact of a shipyard worker. The tremolite burdens for the asbestosis cases were one to two orders of magnitude greater than those for the mesothelioma cases. Our study confirms the relationship between tremolite exposure and the development of asbestos-associated diseases. Furthermore, the finding of relatively modest elevations of tremolite content in some of our mesothelioma cases suggests that, at least for some susceptible individuals, moderate exposures to tremolite-contaminated dust can produce malignant pleural mesothelioma.

Although the association between asbestos exposure and malignant mesothelioma is indisputable, controversy continues regarding the relative contribution of the various types of asbestos fibers to the development of mesothelioma. We examined the types of asbestos fibers recovered from lung parenchyma in more than 90 cases of malignant mesothelioma from the United States, using an analytical scanning electron microscope. Almost half of the patients were former asbestos insulators or shipyard workers. The fibers were recovered from lung tissues obtained at autopsy or surgical resection by means of a sodium hypochlorite digestion procedure. Amosite asbestos was identified in 81% of the cases and accounted for 58% of all fibers 5 microns or greater in length. Tremolite/actinolite/anthophyllite were identified in 55% of the cases and accounted for 10% of all fiber types. Chrysotile was identified in 21% of the cases and accounted for 3% of fibers exceeding 5 microns in length. Crocidolite was found in 16% of the cases and accounted for 3% of fibers exceeding 5 microns in length. Nonasbestos mineral fibers (commonly found in the lungs of the general population) were observed in 71% of the cases and accounted for 25% of all fibers 5 microns or greater in length. The findings in this study are at odds with the assertion that crocidolite asbestos is responsible for most mesotheliomas in the United States.

We objectively examined the extent of tumor necrosis by computer-assisted morphometry in 28 patients with surgically resected Stage I non-small cell carcinoma of lung. Fourteen of the 28 patients were long-term survivors (mean survival after diagnosis 94 mo) and 14 were short-term survivors (up to 62 mo after diagnosis). The extent of tumor necrosis was determined by means of a computer assisted digitizing system. The two sample t test and the two-tailed Wilcoxon rank score tests were used for statistical analysis of comparison of the extent of tumor necrosis between the two groups of patients. This morphometric study showed that the extent of tumor necrosis was significantly associated to the probability of long-term survival, with long surviving patients having a lesser degree of tumor necrosis (t = 2.75, p < 0.02, 2 sample t test, two-tailed, df = 26). These findings reaffirm previous subjective data, derived from pathologist assessment of tumor necrosis, and suggest that morphometric evaluation of tumor necrosis may play a useful adjunct role in predicting prognosis of carcinoma of lung.

To evaluate the utility of nuclear morphometry as a prognostic indicator in lung cancer, 5-year follow-up information was obtained in 46 cases of surgically resected Stage I non-small cell lung cancer (NSCLC). Nuclear area, perimeter, major diameter, minor diameter, and nuclear shape factor were determined from representative histologic sections of the tumors with a computer-assisted digitizing system. The morphometric parameters were compared between patients with favorable outcome (Group I: alive with no evidence of disease, n = 17) and those with poor outcome (Group II: dead of disease or with recurrence of disease, n = 29). No significant differences in any of the morphometric parameters were found between tumors in Groups I and II for individual tumor cell types or the combined cases. Failure to demonstrate a correlation between morphometric parameters and prognosis in Stage I NSCLC indicates that future efforts to determine objective prognostic factors should concentrate on other variables, such as specific genetic abnormalities.

We conducted a clinical, environmental, pathologic, and mineral lung burden investigation of a 61-year-old man with malignant mesothelioma. For 35 years, up until three weeks prior to pneumonectomy, the patient made asbestos soldering forms at a costume jewelry production facility. Only chrysotile asbestos was used at the plant during the last decade of the patient's employment, and recent environmental sampling of the work-place identified no other asbestos fiber type. Anticipating that the patient would add to the very small number of cases of mesothelioma attributable solely to chrysotile, we found instead that the patient's lung tissue contained large numbers of both coated and uncoated amosite asbestos fibers but, surprisingly, no chrysotile. We subsequently learned that a distributor of both chrysotile and amosite supplied the company during the first 25 years the patient was fabricating soldering forms. The findings underscore the futility of estimating environmental exposure to chrysotile on the basis of fiber counts in lung tissue. Although we previously described non-neoplastic asbestos-related disease among patients engaged in similar work, this case, to the best of our knowledge, represents the first report of mesothelioma in the commercial jewelry industry. As such, it prompted us to initiate a public health campaign to replace asbestos soldering forms in this industry with readily available, safer alternatives.

Intracytoplasmic globules have been described in a variety of neoplastic and nonneoplastic conditions, but remain poorly defined. In a review of 100 consecutive cases of lung carcinomas, six cases of mucin-positive adenocarcinoma demonstrated eosinophilic intracytoplasmic globules that ranged in size from less than 1 to 20 mu in diameter. The globules were often located adjacent to areas of tumor necrosis, and occurred either singly or multiply within individual tumor cells. Globules were similar in morphologic appearance to Russell bodies in plasma cells or the eosinophilic globules in hepatocytes of patients with alpha-1-antitrypsin deficiency, but were morphologically distinct from intracytoplasmic mucin vacuoles. The globules were brightly positive with PAS stain with diastase, were brick red with Masson's trichrome stain, and showed variably positive staining with Mallory's phosphotungstic acid-hematoxylin and Ziehl-Nielson stains. Immunoperoxidase staining showed slight staining of some globules with albumin, IgG, IgA, and alpha-1-antitrypsin. Ultrastructurally the globules had a homogeneous density and were often associated with profiles of rough endoplasmic reticulum. We suggest that these globules represent secretory glycoprotein accumulated in the cytoplasm of tumor cells in areas of tumor cell injury.

The heterogeneity of lung carcinomas was recognized in the past, but few previous studies attempted to quantitate this heterogeneity. In the present study 100 consecutive cases of lung carcinoma (65 surgical resections and 35 autopsies) were collected, and either the entire tumor or ten blocks were examined in a blinded and randomized fashion using the revised (1981) WHO classification. At least three of five panelists agreed on the major histologic type present for 94 per cent of the slides. Agreement for the diagnosis of small cell carcinomas (at least four of five observers) was 98 per cent, but only 72 per cent agreement was attained for the subtyping of small cell carcinomas (e.g., oat cell versus intermediate). Only 34 per cent of the cases were homogeneous according to the majority of the panelists. An additional 21 per cent of the cases showed minor (subtype) heterogeneity (e.g., mixtures of acinar and papillary patterns in adenocarcinoma). Forty-five per cent of the cases showed major heterogeneity, i.e., at least one slide from the case showed a major histologic type different from that of the remainder. Seven small cell carcinomas were homogeneous, whereas in eight cases mixtures of small cell and other cell types were seen. In all but one of the cases involving bronchioloalveolar cell patterns, other patterns of adenocarcinoma were present elsewhere in the tumor. In all six cases involving giant cell carcinoma patterns, adenocarcinoma patterns were also present in some sections. Heterogeneity was identified by extensive sampling of the entire tumor and was seldom recognized in biopsy specimens.

Diseases associated with asbestos exposure include asbestosis, malignant mesothelioma, carcinoma of the lung, and parietal pleural plaques. In this study the asbestos content of lung tissue was examined in groups of cases representing each of these diseases and in several cases with non-occupational idiopathic pulmonary fibrosis. Asbestos bodies (AB), which are the hallmark of asbestos exposure, were present in the lungs of virtually everyone in the general population and present at increased levels in individuals with asbestos associated diseases. The highest numbers of AB occurred in individuals with asbestosis, all of whom had levels greater than or equal to 2000 ABs/g wet lung tissue. Every case with a content of 100,000 ABs/g or higher had asbestosis. Intermediate levels occurred in individuals with malignant mesothelioma and the lowest levels in patients with parietal pleural plaques. There was no overlap between the asbestos content of lung tissue from patients with asbestosis and those with idiopathic pulmonary fibrosis. Lung cancer was present in half the patients with asbestosis, and the distribution of histological patterns did not differ from that in patients with lung cancer without asbestosis. The asbestos body content in patients with lung cancer was highly variable. Control cases had values within our previously established normal range (0-20 ABs/g). There was a significant correlation (p less than 0.001) between AB counted by light microscope and AB and uncoated fibres counted by scanning electron microscopy. The previous observation that the vast majority of asbestos bodies isolated from human tissues have an amphibole core was confirmed.

An investigation was made to correlate autopsy and roentgenographic findings of pleural plaques with occupational exposure to asbestos and occurrence of respiratory tract tumors. Of the 434 autopsies performed over a 2 1/2 year period, 25 (5.8 percent) had pleural plaques but no gross evidence of parenchymal fibrosis. Review of the posterior-anterior chest roentgenograms using the International Labor Office criteria for classification of pneumoconiosis (1980) revealed that only seven of the 25 cases had detectable pleural thickening or calcification, which demonstrates the poor sensitivity of standard x-ray films. There was no detectable difference in frequency of known or presumed exposure to asbestos between the pleural plaque cases and controls as determined by occupational information obtained from chart review. Asbestos bodies were identified in lung tissue digests from all 25 cases with pleural plaques, and exceeded the normal range for our laboratory in 14 cases (56 percent). Of the 25 cases with pleural plaques, four also had bronchogenic and three had laryngeal carcinoma. The prevalence of bronchogenic carcinoma in patients with plaques was not different from those without plaques (p greater than 0.50). However, the association between plaques and laryngeal carcinoma was highly significant (p = 0.004).

The Tyler Asbestos Workers Program is a continuing study of 1,105 former amosite asbestos workers. This report includes a study of six former workers, five of whom died and had autopsies, and one who underwent a lobectomy. Five of these men were exposed to asbestos for three months or less. Four had lung cancer, and one a rectal carcinoma. All were cigarette smokers. Ferruginous (asbestos) body content of the upper and lower lobes of the lungs was quantitated by a digestion technic. Tissue sections from upper and lower lobes were independently quantitated for fibrosis and ferruginous bodies, and chest roentgenograms were examined for interstitial fibrosis. (Control lung tissue was obtained from consecutive autopsies of 52 adults who did not have a known occupational exposure to asbestos.) Relatively low ferruginous body counts (less than 700/g lung tissue) were associated with mild degrees of fibrosis, and higher counts (greater than 10,000/g) with moderate to severe fibrosis. Mild to moderate pulmonary fibrosis could be identified on tissue sections before interstitial changes were detectable by chest roentgenograms.

Dendriform pulmonary ossification (DPO) is a rare condition characterized by branching bony spicules found in association with pulmonary fibrosis. The authors report two cases, the first of which occurred in a patient with acute myeloblastic leukemia and was associated with the unique finding of leukemic involvement of marrow spaces in the metaplastic bone. The second case showed DPO in combination with asbestosis, a heretofore unreported association.

We present a unique case of pulmonary blastoma and describe its histology and ultrastructure. The stromal component exhibited bizarre multinucleated giant cells containing previously undescribed granules. These membrane-limited granules were eosinophilic, periodic acid-Schiff positive, diastase resistant, acid phosphatase and nonspecific esterase negative, immunohistologically negative for lysozyme, albumin, and gamma globulin, and often homogeneously electron dense. A similar electron-dense material accumulated in the rough endoplasmic reticulum of these stromal giant cells, suggesting that the material in the granules is synthetic. The material appeared to be a glycoprotein but was not alpha1-antitrypsin, alpha-fetoprotein, or human chorionic gonadotropin by immunohistologic techniques. These stromal cell granules differ from granules described in epithelial cells of other pulmonary blastomas but resemble granules found in some sarcomas.

Eight primary carcinomas of the lung with a prominent spindle-cell sarcomatoid component were studied by immunocytochemical staining and electron microscopy. The eight tumors were indistinguishable by conventional light microscopy, with the exception of one unusual neoplasm that followed multiple pathways of differentiation with elements of squamous cell carcinoma, rhabdomyosarcoma, chondrosarcoma, and an undifferentiated spindle-cell population. Reticulin fiber production by individual spindle cells and a sharp demarcation of the carcinomatous and sarcomatoid domains by light microscopy were not useful differentiating features. Three of the eight tumors exhibited keratin expression in both the carcinomatous and spindle-cell components. Both immunocytochemical and electron microscopic analyses were required to detect epithelial differentiation, as in one case keratin was identified only by immunocytochemical staining and in another only by ultrastructural examination. Epithelial differentiation was undetectable in the sarcomatoid component of five tumors, and in one case immunoreactive myoglobin was identified in spindle cells; skeletal muscle differentiation was confirmed ultrastructurally. We propose that pulmonary carcinomas exhibiting evidence of epithelial differentiation in a sarcomatoid component be termed spindle-cell carcinomas and that those biphasic tumors exhibiting mesenchymal differentiation into specific tissues, such as neoplastic bone, cartilage, or striated muscle, or lacking epithelial differentiation by light microscopy, immunocytochemistry, and electron microscopy be classified as carcinosarcomas. This distinction may ultimately be unnecessary, because these two tumors may represent different points along a morphologic and biologic continuum.

Calcification has long been a determinant in the radiologic distinction of a benign pulmonary mass. However, rare examples of calcification without ossification in pulmonary adenocarcinoma and ossification in the bronchial carcinoid have led some investigators to warn against this approach. A case of pulmonary adenocarcinoma with stromal ossification is reported herein. The literature is reviewed for neoplasms that exhibit pulmonary ossification either by primary or metastatic lesions. To our knowledge, this case represents the first report of benign osseous stromal metaplasia in the primary lesion of a pulmonary adenocarcinoma.