The concept of mesothelioma in situ, with consideration of its potential impact on cytology diagnosis.

Diffuse malignant mesothelioma (MM) is an incurable tumour of the serosal membranes, which is often caused by exposure to asbestos and commonly diagnosed at advanced stage. Malignant mesothelioma in situ (MMIS) is now included as diagnostic category by the World Health Organization (WHO). However, our international survey of 34 pulmonary pathologists with an interest in MM diagnosis highlights inconsistency regarding how the diagnosis is being made by experts, despite published guidelines. Whilst the WHO restricts the diagnosis to surgical samples, the very concept has implication for cytological diagnosis, which is already regarded as controversial in itself by some. MMIS is currently only applicable as precursor to MM with an epithelioid component, and raises the possibility for different molecular pathways for different histological MM subtypes. The clinical implications of MMIS at this stage are uncertain, but aggressive therapies are being initiated in some instances. Based on the results of the survey we here present a critical appraisal of the concept, its clinical and conceptual implications and provide practice suggestions for diagnosis. A low threshold for ancillary testing is suggested. The designations of 'malignant mesothelioma, cannot exclude MMIS' or 'atypical mesothelial proliferation with molecular indicators of malignancy, so-called MMIS' could be used on cytology samples, adding 'no evidence of invasion in sample provided' for surgical samples. Clinical and radiological correlation are integral to diagnosis and best done at multidisciplinary meetings. Finally, collaborative studies are required to improve our understanding of MMIS.

Comprehensive Molecular and Pathologic Evaluation of Transitional Mesothelioma Assisted by Deep Learning Approach: A Multi-Institutional Study of the International Mesothelioma Panel from the MESOPATH Reference Center.

INTRODUCTION: Histologic subtypes of malignant pleural mesothelioma are a major prognostic indicator and decision denominator for all therapeutic strategies. In an ambiguous case, a rare transitional mesothelioma (TM) pattern may be diagnosed by pathologists either as epithelioid mesothelioma (EM), biphasic mesothelioma (BM), or sarcomatoid mesothelioma (SM). This study aimed to better characterize the TM subtype from a histological, immunohistochemical, and molecular standpoint. Deep learning of pathologic slides was applied to this cohort. METHODS: A random selection of 49 representative digitalized sections from surgical biopsies of TM was reviewed by 16 panelists. We evaluated BAP1 expression and CDKN2A (p16) homozygous deletion. We conducted a comprehensive, integrated, transcriptomic analysis. An unsupervised deep learning algorithm was trained to classify tumors. RESULTS: The 16 panelists recorded 784 diagnoses on the 49 cases. Even though a Kappa value of 0.42 is moderate, the presence of a TM component was diagnosed in 51%. In 49% of the histological evaluation, the reviewers classified the lesion as EM in 53%, SM in 33%, or BM in 14%. Median survival was 6.7 months. Loss of BAP1 observed in 44% was less frequent in TM than in EM and BM. p16 homozygous deletion was higher in TM (73%), followed by BM (63%) and SM (46%). RNA sequencing unsupervised clustering analysis revealed that TM grouped together and were closer to SM than to EM. Deep learning analysis achieved 94% accuracy for TM identification. CONCLUSION: These results revealed that the TM pattern should be classified as non-EM or at minimum as a subgroup of the SM type.

Differential Diagnosis of Epithelioid Malignant Mesothelioma With Lung and Breast Pleural Metastasis: A Systematic Review Compared With a Standardized Panel of Antibodies-A New Proposal That May Influence Pathologic Practice.

CONTEXT.­: Pleural mesothelioma is a rare cancer with an often-challenging diagnosis because of its potential to be a great mimicker of many other tumors. Among them, primary lung and breast cancers are the 2 main causes of pleural metastasis. The development and application of targeted therapeutic agents have made it even more important to achieve an accurate diagnosis. In this setting, international guidelines have recommended the use of 2 positive and 2 negative immunohistochemical biomarkers. OBJECTIVES.­: To define the most highly specific and sensitive minimum set of antibodies for routine practice to use for the separation of epithelioid malignant mesothelioma from lung and breast metastasis and to determine the most relevant expression cutoff. DESIGN.­: To provide information at different levels of expression of 16 mesothelial and epithelial biomarkers, we performed a systematic review of articles published between 1979 and 2017, and we compared those data to results from the Mesothelioma Telepathology Network (MESOPATH) of the standardized panel used in routine practice database since 1998. RESULTS.­: Our results indicate that the following panel of markers-calretinin (poly)/thyroid transcription factor 1 (TTF-1; clone 8G7G3/1) and calretinin (poly)/estrogen receptor-α (ER-α; clone EP1)-should be recommended; ultimately, based on the MESOPATH database, we highlight their relevance which are the most sensitive and specific panel useful to the differential diagnosis at 10% cutoff. CONCLUSIONS.­: Highlighted by their relevance in the large cohort reported, we recommend 2 useful panels to the differential diagnosis at 10% cutoff.

Malignant Mesothelioma and Its Non-Asbestos Causes.

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).

Usual interstitial pneumonia in asbestos-exposed cohorts - concurrent idiopathic pulmonary fibrosis or atypical asbestosis?

AIMS: To determine whether usual interstitial pneumonia (UIP) pattern fibrosis is seen in asbestosis. METHODS AND RESULTS: The occurrence of UIP pattern fibrosis was studied in four asbestos cohorts systematically referred following postmortem to the UK Pneumoconiosis Unit, Cardiff. The combined exposed workforce comprised >25 000 persons. Over the 17-year period, 233 subjects were identified; 210 had degrees of interstitial fibrosis with a fibrotic non-specific interstitial pneumonia pattern and subpleural accentuation, and three showed UIP pattern fibrosis. All three of these cases showed grade 4 fibrosis (honeycombing) with no asbestos fibre dose-response correlation. A Poisson distribution of probability analysis indicated that the observed cases of UIP in this workforce could be wholly accounted for by the prevalence of idiopathic pulmonary fibrosis (IPF) in the population. CONCLUSIONS: UIP pattern fibrosis is rarely observed in asbestos-exposed subjects, and shows no dose-response correlation with asbestos fibres on mineral analysis; this points to an alternative disease, such as IPF. The results indicate that UIP pattern fibrosis should not be regarded as genuine asbestosis, irrespective of the status of asbestos biomarkers, and this impacts upon the postmortem handling of asbestos-related deaths.

The fake fat phenomenon in organizing pleuritis: a source of confusion with desmoplastic malignant mesotheliomas.

We report 9 patients with pleural biopsies referred because of concern about infiltration of what appeared to be chest wall fat by pan-keratin-positive spindled cells, a finding that led to a consideration of desmoplastic mesothelioma. All patients showed pleural effusions/pleural thickening on computed tomographic scan. Pleural biopsy showed a greatly thickened and fibrotic paucicellular pleura with circular fat-like spaces and, sometimes, adjacent oblate spaces mostly deep in the fibrotic area. Indistinct, keratin-positive, spindle cells arranged parallel to the pleural surface coursed between these fat-like spaces. S-100 stains were negative around the fat-like spaces. Vimentin stains showed that the spaces did not have a cellular lining of any kind. Sometimes the spaces contained faintly hematoxyphilic material that was Alcian blue positive, and similar material was seen in the fibrotic stroma. Follow-up with periods ranging from 6 to 30 months revealed that 8 cases had stable disease on chest imaging or by clinical findings. One case had slowly progressive pleural thickening. These observations suggest that spaces resembling fat may be encountered in fibrotic pleurae and that horizontally oriented keratin-positive spindled cells between the fat-like spaces deep in the fibrotic portion of a thickened pleura represent a benign finding seen in some cases of organizing pleuritis/fibrothorax. The spaces themselves are probably artifacts derived from the biopsy procedure and/or cutting artifacts. In contrast, in true desmoplastic mesotheliomas there is downward, rather than horizontal, growth of keratin-positive spindled cells running between clearly definable fat cells.

Alveolar proteinosis with hypersensitivity pneumonitis: a new clinical phenotype.

BACKGROUND AND OBJECTIVE: The aim of the present study was to report the features of five patients with concurrent histopathological features of pulmonary alveolar proteinosis (PAP) and hypersensitivity pneumonitis (HP) and their high-resolution CT (HRCT) appearances. METHODS: Patients with histopathological features of both HP and PAP on surgical lung biopsy referred for tertiary review were retrospectively identified. The pathology and HRCT images were semi-quantitatively scored to evaluate the relative contribution to HP and PAP. RESULTS: Five patients had histopathological features of HP and PAP but had varied HRCT appearances. All had imaging features of PAP to a varying degree with two patients also showing characteristics of HP but three patients had ill-defined thickened interlobular septa, not typical of either disease. CONCLUSIONS: We describe the coexistence of PAP and HP in five patients and discuss possible linkages between these two distinct pathologies.

Pathology of asbestosis- An update of the diagnostic criteria: Report of the asbestosis committee of the college of american pathologists and pulmonary pathology society.

Asbestosis is defined as diffuse pulmonary fibrosis caused by the inhalation of excessive amounts of asbestos fibers. Pathologically, both pulmonary fibrosis of a particular pattern and evidence of excess asbestos in the lungs must be present. Clinically, the disease usually progresses slowly, with a typical latent period of more than 20 years from first exposure to onset of symptoms. DIFFERENTIAL DIAGNOSIS: IDIOPATHIC PULMONARY FIBROSIS: The pulmonary fibrosis of asbestosis is interstitial and has a basal subpleural distribution, similar to that seen in idiopathic pulmonary fibrosis, which is the principal differential diagnosis. However, there are differences between the 2 diseases apart from the presence or absence of asbestos. First, the interstitial fibrosis of asbestosis is accompanied by very little inflammation, which, although not marked, is better developed in idiopathic pulmonary fibrosis. Second, in keeping with the slow tempo of the disease, the fibroblastic foci that characterize idiopathic pulmonary fibrosis are infrequent in asbestosis. Third, asbestosis is almost always accompanied by mild fibrosis of the visceral pleura, a feature that is rare in idiopathic pulmonary fibrosis. DIFFERENTIAL DIAGNOSIS: RESPIRATORY BRONCHIOLITIS: Asbestosis is believed to start in the region of the respiratory bronchiole and gradually extends outward to involve more and more of the lung acinus, until the separate foci of fibrosis link, resulting in the characteristically diffuse pattern of the disease. These early stages of the disease are diagnostically problematic because similar centriacinar fibrosis is often seen in cigarette smokers and is characteristic of mixed-dust pneumoconiosis. Fibrosis limited to the walls of the bronchioles does not represent asbestosis. ROLE OF ASBESTOS BODIES: Histologic evidence of asbestos inhalation is provided by the identification of asbestos bodies either lying freely in the air spaces or embedded in the interstitial fibrosis. Asbestos bodies are distinguished from other ferruginous bodies by their thin, transparent core. Two or more asbestos bodies per square centimeter of a 5- mu m-thick lung section, in combination with interstitial fibrosis of the appropriate pattern, are indicative of asbestosis. Fewer asbestos bodies do not necessarily exclude a diagnosis of asbestosis, but evidence of excess asbestos would then require quantitative studies performed on lung digests. ROLE OF FIBER ANALYSIS: Quantification of asbestos load may be performed on lung digests or bronchoalveolar lavage material, employing either light microscopy, scanning electron microscopy, or transmission electron microscopy. Whichever technique is employed, the results are only dependable if the laboratory is well practiced in the method chosen, frequently performs such analyses, and the results are compared with those obtained by the same laboratory applying the same technique to a control population.

Three decades of experience in the surgical multi-modality management of pleural mesothelioma.

BACKGROUND: Optimal management of diffuse malignant pleural mesothelioma (DMPM) remains unclear. We report our 30-year surgical experience with DMPM with emphasis on surgical procedure and post-operative adjuvant therapy. METHODS: During the period of the study, 217 patients with DMPM were referred for surgical opinion. Patients who only had pleural biopsies were excluded (n=78). Consecutive patients who underwent surgical treatment were included (n=139). Surgical options were extra-pleural pneumonectomy (EPP) for Butchart stage I disease in clinically fit patients (n=49) or pleurectomy/decortication in patients who were either not fit for EPP or had advanced disease (Butchart stage II and III) or both (n=90). Post-operative adjuvant therapy included either chemotherapy, radiotherapy, both or none. RESULTS: The median follow-up was 10.0 months. The longest survival (median 26.0 months, IQR: 11.14-40.9 months) occurred in the pleurectomy/decortication group who received both post-operative chemotherapy and radiotherapy (n=24) (p<0.001). EPP whether or not combined with adjuvant therapy provided no significant survival advantage in comparison to pleurectomy/decortication (overall median survival 10.3 months vs 10.1 months, p=0.09). On univariate analysis, pleurectomy/decortication combined with chemotherapy and radiotherapy was the strongest predictor of prolonged survival (Hazard Ratio=3.6). Multivariate analysis with the inclusion of histological type, surgical procedure and type of adjuvant therapy, EPP without adjuvant therapy was an independent risk-factor for decreased survival (Hazard Ratio=9.2). CONCLUSIONS: In this series, cytoreductive surgery combined with post-operative adjuvant therapy provided better survival despite either advanced disease or surgically less fit patients. Thus, pleurectomy/decortication may be the procedure of choice, given that neither surgical procedure (EPP or PD) is not curative.

Guidelines for pathologic diagnosis of malignant mesothelioma: a consensus statement from the International Mesothelioma Interest Group.

CONTEXT: Malignant mesothelioma (MM) is an uncommon tumor that can be difficult to diagnose. OBJECTIVE: To develop practical guidelines for the pathologic diagnosis of MM. DATA SOURCES: A pathology panel was convened at the International Mesothelioma Interest Group biennial meeting (October 2006). Pathologists with an interest in the field also contributed after the meeting. CONCLUSIONS: There was consensus opinion regarding (1) distinguishing benign from malignant mesothelial proliferations (both epithelioid and spindle cell lesions), (2) cytologic diagnosis of MM, (3) 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 mesothelioma, (7) use of molecular markers in the differential 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 used is dependent on the differential diagnosis and on the antibodies available in a given laboratory. Immunohistochemical panels should contain both positive and negative markers. The International Mesothelioma Interest Group recommends that markers 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 membranous markers). These guidelines are meant to be a practical reference for the pathologist.

An approach to industrial post mortems.

Industrial-related deaths represent a specialized aspect of autopsy practice. The purpose of this review is to assist the pathologist in the handling of such deaths. The diseases associated with the three most significant mineral dusts (asbestos, coal and silica) are described, together with a selection of less well-known mineral dust diseases. This review addresses the complex issues of ascribing disease to industrial exposures and the role of mineral analysis. The authors discuss the common medical legal issues that are encountered at post mortem and at inquest deposition.

Lymphohistiocytoid variant of malignant mesothelioma of the pleura: a series of 22 cases.

The lymphohistiocytoid variant of diffuse malignant mesothelioma is rare with very few cases described in the literature. It is characterized by mesothelial cells with a histiocytelike appearance and an associated dense lymphoid infiltrate. We studied clinicopathologic features and immunohistochemical patterns of a series of 22 cases. The histiocytelike cells had a mesothelial immunophenotype: AE1/AE3 (100%), calretinin (100%), CK5/6 (46%), and EMA (52%). The prominent lymphoid component showed a cytotoxic T-cell immunophenotype. Prognosis was similar to that of a large series of epithelioid diffuse malignant mesotheliomas. Formely, it was classified within the sarcomatoid type. We suggest that it should be reclassified as an epithelioid variant because of its similar behavioural characteristics. There was no evidence of Epstein-Barr virus-related infection.

Pseudomesothelioma resulting from metastatic malignant melanoma.

Isolated pleural metastatic melanoma is an uncommon clinical condition. Clinical diagnosis can be difficult and therapeutic options are limited. We describe a case where there was isolated pleural metastasis, 10 years following complete excision of a superficial melanotic lesion, which presented like a malignant mesothelioma ('pseudomesothelioma').

Localized malignant mesothelioma.

Localized malignant mesotheliomas are uncommon sharply circumscribed tumors of the serosal membranes with the microscopic appearance of diffuse malignant mesothelioma but without any evidence of diffuse spread. Little is known about their behavior. We report 23 new cases. The mean age at presentation was 63 years, and the sex ratio was approximately 2:1 (male/female). Twenty-one tumors were pleural and 2 were peritoneal. Sixteen tumors reproduced microscopic patterns of diffuse epithelial mesotheliomas, 6 had mixed epithelial and sarcomatous patterns, and 1 was purely sarcomatous. After surgical excision of the tumor, 10 of 21 patients with follow-up data were alive without evidence of disease from 18 months to 11 years after diagnosis. Patients who died had developed local recurrences and metastases, but none had diffuse pleural spread. Localized malignant mesotheliomas should be separated from diffuse malignant mesotheliomas because of their localized presentation, quite different biologic behavior, and far better prognosis.

Evidence against a role for SV40 in human mesothelioma.

SV40 has been implicated in the etiology of 40% to 60% of human mesotheliomas. These studies could have important medical implications concerning possible sources of human infection and potential therapies if human tumors are induced by this agent. We did PCR-based analysis to detect SV40 large T antigen DNA in human mesotheliomas. None of 69 tumors in which a single copy gene was readily amplified contained detectable SV40 large T antigen sequences. Under these conditions, it was possible to detect one copy of integrated SV40 DNA per cell in a mixture containing a 5,000-fold excess of normal cells using formalin-fixed preparations. Kidney, a known reservoir of SV40 in monkeys, from some of these individuals were also negative for SV40 large T antigen sequences. A subset of mesotheliomas was analyzed for SV40 large T antigen expression by immunostaining with a highly specific SV40 antibody. These tumors as well as several human mesothelioma cell lines previously reported to contain SV40 large T antigen were negative for detection of the virally encoded oncoprotein. Moreover, mesothelioma cell lines with wild-type p53 showed normal p53 function in response to genotoxic stress, findings inconsistent with p53 inactivation by the putative presence of SV40 large T antigen. Taken together, these findings strongly argue against a role of SV40 by any known transformation mechanism in the etiology of the majority of human malignant mesotheliomas.

Proposed criteria for mixed-dust pneumoconiosis: definition, descriptions, and guidelines for pathologic diagnosis and clinical correlation.

We defined mixed-dust pneumoconiosis (MDP) pathologically as a pneumoconiosis showing dust macules or mixed-dust fibrotic nodules (MDF), with or without silicotic nodules (SN), in an individual with a history of exposure to mixed dust. We defined the latter arbitrarily as a mixture of crystalline silica and nonfibrous silicates. According to our definition of MDP, therefore, MDF should outnumber SN in the lung to make a pathologic diagnosis of MDP. In the absence of confirmation of exposure, mineralogic analyses can be used to support the pathologic diagnosis. The clinical diagnosis of MDP requires the exclusion of other well-defined pneumoconioses, including asbestosis, coal workers' pneumoconiosis, silicosis, hematite miners' pneumoconiosis, welders' pneumoconiosis, berylliosis, hard metal disease, silicate pneumoconiosis, diatomaceous earth pneumoconiosis, carborundum pneumoconiosis, and corundum pneumoconiosis. Typical occupations associated with the diagnosis of MDP include metal miners, quarry workers, foundry workers, pottery and ceramics workers, and stonemasons. Irregular opacities are the major radiographic findings in MDP (ILO 1980), in contrast to silicosis, in which small rounded opacities predominate. Clinical symptoms of MDP are nonspecific. MDP must be distinguished from a variety of nonoccupational interstitial pulmonary disorders.

Pulmonary blastoma: medium-term results from a regional center.

BACKGROUND: Pulmonary blastomas are rare lung tumors that morphologically resemble fetal pulmonary structure and can exist in two forms, biphasic and monophasic. We reviewed our experience over a 12-year period with emphasis on the clinical features, management, and outcome. METHODS: Patients with a diagnosis of pulmonary blastoma from January 1988 to July 1999 were identified from the database of the Department of Histopathology, Llandough Hospital, Cardiff. Specimens had been obtained from bronchoscopy, fine-needle aspiration, trucut biopsy, and thoracotomy. RESULTS: Six patients were identified from 2,720 histologically proven lung cancers (0.2%). Median age was 35.5 years and sex ratio was equal. Overall, 4 patients underwent resection and are all alive (median, 43.5 months). Three of these had advanced tumors at presentation (stage IIIb or IV), two of which were successfully downstaged with neoadjuvant chemotherapy, and the third treated with postoperative radiotherapy. Nonresected cases succumbed at a median of 5.5 months. CONCLUSIONS: Although pulmonary blastomas are rare, those affected represent a group of patients with advanced tumors for whom a coordinated approach from both oncologists and surgeons can achieve excellent medium-term results.