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Aims Methods and results Conclusions BRCA1‐associaed protein‐1 (BAP1) inactivated tumours (BIMT) are rare melanocytic tumours that may be mistaken for Spitz tumours or melanoma. They occur sporadically or in association with the BAP1 tumour predisposition syndrome (BAP1–TPDS), which may be complicated by uveal or cutaneous melanoma, mesothelioma, basal cell carcinoma and renal cell carcinoma. The aim of this study was to characterise the clinicopathological features and the immunohistochemical expression pattern of preferentially expressed antigen in melanoma (PRAME) of BIMT in a large patient cohort.Ethical approval was obtained, haematoxylin and eosin‐stained slides were reviewed, PRAME immunohistochemistry was performed and clinical follow‐up was obtained from patient records. Sixty‐five BIMT from 38 patients (F:M = 4.4:1) were identified. BIMT were typically located on the trunk and head and neck (median size = 0.5 cm). Seven patients with BAP1–TPDS (range = 16–66 years, median = 25) had multiple BIMT (median = 5), while sporadic BIMT were solitary (median patient age = 39 years). One of seven patients with BAP1–TPDS developed additional malignancies (mesothelioma and cutaneous spindle cell melanoma) and died of complications of mesothelioma. All other patients are alive without recurrence of BIMT (median follow‐up = 42 months). BIMT presented as intradermal, nodular aggregates of epithelioid melanocytes with low mitotic activity and moderate to severe cytological atypia in 63% of cases. A background conventional naevus was present in 64%. PRAME immunohistochemistry showed negative or weakly patchy positive staining in all BIMT.BIMT are more common in a sporadic setting and behave indolently, despite worrying cytological atypia. PRAME immunohistochemistry is a reassuring tool in distinguishing BIMT from melanoma. [ABSTRACT FROM AUTHOR]

Aims: Mesothelioma is a rare malignancy of the serosal membranes that is commonly related to exposure to asbestos. Despite extensive research and clinical trials, prognosis to date remains poor. Consistent, comprehensive and reproducible pathology reporting form the basis of all future interventions for an individual patient, but also ensures that meaningful data are collected to identify predictive and prognostic markers. Methods and results: This article details the International Collaboration on Cancer Reporting (ICCR) process and the development of the international consensus mesothelioma reporting data set. It describes the 'core' and 'non‐core' elements to be included in pathology reports for mesothelioma of all sites, inclusive of clinical, macroscopic, microscopic and ancillary testing considerations. An international expert panel consisting of pathologists and a medical oncologist produced a set of data items for biopsy and resection specimens based on a critical review and discussion of current evidence, and in light of the changes in the 2021 WHO Classification of Tumours. The commentary focuses particularly upon new entities such as mesothelioma in situ and provides background on relevant and essential ancillary testing as well as implementation of the new requirement for tumour grading. Conclusion: We recommend widespread and consistent implementation of this data set, which will facilitate accurate reporting and enhance the consistency of data collection, improve the comparison of epidemiological data, support retrospective research and ultimately help to improve clinical outcomes. To this end, all data sets are freely available worldwide on the ICCR website (www.iccr‐cancer.org/data‐sets). [ABSTRACT FROM AUTHOR]

Aim: Diagnosis of mesothelioma in situ (MIS) is historically controversial and, until recently, specific features defining the entity have not been well characterized. Most reported cases of MIS occurred in the pleura; peritoneal MIS is very rare. This study investigates the morphologic features and results of ancillary testing in peritoneal MIS. Methods: We present three patients with peritoneal MIS, as defined by a single layer of mesothelial cells with loss of nuclear BRCA‐1‐associated protein‐1 (BAP1) immunostaining and without evidence of invasive tumour by microscopic evaluation, imaging, or direct examination of the peritoneum. Histology and immunostains were reviewed by three expert thoracic pathologists with multidisciplinary input. Next‐generation sequencing (NGS) was performed in all three cases. A literature review was conducted to characterize this rare precursor lesion. Results: BAP1 was lost in all three lesions, while methylthioadenosine phosphorylase (MTAP) was retained in two (not performed in the third). NGS revealed BAP1 pathogenic alterations in all three cases as well as mutations of SMO, ERCC3, TET2, and U2AF1. Progression to invasive mesothelioma occurred in one patient at 13 months postdiagnosis (case 1). One patient was diagnosed at age 24 and was later found to harbour a BAP1 germline mutation (case 3). Conclusion: This work describes the histologic features and clinicopathologic characteristics of peritoneal MIS in three cases, highlights BAP1 somatic and germline mutations in peritoneal MIS, and strengthens the importance of ancillary studies (including immunohistochemical and molecular studies) in the diagnosis of MIS. [ABSTRACT FROM AUTHOR]

Mesothelioma is a rare disease with an historically poor prognosis. Over the past decade, a grading system has been developed that is a powerful prognostic tool in epithelioid mesothelioma. Grading of epithelioid mesothelioma is now required or strongly recommended by expert consensus, the College of American Pathologists, the World Health Organization, and the International Mesothelioma Interest Group. The original nuclear grading system for epithelioid mesothelioma, developed in the United States, split epithelioid mesotheliomas into three prognostic groups with marked differences in survival. Now, this three‐tiered nuclear grading system has been combined with the presence or absence of necrosis to form the currently recommended two‐tiered grading system of low‐ and high‐grade epithelioid mesothelioma. This review will focus on the development of this grading system in mesothelioma, the grading system's shortcomings, and the application of the grading system to cytology specimens and other extra‐pleural sites. Lastly, this review will briefly discuss alternative grading systems and future considerations. [ABSTRACT FROM AUTHOR]

Aims: Mesothelin (MSLN) is a cancer‐associated antigen that is overexpressed in malignancies such as mesothelioma, pancreatic and ovarian cancer. It is also a target for novel personalised therapies, including antibodies, antibody–drug conjugates and chimeric antigen receptor T cells. Immunohistochemistry may predict those who would best respond to anti‐mesothelin therapies and guide decisions in therapeutic strategy. This study aimed to assess the intensity and distribution of MSLN immunostaining in mesothelioma, and to determine the prognostic value of MSLN expression by histochemical‐score (H‐score). Methods and results: The MN1 anti‐MSLN antibody was used to stain a formalin‐fixed paraffin‐embedded tissue microarray of histologically confirmed mesothelioma from 75 consecutive patients who had undergone pleurectomy with or without decortication. MSLN positivity, the staining intensity, distribution of staining and H‐score were evaluated. The correlation of H‐score with prognosis was investigated. Sixty‐six per cent of epithelioid tumours were MSLN‐positive (with expression in > 5% tumour cells). Of MSLN‐expressing epithelioid tumours, 70.4% had moderate (2+) or strong (3+) intensity MSLN immunostaining, although only 37% of samples had staining in ≥ 50% of tumour cells. In multivariate analysis, MSLN H‐score as a continuous variable and an H‐score ≥ 33 were independent predictors of improved survival (P = 0.04 and P < 0.001, respectively). Conclusions: MSLN expression was more heterogenous in epithelioid mesothelioma than reported previously. Therefore, it would be appropriate to perform an immunohistochemical assessment of MSLN expression to stratify and assess patient suitability for mesothelin‐targeted personalised therapies, such as chimeric antigen receptor T cells. [ABSTRACT FROM AUTHOR]

Separation of mesothelioma from metastatic carcinoma requires immunohistochemical support, with small batteries of stains recommended as a starting‐point, but these numbers commonly expand to 10, 12 or more stains, a process that is not only expensive but frequently generates anomalous or confounding results, leading to even more stains. Here we review data on HEG1 clone SKM9‐2, a new (now commercially available) mesothelioma marker and claudin‐4, a broad‐spectrum carcinoma marker, to ask whether these two stains are sufficient, by themselves, to separate mesotheliomas from non‐small‐cell lung (NSCLC) as well as other carcinomas. Data for HEG1, derived from four laboratories, showed membrane staining in 393 of 434 (91%) epithelioid/biphasic mesotheliomas and one of 360 (0.3%) NSCLC (sensitivity 91%, specificity 99.7%). Reports from seven laboratories evaluating claudin‐4 in NSCLC showed positivity in 469 of 502 (93%) carcinomas and weak positivity in five of 463 (1.0%) epithelioid/biphasic mesotheliomas (sensitivity 93%, specificity 98.9%). Comparable results were found with carcinomas from other sites, except for serous and thyroid carcinomas, some of which react with HEG1 but are also positive for claudin‐4. For sarcomatoid mesotheliomas, HEG1 sensitivity is modest and staining sometimes difficult to interpret. We hypothesise that the combination of HEG1 and claudin‐4 immunostaining will potentially allow the separation of epithelioid/biphasic mesotheliomas from NSCLC carcinomas with high accuracy using only two immunostains in most cases. This combination will probably also work for carcinomas from most other sites, but more reports on HEG1 SKM9‐2 staining of carcinomas other than NSCLC are needed. This approach would greatly simplify the diagnosis of mesothelioma. [ABSTRACT FROM AUTHOR]

This document is a correspondence discussing the time requirements for diagnosing mesothelioma in situ (MIS). The author explains that the original description of MIS included a requirement for no invasive tumor diagnosed within 1 year to ensure that the morphology observed was not just a surface spread of an existing invasive mesothelioma. However, the author argues that with the use of modern techniques and a better understanding of the microscopic appearance of MIS, a time delay is not necessary for making a formal diagnosis. The author emphasizes the importance of conveying to clinicians that MIS has a high likelihood of progressing to invasion and that further workup and therapy are required. The author also acknowledges that some cases showing MIS on biopsy may have a synchronous invasive mesothelioma elsewhere in the pleural or peritoneal cavity, and suggests that evidence of progression, such as radiologic change, strongly suggests invasive disease. The author concludes by stating that patients with a biopsy diagnosis of MIS always need further investigation. [Extracted from the article]

Adenocarcinomas of the rete testis (ACRT) are rare and aggressive testicular neoplasms that present predominantly in older men and have a tendency for early systemic spread. Their morphology spans a wide spectrum, including tumors with glandular, solid, papillary, micropapillary, glomeruloid, cribriform, and sarcomatoid growth patterns, or a combination thereof. The genomic alterations associated with these tumors have not been studied previously. We assessed eight ACRT published in prior clinicopathologic series using a solid tumor DNA sequencing panel. Pathogenic variants were identified in 6/8 cases. More specifically, four cases demonstrated inactivation of genes involved in cell cycle regulation, including CDKN2A, BAP1, TP53, and RB1. CDKN2A was the only recurrently affected gene, with pathogenic variants detected in 3/8 cases. One of these three cases had molecular evidence of concurrent homozygous (i.e. biallelic) NF2 inactivation by a frameshift variant and loss of the wildtype copy of the gene. One case had an internal tandem duplication in AKT, which has been previously described in juvenile granulosa cell tumor and sclerosing pneumocytoma and results in downstream activation of PI3K signaling. The remaining case with positive molecular findings harbored two concurrent truncating SETD2 variants. Multiple arm‐level and chromosome‐level copy number events were present in 3/8 cases, all of which harbored variants in genes involved in cell cycle regulation. In summary, ACRT are rare tumors with frequent inactivation of genes that play a major role cell cycle regulation, and a subset harbors variants that are potentially amenable to targeted therapy. [ABSTRACT FROM AUTHOR]

Aims: Malignant mesothelioma (MM) of the tunica vaginalis (TV) is a rare and aggressive tumour, and the molecular features and staining profile with contemporary immunohistochemical (IHC) biomarkers are largely unexplored. We characterise the clinicopathological, molecular and IHC features of MM (n = 13) and mesothelial neoplasms of uncertain malignant potential (MUMP) (n = 4). Methods and results: Targeted next‐generation sequencing was performed on seven MMs and two MUMPs. IHC was performed for methylthioadenosine phosphorylase (MTAP), BRCA1‐associated protein 1 (BAP1) and SRY‐box transcription factor 6 (SOX6). Thirteen adenomatoid tumours were also assessed with SOX6. MM were epithelioid (seven of 13) or biphasic (six of 13). In MM, NF2 (five of seven; 71%), CDKN2A (three of seven; 43%) and BAP1 (two of seven; 29%) were most frequently altered. Non‐recurrent driver events were identified in PTCH1 and TSC1. In contrast, none of these alterations were identified in MUMPs; however, one MUMP harboured a TRAF7 missense mutation. By IHC, loss of MTAP (two of 12; 17%) and BAP1 (two of nine; 22%) was infrequent in MM, whereas both were retained in the MUMPs. SOX6 was positive in nine of 11 (82%) MMs and negative in all MUMPs and adenomatoid tumours. Conclusions: Testicular MM exhibit a similar mutational profile to those of the pleura/peritoneum; however, alterations in CDKN2A and BAP1 are less common. These findings suggest that although MTAP and BAP1 IHC are specific for MM, their sensitivity in testicular MMs appears lower. In addition, rare tumours may harbour targetable alterations in driver genes (PTCH1 and TSC1) that are unusual in MMs at other anatomical sites. SOX6 is sensitive for MM; accordingly, the presence of SOX6 expression argues against a benign neoplastic process. [ABSTRACT FROM AUTHOR]

Aims: Malignant mesothelioma (MM) of the tunica vaginalis (TV) is a rare and aggressive tumour, and the molecular features and staining profile with contemporary immunohistochemical (IHC) biomarkers are largely unexplored. We characterise the clinicopathological, molecular and IHC features of MM (n = 13) and mesothelial neoplasms of uncertain malignant potential (MUMP) (n = 4). Methods and results: Targeted next‐generation sequencing was performed on seven MMs and two MUMPs. IHC was performed for methylthioadenosine phosphorylase (MTAP), BRCA1‐associated protein 1 (BAP1) and SRY‐box transcription factor 6 (SOX6). Thirteen adenomatoid tumours were also assessed with SOX6. MM were epithelioid (seven of 13) or biphasic (six of 13). In MM, NF2 (five of seven; 71%), CDKN2A (three of seven; 43%) and BAP1 (two of seven; 29%) were most frequently altered. Non‐recurrent driver events were identified in PTCH1 and TSC1. In contrast, none of these alterations were identified in MUMPs; however, one MUMP harboured a TRAF7 missense mutation. By IHC, loss of MTAP (two of 12; 17%) and BAP1 (two of nine; 22%) was infrequent in MM, whereas both were retained in the MUMPs. SOX6 was positive in nine of 11 (82%) MMs and negative in all MUMPs and adenomatoid tumours. Conclusions: Testicular MM exhibit a similar mutational profile to those of the pleura/peritoneum; however, alterations in CDKN2A and BAP1 are less common. These findings suggest that although MTAP and BAP1 IHC are specific for MM, their sensitivity in testicular MMs appears lower. In addition, rare tumours may harbour targetable alterations in driver genes (PTCH1 and TSC1) that are unusual in MMs at other anatomical sites. SOX6 is sensitive for MM; accordingly, the presence of SOX6 expression argues against a benign neoplastic process. [ABSTRACT FROM AUTHOR]

Aims: Methylthioadenosine phosphorylase (MTAP) immunohistochemical expression is a specific marker of CDKN2A deletion in malignant mesothelioma. However, the relationship of MTAP expression with MTAP copy number remains unexplored. Methods and results: Forty malignant pleural mesotheliomas were characterised by targeted next‐generation sequencing (29), single‐nucleotide polymorphism microarray (seven), or both (four). MTAP and CDKN2A copy numbers were correlated with MTAP expression. Twenty‐seven (68%) tumours showed CDKN2A deletion (14 heterozygous; 13 homozygous), of which 20 (74%) showed MTAP codeletion (15 heterozygous; five homozygous). No tumours showed MTAP deletion without CDKN2A codeletion. Loss of MTAP expression was seen in 16 (40%) tumours, and was 75% sensitive and 95% specific for MTAP deletion, and 59% sensitive and 100% specific for CDKN2A deletion. Nine of 40 (23%) tumours showed heterogeneous MTAP staining, and the percentage of tumour cells with MTAP loss correlated with molecular detection of MTAP deletion. Conclusions: MTAP is frequently codeleted with CDKN2A in pleural mesothelioma. However, homozygous deletion of both genes occurs in a minority of tumours (5/40; 13%); CDKN2A deletion often co‐occurs with heterozygous MTAP deletion or neutral MTAP copy number; and MTAP expression correlates inconsistently with heterozygous MTAP deletion. Correspondingly, MTAP immunohistochemistry is a highly specific but only moderately sensitive assay for CDKN2A deletion. [ABSTRACT FROM AUTHOR]

Aims: Nuclear grade has been recently validated as a powerful prognostic tool in epithelioid malignant pleural mesothelioma (E‐MPM). In other studies histological parameters including pleomorphic features and growth patterns were also shown to exert prognostic impact. The primary aims of our study are (i) externally validate the prognostic role of pleomorphic features in E‐MPM and (ii) investigate if evaluating growth pattern in addition to 2‐tier nuclear grade improves prognostication. Methods and results: 614 consecutive cases of E‐MPM from our institution over a period of 15 years were retrospectively reviewed, of which 51 showed pleomorphic features. E‐MPM with pleomorphic features showed significantly worse overall survival compared to those without (5.4 versus 14.7 months). Tumours with predominantly micropapillary pattern showed the worst survival (6.2 months) followed by solid (10.5 months), microcystic (15.3 months), discohesive (16.1 months), trabecular (17.6 months) and tubulo‐papillary (18.6 months). Sub‐classification of growth patterns into high grade (solid, micropapillary) and low grade (all others) led to good separation of overall survival (10.5 versus 18.0 months) but did not predict survival independent of 2‐tier nuclear grade. A composite score comprised of growth pattern and 2‐tier nuclear grade did not improve prognostication compared with nuclear grade alone. Intra‐tumoural heterogeneity in growth patterns is ubiquitous. Conclusions: Our findings support the incorporation of E‐MPM with pleomorphic features in the epithelioid subtype as a highly aggressive variant distinct from 2‐tier nuclear grade. E‐MPM demonstrates extensive heterogeneity in growth pattern but its evaluation does not offer additional prognostic utility to 2‐tier nuclear grade. [ABSTRACT FROM AUTHOR]

Aims: Malignant pleural mesothelioma (MPM) is a rare malignancy with a dismal prognosis. While the epithelioid type is associated with a more favourable outcome, additional factors are needed to further stratify prognosis and to identify patients who can benefit from multimodal treatment. As epithelioid MPM shows remarkable morphological variability, the prognostic role of the five defined morphologies, the impact of the nuclear grading system and the mitosis‐necrosis score were investigated in this study. Methods and results: Tumour specimens of 192 patients with epithelioid MPM from five European centres were histologically subtyped. Nuclear grading and mitosis–necrosis score were determined and correlated with clinicopathological parameters and overall survival (OS). Digital slides of 55 independent cases from The Cancer Genome Atlas (TCGA) database were evaluated for external validation. Histological subtypes were collapsed into three groups based on their overlapping survival curves. The tubulopapillary/microcystic group had a significantly longer OS than the solid/trabecular group (732 days versus 397 days, P = 0.0013). Pleomorphic tumours had the shortest OS (173 days). The solid/trabecular variants showed a significant association with high nuclear grade and mitosis–necrosis score. The mitosis–necrosis score was a robust and independent prognostic factor in our patient cohort. The prognostic significance of all three parameters was externally validated in the TCGA cohort. Patients with tubulopapillary or microcystic tumours showed a greater improvement in OS after receiving multimodal therapy than those with solid or trabecular tumours. Conclusions: Histological subtypes of epithelioid MPM have a prognostic impact, and might help to select patients for intensive multimodal treatment approaches. [ABSTRACT FROM AUTHOR]

Stromal tumour-infiltrating lymphocytes (TILs) assessed using the ITWG system do not predict overall survival in a cohort of 337 cases of mesothelioma Keywords: International TILs Working Group; mesothelioma; tumour-infiltrating lymphocytes (TILs) EN International TILs Working Group mesothelioma tumour-infiltrating lymphocytes (TILs) 1095 1101 7 06/04/20 20200601 NES 200601 I Sir i : Assessment of tumour-infiltrating lymphocytes (TILs) is a subject of considerable interest, as accumulating evidence supports its prognostic value in a range of different malignancies.[[1]] With the ever-increasing use of immunotherapeutic agents, TILs, together with other components of the tumour microenvironment, present an opportunity to identify patients who are most likely to respond to these agents. In conclusion, we were unable to demonstrate a statistically significant association between stromal TILs, scored using the ITWG methodology, and overall survival in our cohort of 337 mesothelioma patients. Assessment of tumor infiltrating lymphocytes using International TILs Working Group (ITWG) system is a strong predictor of overall survival in colorectal carcinoma - a study of 1034 patients. [Extracted from the article]

Aims: The process of differential diagnosis between epithelioid mesothelioma and lung adenocarcinoma has been progressing; however, there are no absolute immunohistochemical markers with which to definitively diagnose epithelioid mesothelioma. The aim of this study was to search for a novel negative marker of epithelioid mesothelioma. Methods and results: We immunohistochemically studied the applicability of mucin 21 (MUC21), which was identified in our previous study, as a novel, negative diagnostic marker for epithelioid mesothelioma. Seventy epithelioid mesotheliomas and 70 lung adenocarcinomas were investigated for the expression of MUC21, along with other previously reported markers, by the use of immunohistochemistry. MUC21 was expressed in only two of the 70 (3%) epithelioid mesotheliomas, as compared with 67 of the 70 (96%) lung adenocarcinomas. The sensitivity, specificity and accuracy of negative MUC21 expression for differentiating epithelioid mesothelioma from lung adenocarcinoma were 97%, 96%, and 96%, respectively; these are similar to those of carcinoembryonic antigen and claudin‐4, and better than those of thyroid transcription factor‐1, napsin‐A, and mucin 4. Conclusion: MUC21 could be used as an additional, novel, negative immunohistochemical marker to differentiate mesothelioma from lung adenocarcinoma. [ABSTRACT FROM AUTHOR]

Aims: The existence of malignant mesothelioma in situ (MIS) is often postulated, but there are no accepted morphological criteria for making such a diagnosis. Methods and results: Here we report two cases that appear to be true MIS on the basis of in‐situ genomic analysis. In one case the patient had repeated unexplained pleural unilateral effusions. Two thoracoscopies 9 months apart revealed only visually normal pleura. Biopsies from both thoracoscopies showed only a single layer of mildly reactive mesothelial cells. However, these cells had lost BRCA1‐associated protein 1 (BAP1) and showed loss of cyclin‐dependent kinase inhibitor 2 (CDKN2A) (p16) by fluorescence in‐situ hybridisation (FISH). NF2 was not deleted by FISH but 28% of the mesothelial cells showed hyperploidy. Six months after the second biopsy the patient has persisting effusions but no evidence of pleural malignancy on imaging. The second patient presented with ascites and minimal omental thickening on imaging, but no visual evidence of tumour at laparoscopy. Omental biopsy showed a single layer of minimally atypical mesothelial cells with rare tiny foci of superficial invasion of fat. BAP1 immunostain showed loss of nuclear BAP1 in all the surface mesothelial cells and the invasive cells. There was CDKN2A deletion, but no deletion of NF2 by FISH. Conclusions: These cases show that morphologically bland single‐layered surface mesothelial proliferations with molecular alterations seen previously only in invasive malignant mesotheliomas exist, and presumably represent malignant MIS. More cases are need to understand the frequency of such changes and the time–course over which invasive tumour develops. [ABSTRACT FROM AUTHOR]

Aims: High mobility group box 1 (HMGB1) is a chromatin structural protein, expressed ubiquitously in the nuclei of mammalian cells. When transported extracellularly, it acts as a tumour suppressor and oncogenic protein. In malignant pleural mesothelioma (MPM), high serum levels of HMGB1 have been related to a poor prognosis. Conversely, the significance of HMGB1 expression in MPM tissues is still unclear. Methods and results: Biopsy samples from 170 patients with MPM were assessed by immunohistochemistry and reverse transcription–polymerase chain reaction (RT–PCR) to evaluate HMGB1 protein and gene expression. The expression level of HMGB1 protein was scored using a semiquantitative system that sums the intensity (0–3) and the percentage (from 0 to 4) of positively stained cells in nuclei, cytoplasm and in both. The final score was considered as high (>3) or low (<3) expression. Gene expression levels were calculated using the ΔΔCt method. High expression levels of HMGB1 as total (P = 0.0011) and cytoplasmic score (P = 0.0462) were related to a worse disease‐specific survival (DSS) in the entire cohort and in the clinicopathological subgroups. No significant correlation was found between HMGB1 gene expression and DSS. Conclusions: These findings indicate that HMGB1 may be a useful prognostic biomarker in MPM when detected by immunohistochemistry. Conversely, as it is also expressed in normal and reactive mesothelial cells, HMGB1 cannot be considered a diagnostic biomarker in histological samples of mesothelioma. [ABSTRACT FROM AUTHOR]

Aims: Mesothelioma is a relatively uncommon but highly malignant neoplasm. Most patients die of disease within 1 year of diagnosis, but some have prolonged survival. Prospective identification of these longer‐term survivors may help to guide treatment. We therefore sought to investigate the role of p16 immunohistochemistry (IHC) both alone and in combination with other markers as a potential predictor of prolonged survival in mesothelioma. Methods and results: P16 IHC was performed on unselected pleural mesotheliomas biopsied from 1991 to 2014; 153 of 208 (74%) cases were p16‐negative, which correlated significantly with poor overall survival in both univariate (median survival 7.6 versus 13.6 months; P = 0.001) and multivariate analysis [hazard ratio (HR): 1.632; 95% confidence interval (CI): 1.103–2.415; P = 0.014]. Other independent factors associated with prolonged survival included loss of expression of BAP1 and epithelioid morphology. We therefore stratified patients further based on these three independent prognostic variables and demonstrated an unusually prolonged survival in mesotheliomas which were epithelioid, BAP1 IHC negative and p16 IHC positive (12% of cases, median survival 31.7 months, P < 0.0001). Conclusions: In conclusion, p16 IHC is an independent prognostic biomarker in pleural mesothelioma. When used in combination with BAP1 IHC and morphological subtyping, patients with exceptionally prolonged survival can potentially be identified. [ABSTRACT FROM AUTHOR]

Aims Malignant mesothelioma is a highly aggressive cancer that is usually diagnosed at advanced stages; thus, highly sensitive and specific markers are necessary for its early definitive diagnosis. The aim of this study was to evaluate the diagnostic utility and prognostic significance of BAP1 and EZH2 in malignant mesothelioma. Methods and results The expression of BAP1 and EZH2 was investigated by immunohistochemistry in 32 malignant mesotheliomas and 44 benign mesothelial proliferative lesions, including well-differentiated papillary mesothelioma ( n = 4), mesothelial inclusion cyst ( n = 22), and reactive mesothelial hyperplasia ( n = 18). BAP1 loss and high EZH2 expression were observed in 17 (53%) and 22 (66%) malignant mesothelioma cases, respectively, whereas none of the benign lesions showed BAP1 loss or high EZH2 expression. The combination of BAP1 loss and high EZH2 expression as markers to differentiate epithelioid/biphasic malignant mesothelioma from benign mesothelial lesions was highly sensitive (90%) and specific (100%). There were no statistically significant associations between parameters such as age and sex of patients, tumour location, asbestos exposure, treatment, histology, and BAP1 or EZH2 expression. Survival analysis revealed that BAP1 loss, but not high EZH2 expression, was associated with a better prognosis. Conclusions BAP1 loss and high EZH2 expression were highly specific to malignant mesothelioma in differentiating it from benign mesothelial proliferations, and the combination of these two markers improved the diagnostic accuracy. [ABSTRACT FROM AUTHOR]

Aims The aims of this study were to clarify the usefulness of immunohistochemistry in the differential diagnosis of epithelioid mesothelioma with a solid growth pattern [solid epithelioid mesothelioma ( SEM)] and poorly differentiated squamous cell carcinoma ( PDSCC), and to confirm the validity of a specific type of antibody panel. Additionally, we aimed to clarify the pitfalls of immunohistochemical analyses. Methods and results Formalin-fixed paraffin-embedded specimens from 36 cases of SEM and 38 cases of PDSCC were immunohistochemically examined for calretinin, podoplanin (D2-40), Wilms' tumour gene product ( WT1), cytokeratin ( CK) 5/6, p40, p63, carcinoembryonic antigen ( CEA), epithelial-related antigen ( MOC31), claudin-4, thyroid transcription factor-1 ( TTF-1), and napsin A. WT1 showed the highest diagnostic accuracy (85.1%) as a mesothelial marker, and CEA, p40 and claudin-4 showed higher diagnostic accuracies (95.9%, 94.6%, and 93.2%, respectively) as carcinoma markers. Calretinin (diagnostic accuracy: 75.7%), D2-40 (diagnostic accuracy: 67.6%), CK5/6 (diagnostic accuracy: 63.5%), TTF-1 (diagnostic accuracy: 55.4%) and napsin A (diagnostic accuracy: 52.7%) could not differentiate between SEM and PDSCC. Among these markers, the combination of calretinin and WT1 showed the highest diagnostic accuracy (86.5%) as a positive marker, and the combination of p40 and CEA showed the highest diagnostic accuracy (97.3%) as a negative marker. The combination of CEA and claudin-4 also showed relatively high diagnostic accuracy (94.6%) as a negative marker. Conclusions We recommend the combination of WT1 and calretinin as a positive maker, and the combination of CEA and claudin-4 as a negative marker, for differential diagnoses of SEM and PDSCC. [ABSTRACT FROM AUTHOR]

Aims The prognostic significance of histological subtyping of epithelioid pleural mesotheliomas has been recently reported, but similar data are lacking for peritoneal mesotheliomas. The aim of this study was to investigate possible relationships between histological growth patterns of epithelioid peritoneal mesotheliomas, clinicopathological features, and patient outcome. Methods and results Eighty-four cases of chemotherapy-naive epithelioid peritoneal mesothelioma were classified into tubulopapillary, micropapillary, papillary, tubular, solid and trabecular growth patterns. Pathological features such as depth of invasion, lymphocytic host response, mitotic count, nuclear grade, lymphovascular invasion, lymph node metastasis and stromal desmoplasia were analysed. The most common histological patterns were solid ( n = 37, 44%), tubulopapillary ( n = 24, 29%), and micropapillary ( n = 11, 13%). The overall median survival was 36 months. Patients with solid mesothelioma had shorter overall survival (median, 29 months) than patients with tubulopapillary and micropapillary growth patterns (median, 51 and 53 months, respectively; P = 0.053). A high mitotic index (>5 in 50 high-power fields) was found to be associated with poor survival ( P < 0.03). A moderate to severe lymphocytic host response was associated with longer median survival ( P = 0.13). Conclusions Our study highlights the prognostic importance of the solid growth pattern among diffuse epithelioid peritoneal mesotheliomas, and reaffirms mitotic index as a predictor of overall survival. [ABSTRACT FROM AUTHOR]

Aims To report a case of paediatric malignant peritoneal mesothelioma ( MPM) with evidence of anaplastic lymphoma kinase ( ALK) translocation. Methods and results We describe a 10-year-old girl who presented with abdominal pain and progressive abdominal distension. She had no history of asbestos exposure. Histopathological, immunohistochemical and ultrastructural analyses were performed and showed a biphasic malignant mesothelioma. In addition, we also studied on a selected set of immunomarkers which may be the potential therapeutic molecular targets including ALK, c-kit ( CD117), epidermal growth factor receptor ( EGFR) and human epidermal growth factor 2 ( HER2)/ neu, as well as corresponding molecular analysis. Consequently, we identified ALK expression by immunohistochemistry, together with evidence of ALK translocation by fluorescent in-situ hybridization ( FISH) analysis. Conclusions Paediatric MPM is associated with ALK translocation in our case. The results may open up a new avenue for the study of molecular genesis of paediatric malignant mesothelioma in the future and help to determine whether patients MMs with ALK translocation would benefit from ALK inhibitor treatment. [ABSTRACT FROM AUTHOR]

Aims We hypothesized that asbestos exposure increases the incidence of macroscopically visible and histologically confirmed usual interstitial pneumonia (histological UIP). Methods and results We retrospectively examined 1718 cases (1202 males; mean age 66.7 years) who underwent lobectomy for resection of pleuropulmonary tumours. Objective markers for asbestos exposure included: the presence of malignant pleural mesothelioma, the presence of pleural plaques (PPs) and asbestos bodies in the histological specimen. Risk factors for histological UIP were examined. Two separate groups were studied: 183 with asbestos exposure, and 239 with histological UIP. The 183 cases with asbestos exposure had higher rates of positive occupational history and histological UIP (31%) than the remaining 1535. Among the asbestos-exposed group, small numbers of asbestos bodies were found in histological specimens of 21 cases of histological UIP. PPs and asbestos bodies were more frequent in the 239 patients with histological UIP than in the remaining 1479 UIP-negative patients. Multivariate analysis showed that asbestos exposure, especially positivity for asbestos bodies, that does not meet the current criteria for asbestosis increases the risk of histological UIP ( P < 0.0001). Conclusions Asbestos exposure causes asbestosis and increases the incidence of histological UIP. [ABSTRACT FROM AUTHOR]

Aims To present our experience with 18 cases of well-differentiated papillary mesothelioma ( WDPM), with an emphasis on its relationship to adenomatoid tumour and multicystic mesothelioma. Methods and results Eighteen cases of WDPM were retrieved. Twenty cases of multicystic mesothelioma were selected for comparative study. The WDPM patients comprised 14 females and four males, with age ranging from 18 to 60 years (median 37 years). The tumour involved the abdominal or pelvic peritoneum (14 cases), the pleura (two cases), and the testicular tunica vaginalis (two cases). The majority of WDPMs were incidental findings during surgery for a wide variety of conditions. Histologically, 13 cases were consistent with classical WDPM. Two cases had a combined component of adenomatoid tumour, and three cases contained coexisting areas of multicystic mesothelioma. Among the multicystic mesothelioma cases, four had adenomatoid tumour-like foci present in the stroma. Immunohistochemically, all cases of WDPM and multicystic mesothelioma, as well as the coexisting combined components, were positive for mesothelial markers, with a low Ki67 index. This study also showed that WDPM was negative for epithelial membrane antigen and desmin. Conclusions The simultaneous occurrence of WDPM, adenomatoid tumour and multicystic mesothelioma in some cases suggested histogenetic relationships among these three less aggressive mesotheliomas. [ABSTRACT FROM AUTHOR]

Aims: Malignant mesothelioma (MM) of the tunica vaginalis (TV) is a rare and aggressive tumour, and the molecular features and staining profile with contemporary immunohistochemical (IHC) biomarkers are largely unexplored. We characterise the clinicopathological, molecular and IHC features of MM (n = 13) and mesothelial neoplasms of uncertain malignant potential (MUMP) (n = 4)., Methods and Results: Targeted next-generation sequencing was performed on seven MMs and two MUMPs. IHC was performed for methylthioadenosine phosphorylase (MTAP), BRCA1-associated protein 1 (BAP1) and SRY-box transcription factor 6 (SOX6). Thirteen adenomatoid tumours were also assessed with SOX6. MM were epithelioid (seven of 13) or biphasic (six of 13). In MM, NF2 (five of seven; 71%), CDKN2A (three of seven; 43%) and BAP1 (two of seven; 29%) were most frequently altered. Non-recurrent driver events were identified in PTCH1 and TSC1. In contrast, none of these alterations were identified in MUMPs; however, one MUMP harboured a TRAF7 missense mutation. By IHC, loss of MTAP (two of 12; 17%) and BAP1 (two of nine; 22%) was infrequent in MM, whereas both were retained in the MUMPs. SOX6 was positive in nine of 11 (82%) MMs and negative in all MUMPs and adenomatoid tumours., Conclusions: Testicular MM exhibit a similar mutational profile to those of the pleura/peritoneum; however, alterations in CDKN2A and BAP1 are less common. These findings suggest that although MTAP and BAP1 IHC are specific for MM, their sensitivity in testicular MMs appears lower. In addition, rare tumours may harbour targetable alterations in driver genes (PTCH1 and TSC1) that are unusual in MMs at other anatomical sites. SOX6 is sensitive for MM; accordingly, the presence of SOX6 expression argues against a benign neoplastic process., (© 2022 John Wiley & Sons Ltd.)

The article presents abstracts on environmental pathology which include a study on exposure to particulate matter (PM) concentration in São Paulo, Brazil, "Arsenic—a beneficial therapeutic, an environmental poison, and a public health hazard" by J. A. Centeno, and "Peritoneal epithelioid mesothelioma: a case report" by H. Jean-Marie, G. Magg, and T. Olga.

Zimling Z G, Jørgensen A & Santoni-Rugiu E (2012) Histopathology 60, E96-E105 The diagnostic value of immunohistochemically detected methylthioadenosine phosphorylase deficiency in malignant pleural mesotheliomas Aims: Malignant pleural mesothelioma (MPM) often causes diagnostic difficulties for pathologists. We assessed whether loss of methylthioadenosine phosphorylase (MTAP), a key enzyme in the intracellular recycling of adenosine triphosphate (ATP) often deleted in MPM, could be detected with immunohistochemistry (IHC) and used as a diagnostic marker for MPM. Methods and results: We used IHC to detect MTAP in a cohort of 99 MPMs and 39 reactive mesothelial proliferations (RP) (reactive mesothelial hyperplasia n = 33, reactive pleural fibrosis n = 6). MTAP staining was assessed by an H score. The median H score of the RP cohort was set as a reference point. Cases with H scores below this reference point were considered to have decreased MTAP expression. We found that 64 of 99 (65%) of the investigated MPMs had decreased MTAP expression, while this was only true for nine of 39 (23%) of the RPs ( P = 0.001). We further evaluated MTAP expression in a cohort of coagulated pleural effusions from 14 patients with MPM and 20 patients with RP by using a double-staining technique with Wilms tumour 1 (WT1) as a mesothelial marker. In these samples, decreased MTAP expression diagnosed MPM with a sensitivity of 71% and a specificity of 90%. Conclusions: Decreased MTAP expression could potentially be useful in combination with other markers in the diagnosis of MPM. [ABSTRACT FROM AUTHOR]

Powell G, Roche H & Roche W R (2011) Histopathology 59, 950-956 Expression of calretinin by breast carcinoma and the potential for misdiagnosis of mesothelioma Aims: Calretinin and cytokeratin (CK)5/6 are frequently used to differentiate between metastatic breast cancer and primary malignant mesothelioma in pleural biopsies, but both tumours may express these markers. This study was aimed at evaluating the frequency of calretinin expression in primary breast carcinomas, and assessing the characteristics of the calretinin-positive tumours. Methods and results: Fifty-three primary breast adenocarcinomas were analysed for immunohistochemical expression of calretinin. CK5/6 and epidermal growth factor receptor (EGFR) immunostaining were performed on the calretinin-positive subset. Tumours were classified as basal-like if they met standard morphological and immunohistochemical criteria. Fifteen per cent (8/53) of the breast tumours were positive for calretinin. Eighty-eight per cent (7/8) of the calretinin-positive tumours were grade 3, as compared with 20% (9/45) of the calretinin-negative tumours ( P < 0.001). Only 13% (1/8) of the calretinin-positive tumours were also oestrogen receptor (ER)-positive, as compared with 87% (39/45) of the calretinin-negative tumours ( P < 0.001). Eleven per cent (6/53) of the tumours were classified as basal-like. Of these, four were positive for calretinin and two were negative ( P = 0.003). Conclusions: Fifteen per cent of breast carcinomas stain with calretinin. These tumours are more likely to be high-grade, ER-negative, and display a basal-like phenotype. These tumours may be misdiagnosed as malignant mesothelioma when they metastasize to the pleura. [ABSTRACT FROM AUTHOR]

The article discusses several pulmonary pathology research including study of lung sirtuin and hystone deacetylase-2 expression in smokers, pulmonary neuroendocrine (NE) tumors and mesothelioma with prominent adenomatoid feature. Topics discussed include expression of sirtuin (SIRT) and hystone deacetylase- 2 (HDAC-2), immunohistochemical detection of FoxM and cases of adenomatoid malignant mesothelioma.

The article focuses on a study which assesses the usefulness of desmin and other myogenic markers in differentiating epithelioid mesothelioma (EM) from reactive mesothelial cell hyperplasia (RH) or reactive mesothelial cells (RMC). It notes that researchers grouped non-neoplastic mesothelial cells (NMCs) into three categories and used immunohistochemical analysis for tissue sections. It reveals that desmin immunoreactivity in NMCs was significantly higher compared to that in EMs.

Aims: The incidence of mesothelioma is increasing in Europe, Japan and other developing countries. There is difficulty in the accurate diagnosis of mesothelioma and its differentiation from lung adenocarcinoma. Mesothelioma shows a complex immunohistochemical profile. Therefore, the use of a immunohistochemical panel that includes both positive and negative mesothelial markers has become a general rule for its accurate diagnosis. However, they are still not sufficient. The aim was to assess the diagnostic utility of caveolin-1 (Cav-1), which is expressed in endothelial cells, alveolar type I pneumocytes and mesothelial cells, as a novel positive marker of mesothelioma. Methods and results: An immunohistochemical study of 80 cases of epithelioid mesothelioma and 80 cases of lung adenocarcinoma was performed for the analysis of the expression of Cav-1 and other markers. Cav-1 expression with a membranous and/or cytoplasmic pattern was found in all of the epithelioid mesothelioma. Of these, 42 cases (52.5%) showed Cav-1 expression in >50% of tumour cells, 34 cases (42.5%) in 6–50% of tumour cells, and four cases (5.0%) in <5% of tumour cells. In contrast, only six cases (7.5%) of lung adenocarcinoma showed focal Cav-1 expression in the cytoplasm of the tumour cells. The sensitivity and specificity of Cav-1 expression for the differentiation of epithelioid mesothelioma from lung adenocarcinoma were 100 and 92.5%, respectively. This is comparable or even superior to that of currently available positive markers such as calretinin or D2-40. Conclusions: Cav-1 is a novel immunohistochemical marker for the differentiation of epithelioid mesothelioma from lung adenocarcinoma. [ABSTRACT FROM AUTHOR]

Aims: The differential diagnosis of pleural sarcomatoid mesothelioma (SM) from lung sarcomatoid carcinoma (LSC) invading parietal pleura and chest wall is a challenging issue. The aim of this study was to identify useful antibodies that can be used for the differential diagnosis of pleural SM from LSC. Methods and results: Forty-five cases of pleural SM and 27 cases of LSC were immunohistochemically analysed by using 15 commercially available antibodies, including D2-40 and antibodies to calretinin, thrombomodulin, Wilms’ Tumour 1, carcinoembryonic antigen (CEA), Napsin A, thyroid transcription factor (TTF)-1, pan-cytokeratin, CAM5.2, epithelial membrane antigen, Ber-EP4, MOC-31, α-smooth muscle actin, h-caldesmon and desmin. The results revealed that D2-40 positivity was significantly higher in pleural SM (86.7%) than in LSC (25.9%). The positivity of the adenocarcinoma markers, including CEA, Napsin A, and TTF-1, was low even in LSC. Conclusions: Evaluating the positivity and degree of staining of the well-known mesothelial marker D2-40 could be applied to differentiate pleural SM from the sarcomatoid component of LSC, in addition to assessing clinical and radiological information. [ABSTRACT FROM AUTHOR]

Many centres are now seeing increasing numbers of patients with malignant mesothelioma. This presents pathologists involved in making the diagnosis with a number of problems, which can be divided into those encountered in making the distinction between mesothelioma and benign changes and those experienced in separating mesotheliomas from other types of epithelial and connective tissue tumours. Immunohistochemistry plays a major role in helping to make the diagnosis, but it should be interpreted with due regard to the clinical setting and radiological features, and with a knowledge of the wide morphological variations seen in mesothelioma. This review identifies some of these problems and addresses the uses and limitations of immunohistochemistry in different situations. It includes a discussion of some of the less common variants of mesothelioma and other pleural-based tumours that enter into the differential diagnosis. [ABSTRACT FROM AUTHOR]

Aims: To evaluate the diagnostic accuracy of closed and open pleural biopsies in diagnosing malignant pleural mesothelioma. Methods and results: The autopsy study group comprised 45 malignant mesotheliomas. All prior pleural biopsy investigations were reviewed. Forty-one of 45 (91%) had had an antemortem diagnosis of malignant mesothelioma. In these 41 cases, 57 prior diagnostic pleural biopsies had been performed [36 closed needle biopsies: 31 blind; five computed tomography (CT)-guided and 21 open pleural biopsies]. For definitive diagnosis open pleural biopsy yielded a sensitivity of 95% and specificity of 100%. For definitive diagnosis closed blind pleural biopsies yielded a sensitivity of 16% and specificity of 94%. Thirty-two per cent of ‘blind’ biopsies were inadequate. CT-guided pleural biopsies yielded a definitive diagnostic accuracy of 100% (5/5). Biopsy specimen size was important in obtaining a positive definitive diagnosis. Diagnosis was attained in 75% of specimens >10 mm in size compared with 8% <10 mm in size. Conclusions: Overall, all procedures had utility but definitive diagnostic accuracy for ‘blind’ closed pleural biopsy was low (16%), dependent on biopsy specimen size and tumour subtype. Sarcomatoid subtype malignant mesothelioma yielded the lowest diagnostic accuracy. For all subtypes of malignant mesothelioma, open pleural biopsy produced the highest diagnostic accuracy (100% sensitivity, 95% specificity). [ABSTRACT FROM AUTHOR]

Aims: To present eight cases of primary diffuse peritoneal malignant mesothelioma in children <15 years old, with a discussion of the pitfalls of this diagnosis in the paediatric age group. Methods and results: The cases were selected based on the following criteria: (i) primary peritoneal neoplasms confined grossly or radiographically to the abdominal cavity; (ii) negative history of previous or another associated malignancy; (iii) histopathological confirmation. All patients (five female, three male) presented clinically with symptoms of abdominal pain, distention and ascites. Grossly, the tumours showed multiple, diffuse peritoneal nodules. Histologically, seven cases corresponded to epithelioid mesotheliomas and one case displayed biphasic (epithelioid and spindle) cellular proliferation. Immunohistochemical studies for cytokeratin (CK) 5/6, calretinin and low-molecular-weight CK (CAM5.2) showed strong cytoplasmic positivity in the neoplastic cells. Three patients were treated by chemotherapy. On clinical follow-up, four patients with epithelioid mesotheliomas were alive and well from 12 to 18 months after initial diagnosis; one patient with a mixed (biphasic epithelioid/sarcomatoid) mesothelioma died of tumour 24 months after diagnosis. Conclusions: Peritoneal malignant mesothelioma in children is a rare condition that can introduce difficulties in histopathological diagnosis. [ABSTRACT FROM AUTHOR]

Aims: A systematic review of published reports that have evaluated the ability of immunohistochemistry and argyrophil nucleolar organizing region (AgNOR) staining to distinguish between benign and malignant pleural disease. Methods: Nineteen relevant papers published during the period 1979–2005 were identified. Individual results of immunohistochemistry for five diagnostic antibodies were extracted to calculate diagnostic sensitivity and specificity. Results from five of these studies that had evaluated proliferation markers or AgNOR staining techniques were also summarized. Results: Most antibodies demonstrated poor to moderate diagnostic ability. Desmin and epithelial membrane antigen (EMA) were the most useful, with sensitivity and specificity both above 74%. The combination of EMA and AgNOR was reported as having 95% diagnostic sensitivity. A high MCM2 labelling index also differentiated between benign and malignant pleural disease. Conclusions: Immunohistochemistry is of limited value, but newer diagnostic methods may be useful additions in this area of pathology. The diagnostic importance of histological features seen on plain tissue sections is emphasized as vital for correctly differentiating between benign pleural disease and malignant pleural mesothelioma. [ABSTRACT FROM AUTHOR]

Aims : Immunohistochemistry is frequently employed to aid the distinction between mesothelioma and pulmonary adenocarcinoma metastatic to the pleura, but there is uncertainty as to which antibodies are most useful. We analysed published data in order to establish sensitivity and specificity of antibodies used to distinguish between these tumours with a view to defining the most appropriate immunohistochemical panel to use when faced with this diagnostic problem. Methods and results : A systematic analysis of the results of 88 published papers comparing immunohistochemical staining of a panel of antibodies in mesothelioma with epithelioid areas, and pulmonary adenocarcinoma metastatic to the pleura. Results for a total of 15 antibodies were analysed and expressed in terms of sensitivity and specificity. The most sensitive antibodies for identifying pulmonary adenocarcinoma were MOC-31 and BG8 (both 93%), whilst the most specific were monoclonal CEA (97%) and TTF-1 (100%). The most sensitive antibodies to identify epithelioid mesothelioma were CK5/6 (83%) and HBME-1 (85%). The most specific antibodies were CK5/6 (85%) and WT1 (96%). Conclusions : No single antibody is able to differentiate reliably between these two tumours. The use of a small panel of antibodies with a high combined sensitivity and specificity is recommended. [ABSTRACT FROM AUTHOR]

The ovary is a common site of metastatic tumour. In many cases of ovarian metastasis there is a known history of malignancy but in other cases the ovarian tumour is the first manifestation of disease. In this review metastatic colorectal, appendiceal, gastric, breast, pancreatic and biliary tract, hepatocellular, renal, transitional and cervical carcinomas and metastatic malignant melanoma involving the ovary are discussed, as is the issue of synchronous ovarian and endometrial carcinomas. Peritoneal tumours, including primary peritoneal carcinoma, mesothelioma and intra-abdominal desmoplastic small round cell tumour, involving the ovary are also discussed, together with a variety of other rare, metastatic ovarian neoplasms. Many metastatic adenocarcinomas involving the ovary, especially those exhibiting mucinous differentiation, closely mimic primary ovarian adenocarcinomas with morphologically bland areas simulating benign and borderline cystadenoma. This is referred to as a maturation phenomenon. In recent years immunohistochemistry, especially but not exclusively differential cytokeratin (CK7 and CK20) staining, has been widely used as an aid to distinguish between a primary and secondary ovarian adenocarcinoma. While immunohistochemistry undoubtedly has a valuable role to play and is paramount in diagnosis in some cases, the results must be interepreted with caution, especially in mucinous tumours, and within the relevant clinical context. We feel the significance of differential cytoker attn staining is not always understood by histopathologists and this can result in erroneous interpretation. We critically discuss the value of immunohistochemistry and associated pitfalls with each tumour type described. [ABSTRACT FROM AUTHOR]

Attanoos R L&Gibbs A R(2004)Histopathology45,393–397The pathology associated with therapeutic procedures in malignant mesothelioma: To describe iatrogenic pathological lesions in malignant pleural mesothelioma.: All cases of malignant pleural mesothelioma confirmed by antemortem pleural biopsy and undergoing post mortem examination over a 7-year period (1995–2001) formed the study group. This comprised 48 malignant pleural mesotheliomas[epithelioid (n = 21), biphasic (n = 14) and sarcomatoid (n = 13)]. Twenty-eight of 48 (58%) had received chemical (talc) pleurodesis, 30/48 (63%) palliative localized radiotherapy, 6/48 (13%) chemotherapy, and 14/48 (30%) surgery[12/48 (26%) pleural decortication and 2/48 (4%) pleuropneumonectomy].: Talc pleurodesis induces a marked pseudosarcomatous fibroblastic proliferation which may impart a biphasic pattern to the neoplasm. In more chronic cases, paucicellular fibrosis with a foreign body giant cell reaction is noted. The talc is polarizable and deposited in linear fashion within the tumour. In 2/28 (7%) pleurodesis cases platyform ferruginous bodies were seen in the peripheral alveolated lung parenchyma and these mimicked asbestos bodies. An awareness of this is important to prevent false attribution to asbestos. Talc could be identified by transmission electron microscopic mineral analysis in 5/15 (33%) cases examined. Tumour nodules developing subjacent to iatrogenic wound sites were noted in 8/48 (17%) cases. In 6/8 (75%) of these cases, comparative assessment of the locally irradiated subcutaneous chest wall tumour, with background pleural mesothelioma, showed no morphological difference in architectural tumour growth pattern, extent of necrosis, cytological or nuclear pleomorphism, mitotic activity or tumour immunophenotype. In 2/8 (25%) cases the locally irradiated tumour showed prominent bizarre multinucleated tumour giant cells and intense mixed inflammation, a feature not seen in the background (non-irradiated) tumour. All six malignant pleural mesotheliomas receiving chemotherapy appeared refractory to treatment in that chemotherapy did not appear to have any significant effect on the tumour morphology, cytonuclear pleomorphism, mitotic activity, extent of necrosis or immunophenotype. In the 12 decortication specimens and two pleuropneumonectomy resections, post mortem examination identified evidence of residual malignant mesothelioma of similar morphological subtype and immunophenotype to the resected tumour. [ABSTRACT FROM AUTHOR]

Lumb P D & Suvarna S K (2004) Histopathology 44, 345–352 Metastasis in pleural mesothelioma. Immunohistochemical markers for disseminated disease To examine 13 cases of mesothelioma with metastases and compare these with 29 biopsy samples of patients without metastases. Metastatic disease was defined as tumour in which tumour appeared in a different cavity/tissue of the body and which showed no direct spread. Consequently, mediastinal nodal and parenchymal lung spread was excluded. Standard sections were prepared and stained according to the manufacturers' protocols. The antibodies used were MIB-1, nm23, Bcl-2, MMP-9, EMMPRIN (CD147) and α-catenin. Scoring employed a grading system (0/1/2/3), and was performed by two pathologists independently. The tissues revealed no significant staining differences for MIB-1, Bcl-2, MMP-9 or EMMPRIN, and therefore no linkage to metastatic potential was determined. α-Catenin showed a diminished level of expression in cases of metastatic mesothelioma ( P = 0.024), possibly reflecting dimished catenin–cadherin binding and paralleling data from other tumours. nm23 showed greater staining in metastatic tumours when compared with the controls ( P = 0.001). Intriguingly, the nm23 staining pattern was the reverse of that expected. This reversed pattern has been noted before in other tumours and therefore a biological prognostic event may exist for this antibody test and mesothelioma metastasis. There may be a place for nm23 and possibly α-catenin in immunohistochemical assessment of mesothelioma metastatic potential. However, MIB-1, Bcl-2, MMP-9 and EMMPRIN (CD147) do not show significant staining results. [ABSTRACT FROM AUTHOR]

Attanoos R L & Gibbs A R (2003) Histopathology 43, 444–452 ‘Pseudomesotheliomatous’ carcinomas of the pleura: a 10-year analysis of cases from the Environmental Lung Disease Research Group, Cardiff To undertake a clinicopathological study of diffuse serosal neoplasms of epithelial histogenesis which clinically and pathologically mimic malignant pleural mesothelioma. Over a 10-year (1990–2000) study period 53 carcinomas mimicking diffuse pleural mesothelioma (‘pseudomesotheliomatous’ carcinoma) were identified. The study group comprised 50 men and three females, age range 33–77 (median 68) years. In 46 (87%) cases there was a history of smoking and in 40 (76%) cases a history of asbestos exposure. Histologically the pleural ‘pseudomesotheliomatous’ carcinomas could be divided into two broad groups: primary pulmonary carcinomas with florid pleurotropic growth ( n = 47), of which 34 (70%) were adenocarcinomas; and diffuse carcinomatous involvement of the pleura by metastatic tumour ( n = 6). This latter group comprised two transitional cell carcinomas of bladder, one renal (clear) cell carcinoma, one ductal pancreatic adenocarcinoma, one prostatic adenocarcinoma and one squamous cell carcinoma of parotid gland origin. Follow-up data were available in 35 cases. Regardless of tumour type, survival was poor (median 8 months) and comparable to diffuse pleural mesothelioma. Pleural ‘pseudomesotheliomatous’ carcinomas are uncommon (comprising 6% of referrals), pathologically heterogeneous tumours with poor prognosis. Tissue diagnosis should be obtained in all cases of suspected diffuse pleural neoplasia. By light microscopy and immunophenotype many of the tumours mimicked malignant mesothelioma. In particular, an awareness that all neoplasms exhibiting squamous differentiation may express cytokeratin 5/6 and thrombomodulin is important to prevent misinterpretation. In this respect, calretinin is regarded as the most specific and sensitive mesothelial marker. Misdiagnosis may have medico–legal implications in asbestos-related compensation claims. [ABSTRACT FROM AUTHOR]