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Benign mesothelial tumors are rarer than malignant mesotheliomas and are often found in the peritoneum as incidental findings in women. They include the adenomatoid tumor (AT), the well-differentiated mesothelial tumor (WDPMT), the mesothelioma in situ (MIS), and the solid papillary mesothelial tumor (SPMT). ATs are always benign and predominantly manifest in the genital tract. WDPMTs can develop multifocally and are prone to recurrence, particularly in the case of incomplete resection. Only MISs are considered a confirmed precursor lesion of malignant mesothelioma according to the currently valid World Health Organization (WHO) classifications. As with malignant mesothelioma, alterations of BAP1, MTAP, and p16 are detectable for MIS in contrast to the other three tumors. SPMTs cannot be clearly assigned to the other mesothelial tumors and have so far only been described in the peritoneum in women with a benign course., (© 2024. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

The mesothelium, which consists of a monolayer of mesothelial cells, extends over the surface of the serosal cavities (pleura, pericardium, peritoneum and tunica vaginalis). Mesothelial tumours of the tunica vaginalis is rare compared with those arise from pleura or peritoneum. According to World Health Organization 2022 Classification of Urinary and Male Genital Tumours (5th edition), mesothelial tumours of the tunica vaginalis were categorized into adenomatoid tumour, well-differentiated papillary mesothelial tumour (WDPMT) and mesothelioma. Since WDPMT of tunica vaginalis was rare, there was no consensus concerning the treatment of it. In this case report, a 29-year-old man who had endured intermittent right scrotal pain for 8 months, aggravating scrotal pain for 2 weeks was admitted. No symptoms, such as frequent, urgent, or painful urination were shown. Physical examination revealed the enlargement and tenderness of right scrotum, with no signs of lifting pain. The most recent scrotal ultrasonography before surgery revealed right hydrocele with maximum depth of 4 centimeters and poor blood flow of right testis. Under the circumstance of patient' s chronic history of testicular hydrocele, he underwent an emergency operation of right scrotal exploration and hydrocelectomy under epidural anesthesia. After opening the vagina tunic cavity, spot-like bleeding was observed on the right testicle, epididymis and vaginalis surface. The vaginalis was obviously thickened and the inner and outer walls were smooth. The post-operative histopathology revealed a grayish-brown tissue with a thickness of 0.3-0.5 cm, smooth inner and outer walls, and a suspected WDPMT with a diameter of 1. 5 cm. Immunohistochemical staining showed positive for Calretinin, BAP1, WT-1, CK5/6, D2-40 and P16，which confirmed the diagnosis of WDPMT. To sum up, the purpose of this case report was to raise awareness of a rare disease WDPMT, which was usually asymptomatic and could be diagnosed by pathology and immunohistochemistry. The disease should be differentiated from testicular torsion, epididymitis, orchitis and oblique inguinal hernia in symptoms, and from malignant mesothelioma and adenomatoid tumour in pathology. Because of the rarity of the cases, there was no unified standard for the treatment of WDPMT at present. The common treatment methods reported in literature included orchidectomy and vaginectomy. Due to the lack of understanding of this disease, postoperative follow-up was still recommended for at least 5 years.

The nomenclature and diagnostic criteria of well-differentiated papillary mesothelial tumour (WDPMT) have been changed in the 2021 World Health Organization (WHO) classification of thoracic tumours, and a new entity, mesothelioma in situ (MIS), introduced. Histologically these two entities may be similar. However, MIS is regarded as a precursor to invasive mesothelioma and requires demonstration of loss of BAP1 and/or MTAP/CDKN2A for diagnosis, whereas performance of these ancillary tests is desirable but not essential for a diagnosis of WDPMT, in which the significance of BAP1 and/or MTAP/CDKN2A loss is not well understood or well defined. Against this backdrop, we undertook an investigation of 21 cases of WDPMT, identified from our case files and diagnosed according to 2021 WHO criteria, to explore the relationship between histology and BAP1 and MTAP/CDKN2A expression with clinical features including asbestos exposure, focality of tumours and clinical outcome. There were 18 women and three men, with ages ranging from 23-77 years (median 62 years), in which six had a history of asbestos exposure, two had no exposure, and in 13 exposure history was unavailable. Of 20 peritoneal tumours and one pleural tumour, 13 were detected incidentally at the time of surgery for unrelated conditions and eight peritoneal tumours were multifocal at the time of diagnosis. BAP1 immunohistochemistry (IHC) was performed in all 21 tumours, with nine tumours showing BAP1 expression loss. MTAP/CDKN2A testing was performed in 14 tumours, comprising MTAP IHC in 12 and CDKN2A fluorescence in situ hybridisation (FISH) in two, with three tumours showing MTAP/CDKN2A expression loss. Two tumours with MTAP/CDKN2A loss also showed BAP1 expression loss. Four patients progressed to invasive mesothelioma, including one male with a pleural tumour and asbestos exposure, and three females with multifocal peritoneal tumours, two with asbestos exposure and one without exposure. BAP1 expression loss was seen in all tumours from the four patients who progressed to invasive mesothelioma, whilst two of these tumours showed retained MTAP IHC and two were not tested. There was one patient with a tumour with MTAP loss and retained BAP1 who died from unrelated causes 5 months after diagnosis. Eight patients received WDPMT-specific treatment in addition to the initial excision. Survival for all patients ranged from 4-218 months, with one patient dying of mesothelioma at 49 months. Based on our results in this series of 21 patients with WDPMT diagnosed according to 2021 WHO criteria, we propose that WDPMT with BAP1 expression loss may best be regarded as papillary MIS and that a history of asbestos exposure and the presence of multifocal tumours in patients diagnosed with WDPMT should prompt ancillary testing with BAP1 IHC. Further we propose that BAP1 IHC should be essential in the diagnosis of WDPMT, with the diagnosis restricted to those tumours which show retained BAP1 expression. However more studies in larger cohorts of patients are needed to explore the relationship between BAP1 expression and MTAP loss in WDPMT, which will help to define this entity and separate it more clearly from MIS and invasive mesothelioma., (Copyright © 2024. Published by Elsevier B.V.)

Context.—: Molecular testing has increasingly been utilized in the evaluation of mesothelioma. Diffuse mesothelioma comprises multiple distinct genetic subgroups. While most diffuse mesotheliomas lack oncogenic kinase mutations and instead harbor alterations involving tumor suppressors and chromatin regulators, a minor subset of tumors is characterized by uncommon alterations such as germline mutations, genomic near-haploidization, ALK rearrangement, ATF1 rearrangement, or EWSR1::YY1 fusion., Objective.—: To provide updates on the salient molecular features of diffuse mesothelioma, mesothelioma in situ, and other mesothelial lesions: well-differentiated papillary mesothelial tumor, adenomatoid tumor, peritoneal inclusion cyst, and others. We consider the diagnostic, prognostic, and predictive utility of molecular testing in mesothelial lesions., Data Sources.—: We performed a literature review of recently described genetic features, molecular approaches, and immunohistochemical tools, including BAP1, MTAP, and merlin in mesothelioma and other mesothelial lesions., Conclusions.—: Our evolving understanding of the molecular diversity of diffuse mesothelioma and other mesothelial lesions has led to considerable changes in pathology diagnostic practice, including the application of immunohistochemical markers such as BAP1, MTAP, and merlin (NF2), which are surrogates of mutation status. In young patients and/or those without significant asbestos exposure, unusual mesothelioma genetics such as germline mutations, ALK rearrangement, and ATF1 rearrangement should be considered., Competing Interests: Hung has no relevant financial interest in the products or companies described in this article; Chirieac undertakes medicolegal work related to mesothelioma., (© 2024 College of American Pathologists.)

This review article examines some new and some problem areas in mesothelial pathology, four of which are discussed, as follows. (1) The concept of mesothelioma in situ: this lesion is defined as a single layer of bland mesothelial cells without evidence of invasion, but that have lost BAP1 and/or MTAP by immunohistochemistry. Benign reactions can exactly mimic mesothelioma in situ, but a hint to the correct diagnosis is a story of recurrent pleural effusions/ascites of unknown aetiology without radiological or direct visual evidence of tumour. (2) The nature of well-differentiated papillary mesothelial tumour (WDPMT): WDPMT has a long history of arguments regarding its behaviour, and this uncertainty can now be seen to arise, in part, from the observation that some forms of mesothelioma in situ microscopically look exactly like WDPMT. Hence, it is recommended to always run at least a BAP1 stain on any lesion that looks like WDPMT. Both flat and WDPMT-like mesothelioma in situ are strongly associated with eventual development of invasive mesothelioma, but this process is relatively slow. (3) New immunostains for separating mesothelioma from other tumours: here, it is proposed that in most cases, and particularly when the differential is epithelioid mesothelioma versus non-small cell lung cancer, one can make this separation with extremely high sensitivity and specificity using just two stains: HEG1 and claudin-4. (4) Markers for separating benign from malignant mesothelial proliferations: this topic is briefly reviewed, with an indication of which markers are generally accepted and the best utilisation and possible limitations of each marker., (© 2023 John Wiley & Sons Ltd.)

Fluoro-edenite (FE) is a silicate mineral identified in the lava products of Monte Calvario from stone quarries located in the southeast of Biancavilla, a small city of the Etnean volcanic complex (Sicily, Italy). Inhalation of FE fibers has been associated with a higher incidence of Malignant Mesothelioma (MM), a highly aggressive neoplasm of the serosal membranes lining the pleural cavity. Only 5% of MM patients are diagnosed at an early stage and the median survival is approximate 6-12 months. Many diagnostic biomarkers have been proposed for MM. Several studies demonstrated that microRNAs (miRNAs) may be used as good non-invasive diagnostics, as well as prognostic biomarkers for various human diseases, including cancer. On these bases, the aim of the present study was to identify a set of miRNAs involved in the development and progression of MM and potentially used as diagnostic biomarkers. For these purposes, in silico analyses were performed on healthy/exposed to asbestos fibers subjects vs. patients with MM. These analyses revealed a set of miRNAs strictly involved in MM by merging the lists of miRNAs found differentially expressed in the three miRNA expression datasets analyzed. The result of these computational evaluations allowed the execution of functional in vitro experiments performed on normal pleural mesothelial cell line (MeT-5A) and MM cell line (JU77) in order to test the carcinogenetic effects and epigenetic modulation induced by FE exposure. The in vitro results showed that the expression levels of hsa-miR-323a-3p vary significantly in both supernatant- and cell-derived miRNAs derived from treated and untreated cells. Secreted and cellular hsa-miR-101-3p in MeT-5A treated with FE fibers and JU77 cells showed different trends of expression. As regard hsa-miR-20b-5p, there was no differential expression between secreted and cellular hsa-miR-20b-5p. This miRNA has been shown a significant up-regulation in JU77 cells vs. control and treated MeT-5A. As a future plan, translational analyses will be performed on a subset of patients chronically exposed to FE fibers to further verify the clinical role of such miRNAs in high-risk individuals and their possible use as biomarkers of FE exposure or MM early onset., Competing Interests: Declaration of competing interest The authors report that they have no conflict of interests., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objective: The aim of this study was to investigate the utility of BRCA1-associated protein-1 (BAP1), glucose transporter (GLUT)-1 and desmin expression by immunohistochemistry in the discrimination between reactive and malignant mesothelial proliferations., Methods: A total of 88 biopsies and 30 effusions from mesothelioma cases were studied. Control groups were composed of 35 tissues and 30 cell blocks. The 88 mesothelioma cases were from 43 males and 45 females (mean age 56 years). Tumours were mostly localised to pleura (66/88, 75%) and of epithelioid histology (75/88, 85%). Cytology samples were from 17 males and 13 females (mean age 58 years), and 16 pleural and 14 peritoneal effusions. Twenty cytology cases had corresponding tissue biopsies., Results: BAP1 loss was detected in 61/88 (69%) tissues and in 20/30 (67%) cytology samples from mesothelioma with a specificity of 100% for both sampling methods. BAP1 loss was observed more frequently in pleural and biphasic tumours. GLUT-1 immunoreactivity was identified in 54/81 (67%) and 23/25 (92%) malignant tissues and effusions, and in 6/33 (18%) and 6/30 (20%) benign tissues and effusions, respectively. Desmin loss was observed in 74/80 (92%) malignant biopsy samples, 16/21 (76%) malignant effusions and 10/34 (29%) of benign tissues, but in none of the reactive effusions. Concordance rate of results between biopsy and cytology was as follows: BAP1 20/20 (100%); GLUT-1 13/18 (72%); and desmin 10/14 (71%)., Conclusions: BAP1, GLUT-1 and desmin are useful markers in the discrimination between reactive and malignant mesothelial proliferations. BAP1 loss seems to be diagnostic for mesotheliomas both in biopsy and cytology samples., (© 2019 John Wiley & Sons Ltd.)

The cytology of peritoneal washing fluids for gastric cancer is the most basic method for judging peritoneal micrometastasis. However, the clinical value of this method is not clear at present. A retrospective analysis was performed on 277 patients with pathologically proven and surgically treated gastric cancer. The peritoneal washing fluids were collected after opening the abdomen and before the operation, and were sent to the cytology laboratory for screening of occult cancer cells in the collected washing fluids. The number of cases diagnosed as cancer cells, reactive mesothelial cells, serosal balls, and traumatic mesothelial cells were 42, 18, 27, and 190, respectively. Typical adenocarcinoma cell nests were found in eight of 10 T4b samples, whereas 34 cases of cancer cells in T3 and T4a showed that these cell nests usually contained mesothelial cells, and the three-dimensional stereoscopic sense of the nests was not obvious. In the specific subcellular morphological changes of both reactive mesothelial cells and serosal balls, the changes of both the contour of nuclear membrane and the polarity of cell alignment were present only in stage T3 and T4a. The presence or absence of mesothelial cells in the nests of cancer cells and the changes of the contour of nuclear membrane and of the polarity of cell alignment in reactive mesothelial cells or serosal balls may help us to predict the depth of invasion of cancer cells.

Background: The aim of this study was to monitor the effect of humidified-warm carbon dioxide (HWCO 2 ) delivered into the open abdomen of mice, simulating laparotomy., Methods: Mice were anaesthetized, ventilated and subjected to an abdominal incision followed by wound retraction. In the experimental group, a diffuser device was used to deliver HWCO 2 ; the control group was exposed to passive air flow. In each group of mice, surgical damage was produced on one side of the peritoneal wall. Vital signs and core temperature were monitored throughout the 1-h procedure. The peritoneum was closed and mice were allowed to recover for 24 h or 10 days. Tumour cells were delivered into half of the mice in each cohort. Tissue was then examined using scanning electron microscopy and immunohistochemistry., Results: Passive air flow generated ultrastructural damage including mesothelial cell bulging/retraction and loss of microvilli, as assessed at 24 h. Evidence of surgical damage was still measurable on day 10. HWCO 2 maintained normothermia, whereas open surgery alone led to hypothermia. The degree of tissue damage was significantly reduced by HWCO 2 compared with that in controls. Peritoneal expression of hypoxia inducible factor 1α and vascular endothelial growth factor A was lowered by HWCO 2 . These effects were also evident at the surgical damage sites, where protection from tissue trauma extended to 10 days. HWCO 2 did not reduce tumorigenesis in surgically damaged sites compared with passive air flow., Conclusion: HWCO 2 diffusion into the abdomen in the context of open surgery afforded tissue protection and accelerated tissue repair in mice, while preserving normothermia. Surgical relevance Damage to the peritoneum always occurs during open abdominal surgery, by exposure to desiccating air and by mechanical trauma/damage owing to the surgical intervention. Previous experimental studies showed that humidified-warm carbon dioxide (HWCO 2 ) reduced peritoneal damage during laparoscopic insufflation. Additionally, this intervention decreased experimental peritoneal carcinomatosis compared with the use of conventional dry-cold carbon dioxide. In the present experimental study, the simple delivery of HWCO 2 into the open abdomen reduced the amount of cellular damage and inflammation, and accelerated tissue repair. Sites of surgical intervention serve as ideal locations for cancer cell adhesion and subsequent tumour formation, but this was not changed measurably by the delivery of HWCO 2 ., (© 2017 The Authors. BJS published by John Wiley & Sons Ltd on behalf of BJS Society Ltd.)

Malignant mesothelioma (MM) is a rare form of cancer. Its histopathological diagnosis is very difficult, as it exhibits a number of different appearances that can be misinterpreted as metastatic invasion or atypical hyperplasia. Thus, there is an urgent need to identify adequate markers to distinguish between benign and malignant cells, allowing the implementation of appropriate therapies and, possibly, specific directed therapies. MM, like other tumors, show an increase in glucose uptake, due to high rates of glycolysis, inducing an intracellular overload of acids. In this context, monocarboxylate transporters (MCTs) emerge as important players, by mediating the transmembranar co-transport of lactate with a proton, thereby, regulating pH and allowing continuous glycolysis. Importantly, proper MCT expression and activity depend on its co-expression with a chaperone, CD147, which is associated with poor prognosis in cancer. Twenty-two samples including reactive mesothelial cells, MM, and atypical mesothelial hyperplasias were evaluated for immunoexpression of MCT1, MCT4, and CD147. Expression of these proteins was compared with GLUT1 as a new promising marker for MM. Although MCT isoforms were not differentially expressed in the two types of cytological specimens, CD147, as GLUT1, was almost exclusively expressed in MM. Both MCT1 and MCT4 are not able to discriminate between mesothelial reactive cells and mesothelial malignant cells, while CD147 was able to distinguish these two proliferations. If confirmed, besides being a good marker for identification of MM, CD147 may also be a target for therapeutical strategies in this rare type of tumor., (Copyright © 2012 Wiley Periodicals, Inc.)

We present the first reported case of papillary cystadenofibroma of the epididymis. The tumor occurred in a 46-year-old man. The mass was 3.7 cm and included a hemorrhagic fluid-filled cyst. Microscopically, stromal-filled papillae were lined by low cuboidal to columnar epithelium. Epithelial cells were reactive for cytokeratin 7, cytokeratins AE1/3, and focally in the apical cytoplasm for CD10. Focal CD10 reactivity was also noted in the stroma. The lesion was negative for alpha-fetoprotein. These findings ruled out other lesions, including metastatic renal cell carcinoma.

The identification of metastatic cells in serous effusions has prognostic and therapeutic implications, thus leading to a continuous search for improvement of the existing diagnostic procedures, including immunocytochemistry. To evaluate the usefulness of an antibody recognizing the tight junction-associated protein Claudin 4 in detecting metastatic tumor cells and in the differential with reactive and neoplastic mesothelium, we stained 345 cases of benign and neoplastic serous effusions obtained from pleura, peritoneum, and pericardium. Two-hundred and twenty-eight of 230 cases (99.1%) of epithelial metastasis of different origin were strongly stained by anti-Claudin 4, whereas all cases of reactive mesothelitis (78) and malignant mesothelioma (37) were negative. With the exception of a single case of ovarian carcinoma hypercalcemic-type, all tumors originating from the anatomical sites that most frequently metastasize to the serosae, including lung (61), breast (23), female genital tract (67), gastrointestinal tract (27), and peritoneum (6), were found to be positive. Claudin 4 was also extremely useful in detecting single-tumor cells dispersed among heavy inflammatory reaction. Because of its high sensitivity (99.1%) and specificity (100%), Claudin 4 might be used as an ideal "single-shot" marker for the identification of metastatic epithelial cells in serous effusions., (Copyright © 2010 Wiley-Liss, Inc.)

Objectives: In a cohort study non-response might lead to a biased selection of cohort members and may affect the validity and reliability of the study outcome. To detect the possible effects of a non-response bias on study results, we evaluated the reasons for non-participation and the differences of respondents and non-respondents in a health surveillance program for power industry workers, formerly exposed to asbestos., Methods: A cohort of former power plant workers was formed to participate in an early detection program for lung cancer. We evaluated the results of 1,019 individuals (mean age 66 yr), of which 839 took part in at least one examination, 180 refused to participate or did not respond. To obtain the reasons for non-response, we interviewed the cohort members by telephone or we requested them by mail to complete and return a brief questionnaire. Further sources of information were the communal registration offices and local health offices., Results: The main reasons for non-participation were refusal (35%), illness (23.3%), death (16.7%) and difficulties with traveling (13.3%). It was impossible to make contact with or obtain an explanation from 11.7%. In a logistic regression model we demonstrated that advanced age and a long travel distance from the study center negatively affected the participation rate (p<0.001). There was no difference between respondents and non-respondents regarding prevalence (p=0.559) and incidence of lung cancer (p=0.882)., Conclusion: We concluded that in our cohort non-participation did not cause a selection bias in terms of lung cancer rates.

Inguinal hernias are common in the pediatric population. We describe a 10-year-old child who presented with signs and symptoms suggestive of an incarcerated inguinal hernia. Ultrasound examination demonstrated an aperistaltic multicystic inguinal mass of uncertain origin. The mass was resected, and the adjacent hernia was repaired. Histologic examination identified the mass as a mesothelial cyst. Mesothelial cysts are rare groin lesions in children that can masquerade as an incarcerated inguinal hernia in a child., (Copyright 2010 Elsevier Inc. All rights reserved.)

Immunohistochemistry is frequently employed to differentiate between malignant mesothelioma (MM) and pulmonary adenocarcinoma (AC) infiltrating the pleura, but there is uncertainty as to which antibodies are most useful. The present study investigated the presence of the serine protease, maspin, in epithelioid MMs and evaluated the diagnostic utility of maspin for the differential diagnosis between epithelioid MM and pulmonary AC with pleural involvement. The results showed more frequent maspin immunostaining among AC cases compared with MM cases. Maspin positivity was significantly higher among AC cases with respect to both the extent and intensity of staining. A significant difference also existed between the two tumour types with respect to the overall maspin score. Despite these findings, the sensitivity and specificity of maspin positivity to detect AC were only 59% and 73%, respectively, indicating that detection of maspin is of no value for the differential diagnosis of AC and MM.

To evaluate the role of the scoring of micronucleated cell (MNC) to distinguish reactive mesothelial cells from adenocarcinoma cells in effusion fluid. A total of 20 cases of unequivocal metastatic adenocarcinoma and 15 controls with reactive mesothelial cell proliferation in ascetic fluid were selected for scoring of the MNC. The numbers of cells having micronuclei were counted per 1000 of the well-preserved cells in May Grunwald Giemsa stained slides in each case. The mean number of MNC in metastatic adenocarcinoma and reactive mesothelial cells were 21 + 6.53 and 2.93 + 2.63, respectively, per 1000 cells. Micronuclei frequency was significantly increased in adenocarcinoma patients compared with controls (Student's t-test, P < 0.001). The scoring of MNC can be used as an additional biomarker and to discriminate between benign reactive mesothelial cells versus metastatic adenocarcinoma in effusion fluids in difficult situation.

Tumors and tumorlike lesions that secondarily involve the mesothelial or submesothelial layers of the peritoneum are a diverse group of disorders that range in biologic behavior from benign to highly malignant. The anatomy of peritoneal ligaments and mesenteries and the normal circulation of peritoneal fluid dictate location and distribution of these diseases within the peritoneal cavity. Peritoneal carcinomatosis is the most common secondary tumor to affect the peritoneal cavity. When it arises from carcinomas of the gastrointestinal tract or ovary, the prognosis is grave. However, when low-grade mucinous adenocarcinoma of the appendix spreads to the peritoneal cavity, the consequence is typically pseudomyxoma peritonei, which is a clinical syndrome, characterized by recurrent and recalcitrant voluminous mucinous ascites due to surface growth on the peritoneum without significant invasion of underlying tissues. Carcinomas from elsewhere in the body, as well as lymphomas and sarcomas, may also produce diffuse peritoneal metastasis. Granulomatous peritonitis is the consequence of disseminated infection such as tuberculosis or histoplasmosis, foreign materials, or rupture of a tumor or hollow viscus. Finally, a group of benign miscellaneous conditions that range from common disorders such as endometriosis and splenosis to very rare conditions such as gliomatosis peritonei and melanosis may also affect the peritoneum diffusely. Secondary tumors and tumorlike lesions of the peritoneum have overlapping imaging features when compared with each other and primary peritoneal tumors. Knowledge of peritoneal anatomy, normal fluid circulation within the peritoneal cavity, and clinical and pathologic features of secondary peritoneal lesions is essential for identification of these lesions.

Distinguishing malignant mesothelioma, adenocarcinoma and reactive mesothelial proliferation in both cytologic and surgical pathologic specimens is often a diagnostic challenge. Conventional cytomorphologic assessment is an important step in the differential diagnosis of these entities.The pleural effusion cytologies from 40 cases of malignant mesothelioma, 40 cases of adenocarcinoma and 30 cases of reactive mesothelial proliferation diagnosed between 1997 and 2007 were reviewed. Twenty-seven cytologic features which are regarded as useful in the differential diagnosis of mesothelioma, adenocarcinoma and benign mesothelial proliferation were assessed. These cytologic features were subjected to a stepwise logistic regression analysis. Three features were selected to distinguish malignant mesothelioma from adenocarcinoma: giant atypical mesothelial cell (P = 0.0001), nuclear pleomorphism (P = 0.0001) and acinar structures (P = 0.0001), the latter two being characteristics of adenocarcinoma. The variables selected to differentiate malignant mesothelioma from reactive mesothelial cells were: cell ball formation (P = 0.0001), cell in cell engulfment (P = 0.0001) and monolayer cell groups (P = 0.0001), the latter being a feature of benign mesothelial proliferation. When these selected variables were subjected to a stepwise logistic regression analysis, the logistic model correctly predicted 90% of cases of benign mesothelial proliferation versus 97.5% of malignant mesothelioma and 92.5% of malignant mesothelioma versus 92.5% of adenocarcinoma.Conventional cytomorphologic assessment is the first step to establish an accurate diagnosis in pleural effusions. Several cytologic features have predictive value to separate malignant mesothelioma from adenocarcinoma and reactive mesothelial proliferation., ((c) 2008 Wiley-Liss, Inc.)

Objective: The aim of this study was to evaluate the individual and combined diagnostic utility of carcinoembryonic antigen (CEA), cytokeratin 19 fragments (CK19) and HBME-1 in pleural effusions of patients with lung cancer., Study Design: CEA, CK19 and HBME-1 were detected by immunocytochemistry in pleural effusions from patients with lung cancer (86 cases) and without lung cancer (40 cases)., Results: CEA and CK19 expression were significantly higher in the carcinoma cell group and in three subgrouped as adenocarcinoma (AC), squamous cell carcinoma (SCC) and small cell lung cancer than in the mesothelial cell group, whereas HBME-1 expression was lower in the former group (P < 0.01). In the subgrouped tumours, CEA expression was higher in AC than in SCC (P < 0.05), whereas HBME-1 expression was higher in SCC than in AC (P < 0.01). Used alone, CK19 had the highest sensitivity (95.3%) and accuracy (93.7%), whereas CEA had the highest specificity (97.5%). When combinations of antibodies were evaluated together and membrane staining with HBME-1 taken as a negative outcome, CK19 and HBME-1 gave a high diagnostic performance: sensitivity of 100.0% and accuracy of 95.2% respectively., Conclusion: A panel of CEA, CK19 and HBME-1 monoclonal antibodies proved to be suitable for distinguishing carcinoma cells from reactive mesothelial cells in pleural effusions.

Context: The differentiation of benign mesothelial proliferations from malignant mesotheliomas may be difficult, especially when evaluating small specimens from pleural biopsies., Objective: To explore the potential value of 2 proliferative cell markers, Ki-67 and restrictedly expressed proliferation-associated protein 86 kDa (repp86), in distinguishing between malignant mesothelioma (MM) and benign reactive mesothelial hyperplasia (MH)., Design: Thirty-six cases of MM from 26 men and 10 women with a mean age of 62.9 years (range, 36-80 years) and 22 cases of benign reactive MH from 14 male and 8 female patients with a mean age of 51.5 years (range, 15- 88 years) were included in this study. The proliferative status of the lesions was assessed by immunohistochemistry using monoclonal antibodies to Ki-S2 (repp86) and Ki-S5 (Ki-67). The labeling indices were quantified., Results: The mean labeling indexes for Ki-67 in MM and benign reactive MH were 24.6% (range, 1%-66%) and 6.23% (range, 0%-25%), respectively. The mean labeling indexes for repp86 in MM and benign reactive MH were 26.3% (range, 0%-50%) and 3.26% (range, 0%- 21%), respectively. The average proliferative cell count was significantly higher in MM compared with benign reactive MH (P < .001). Furthermore, both markers showed a significant correlation in their expression in MM and benign reactive MH (r = 77.5, P < .001). Sensitivities of 88% and 92% and specificities of 92% and 94% were obtained at a cutoff point of 9% for Ki-67 and repp86, respectively., Conclusions: Used in combination, Ki-67 and repp86 appear to be useful markers in differentiating MM from benign reactive MH.

Objective: To compare the performances of 2 methods, telomerase repeat amplification protocol (TRAP) in situ and antibodies to the hTERT protein, in assessing telomerase activity., Study Design: TRAP in situ and immunohistochemistry with a commercial antibody (NCL-hTERT) was performed on 54 body cavity effusions. The results were compared and correlated to diagnosis., Results: Thirty-four effusions from patients with verified malignant disease contained cytologically malignant cells. Both methods were positive in 33 of the cases, whereas only hTERT was positive in 1 case. Twenty effusions, all containing mesothelial cells, came from patients with benign conditions. In 2 fluids atypical, hyperplastic mesothelial cells were both TRAP in situ and hTERT positive. All remaining 18 fluids were TRAP in situ negative, whereas 12 of 18 were hTERT positive. Thus the results of TRAP in situ and hTERT immunohistochemistry disagreed in 1 of 34 (3%) malignant and 12 of 20 (60%) benign cases., Conclusion: The sensitivities for malignancy were similar for TRAP in situ and hTERT immunohistochemistry. The specificity of the applied hTERT antibody was significantly lower, due to hTERT reactivity in mesothelial cells.

Aims: The differential diagnosis of malignant mesothelioma (MM) from benign mesothelial lesions (BML) based on histopathological criteria is sometimes not satisfying and causes diagnostic problems for histopathologists. We aimed to investigate whether the immunohistochemically determined cell proliferation rate and telomerase activity, using Ki-67 and human telomerase reverse transcriptase (hTERT) immunohistochemistry, respectively, are useful in the differential diagnosis of MM from BML., Methods: Sixty-six cases of MM (33 epithelioid, 30 biphasic and 3 sarcomatoid) and 22 cases of BML (15 reactive mesothelial proliferations and 7 fibrous pleuritis/pericarditis) were included in this study. We evaluated the proliferative activity by Ki-67 and telomerase activity by hTERT immunohistochemistries for each case., Results: The mean value of the Ki-67 proliferation index (PI) in MMs was significantly higher than that of BMLs. Biphasic MMs have higher a Ki-67 PI than epithelioid and sarcomatoid types. Ki-67 immunohistochemistry has a sensitivity of 74%, specificity of 86% and positive predictive value of 94% in detecting MM. hTERT immunohistochemistry detected MM with sensitivity and specificity of 68%., Conclusion: As a result, being cheap and simple methods, Ki-67 and hTERT immunohistochemistries can be used in differentiating malignant and benign mesothelial lesions in routine formalin-fixed, paraffin-embedded material.

A 55-year-old man, diagnosed with systemic sclerosis (SSc) for 20 years, was admitted to our hospital for exertional dyspnea and pleural effusion. Computed tomography scan and cytological findings of the pleural fluid suggested malignant mesothelioma. In the postmortem examination, the tumor was pathologically diagnosed as pseudomesotheliomatous adenocarcinoma (PMA) of the lung, classified into pleomorphic carcinoma with adenocarcinoma component according to the new World Health Organization guidelines. This is the first case report of SSc with PMA.

Objective: To evaluate the extent to which adenocarcinomas in body cavity fluids express GLUT-1 in comparison to currently available markers for adenocarcinomas., Study Design: Archival paraffin-embedded cell blocks of serous fluids from 25 cases of benign effusions containing reactive mesothelial cells and 39 cases of malignant effusions with metastatic adenocarcinoma (11 ovarian, 11 pulmonary, 9 gastrointestinal and 8 breast) were retrieved from the surgical pathology files. All cases were stained with antibodies for GLUT-1, Ber-Ep4, B72.3 and CEA. Positive staining was defined as distinct linear membrane staining for GLUT-1 and Ber-EP4, cytoplasmic staining for CEA, and cytoplasmic or membrane staining for B72.3. Strong staining in at least 10% of the tumor cells was required in order to consider the case positive for the particular marker., Results: GLUT-1 was expressed in 72% (28 of 39) of cases of malignant effusions: 100% (11 of 11) from the ovary, 91% (10 of 11) from the lung, 67% (6 of 9) from the gastrointestinal tract and 12% (1 of 8) from the breast. None (0 of 25) of the benign effusions expressed GLUT-1. Malignant effusions expressed CEA in 74% (29 of 39), Ber-Ep4 in 85% (33 of 39), and B72.3 in 62% (24 of 39). Benign effusions expressed CEA in 3 cases and B72.3 in 2 cases., Conclusion: GLUT-1 is a useful marker that can be applied to cytologic specimens. It can be used as a reliable component of an antibody panel to distinguish reactive mesothelial cells from metastatic adenocarcinoma in particular adenocarcinomas of body cavity effusions, in particular adenocarcinomas of ovarian and pulmonary origin.

Mesenchymal tumors are a heterogeneous group of tumors often arising in the skin and soft tissue. The tumors have been reclassified by the WHO in 2002. Benign mesenchymal tumors are about a hundred times more frequent than malignant mesenchymal tumors. Clinically, mesenchymal tumors often present as skin-colored nodes. Overall, elderly persons are more affected than younger individuals. The etiology is often unknown, sometimes there is an association with insults such as radiation, scars, or lymphedematous or venous stasis. Whereas some years ago a wide excision with a margin of 3-5 cm was performed for malignant variants, today micrographic surgery is preferred, as it can avoid mutilating procedures. Early detection and removal is critical since mesenchymal skin tumors often cannot be cured by radiation or chemotherapy.

Objective: To distinguish reactive mesothelial cells from malignant cells in serous effusions using manual and automated methods of enumeration of argyrophilic nucleolar organizer regions (AgNORs)., Study Design: In this prospective study, 38 samples of benign (19 cases) and malignant (19 cases) serous effusions were included. AgNOR stain was used in each case along with routine Papanicolaou stain. The smears were examined under an oil immersion objective, and AgNOR dots were counted by direct observation independently by 2 observers. Automated AgNOR counting and morphometry were performed with a Quantimet 600 image cytometer (Leica, Cambridge, England). At least 100 cells were counted in each case. The number of AgNOR dots in individual cells, AgNOR area, nuclear area, AgNOR vs. nuclear area and nuclear perimeter were measured. Data on benign and malignant cells were compared., Results: The AgNOR dots were discrete and smaller in benign effusion cases as compared to coarse and aggregated in malignant effusion cases. In benign reactive effusion cases the mean number of AgNOR dots per nucleus was 2.33 +/- 0.71 and 2.83 +/- 1.15 by the manual and automated method, respectively, whereas that for malignant effusion cases was 7.48 +/- 2.51 and 8.09 +/- 1.69 by the manual and automated method, respectively. Mean total AgNOR areas in benign and malignant groups were 4.77 +/- 2.66 microns 2 and 38.22 +/- 13.71 microns 2, respectively. Mean nuclear area, nuclear perimeter and ratio of AgNORs vs. nuclear area were 48.72 +/- 19.30 microns 2, 24.68 +/- 10.25 microns and .098 in benign effusion cases as compared to 174.25 +/- 82.36 microns 2, 69.03 +/- 27.23 microns and 0.22 in malignant effusion samples. All these values were significantly higher (P < .001, Student's t test) in malignant cells as compared to benign reactive cells., Conclusion: AgNOR dot enumeration, AgNOR area and ratio of AgNORs to nuclear area are valuable adjuncts to cytomorphology in differentiating reactive mesothelial cells from malignant cells in serous effusions. Automated AgNOR counting is rapid and less cumbersome.

Unlabelled: Peritoneal carcinomatosis can be difficult to diagnose, as CT is insensitive, with peritoneal biopsy and lavage often subject to problems of sampling error. The aim of our study was to evaluate the role of (18)F-FDG PET in detecting peritoneal carcinomatosis in patients with stomach, ovarian, and adrenal cancer and mesothelioma and to compare the results with CT scans in the same patient group. Our secondary aim was to identify characteristic patterns of abdominal (18)F-FDG uptake in biopsy-proven peritoneal disease and to correlate these patterns with available histologic and anatomic findings after surgery and structural imaging., Methods: The medical records of 88 patients with stomach (n = 48), ovarian (n = 13), and adrenal cancer (n = 6) and mesothelioma (n = 21) were reviewed for the presence of peritoneal tumor on (18)F-FDG PET and CT scans. The results were correlated with either contemporaneous peritoneal biopsy or ascitic aspirate or with radiographic or clinical follow-up if histology was negative or unavailable. Of 24 patients with suspected peritoneal tumor, 17 had biopsy-proven findings of peritoneal disease., Results: Of the 24 patients with suspected peritoneal tumor, (18)F-FDG PET was positive in 14 patients, with 1 of these scans being false-positive, CT was positive in 10 patients, and either PET or CT was positive in 18 patients. This yielded sensitivities of 57% (13/23), 42% (10/23), and 78% (18/23), with uniformly high positive predictive values of 93% (13/14), 100% (10/10), and 95% (18/19), respectively. We identified 2 distinctly abnormal scintigraphic patterns of focal and uniform (18)F-FDG uptake corresponding to nodular and diffuse peritoneal disease on pathologic examination., Conclusion: (18)F-FDG PET adds to conventional imaging in the staging of peritoneal carcinomatosis. It is also a useful diagnostic tool when peritoneal biopsy is either unavailable or inappropriate. We have identified 2 distinct scintigraphic patterns that appear to predict the presence of either nodular or diffuse peritoneal pathology.

Purpose: Gastrointestinal stromal tumors (GISTs) are rare tumors of the gastrointestinal tract with an increasing detection rate due to improved differentiating methods in current diagnostic pathology. This study evaluates the radiologic characteristics of these neoplasms to discover specific signs leading to an earlier diagnosis., Materials and Methods: As part of a randomized phase III clinical trial of the European Organization for Research and Treatment of Cancer (EORTC), 72 patients with advanced stage GIST were treated with the selective tyrosine-kinase-inhibitor imatinib (Glivec, Novartis, Switzerland). For initial staging, 60 patients underwent MRI and 12 patients underwent CT., Results: GISTs are mesenchymal tumors that grow submucosally and exophytically and become multiple, nodular or ovoid in the advanced stage. The predominant findings are peripheral solid structures with strong contrast enhancement and a central necrosis. Metastases are primarily located in the liver, where they appear as oval or round, sharply delineated solitary lesions with central necrosis. CT demonstrates the primary tumors and local recurrences as nearly isodense with the liver. On MRI, the lesions are hypointense on T 1 -weighted sequences and hyperintense on T 2 -weighted sequences, compared to the liver., Conclusion: Immunopathology now enables the exact histologic separation of GISTs from other mesenchymal tumors. The radiological morphology is not sufficiently specific to differentiate GISTs from other mesenchymal tumors. In view of new therapeutic options, cognizance of their typical manifestations is of increasing importance for radiologists.

Primary neoplasms of the greater omentum are rare. We report a case of omental tumors occurring in 58-year-old Japanese man. Ultrasonography showed multiple solid tumors in the abdomen and angiography identified the greater omentum as the precise location. The tumors were completely resected with the major part of the greater omentum and analyzed histologically, immunohistochemically, and genetically. Positive reactivity for CD117 (c-kit, a transmembrane tyrosine kinase receptor) and CD34, and the absence of TLS/FUS-CHOP rearrangement confirmed that the tumors were extragastrointestinal counterparts of a gastrointestinal stromal tumor. Although the higher mitotic activity measured by the Ki-67 labeling ratio suggests the malignant potential of this tumor, there was no recurrence at the 20-month follow-up.

Objective: To evaluate the diagnostic utility of the immunohistochemical expression of thyroid transcription factor-1 (TTF-1) in adenocarcinomas from serous fluid specimens., Study Design: Archival paraffin-embedded cell blocks of serous fluids from 82 cases, including 34 cases of metastatic lung adenocarcinoma, 12 of metastatic ovarian adenocarcinoma, 12 of metastatic breast adenocarcinoma, 12 of metastatic gastrointestinal adenocarcinoma and 12 of malignant mesothelioma, were immunostained with anti-TTF-1. All the staining was carried out using a Ventana Automated System. Staining was evaluated according to the intensity of the nuclear staining (1+ to 4+) by two observers., Results: Of the metastatic lung adenocarcinomas, 79% (27/34) expressed 3+ to 4+ reactivity against TTF-1. None of the malignant mesotheliomas or other metastatic adenocarcinomas expressed nuclear reactivity., Conclusion: Immunostaining with TTF-1 is a useful marker that can be applied to cytologic specimens. Anti-TTF-1 can be used as a reliable component of an antibody panel to support the diagnosis of adenocarcinoma of pulmonary origin in patients presenting with metastatic adenocarcinoma in serous fluid with an unknown primary site.

Angiogenesis is essential for tumour growth beyond 1 to 2 mm in diameter. The clinical relevance of angiogenesis, as assessed by microvessel density (MVD), is unclear in malignant mesothelioma (MM). Immunohistochemistry was performed on 104 archival, paraffin-embedded, surgically resected MM samples with an anti-CD34 monoclonal antibody, using the Streptavidin-biotin complex immunoperoxidase technique. 93 cases were suitable for microvessel quantification. MVD was obtained from 3 intratumoural hotspots, using a Chalkley eyepiece graticule at x 250 power. MVD was correlated with survival by Kaplan-Meier and log-rank analysis. A stepwise, multivariate Cox model was used to compare MVD with known prognostic factors and the EORTC and CALGB prognostic scoring systems. Overall median survival from the date of diagnosis was 5.0 months. Increasing MVD was a poor prognostic factor in univariate analysis (P = 0.02). Independent indicators of poor prognosis in multivariate analysis were non-epithelial cell type (P = 0.002), performance status > 0 (P = 0.003) and increasing MVD (P = 0.01). In multivariate Cox analysis, MVD contributed independently to the EORTC (P = 0.006), but not to the CALGB (P = 0.1), prognostic groups. Angiogenesis, as assessed by MVD, is a poor prognostic factor in MM, independent of other clinicopathological variables and the EORTC prognostic scoring system. Further work is required to assess the prognostic importance of angiogenic regulatory factors in this disease., (Copyright 2001 Cancer Research Campaign http://www.bjcancer.com.)

Objective: To analyze the role of immunochemistry in serous effusions., Study Design: We analyzed cell blocks of 18 pleural and 18 peritoneal effusions diagnosed as malignant (18), benign (14) and suspicious (4). They were immunostained by the avidin-biotin complex method with a panel of four monoclonal antibodies--CEA, Ber-EP4, LeuM1 (CD15) and p53--and, for lectins (Ulex europaeus) UEA-l, ConA and ConBr., Results: Seventeen of the 18 cases of adenocarcinoma were positive for CEA (95%), 12 (66.6%) for Ber-EP4, 11 (61%) for CD15 and 11 (61%) for p53. Twelve of the 18 (66.6%) were positive for UEA-1, CEA, Ber-EP4 and CD15. UEA-1 did not react with mesothelial cells. p53 Gave a positive reaction in only one case, reactive mesothelial cells. ConA and ConBr reacted indiscriminately with benign and malignant cells; thus, it was not useful in distinguishing between these cells., Conclusion: In this context no antibody used alone is reliable for corroborating a diagnosis, but the selective use of a small panel of three markers (CEA, Ber-EP4 and LeuM1) can be very useful in solving diagnostic difficulties in the cytodiagnosis of serous effusions.

In effusion cytology the distinction of reactive mesothelia from metastatic carcinoma cells may be a diagnostic challenge. Immunocytochemistry using antibodies suitable to detect epithelial cells must be considered carefully due to limited sensitivity and specificity of these antibodies. Efficient results in histological differential diagnosis of malignant mesothelioma versus lung-adenocarcinoma applying a novel antiserum against the calcium binding protein calretinin inspirated us to investigate the value of anti-calretinin antibody in effusion cytology combined with an epithelial marker. Cytoslides prepared by cytocentrifugation from 42 malignant and 65 reactive effusion specimens were immunostained using antibodies against calretinin and the epithelial marker Ber-EP4. Positive immunoreaction for calretinin in normal and reactive mesothelial cells was noted in 93% of the cases, whereas immunoreaction for calretinin was completely negative in the metastatic cells in 95% of the malignant effusions. Metastatic carcinoma cells were detected with anti-Ber-EP4 in 83% of malignant effusions. Non-specific positive reactions for Ber-EP4 in single mesothelial cells were observed in 16% of all cases and, moreover, frequently with macrophages or neutrophilic granulocytes. Our results demonstrate high sensitivity and specificity of anti-calretinin antibody for mesothelial cells in effusion specimens. They support its application to improve the diagnostic reliability of epithelial markers, especially because anti-calretinin antibody could be helpful in the assessment of false positive and false negative reactions of epithelial markers.