Virchows Archiv

Our medical research library holds 38 studies published in Virchows Archiv (1999–2026). Each entry links to the study's record on PubMed and, where there is one, to the publisher's page and a free full text. 37 have an abstract, the authors' own summary as PubMed records it: open "Abstract" to read it.

About the journal

• Publisher: Springer International
• Published: 1994 to the present, Germany
• Language: English
• ISSN: 0945-6317 (print), 1432-2307 (electronic)
• Merged from: Virchows Archiv. A, Pathological Anatomy and Histopathology
• Merged from: Virchows Archiv. B, Cell Pathology Including Molecular Pathology
• Its record in the NLM Catalog

2020s

• The specificity of HEG1 as mesothelioma marker depends on the differential diagnosis. B. Davidson, L.M. Stričak, A. Holth, et al. 2026;488(3):617-626. PubMed · Publisher · Free full text

  Abstract

  The objective of this study was to analyze the diagnostic role of HEG homolog 1 (HEG1) in cancers affecting the serosal cavities. HEG1 protein expression by immunohistochemistry was analyzed in 534 specimens (341 effusions and 193 surgical specimens). Effusions consisted of 151 tubo-ovarian carcinomas, 59 breast carcinomas, 44 mesotheliomas, 37 lung carcinomas, 29 uterine corpus and cervical carcinomas, 17 gastrointestinal carcinomas and 4 genitourinary carcinomas. Surgical specimens consisted of 139 tubo-ovarian carcinomas, 42 mesotheliomas, 7 multicystic mesothelial proliferations and 5 papillary mesothelial tumors. HEG1 expression was found in 43/44 (98%) mesothelioma effusions and 39/42 (93%) surgical mesothelioma specimens, as well as all multicystic and papillary mesothelial tumors. HEG1 was infrequently expressed in breast carcinoma (4/59; 7%), lung carcinoma (2/37; 5%) and cervical/uterine carcinoma effusions (3/29; 10%), but was often detected in tubo-ovarian carcinoma effusions (80/151; 53%) and surgical specimens (99/139, 71%). HEG1 was additionally consistently expressed by reactive mesothelial cells in effusions and in endothelial cells in surgical specimens. HEG1 had sensitivity of 95% for diagnosing malignant mesothelioma in all studied specimens, with a specificity of 38% in the differential diagnosis from tubo-ovarian carcinoma and 93% in the differential diagnosis from non-tubo-ovarian carcinomas. Of 179 HEG1-positive carcinomas, 172 expressed the epithelial marker claudin-4. In conclusion, HEG1 is a highly sensitive marker of both benign and malignant mesothelial cells. It shows high specificity in the differentiation of mesothelioma from lung or breast carcinoma but is of little value in differentiating mesothelioma from tubo-ovarian carcinoma. The potential role of HEG1 as vascular marker merits further research.

  © 2026. The Author(s).

• Claudin-10 is a new candidate prognostic marker in metastatic high-grade serous carcinoma. B. Davidson, D. Doutel, A. Holth, et al. 2023;482(6):975-982. PubMed · Publisher · Free full text

  Abstract

  The objective of this study was to analyze the expression and prognostic role of the tight junction protein claudin-10 in high-grade serous carcinoma (HGSC). Claudin-10 protein expression by immunohistochemistry was analyzed in 588 HGSC (414 effusions, 174 surgical specimens). Expression in mesotheliomas (n = 97; 47 effusions, 50 surgical specimens) was studied for comparative purposes. CLDN10 mRNA expression by quantitative RT-PCR (qRT-PCR) was analyzed in 40 HGSC effusions. Claudin-10 protein expression was found in 360/588 (61%) HGSC vs. 19/97 (20%) mesotheliomas (p < 0.001), and was higher in HGSC surgical specimens compared to effusions (p < 0.001). qRT-PCR confirmed the presence of CLDN10 mRNA in HGSC effusions. High (> 25%) claudin-10 expression in HGSC effusions was significantly associated with shorter overall survival (OS; p = 0.036) and progression-free survival (PFS; p = 0.045) in univariate analysis, and was an independent prognosticator of OS in multivariate analysis (p = 0.045). In conclusion, claudin-10 protein expression is higher in HGSC compared to mesothelioma, although the diagnostic power of this marker appear to be lesser than other claudin family members. Claudin-10 expression in HGSC effusions is marker of more aggressive disease.

  © 2023. The Author(s).

• Correction to: Micro-RNA-215 and -375 regulate thymidylate synthase protein expression in pleural mesothelioma and mediate epithelial to mesenchymal transition. F. Napoli, I. Rapa, S. Izzo, et al. 2022;481(2):331. PubMed · Publisher · Free full text

• Cytokeratin 5 and cytokeratin 6 expressions are unconnected in normal and cancerous tissues and have separate diagnostic implications. C. Völkel, N. De Wispelaere, S. Weidemann, et al. 2022;480(2):433-447. PubMed · Publisher · Free full text

  Abstract

  Cytokeratins (CKs) 5 and 6 are functionally unrelated but often analyzed together using bispecific antibodies in diagnostic immunohistochemistry. To better understand the diagnostic utility of CK5 or CK6 alone, tissue microarrays with > 15,000 samples from 120 different tumor types as well as 608 samples of 76 different normal tissues were analyzed by immunohistochemistry. In normal tissues, both CKs occurred in the squamous epithelium; CK5 dominated in basal and CK6 in suprabasal layers. CK5 (not CK6) stained basal cells in various other organs. Within tumors, both CK5 and CK6 were seen in > 95% of squamous cell carcinomas, but other tumor entities showed different results: CK5 predominated in urothelial carcinoma and mesothelioma, but CK6 in adenocarcinomas. Joint analysis of both CK5 and CK6 obscured the discrimination of epithelioid mesothelioma (100% positive for CK5 alone and for CK5/6) from adenocarcinoma of the lung (12.8% positive for CK5 alone; 23.7% positive for CK5/6). CK5 and CK6 expressions were both linked to high grade, estrogen receptor, and progesterone receptor negativity in breast cancer (p < 0.0001 each), grade/stage progression in urothelial cancer (p < 0.0001), and RAS mutations in colorectal cancer (p < 0.01). Useful diagnostic properties which are commonly attributed to CK5/6 antibodies such as basal cell staining in the prostate, distinction of adenocarcinoma of the lung from squamous cell carcinoma and epithelioid mesothelioma, and identification of basal-type features in urothelial cancer are solely driven by CK5. At least for the purpose of distinguishing thoracic tumors, monospecific CK5 antibodies may be better suited than bispecific CK5/6 antibodies.

  © 2021. The Author(s).

• Micro-RNA-215 and -375 regulate thymidylate synthase protein expression in pleural mesothelioma and mediate epithelial to mesenchymal transition. F. Napoli, I. Rapa, S. Izzo, et al. 2022;481(2):233-244. PubMed · Publisher · Free full text

  Abstract

  The standard front-line treatment for pleural mesothelioma (PM) is pemetrexed-based chemotherapy, whose major target is thymidylate synthase (TS). In several cancer models, miR-215 and miR-375 have been shown to target TS, while information on these miRNAs in PM are still limited although suggest their role in epithelial to mesenchymal transition. Seventy-one consecutive PM tissues (4 biphasic, 7 sarcomatoid, and 60 epithelioid types) and 16 commercial and patient-derived PM cell lines were screened for TS, miR-215, and miR-375 expression. REN and 570B cells were selected for miR-215 and miR-375 transient transfections to test TS modulation. ZEB1 protein expression in tumor samples was also tested. Moreover, genetic profile was investigated by means of BAP1 and p53 immunohistochemistry. Expression of both miR-215 and miR-375 was significantly higher in epithelioid histotype. Furthermore, inverse correlation between TS protein and both miR-215 and miR-375 expression was found. Efficiently transfected REN and 570B cell lines overexpressing miR-215 and miR-375 showed decreased TS protein levels. Epithelioid PM with a mesenchymal component highlighted by reticulin stain showed significantly higher TS and ZEB1 protein and lower miRNA expression. A better survival was recorded for BAP1 lost/TS low cases. Our data indicate that miR-215 and miR-375 are involved in TS regulation as well as in epithelial-to-mesenchymal transition in PM.

  © 2022. The Author(s).

• A potential cause of asbestos-related granulomatosis due to adulterant contamination in a drug abuser. M.C. Lazzaro, S. Romanò, S. Santoro, et al. 2021;478(2):361-366. Case report PubMed · Publisher

  Abstract

  Drug adulterants containing contaminants have been known to cause lung disease by inhalation or intravenous intake. Talcosis due to intravenous talc injection has been widely described in the literature, whereas the hypothesis of granulomatosis due to asbestos related to adulterated cocaine injection has not yet been explored. Herein, a case of pulmonary granulomatosis due to asbestos fibres related to cocaine injection in a young woman is described. Inorganic material in the lung was first individuated by light microscopy and last was identified using the SEM-EDX method. This case is unique since the occupational and passive inhalation of asbestos was excluded with absolute certainty.

• CD146 immunohistochemical staining for the separation of benign from malignant mesothelial proliferations. T. Salisbury, A. Churg. 2021;479(5):1047-1050. PubMed · Publisher

  Abstract

  The separation of benign from malignant mesothelial cells is often a challenging problem. Some studies have suggested that immunohistochemical staining of CD146 can be used to make this distinction, but there are marked differences in the reported results. Here, we assessed CD146 expression in tissue microarray specimens of 32 epithelioid reactive mesothelial hyperplasias, 17 spindle cell reactive mesothelial proliferations, 43 epithelioid mesotheliomas, and 31 sarcomatoid mesotheliomas. We found that, although the specificity of CD146 for epithelioid mesotheliomas versus reactive epithelial mesothelial proliferations was high (94%), staining intensity and extent was usually low and sensitivity was poor (23%). For sarcomatoid mesotheliomas versus reactive spindle cell mesothelial processes, both measures (33% sensitivity, 76% specificity) were inadequate. Furthermore, strong staining of endothelial cells and fibroblasts often created difficulties in interpretation. In comparison, BAP1 was lost in 21/43 (49%) epithelioid and 9/31 (29%) sarcomatoid mesotheliomas and methylthioadenosine phosphorylase (MTAP) was lost in 9/40 (23%) epithelioid and 7/29 (24%) sarcomatoid mesotheliomas from these TMAs. There was no association between CD146 staining and BAP1 or MTAP retention/loss. We conclude that CD146 staining is probably not useful for separating malignant from benign mesothelial proliferations.

  © 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.

• Combined grade and nuclear grade are prognosis predictors of epithelioid malignant peritoneal mesothelioma: a multi-institutional retrospective study. N. Benzerdjeb, P. Dartigues, V. Kepenekian, et al. 2021;479(5):927-936. PubMed · Publisher

  Abstract

  Epithelioid mesothelioma is the most prevalent subtype of diffuse malignant peritoneal mesothelioma. A recently described nuclear-grading system predicted survival in patients with epithelioid malignant pleural mesothelioma. The present study was undertaken to validate this grading system in epithelioid malignant peritoneal mesothelioma (EMPM) and to compare to combined grade, including nuclear atypia, mitotic count, and tumor necrosis. Cases of EMPM, from 1995 to 2018, were analyzed from 7 French institutions from RENAPE network. Solid growth, tumor necrosis, nuclear atypia, and mitotic count were evaluated by at least 3 pathologists from the RENAPATH group. The predictions in terms of OS and PFS of nuclear grade and combined grade were analyzed. Nuclear grade was computed combining nuclear atypia score and mitotic count into a grade of I-III. Another system combining nuclear atypia score, mitotic score, and tumor necrosis was evaluated and defined as a combined grade I-III. A total of 138 cases were identified. The median follow-up was 38.9 months (range: 1.1-196.6). Nuclear and combined grades III were independently associated with a shorter OS (p < 0.05), and a shorter PFS (p < 0.05). Patients with combined grade I tumors had the best overall and progression-free survivals, in comparison to nuclear grade I. In this large multicentric study, combined grade and nuclear grade were the best independent predictors of OS and PFS in EMPM. These systems should be easily described by pathologists involved into the management of malignant peritoneal mesothelioma, because of their potential therapeutic implications.

  © 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.

• GATA3 is a useful immunohistochemical marker for distinguishing sarcomatoid malignant mesothelioma from lung sarcomatoid carcinoma and organizing pleuritis. Z.H. Piao, X.C. Zhou, J.Y. Chen. 2021;479(2):257-263. PubMed · Publisher

  Abstract

  Sarcomatoid malignant mesothelioma (SMM) tends to occur in the pleura and is morphologically similar to lung sarcomatoid carcinoma (LSC) and organizing pleuritis (OP). Because SMM often does not express mesothelial markers, it is very difficult to distinguish from LSC and OP. GATA-binding protein 3 (GATA3) is a specific immunohistochemical (IHC) marker of breast and urothelial carcinoma. We routinely find that GATA is expressed in MM; however, GATA3 expression in SMM and its reference value for distinguishing SMM from LSC and OP remain unclear. Here, we used IHC methods to detect the expression of GATA3 and classic mesothelial markers in 17 SMM, 12 LSC, and 7 OP cases. We detected the following expression rates in SMM versus LSC cases: GATA3 (70.6% vs. 16.7%, p = 0.008), calretinin (52.9% vs. 8.3%, p = 0.019), Wilms tumor (WT)-1 (64.7% vs. 0%, p = 0.000), D2-40 (47.1% vs. 16.7%, p = 0.126), CK5/6 (35.3% vs. 25.0%, p = 0.694), and pan-cytokeratin (CKpan) (88.2% vs. 100.0%, p = 0.498). The specificities of calretinin, WT-1, and GATA3 in distinguishing SMM from LSC were 91.7%, 100%, and 83.3%, respectively, and combinations of any two of these three markers exhibited 100% specificity for SMM. Notably, the sensitivity of calretinin+/WT1+ staining for SMM was only 23.5%, which increased to 64.7% after including GATA3. Furthermore, all OP cases showed partial or diffuse expression of CKpan, WT-1, and D2-40 but no GATA3 and calretinin expression. In conclusion, GATA3 is an IHC marker with excellent sensitivity and specificity for SMM, and the combined consideration of GATA3, calretinin, and WT-1 was best for distinguishing SMM from LSC. Moreover, CKpan, WT-1, and D2-40 had no value for distinguishing SMM from OP, and GATA3 and calretinin were the most specific markers for distinguishing these two lesions.

  © 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH, DE part of Springer Nature.

• Tertiary lymphoid structures in epithelioid malignant peritoneal mesothelioma are associated with neoadjuvant chemotherapy, but not with prognosis. N. Benzerdjeb, P. Dartigues, V. Kepenekian, et al. 2021;479(4):765-772. PubMed · Publisher

  Abstract

  Epithelioid mesothelioma is the most prevalent subtype of diffuse malignant peritoneal mesothelioma. The relationship between a strong adaptive immune response and a better prognosis in malignant solid tumors is widely known. Due to the low incidence of epithelioid malignant peritoneal mesothelioma (EMPM), very little is known about their immune micro-environment. We encountered several cases of tertiary lymphoid structures in EMPM in a previous study and aimed to investigate in the same series the prevalence, clinicopathological features, and the prognostic impact associated with tertiary lymphoid structures in EMPM (TLS-EMPM). Cases of EMPM, from 1995 to 2018, were retrieved from 7 French institutions from the RENAPE Network. The predictions in terms of overall survival (OS) and progression-free survival (PFS) of TLS-EMPM were analyzed. We report 52 cases of TLS-EMPM among a series of 138 cases of EMPM. TLS-EMPM was significantly associated with neoadjuvant chemotherapy, and was not a prognostic indicator for OS (p = 0.652) and PFS (p = 0.804) in our series. TLS is a component of the host immune response to EMPM significantly associated with neoadjuvant chemotherapy, but was not a predictor of prognosis for overall and progression-free survivals in this series. These findings provide another possible etiology for tertiary lymphoid structures.

  © 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.

• Malignant mesothelioma in situ diagnosed by methylthioadenosine phosphorylase loss and homozygous deletion of CDKN2A: a case report. K. Minami, N. Jimbo, Y. Tanaka, et al. 2020;476(3):469-473. Case report PubMed · Publisher

  Abstract

  Malignant pleural mesothelioma (MPM), associated with unfavorable outcomes, is closely associated with asbestos exposure. Early detection and treatment are critical to prolong survival of patients with MPM because of the rapid progression and resistance to treatment. The recently defined malignant mesothelioma in situ (MIS) has been gaining increasing attention with advances in genome-based methods including fluorescence in situ hybridization (FISH) as well as immunohistochemistry. We herein report the case of a MIS in a 73-year-old male with a history of asbestos exposure presenting with massive pleural effusion in the right thoracic cavity. Video-assisted thoracoscopic surgery with pleural biopsy of the right side revealed a single layer of atypical mesothelial cells without invasive lesions by hematoxylin and eosin staining. However, these mesothelial cells exhibited a loss of methylthioadenosine phosphorylase (MTAP) by immunohistochemistry and homozygous deletion of CDKN2A (p16) by FISH, leading to the diagnosis of MIS.

• Occult primary cardiac lymphomas causing unexpected/sudden death or acute heart failure. A. De Martino, F. Del Re, C. Barzaghi, et al. 2020;477(4):603-607. Case report PubMed · Publisher

  Abstract

  Three cases of unexpected/sudden death (N = 2) or acute heart failure (N = 1) were investigated in our centre. The first patient died unexpectedly after surgery for cardiac tamponade and constrictive pericarditis; at autopsy, gross features mimicked a pericardial mesothelioma. The second patient died suddenly after recovering from a respiratory insufficiency episode; autopsy revealed an epicardial mass encircling the right coronary artery. The third patient presenting symptoms mimicked a fulminant myocarditis and she underwent endomyocardial biopsy. In all cases, histology disclosed a diffuse large B cell non-Hodgkin lymphoma, localized to the pericardium together with the right ventricle and the conduction system, to the epicardium and the right coronary artery or to the myocardium, respectively. Histology was crucial for the diagnosis, the atypical presentation favouring other diagnostic hypotheses. Although primary cardiac lymphoma is uncommon and usually shows a sub-acute onset, it may also cause unexpected/sudden death or acute heart failure.

2010s

• The diagnostic role of PTEN and ARID1A in serous effusions. B. Davidson, M. Pinamonti, D. Cuevas, et al. 2018;472(3):425-432. PubMed · Publisher

  Abstract

  The aim of this study was to analyze the diagnostic role of PTEN and ARID1A in effusion cytology. Effusions (n = 279), consisting of 226 carcinomas (70 ovarian, 64 breast, 36 lung, and 15 uterine corpus carcinomas; 41 carcinomas of other origin) and 53 malignant mesotheliomas, were analyzed for PTEN and ARID1A expression using immunohistochemistry. PTEN was preserved in 166 (59%) tumors, partially lost in 38 (14%), and absent in 75 (27%), with lower expression in malignant mesotheliomas compared to carcinomas, though not significantly (p = 0.084). ARID1A was preserved in 243 (88%) tumors, partially lost in 18 (6%), and absent in 18 (6%). The majority of tumors with absent ARID1A were ovarian carcinomas, predominantly of clear cell or low-grade serous type. Reactive mesothelial cells in carcinoma specimens were uniformly positive for both proteins. ARID1A mutation analysis showed no mutations in eight analyzed specimens negative by immunohistochemistry. Loss of PTEN and ARID1A expression is highly specific for malignancy in effusion pathology. Loss of PTEN is not informative of organ of origin, whereas absence of ARID1A should raise suspicion of an ovarian primary.

• Histopathologic features predict survival in diffuse pleural malignant mesothelioma on pleural biopsies. C. Habougit, B. Trombert-Paviot, G. Karpathiou, et al. 2017;470(6):639-646. PubMed · Publisher

  Abstract

  Malignant pleural mesothelioma is a rare tumor with a poor prognosis. The only universally recognized pathological prognostic factor is histopathological subtype with a shorter survival in non-epithelioid subtypes. Recently, a grading of epithelioid mesothelioma on surgical resection has been proposed. The aim of our work is to assess the prognostic role of several histopathological factors on a retrospective cohort of 116 patients diagnosed as a pleural mesothelioma for more than 95% of patients on pleural biopsy. Our work shows that mitotic count <3/10 HPF (p < 0.0001), the lack of necrosis (p = 0.0379), mild nuclear atypia (p = 0.0054), the lack of atypical mitoses (p = 0.0265), a nucleoli size <3 μm (p = 0.0139), and a nucleoli absent or visible at 200× or higher magnification (p = 0.0170) are significantly associated with a better median overall survival in epithelioid mesothelioma. The presence of atypical mitoses was found to be related to a worse median survival in non-epithelioid mesothelioma. Mitotic count, necrosis, nuclear atypia, and nucleoli size are not associated with overall survival in non-epithelioid mesothelioma. Our work highlights that histopathological prognostic factors can be assessed on pleural biopsies and can predict reliably median overall survival. This is of interest in order to define subgroups of patients who could benefit of different therapies and select patients who could benefit of surgical excision.

• miRNA regulation is important for DNA damage repair and recognition in malignant pleural mesothelioma. F.D. Mairinger, R. Werner, E. Flom, et al. 2017;470(6):627-637. PubMed · Publisher

  Abstract

  Platin-containing regimes are currently considered as state-of-the-art therapies in malignant pleural mesotheliomas (MPM) but show dissatisfying response rates ranging from 6 to 16% only. Still, the reasons for the rather poor efficacy remain largely unknown. A clear stratification of patients based on new biomarkers seems to be a promising approach to enhance clinical management, which would be a long-needed improvement for MPM patients but does not seem likely soon unless new biomarkers can be validated. Twenty-four formalin-fixed, paraffin-embedded (FFPE) tumour specimens were subjected to a miRNA expression screening of 800 important miRNAs using digital quantification via the nCounter technique (NanoString). We defined a small subset of miRNAs regulating the key enzymes involved in the repair of platin-associated DNA damage. Particularly, the TP53 pathway network for DNA damage recognition as well as genes related to the term "BRCAness" are the main miRNA targets within this context. The TP53 pathway network for DNA damage recognition as well as genes related to the term "BRCAness" are the main players for risk stratification in patients suffering from this severe disease. Taking the specific molecular profile of the tumour into account can help to enhance the clinical management prospectively and to smooth the way to better response prediction.

• Leser–Trélat syndrome in malignant mesothelioma and pulmonary adenocarcinoma: is the EGFR pathway part of the syndrome?. R.K. Jepsen, A.G. Skov, B.G. Skov. 2014;464(1):117-20. Case report PubMed · Publisher

  Abstract

  The syndrome of Leser–Trélat (LT) is characterized by the sudden appearance of multiple seborrhoeic keratoses (SKs) in association with internal occult malignancy. Usually, the syndrome has been associated with adenocarcinoma, most frequently of the gastrointestinal tract and breast. The pathogenesis is unclear but might be explained by circulating tumor-associated growth factors. We present two thoracic malignancies associated with LT: adenocarcinoma of the lung (ACL) and pleural malignant mesothelioma (MM). Both malignant tumors expressed high levels of epidermal growth factor receptors (EGFR) detected by immunohistochemistry (IHC), with membranous staining on the majority of malignant cells corresponding to maximum IHC scores of 290 and 300, respectively, for the MM and the ACL. SKs revealed a universal membranous staining throughout the entire epithelium with no difference in EGFR expression between the two cases and two controls with no malignant history. By fluorescence in situ hybridization, no amplification of the EGFR gene in malignant tumors as well as in SK lesions was observed. Further investigations are needed to see whether tumor-associated EGFR ligands/EGFR autocrine loops in malignant cells expressing high levels of EGFR protein on the surface might play a role for the development of SKs, as well as for the growth of malignant tumors in LT.

• Reproducibility of histological subtyping of malignant pleural mesothelioma. L. Brčić, M. Jakopović, I. Brčić, et al. 2014;465(6):679-85. PubMed · Publisher

  Abstract

  Malignant pleural mesothelioma (MPM) has a very poor prognosis. Although clinical stage is currently the only reliable prognostic factor, histologic subtyping reportedly also affects prognosis. Some studies propose reclassification of pleomorphic epithelioid as biphasic or sarcomatoid MPM. This study assessed prognostic significance and interobserver agreement in MPM subtyping of small biopsy specimens. We analyzed biopsy specimens, and clinical and survival data from records of 108 patients who were diagnosed between 2000 and 2010 at the Institute of Pathology University of Zagreb School of Medicine, of whom 98 had epithelioid MPM, six biphasic MPM, and four sarcomatoid MPM. Among epithelioid subtypes, 44 (44.9 %) were solid, 19 (19.4 %) tubulopapillary, 18 (18.4 %) acinar, six (6.1 %) adenomatoid, five (5.1 %) pleomorphic, four (4.1 %) trabecular, and two (2.0 %) micropapillary subtype. Interobserver reliability for histological diagnosis was found to be κ = 0.72 (P < 0.001). Median overall survival for epithelioid MPM was 10.5 months with an interquartile range (IQR) of 5.8-28.0 months but significantly shorter for the pleomorphic subtype (3 [IQR 3.0-8.0] months; P = 0.034), but not significantly different from biphasic (6.5 [IQR 3.5-15.3] months) and sarcomatoid mesothelioma (4.0 [IQR 1.3-6.8] months; P = 0.270). We found strong reproducibility of MPM subtyping with good interobserver agreement. Furthermore, our results indicate that pleomorphic subtype to be a predictor of poor prognosis and support classifying it with sarcomatoid or biphasic MPM, as patients with the pleomorphic, biphasic, or sarcomatoid subtype show similarly poor overall survival.

• Signal transducer and activator of transcription 1 (STAT1) acts like an oncogene in malignant pleural mesothelioma. L. Arzt, H. Kothmaier, I. Halbwedl, et al. 2014;465(1):79-88. PubMed · Publisher

  Abstract

  Malignant pleural mesothelioma (MPM) is the most common primary tumor of the pleura. Its incidence is increasing in Europe and the prognosis remains poor. We compared epithelioid MPM in short and long survivors, and identified signal transducer and activator of transcription 1 (STAT1) as probably being responsible for antiapoptotic signaling and chemoresistance. Six mesothelioma cell lines were evaluated by Western Blot. We also analyzed 16 epithelioid MPM tissue samples for the phosphorylation status of STAT1 and the expression of its negative regulator, the suppressor of cytokine signaling 1 (SOCS1). Formalin-fixed and paraffin-embedded tissue specimens were evaluated by protein-lysate microarray and immunohistochemistry. We found STAT1 to be highly expressed and STAT3 downregulated in MPM cell lines. The expression of STAT1 phosphorylated on tyrosine 701 (Y701) was increased by interferon-gamma (IFN-γ) treatment, whereas SOCS1 was not expressed. The expression of STAT1 phosphorylated on serine 727 (S727) was not detected in mesothelioma cell lines and was not stimulated by IFN-γ. STAT1 was phosphorylated on tyrosine 701 and serine 727 in MPM tissue samples. The expression of pSTAT1-Y701 was increased compared to pSTAT1-S727. SOCS1 was again not detectable. STAT1 is upregulated in MPM, and its action may be prolonged by a loss of the negative regulator SOCS1. STAT1 might, therefore, be a target for therapeutic intervention, with the intention to restore apoptotic mechanisms and sensitivity to chemotherapy. However, other regulatory mechanisms need to be investigated to clarify if lack of expression of SOCS1 is the only reason for sustained STAT1 expression in MPM.

• Expression and role of GLUT-1, MCT-1, and MCT-4 in malignant pleural mesothelioma. A. Mogi, K. Koga, M. Aoki, et al. 2013;462(1):83-93. PubMed · Publisher

  Abstract

  Malignant cells supply their energy needs through increased glucose consumption, producing large quantities of lactic acid via glycolysis. Glucose transporters (GLUTs) and monocarboxylate transporters (MCTs) are therefore commonly up-regulated in human malignancies to mediate glucose influx and lactic acid efflux, respectively. However, their roles in malignant pleural mesothelioma (MPM) have not been fully elucidated. Here, we evaluated GLUT-1, MCT-1, and MCT-4 expression in human MPM and reactive mesothelial hyperplasia (RMH) and elucidated their biological role in vitro. GLUT-1, MCT-1, and MCT-4 expression was determined in human MPM (n = 35) and RMH (n = 20) specimens by immunohistochemistry and in frozen tissue, and MPM cell lines, by real-time reverse transcription-polymerase chain reaction and western blot analysis. GLUT-1, MCT-1, and MCT-4 functions in MPM were evaluated by transfection with small interfering RNA. Immunohistochemical analysis revealed higher levels of GLUT-1, MCT-1, and MCT-4 in MPM than in RMH. Additionally, GLUT-1, MCT-1, and MCT-4 mRNA levels were higher in MPM than in non-neoplastic mesothelial cell lines. The siRNA-mediated knockdown of GLUT-1 or MCT-1 significantly suppressed tumor cell proliferation, and MCT-1 silencing inhibited invasion and induced apoptosis. Taken together, these results indicate that combined application of GLUT-1, MCT-1, and MCT-4 immunohistochemistry might be useful in differentiating MPM from RMH and suggest that MCT-1plays an important biological role.

• Is survivin expression prognostic or predictive in malignant pleural mesothelioma?. J. Hmeljak, N. Erčulj, V. Dolžan, et al. 2013;462(3):315-21. PubMed · Publisher

  Abstract

  Malignant pleural mesothelioma is an incurable cancer strongly associated with asbestos exposure and characterised by poor response to treatment. The inhibitor-of-apoptosis protein family member survivin is involved in apoptosis and proliferation and is expressed in cancer cells only. The aims of the present study were to elucidate whether survivin expression is associated with tumour cell apoptosis and proliferation and to assess the prognostic and predictive value of survivin expression in malignant pleural mesothelioma. Archival pleural mesothelioma tissue samples from 101 patients were immunohistochemically analysed for nuclear expression of survivin, for proliferation with the use of Ki-67 as marker and for apoptosis using active caspase-3 as a marker. Staining results and clinical data were included in a survival analysis. Survivin was highly expressed in tumour cell nuclei in all samples and this correlated positively with both apoptosis and proliferation, but did not have a significant prognostic value. We found significantly higher survivin expression in patients who responded to chemotherapy compared to patients with progressive disease. Survivin expression might contribute to treatment response prediction, but survivin expression in malignant pleural mesothelioma did not have prognostic significance.

• Monoclonal antibody HBME-1 reacts with a minor subset of B cells with villous surface and can be useful in the diagnosis of hairy cell leukemia and other indolent lymphoproliferations of villous B lymphocytes. L. Krenács, J. Tóth-Lipták, J. Demeter, et al. 2013;463(6):787-94. PubMed · Publisher

  Abstract

  The Hector Battifora mesothelial epitope-1 (HBME-1) monoclonal antibody has been generated against human mesothelioma cells and recognizes a biochemically unknown membrane epitope. We have accidentally found that the HBME-1 reacts with scattered lymphocytes showing villous surface in hyperplastic lymphoid tissue. To evaluate its reactivity pattern, we have performed a consecutive immunohistochemical study in nonneoplastic bone marrow and lymphoid samples (n = 40), as well as in malignant lymphoproliferations (n = 427), including hairy cell leukemia (HCL) (n = 72), HCL variant (HCL-v) (n = 13), splenic diffuse red pulp small B cell lymphoma (SDRPL) (n = 8), splenic B cell marginal zone lymphoma (SMZL) (n = 59), and splenic B cell lymphoma/leukemia, not further classifiable on bone marrow morphology (SBCL) (n = 37) cases. The staining pattern of HBME-1 was compared to DBA.44. HBME-1(+) villous lymphocytes were constantly detected in low number in nonneoplastic lymphoid tissues. With multicolor immunofluorescence staining, HBME-1(+) lymphocytes showed a CD20(+)/CD79a(+)/IgM(+) B cell phenotype. In B cell lymphoproliferations of villous lymphocytes, HBME-1 reactivity was demonstrated in 96 % of HCL, 39 % of HCL-v, 50 % of SDRPL, 12 % of SMZL, and 19 % of SBCL cases. Nodal and extranodal marginal zone lymphoma cases were positive in 12 % of the cases. A small minority (4 %) of the other B cell lymphomas and no T cell lymphoma revealed tumor cell reactivity with HBME-1. In conclusion, our study has established that HBME-1 reacts with a minor subset of B lymphocytes and a small proportion of B cell lymphomas, which has not been described previously. We suggest that HBME-1 can be a useful marker in the diagnosis of HCL and other indolent lymphoproliferations of villous B lymphocytes.

• Carbonic anhydrase IX is expressed in mesothelioma and metastatic clear cell renal cell carcinoma of the lung. M.L. Ramsey, B.J. Yuh, M.T. Johnson, et al. 2012;460(1):89-93. PubMed · Publisher

  Abstract

  High immunohistochemical expression of carbonic anhydrase IX (CAIX) is found in clear cell renal cell carcinoma (ccRCC), but no studies have assessed CAIX in metastatic ccRCC (mccRCC) of the lung. As 75% of patients with mccRCC show lung involvement, characterization of protein expression in these lesions is warranted. This investigation analyzed CAIX immunohistochemical expression in pulmonary/pleural tumors including mccRCC (n = 22), mesothelioma (n = 19), squamous cell carcinoma (n = 27), small cell carcinoma (n = 9), and adenocarcinoma (n = 49), as well as other mesothelial lesions (n = 4). Membranous immunoreactivity was semiquantitatively evaluated for percent of cells stained and intensity. All cases of mccRCC (1+, 4.5%; 3+, 95.5%) and mesothelioma (2+, 10.5%; 3+, 89.5%) expressed CAIX. Most cases of lung squamous cell carcinoma (0, 11.1%; 1+, 25.9%; 2+, 22.2%; 3+, 40.7%) and small cell carcinoma were reactive (0, 11.1%; 1+, 22.2%; 2+, 33.3%; 3+, 33.3%), while CAIX was detected less frequently in pulmonary adenocarcinoma (0, 61.2%; 1+, 16.3%; 2+, 12.2%; 3+, 10.2%). In addition, CAIX was positive in adenomatoid tumor (3+, 100%) and mesothelial hyperplasia (3+, 100%). We demonstrate that CAIX is sensitive for mccRCC within the lung and a novel immunohistochemical marker for mesothelial proliferations, notably mesothelioma. Variable immunoreactivity is present among primary pulmonary epithelial tumors. Knowledge of expression overlap between these entities may prevent an incorrect interpretation of immunohistochemical results, particularly when limited tissue is available. As new carbonic anhydrase inhibitors are being evaluated, testing additional tumors for CAIX may lead to novel treatment options.

• Rab25 is overexpressed in Müllerian serous carcinoma compared to malignant mesothelioma. K. Brusegard, H.T. Stavnes, D.A. Nymoen, et al. 2012;460(2):193-202. PubMed · Publisher

  Abstract

  Rab25, an epithelial-specific member of the Rab family of small GTPases, was previously shown to be overexpressed in ovarian/primary peritoneal serous carcinoma compared to malignant mesothelioma using gene expression arrays. The objective of this study was to validate this finding at the mRNA and protein level. Quantitative PCR analysis of 112 Müllerian serous carcinomas (84 effusions, 28 primary ovarian carcinomas) and 22 malignant mesotheliomas (19 effusions, 3 solid specimens) showed significantly higher RAB25 mRNA expression in the former tumor (p < 0.001). Immunohistochemical analysis of Rab25 protein expression in 245 effusions showed significantly higher expression of this protein in Müllerian serous carcinoma compared to malignant mesothelioma (189/209 vs. 12/36 positive tumors, respectively; p < 0.001). Immunostaining of 101 patient-matched solid Müllerian carcinoma specimens (34 primary carcinomas, 67 metastases) showed expression levels comparable to effusions (94/101 positive specimens; p > 0.05). Rab25 mRNA and protein expression levels in Müllerian carcinoma effusions did not correlate with overall or progression-free survival. Our data confirm that Rab25 effectively differentiates Müllerian carcinomas from malignant mesothelioma at the mRNA and protein level, suggesting a role in the diagnostic work-up of serosal cancers.

• Periostin expression and epithelial-mesenchymal transition in cancer: a review and an update. L. Morra, H. Moch. 2011;459(5):465-75. Review PubMed · Publisher · Free full text

  Abstract

  Periostin, also called osteoblast-specific factor 2, is a secreted cell adhesion protein, which shares a homology with the insect cell adhesion molecule fasciclin I. It has been shown to be an important regulator of bone and tooth formation and maintenance, and of cardiac development and healing. Recent studies revealed that periostin plays an important role in tumor development and is upregulated in a wide variety of cancers such as colon, pancreatic, ovarian, breast, head and neck, thyroid, and gastric cancer as well as in neuroblastoma. Periostin binding to the integrins activates the Akt/PKB- and FAK-mediated signaling pathways which lead to increased cell survival, angiogenesis, invasion, metastasis, and importantly, epithelial-mesenchymal transition of carcinoma cells. In this review we summarize recent clinicopathological studies that have investigated periostin expression in lung, kidney, prostate, liver cancer, and malignant pleural mesothelioma and discuss the role of periostin isoforms in tumorigenesis and their potential as targets for stroma-targeted anticancer therapy.

• TLE1 is expressed in the majority of primary pleuropulmonary synovial sarcomas. L.S. Lino-Silva, J.P. Flores-Gutiérrez, N. Vilches-Cisneros, et al. 2011;459(6):615-21. PubMed · Publisher

  Abstract

  Pleuropulmonary synovial sarcoma (PPSS) is a rare entity, similar to synovial sarcoma of soft tissue (STSS). There are 120 published cases of PPSS, but no studies have explored the expression of TLE1. In soft tissues, it has been proven a useful marker, but in tumors of other sites, its expression has not been explored. The main objective was to study the expression and diagnostic sensitivity and specificity of TLE1 in a group of PPSS, of which the diagnosis was corroborated by fluorescence in situ hybridization confirming t(X;18) in a tissue microarray. Immunohistochemistry including TLE1, vimentin, CD99, CD56, bcl-2, AE1-AE3, EMA, CD34, CK7, CK19, calponin, and S-100 was performed on all PPSS and on 25 control cases (five carcinomas, ten mesotheliomas, and ten thoracic sarcomas). TLE1 was positive in 11 cases (73.3%); bcl-2 and vimentin in 100%; calponin and CD56 in 26.6%; CD99, CK AE1-AE3, CK19, CK7, and EMA in 80%; and S100 negative in all. The only biphasic PPSS was positive for epithelial markers only in the epithelial component. TLE1 was negative in all control cases. TLE1 is expressed in 73% of PPSS, a value inferior to that reported in STSS, but is highly specific for PPSS. TLE1 may therefore be of value in the differential diagnosis of PPSS, but should be used in a panel of antibodies.

  © Springer-Verlag 2011

• Localized intrapancreatic malignant mesothelioma: a rare entity that may be confused with other pancreatic neoplasms. R. Espinal-Witter, E.L. Servais, D.S. Klimstra, et al. 2010;456(4):455-61. Case report · Review PubMed · Publisher

  Abstract

  Malignant mesothelioma usually presents with diffuse involvement of the pleura or peritoneum. Circumscribed or localized malignant mesothelioma has been described in these locations, as well as the viscera, in which case it may cause diagnostic confusion with other, more common entities. Herein, we describe the first well-documented case of primary intrapancreatic malignant mesothelioma in the English literature. The patient was an otherwise healthy 39-year-old woman who presented with a symptomatic mass in the head of the pancreas that was completely resected via pancreaticoduodenectomy. The tumor was composed of cysts, papillae, and tubules lined by cells with abundant eosinophilic cytoplasm and immunohistochemically expressed CA-125, calretinin, and D2-40. Follow-up revealed no evidence of residual or recurrent disease 32 months after surgery. This report also describes the clinical and pathologic characteristics of an intrapancreatic mesothelioma and provides a review of the literature regarding entities that may be considered in the differential diagnosis of this tumor.

• TLE1 expression in malignant mesothelioma. A. Matsuyama, M. Hisaoka, M. Iwasaki, et al. 2010;457(5):577-83. PubMed · Publisher

  Abstract

  Malignant mesothelioma, an aggressive and often lethal tumor commonly associated with asbestos exposure, has been morphologically classified into epithelial, biphasic, and sarcomatoid subtypes. Histological distinction between biphasic or sarcomatoid mesothelioma and synovial sarcoma may be problematic in certain circumstances of intrathoracic location because of their similar clinicopathologic features, including not only their morphology but also occasional positive immunoreaction of mesothelioma markers. TLE1, which plays an important role in Wnt pathway, has been shown to be a specific marker for synovial sarcoma and diagnostically is useful; however, TLE1 expression in malignant mesotheliomas has not been fully evaluated. We immunohistochemically examined the expression of TLE1, factors related to the Wnt pathway including β-catenin and cyclin D1, and mesothelioma markers including calretinin, HBME-1, cytokeratin 5/6, and thrombomodulin in 29 malignant mesotheliomas. TLE1 was variably expressed in 28 malignant mesotheliomas regardless of histomorphological subtype with >25% of positive cells in 20 cases (69.0%). There was no evidence of association of TLE1 expression with immunoreactivity to other markers. Our study showed no or limited value of the immunohistochemical TLE1 expression in distinguishing malignant mesothelioma and synovial sarcoma.

2000s

• Lymphangiomatoid pattern in diffuse malignant mesothelioma of the pleura: a report of six cases. R. Ruangchira-urai, E.J. Mark. 2009;455(2):143-8. Case report PubMed · Publisher

  Abstract

  The multiplicity of epithelioid and mesenchymal forms of diffuse malignant mesothelioma includes patterns that may mimic another process. Identification of the multiplicity of patterns may help in the diagnosis of diffuse malignant mesothelioma. One pattern that has not been described is lymphangiomatoid. We observed six cases with ovoid or elongated or irregular anastomosing vascular-like spaces lined by flattened cells simulating lymphangioma. The luminal spaces could contain proteinaceous material simulating lymph but not erythrocytes. The cells lining the spaces were mesothelial by immunohistochemical staining. The lymphangiomatoid areas never constituted more than 40% of the area of the tumor on the slides. When seen in more solid areas of tumor, the lymphangiomatoid structures generally did not produce diagnostic difficulty. However, when seen at the edge of solid tumor or forming an irregular nodule or invading into adjacent adipose tissue, these lymphangiomatoid structures could be confusing. All six patients had been exposed to asbestos either by occupation or by spousal exposure. Three patients received chemotherapy. One patient died of diffuse malignant mesothelioma of the pleura.

• Nodular glomeruloid pleuroblastoma: a biphasic pleural-based malignant tumor with immature elements. P. Mukonoweshuro, R.L. Attanoos, M.E. Smith. 2006;449(2):253-7. Case report PubMed · Publisher

  Abstract

  An unusual diffuse pleural-based tumor arising in an elderly asbestos-exposed male is presented. The tumor presented in a 72-year-old male with a 30-year history of dockyard work and likely significant asbestos exposure. Macroscopically, at post mortem, the pleural tumor diffusely encased the right lung and was composed of an admixture of neoplastic macro-, and by light microscopy, micro-nodules. Histologically, the tumor had a biphasic growth pattern with glomeruloid epithelioid elements and immature blastematous mesenchymal stroma. Immunophenotypically, the tumor had a complex pattern with epithelioid elements expressing cytokeratins, desmin, carcinoembryonic antigen (CEA), Ber EP4 and E-cadherin. The diagnostic problems and medicolegal issues surrounding the diagnosis and differentiation from malignant pleural mesothelioma and other tumors are discussed.

• Clear cell mesothelioma presenting as an incarcerated abdominal hernia. N.G. Ordóñez. 2005;447(5):823-7. Case report PubMed · Publisher

  Abstract

  A clear cell mesothelioma presenting as an incarcerated ventral abdominal hernia in a 67-year-old man who had no history of asbestos exposure is described. The cause of the cytoplasmic clearing was the presence of large amounts of glycogen. Although uncommon, this variant of mesothelioma is important to recognize because it can be easily confused with other clear cell tumors involving the serosal membranes. Significant recent advances in the immunohistochemistry of epithelioid mesothelioma are briefly reviewed because immunohistochemical studies can be helpful in establishing the correct diagnosis.

• Malignant mesothelioma with a pronounced myxoid stroma: a clinical and pathological evaluation of 19 cases. J. Shia, J. Qin, R.A. Erlandson, et al. 2005;447(5):828-34. PubMed · Publisher

  Abstract

  Mesothelioma with a pronounced myxoid stroma has been identified as a morphological pattern that might portend a better prognosis. Reports on this type of cases are few. Its clinical and pathological features are not defined. In this study, we identified 19 such cases from a series of 234 pleural mesotheliomas and performed a comprehensive clinical and pathological analysis. The inclusion criteria were mesotheliomas with at least 50% of the tumor exhibiting a pronounced myxoid stroma that occupied more than 50% of the tumor volume (designated as myxoid mesothelioma). There were ten males and nine females, with a median age of 58 years. Forty seven percent of the patients had probable or definite asbestos exposure. Patients presented at various stages [International Mesothelioma Interest Group (IMIG) stage II, 4; stage III, 9; and stage IV, 6]. Most (16/19) patients were treated by extrapleural pneumonectomy with adjuvant radiation or chemotherapy or both. Overall, the median survival rate was 36 months (median follow-up time, 17 months), and the 2-year survival rate was 79%. Histologically, the tumor cell component was entirely epithelioid without significant cytologic atypia. The myxoid material stained positive for Alcian blue, and the staining diminished after treatment with hyaluronidase in 12 of 12 cases. The tumor cells showed a typical mesothelial immunophenotype. Ultrastructurally, all six tumors examined had typical mesothelial-type surface microvilli and a moderately electron-dense extracellular amorphous material that often formed a haze enmeshing the surface microvilli. Hyaluronic acid-type, fern-like crystals were noted in all cases. These findings show that myxoid mesotheliomas represent a group of epithelioid mesotheliomas that have retained the secretory activity of normal mesothelium. Patients may present at different stages, but survival appears to be superior to that of epithelioid mesotheliomas in general. Our study emphasizes the need for better attention to histologic subtypes, particularly in the context of prognostically or therapeutically oriented investigations of this lethal disease.

• Reduced Fhit protein expression in human malignant mesothelioma. L. Pylkkänen, H. Wolff, T. Stjernvall, et al. 2004;444(1):43-8. PubMed · Publisher

  Abstract

  Human malignant mesothelioma (MM) is an aggressive neoplasm related to occupational exposure to asbestos and characterised by a long latency time. Multiple chromosomal deletions and DNA losses have been revealed in MM by studies performed with karyotypic, comparative genomic hybridisation and loss of heterozygosity (LOH) analyses. Among frequently deleted chromosomal sites, LOH at chromosome 3p has been detected in MM, suggesting the presence of one or several tumour suppressor genes that have an important role in development of the disease. The FHIT (fragile histidine triad) tumour suppressor gene, located at 3p14.2, has been proposed to be a target to major human lung carcinogens, such as tobacco smoke and asbestos. Although many studies have indicated decreased Fhit protein expression in a variety of malignancies, there is no report of FHIT gene aberrations or Fhit protein abnormalities in MM. We examined expression of the Fhit protein and LOH at the FHIT gene in malignant mesothelioma. Altogether, 13 paraffin embedded MM tumours were analysed for Fhit protein expression, and 21 fresh tumours and 10 cell cultures for LOH at the FHIT gene with two intragenic microsatellite markers. All tumours showed less intense immunostaining than normal bronchial epithelium or mesothelium. Fhit expression was absent or reduced in 54% (7 of 13) of the tumours, with the weakest staining observed in poorly differentiated areas. Allele loss was seen in 3 of 10 (30%) of the MM cell lines, but only in 1 of the 21 fresh tumours studied, suggesting concealment of LOH by normal cells present in MM tumours. In conclusion, our present data indicate a frequent decrease of Fhit protein expression, thus supporting the significance of FHIT inactivation in development of MM.

• E-cadherin, E-selectin and vascular cell adhesion molecule: immunohistochemical markers for differentiation between mesothelioma and metastatic pulmonary adenocarcinoma?. A.M. Müller, A. Weichert, K.M. Müller. 2002;441(1):41-6. PubMed · Publisher

  Abstract

  Pleural mesotheliomas, especially pure epithelioid mesotheliomas, may histologically be easily confused with peripheral pulmonary adenocarcinomas or pleural carcinosis. As there is no specific antibody for mesotheliomas, today a panel of immunohistochemical markers is used for the differential diagnosis of these two tumour entities. In search of further significant antibodies for application onto formalin-fixed, paraffin-embedded tissue, we immunohistochemically investigated the expression pattern of three adhesion molecules: vascular cell adhesion molecule (VCAM), E-selectin and E-cadherin. A comparatively large number of 44 mesotheliomas (15 epithelioid, 15 biphasic, 14 sarcomatoid) and 18 peripheral pulmonary adenocarcinomas were analysed. While for these two tumour entities there were no significant differences of the staining patterns for VCAM and E-selectin, there were significant differences in the expression of E-cadherin: while nearly all adenocarcinomas stained positively, there was almost no staining reaction of the mesotheliomas. Therefore, E-cadherin -- in contrast to E-selectin and VCAM -- appears to be a further relevant immunohistochemical marker for the distinction between adenocarcinomas and mesotheliomas.

• Patterns of chromosomal imbalances in benign solitary fibrous tumours of the pleura. M. Krismann, H. Adams, M. Jaworska, et al. 2000;437(3):248-55. PubMed · Publisher

  Abstract

  Solitary fibrous tumours (SFTs) of the pleura, in contrast to malignant mesothelioma, occur independently of previous asbestos exposure. They are benign tumours, but may recur if the stalk to the adjacent pleural or lung tissue remains in situ during surgical removal. The molecular pathology of SFTs is largely unknown. We used comparative genomic hybridisation (CGH) to characterise 12 localised SFTs and 12 predominantly sarcomatoid mesotheliomas. Fifty-eight percent of the investigated SFTs did not show any chromosomal imbalances. The most frequent defects were losses on chromosome arms 13q (33%), 4q and 21q (17% each). Significant gains were seen at chromosome 8 and at 15q in two cases each. There was no correlation between tumour size and molecular pathology findings. In contrast, 75% of the mesotheliomas carried chromosomal defects. On average, the mesotheliomas showed over three times as many defects per tumour as the SFTs. Localisation of several frequent losses and gains were similar to those of the SFTs. Therefore, in individual cases, a clear distinction between SFTs and sarcomatoid mesotheliomas is not possible based on CGH analysis alone. Further molecular characterisation of this rare tumour entity will be necessary to elucidate possible genes involved in early tumorigenesis.

1990s

• Detection of cancer cells in effusions from patients diagnosed with gynaecological malignancies. Evaluation of five epithelial markers. B. Davidson, B. Risberg, G. Kristensen, et al. 1999;435(1):43-9. PubMed · Publisher

  Abstract

  The detection of malignant cells in pleural, peritoneal, and pericardial fluids of cancer patients marks the presence of metastatic disease and is associated with a grave prognosis. We evaluated five epithelial markers for the detection of cancer cells in 94 fresh pleural, peritoneal and pericardial effusions. Eighty-four of the samples were regarded as adequate for analysis after evaluation of cytological smears, including 61 samples from patients known to have gynaecological neoplasms. The other 23 samples were from patients with various non-gynaecological malignancies or tumours of unknown origin. Our control cases were 10 fallopian tubes not affected by any malignancy and 12 malignant mesotheliomas. Cell blocks from all cases were stained for CA-125, BerEP4, carcinoembryonic antigen (CEA), BG8 (Lewis Y blood antigen), and B72.3 (TAG-72). Fifty-one of 84 cases were diagnosed as malignant or suggestive of malignancy in cytological smears and/or cell block sections. However, staining for epithelial markers highlighted the presence of malignant cells in 7 additional cases. When membrane staining was evaluated, the sensitivity of the markers studied in detecting malignant cells was as follows: CA-125: 88%, BerEP4: 78%, CEA: 26%, BG8: 86%, B72.3: 79%. Membrane positivity for CEA, B72.3 and BerEP4 was not detected in reactive mesothelial cells. However, membranous staining in mesothelial cells was evident in 13% and 31% of cases with the use of BG8 and CA-125, respectively. Weak cytoplasmic staining for CEA was observed in mesothelial cells in 2 cases. When Ber-EP4, B72.3, and BG8 staining results in cancer cells were combined, the following sensitivity levels were observed: BG8+B72.3: 91%; BG8+Ber-EP4: 90%; B72.3+Ber-EP4: 93%; BG8+Ber-EP4+B72.3: 95%. The detection of malignant cells in effusions is facilitated by the use of immunocytochemistry using a wide panel of antibodies. BerEP4 and B72.3 appear to be the best markers when both sensitivity and specificity are considered, followed by BG8, while CEA and CA-125 have a limited role in the detection of metastases from gynaecological tumours owing to the low sensitivity of the former and the low specificity of the latter. Analysis of all staining results should be based on a thorough morphological examination.

• Expression of vascular endothelial growth factor in diffuse malignant pleural mesothelioma. J.E. König, E. Tolnay, T. Wiethege, et al. 1999;435(1):8-12. PubMed · Publisher

  Abstract

  Angiogenesis is an important part of normal and pathological processes, including tumour growth, metastasis, inflammation and wound healing. VEGF is the best known angiogenic factor, implicated in tumour-associated microvascular hyperpermeability and carcinogenesis. We investigated 103 malignant pleural mesotheliomas, analysing the expression of vascular endothelial growth factor using immunohistochemistry and in situ hybridization. The grade of microvessel density was assessed with the aid of anti-factor-VIII antibodies. An increased expression of VEGF was found in biphasic and epithelioid mesotheliomas, correlating in a statistically significant manner (P<0.042). In situ hybridization confirmed the specificity of VEGF mRNA expression. There was a robust correlation between VEGF expression and increased microvessel density (P<0.001), and positive mesotheliomas had significantly higher microvessel densities than negative specimens. There was also a significant correlation between microvessel density and histological pattern. As growth pattern tended towards biphasic and sarcomatoid mesotheliomas the density of micovessels decreased (P<0.05).

• Kaposi's sarcoma following malignant mesothelioma. V. Ascoli, C.C. Scalzo, M. Andreoni, et al. 1999;435(6):612-5. Case report PubMed · Publisher

  Abstract

  We report the unusual occurrence of Kaposi's sarcoma following asbestos-related malignant mesothelioma, in a human deficiency virus (HIV)-negative Italian man. Seropositivity to human herpes virus 8 (HHV8) was documented at the time of mesothelioma diagnosis and preceded the onset of Kaposi' sarcoma with a time lapse of 13 months. HHV8 DNA was detected by polymerase chain reaction in lesional Kaposi's sarcoma but not within mesothelioma. By immunostaining, mesothelioma cells expressed interleukin-6 and platelet-derived growth factor, which are important for survival of Kaposi's sarcoma cells. Besides the possibility of a casual association, we hypothesize that mesothelioma-linked factors may have contributed to the development of Kaposi's sarcoma in the presence of HHV8 infection.

• SV40 large T-antigen and human pleural mesothelioma. Screening by polymerase chain reaction and tyramine-amplified immunohistochemistry. K. Dhaene, A. Verhulst, E. Van Marck. 1999;435(1):1-7. PubMed · Publisher

  Abstract

  DNA-like sequences of the p53 and pRB-inactivating simian virus 40 large T-antigen (SV40 LTag) have recently been found in mesotheliomas in the United States and several European countries. Nuclear expression of SV40 LTag, possibly in concert with detectable telomerase activity, could be responsible for immortalisation of (pre)malignant clones, as suggested by the mesothelioma-specific latency period. Depending on the antibody used, different results have been observed regarding the subcellular expression of SV40 LTag in mesotheliomas with SV40 LTag-like DNA sequences. In this study, we screened 28 Belgian mesothelioma tumour samples for the presence of SV40 LTag-like DNA and its gene product by polymerase chain reaction amplification, using the SV.for3/SV.rev primer set, and by tyramine-amplified immunohistochemistry, using the pAb419 and the pAb101 SV40 LTag antibodies. Amplicons were found in 13 of the 28 (46%) mesotheliomas. Cytoplasmic, but no nuclear, staining was found in 10 of these 13 cases. Although our study confirms the presence of SV40 LTag-like DNA sequences in Belgian mesotheliomas, we did not detect nuclear expression of the viral oncoprotein, which makes a pathogenic role of SV40 LTag in mesothelioma carcinogenesis questionable.

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