Kao SC, Lee K, Armstrong NJ, Clarke S, Vardy J, van Zandwijk N, Reid G, Burn J, McCaughan BC, Henderson DW, Klebe S.

*Asbestos Diseases Research Institute, Bernie Banton Centre, Concord, Australia †Department of Medical Oncology, Sydney Cancer Centre, Concord, Australia ‡The University of Sydney, Sydney, Australia §Department of Anatomical Pathology, Concord Repatriation General Hospital, Concord, Australia ||Cancer Program, Garvan Institute of Medical Research, Darlinghurst, Australia ¶Davies Campbell de Lambert Pathology, Sydney, Australia **Department of Cardiothoracic Surgery, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia ††Department of Anatomical Pathology, Flinders Medical Centre and SA Pathology, Adelaide, South Australia, Australia.

Abstract

Aims: Tissue microarray (TMA) technology has been utilised for assessment of cancers including malignant pleural mesothelioma (MPM). Given the intralesional heterogeneity of MPM, it is questionable if TMAs can adequately represent MPMs. We here investigate the validity of TMAs for MPM.

Methods: TMAs were constructed from at least five cores for each of 80 archival tumours processed by two centres between 1994 and 2009. The percentage of cases correctly subtyped on TMAs compared with whole sections, in relation to the number of cores analysed, was calculated. Immunohistochemical labelling for calretinin and D2-40 was performed on TMAs and whole sections. To evaluate the validity of quantitative immunohistochemistry, percentages of positive cells were recorded and two-way analysis of variance (ANOVA) performed.

Results: Five cores were assessable for 91% of patients. Four cores were sufficient to reach concordance with the whole-section result in 98% of cases for calretinin and 99% for D2-40. The correlation of the quantitative scores between the whole section and TMA cores was statistically significant (D2-40, rho = 0.84, p < 2.2e-16; calretinin, rho = 0.65, p = 7.9e-11). Neither the origin nor age of the blocks affected the results.

Conclusion: If a minimum of four cores is used, TMA is an appropriate method for immunohistochemistry in MPM.

Goyal M, Kodandapani S, Sharanabasappa SN, Palanki SD.

Department of Laboratory Medicine, Indo-American Cancer Institute and Research Centre, Hyderabad, India.

Abstract

Mesothelial cell inclusions in lymph nodes are of rare occurrence and can be mistaken as metastatic adenocarcinomas, mesothelioma or sinus histiocytosis. These are usually found in mediastinal and abdominal lymph nodes and are associated with effusions. We report a case of benign mesothelial cell inclusions in cervical lymph nodes, which was associated with chylous effusion, and immunohistochemistry revealed unusual weak cytoplasmic epithelial membrane antigen positivity in the cells.

Keywords: Adenocarcinoma, chylous effusion, epithelial membrane antigen, mesothelial cell inclusions

Ana Slipicevic, MSca, Geir Frode Øy, MScb, Inger Cecilie Askildt, BSca, Arild Holth, BSca, Ellen Hellesylt, BSca, Vivi Ann Flørenes, PhDa, Ben Davidson, MD, PhD

Division of Pathology, Norwegian Radium Hospital, Rikshospitalet Medical Center, N-0310 Oslo, Norway.

Abstract

We recently reported on higher expression of the insulin-like growth factor pathway genes IGF-II and IGFBP3 in serous ovarian/peritoneal carcinoma compared to malignant peritoneal mesothelioma. The present study analyzed the diagnostic and clinical role of these proteins in serous effusions. Effusions (n = 327), including 294 carcinomas (205 ovarian, 48 breast, 17 cervical/endometrial, 12 lung, 12 gastrointestinal/genitourinary) and 33 malignant mesotheliomas, were immunostained for insulin-like growth factor-II and insulin-like growth factor binding protein-3. Surgical ovarian carcinoma (n = 124) and peritoneal mesothelioma (n = 18) specimens were additionally studied. Insulin-like growth factor binding protein-3 levels were measured in 148 effusion supernatants (114 ovarian carcinomas, 18 breast carcinomas, 16 mesotheliomas) using enzyme-linked immunosorbent assay. Insulin-like growth factor binding protein-3 promoter methylation was analyzed in 11 ovarian carcinoma effusions. Insulin-like growth factor binding protein-3 (P = .002) and insulin-like growth factor-II (P < .001) expression by immunohistochemistry was significantly higher in carcinomas compared to mesotheliomas, with diagnostic sensitivity of 77% and 70% and specificity of 55% and 70%, respectively. In surgical specimens, insulin-like growth factor binding protein-3 expression was higher in ovarian carcinomas compared to peritoneal mesotheliomas (P = .007), whereas insulin-like growth factor-II expression was comparable (P = .505). Insulin-like growth factor binding protein-3 levels by enzyme-linked immunosorbent assay were comparable in the 3 analyzed cancer types. Insulin-like growth factor binding protein-3 promoter methylation was found in 6 of 11 effusions. High insulin-like growth factor binding protein-3 expression in prechemotherapy and high insulin-like growth factor-II expression in postchemotherapy ovarian carcinoma effusions correlated with poor overall survival (P = .031 and P = .024, respectively). Insulin-like growth factor-II expression in postchemotherapy effusions was an independent prognostic factor in Cox multivariate analysis (P = .04). In conclusion, insulin-like growth factor-II and insulin-like growth factor binding protein-3 are more frequently expressed in metastatic carcinomas compared to mesothelioma in effusions but are less specific than currently used markers. Insulin-like growth factor-II and insulin-like growth factor binding protein-3 may be novel prognostic markers in metastatic ovarian carcinoma.

Keywords: Insulin-like growth factor, Effusions, Carcinoma, Mesothelioma, Survival

Davidson B.

Division of Pathology, Norwegian Radium Hospital, Rikshospitalet University Hospital, Oslo, Norway. ben.davidson@medisin.uio.no

Abstract

Malignant mesothelioma is a primary cancer of the serosal cavities, an anatomic site that is also frequently affected by metastatic disease, predominantly from primary carcinomas of the lung, breast, and ovary. Advances in immunohistochemistry have resulted in improved diagnostic sensitivity and specificity in the differential diagnosis between metastatic adenocarcinoma and malignant mesothelioma in both cytological and histological material. Recently, the author’s group applied high throughput technology to the identification of new markers that may aid in differentiating malignant mesothelioma from ovarian and peritoneal serous carcinoma, tumors with closely related histogenesis and antigenic profile. In addition to the improved tools available for serosal cancer diagnosis, knowledge regarding the biology of malignant mesothelioma has been accumulating in recent years. This review presents current data regarding the diagnostic and biological aspects of malignant mesothelioma.

Kalof AN, Cooper K.

Department of Pathology, University of Vermont/Fletcher Allen Health Care, Burlington, VT 05401, USA. alexandra.kalof@vtmednet.org Abstract

D2-40 is a commercially available monoclonal antibody directed against human podoplanin, a transmembrane mucoprotein that is expressed in lymphatic endothelial cells. Since its introduction, D2-40 immunoexpression has been described in a variety of lymphovascular neoplasms including lymphangioma, Kaposi sarcoma, and hemangioendothelioma, as well as nonvascular neoplasms such as epithelioid mesothelioma, seminoma, and hemangioblastoma. More recently, D2-40 immunoexpression has been reported in primary adrenal cortical tumors, schwannomas, and adnexal tumors of the skin. This brief review provides an update on the ever-expanding proposed applications of D2-40 immunohistochemistry in surgical pathology.

Lee JM, Pou K, Sadow PM, Chen H, Hu B, Hewison M, Adams JS, Sugarbaker DJ, Fisher ND.

Division of Thoracic Surgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA. jaymoonlee@mednet.ucla.edu

Abstract

Objective: To report a case of coincident hypercalcemia and Cushing syndrome arising from mesothelioma.

Methods: We describe the clinical, laboratory, imaging, and pathologic findings of a patient with malignant pleural mesothelioma and elucidate the underlying biologic mechanisms resulting in concurrent overexpression of steroid and polypeptide hormones.

Results: A 62-year-old woman presented with chest discomfort and cough. Radiologic imaging revealed a diffuse pleural-based mass encasing the right lung. There was no invasion into the chest wall, diaphragm, or mediastinum, and there was no distant disease. Laboratory analyses documented hypercalcemia and Cushing syndrome, which were due to ectopic overproduction of 1,25-dihydroxyvitamin D (1,25[OH]₂D) and corticotropin. Surgical resection resulted in normocalcemia with normalization of serum 1,25(OH)₂D and reduction in hypercortisolemia. The extrapleural pneumonectomy specimen revealed overexpression of the 1,25(OH)₂D synthetic enzyme 25-hydroxyvitamin-D-1alpha-hydroxylase (1alpha-hydroxylase) and underexpression of the 1,25(OH)₂D catabolic enzyme 24-hydroxylase. Immunohistochemistry and electron microscopy demonstrated corticotropin and secretory granules in the tumor tissue.

Conclusion: These findings support the evidence for a paracrine role of vitamin D in the resistance of the human host to antigen.

Tamiya M, Yamane H, Terada H, Matsuno O, Yamamoto S.

Respiratory Department, NHO Osakaminami Medical Center.

Abstract

A 62-year-old man with pain in his hip joints and back was admitted to our hospital. His chest radiograph and CT showed a huge mass extending from the left upper pericardium to the left hilum, but no pleural effusion or other lesions. A contrast-enhanced abdominal CT showed multiple metastases to bones and both kidneys. Bronchoscopy revealed obstruction of the left B3 by a visible tumor. The biopsy specimens of the initial immunohistochemical staining were slightly positive for calretinin. However, we diagnosed the condition as sarcomatoid carcinoma of the lung on the basis of the clinical evaluation. Although radiotherapy was administered, his condition rapidly deteriorated and he died due to progression of the disease. Autopsy revealed extensive invasion, suggesting mesothelioma. Therefore, immunohistochemical staining was performed; the findings revealed sarcomatoid malignant mesothelioma. In conclusion, we encountered a rare case of sarcomatoid malignant mesothelioma (stage IV).

Kaneko O, Gong L, Zhang J, Hansen JK, Hassan R, Lee B, Ho M.

Laboratory of Molecular Biology, Center for Cancer Research, NCI, National Institutes of Health, Bethesda, Maryland 20892, USA.

Abstract

Ovarian cancer and malignant mesothelioma frequently express both mesothelin and CA125 (also known as MUC16) at high levels on the cell surface. The interaction between mesothelin and CA125 may facilitate the implantation and peritoneal spread of tumors by cell adhesion, whereas the detailed nature of this interaction is still unknown. Here, we used truncated mutagenesis and alanine replacement techniques to identify a binding site on mesothelin for CA125. We examined the molecular interaction by Western blot overlay assays and further quantitatively analyzed by enzyme-linked immunosorbent assay. We also evaluated the binding on cancer cells by flow cytometry. We identified the region (296-359) consisting of 64 amino acids at the N-terminal of cell surface mesothelin as the minimum fragment for complete binding activity to CA125. We found that substitution of tyrosine 318 with an alanine abolished CA125 binding. Replacement of tryptophan 321 and glutamic acid 324 with alanine could partially decrease binding to CA125, whereas mutation of histidine 354 had no effect. These results indicate that a conformation-sensitive structure of the region (296-359) is required and sufficient for the binding of mesothelin to CA125. In addition, we have shown that a single chain monoclonal antibody (SS1) recognizes this CA125-binding domain and blocks the mesothelin-CA125 interaction on cancer cells. The identified CA125-binding domain significantly inhibits cancer cell adhesion and merits evaluation as a new therapeutic agent for preventing or treating peritoneal malignant tumors.

Addis B, Roche H.

Department of Cellular Pathology, Southampton University Hospitals NHS Trust, Southampton, UK. bruce.addis@suht.swest.nhs.uk

Abstract

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

Expression of GATA-6 transcription factor in pleural malignant mesothelioma and metastatic pulmonary adenocarcinoma.

Lindholm PM, Soini Y, Myllärniemi M, Knuutila S, Heikinheimo M, Kinnula VL, Salmenkivi K.

Department of Medicine, University of Helsinki and Helsinki University Central Hospital, Finland.

Abstract

Background: Malignant mesothelioma (MM) is a highly aggressive tumour with poor prognosis and limited response to therapy. New markers for the prediction of prognosis in MM and in pulmonary adenocarcinoma of the pleura are valuable. GATA-6 belongs to a six member zinc finger transcription factor family named after their recognition motif W-GATA-R. AIM: To clarify the distribution and possible function of GATA-6 transcription factor in MM and in pleural metastasis of lung adenocarcinomas.

Methods: 63 pleural MM and 36 pleural metastatic pulmonary adenocarcinomas were studied for GATA-6 expression by immunohistochemistry using tissue microarrays. Expression of GATA-6 was examined in relation to thyroid transcription factor-1 expression, survival, proliferation and apoptosis.

Results: Nuclear immunoreactivity for GATA-6 was stronger and more frequent in MM than in metastatic pleural adenocarcinoma. Prognosis was better in patients with GATA-6 expression when compared to those with no GATA-6 expression (p = 0.002); in the subgroup analysis the difference was significant in epithelial and sarcomatous mesothelioma. GATA-6 was not associated with spontaneous proliferation or apoptosis of the tumour cells in situ.

Conclusion: Results suggest that GATA-6 plays a role in pleural malignancies, predicting longer survival in subgroups of MM.