Kao SC, Yan TD, Lee K, Burn J, Henderson DW, Klebe S, Kennedy C, Vardy J, Clarke S, van Zandwijk N, McCaughan BC.

Asbestos Diseases Research Institute, Bernie Banton Centre, Sydney, Australia.

Abstract

Introduction: Histological subtype is an established prognostic factor in malignant pleural mesothelioma (MPM). We retrospectively investigated the accuracy of classifying histological subtype on diagnostic biopsies and examined the impact of different diagnostic procedures on the outcome.

Methods: Consecutive patients with histologically confirmed MPM who underwent extrapleural pneumonectomy (EPP) from 1994 to 2009 were included. Patient records were reviewed, and the initial diagnoses of histological subtype were obtained. The archival EPP specimens were reviewed by a panel of pathologists. The histological subtype obtained at review was compared with the initial diagnosis.

Results: Eighty-five patients underwent EPP. Two patients achieved a pathological complete response after neoadjuvant chemotherapy, leaving 83 patients to be included in this review. Different diagnostic methods were used before EPP: 81% thoracoscopy; 7% thoracotomy; 11% computed tomography-guided procedure; and 1% other. Patients determined to have an epithelial subtype (n = 64) at EPP were diagnosed correctly at initial diagnostic biopsy in 84% of cases, whereas patients considered to have a biphasic subtype (n = 19) at EPP were diagnosed correctly at diagnostic biopsy in 26% of cases. The sensitivity and specificity of diagnostic biopsy for epithelial MPM was 93% and 31%, respectively. The overall subtype misclassification rate was 20%. Biopsy by thoracotomy was most accurate in subtype classification (83%) compared with thoracoscopy (74%) and computed tomography-guided procedure (44%).

Conclusions: The determination of histological subtype from a diagnostic biopsy is difficult due to sampling error, but an adequate specimen obtained from surgical biopsy increases the accuracy of subtype classification compared with radiological-guided biopsies.

Junker K, Krismann M.

Zentrum für Pathologie, Klinikum Bremen-Mitte, Bremen. klaus.junker@klinikum-bremen-mitte.de

Abstract

In the WHO classification, pleural tumours of mesothelial and mesenchymal origin as well as lymphoproliferative disorders are distinguished, with malignant mesotheliomas forming the most common primary pleural tumour. Histologically, a prognostically relevant differentiation between epitheloid (40-60 %), sarcomatoid (20-30 %), and biphasic mesotheliomas (20-30 %) is made. Besides other rare primary tumours of the pleura, the differential diagnoses of malignant mesotheliomas comprise carcinomatous pleuritis of intra- and extrapulmonary malignancies. Especially in early tumour stages, the differentiation from reactive pleural changes requires a close interdisciplinary cooperation with a careful correlation between histopathological findings and clinical presentation.

Keywords: malignant pleural mesothelioma – carcinomatous pleuritis – solitary fibrous tumour of the pleura – WHO classification

Ishiwata I, Ishiwata E, Hirano T.

Department of Obstetrics and Gynecology, School of Medicine, Jikei University, Tokyo, Japan.

Abstract

Two human malignant mesothelioma cell lines, which we designated "epithelial mesothelioma cells" and "fibrous mesothelioma cells", were established from the pleural fluid containing malignant mesothelial cells of a 72-year-old Japanese man. These cell lines were separated by the colonial techniques from the initiation of the primary cultures and grew well without interruption for 12 years. They were characterized as producing hyaluronic acid. These cell lines displayed different biological characteristics, including morphology, heterotransplantability and genetics using with BAC array CGH. The epithelial mesothelioma cells were epithelial in shape and transplantable into the subcutis of nude mice, while the cells of the fibrous mesothelioma line were fibroblast-like and transplantable into the submucosa of Hamster’s cheek pouches but not into the subcutis of nude mice. The mesotheliomas are classified into three types: epithelial mesothelioma, fibrous mesothelioma and mixed type. The gene copy number losses observed on 9p21.3, 9p21.2, 9p21.1, among others may be a major mechanism of malignant mesothelioma carcinogenesis. We considered and supported the combination theory for the histogenesis of malignant mesothelioma.

Keywords: biological characteristics, cell lines, histogenesis, mesothelioma

Neragi-Miandoab S, Richards WG, Sugarbaker DJ.

Department of Surgery, Cardiothoracic Surgery, Boston University Medical Center, School of Medicine, One Boston Medical Center Place, Boston MA 02118, United States.

Abstract

Aim: The survival of patients with malignant pleural mesothelioma (MPM) who do not seek treatment ranges from 4 to 12 months. To date, the optimal procedure for resection of malignant pleural mesothelioma is controversial, extrapleural pneumonectomy has been most consistently associated with long-term survival and has provided the most radical cytoreduction; but, unfortunately, not all patients qualify for this invasive surgical approach.

Methods: Between 1992 and 2000, 64 patients underwent pleurectomy as a palliative treatment for MPM. This retrospective study evaluates the operative outcome and the impact of some prognostic factors on patients’ survival. Preoperative evaluation included chest X-ray, CT and/or MRI. Diagnosis was made by pleural biopsy via needle, open, or VATS biopsy. The Kaplan-Meier curve and the Log-Rank test were used to analyze the data.

Results: The median age of the study group was 65 (with a range of 29-84 years). Thirty-six patients had epithelial histology, and 28 patients had sarcomatoid or mixed type (e.g., epithelial+spindle, epithelial+sarcomatoid). The 30-day mortality rate was 3.1%. The overall survival rate was 43%, 28%, and 10% at 1, 2, and 3 years, respectively. The overall median survival was 9.4 months (ranging from 1.15 to 52.7 months). The overall median survival with epithelial histology (n=36, 56%) was 21.7 months (with a range of 1.4-52.7 months) versus 5.8 months (with a range of 1.15-18.3 months) for the sarcomatoid or mixed type (n=28, 44%), p=0.0001. The morbidity included atrial fibrillation (n=5), wound infection (n=2), prolonged intubation (longer than 24h, n=8), reintubation for respiratory failure (n=2), pulmonary emboli (n=1), UTI (n=16), DVT (n=5), MI (n=4), and postoperative bleeding (n=7). Univariant analysis demonstrated that the only prognostic factors influencing survival in our series was the histologic type. Age, gender, and the affected side of the lung did not affect the median survival.

Conclusion: Our results show that pleurectomy can be performed as a means of palliation for advanced-stage disease with a low mortality rate and may, in fact, improve survival in patients with epithelial subtype as compared with historical controls in the literature with no surgical intervention.

Klebe S, Mahar A, Henderson DW, Roggli VL.

Department of Anatomical Pathology, Flinders University of South Australia, Adelaide, SA, Australia.

Abstract

Only a small number of malignant mesotheliomas with heterologous elements have been described. There are currently no criteria for diagnosis and little data regarding prognosis. We suggest that the term heterologous mesothelioma should be reserved for tumours that show malignant heterologous elements, notably osteosarcomatous, chondrosarcomatous, or rhabdomyoblastic elements but have immunohistochemical and clinical characteristics of mesothelioma. We identified 27 such cases and characterized the clinical and pathological characteristics of these tumours. In our series, 89% originated in the pleura, and 11% from the peritoneal cavity. The median age at diagnosis was 68 years, ranging from 27 to 85 years. Of these cases, 93% occurred in males and 7% in women. Of the 27 mesothelioma cases 16 (59%) were sarcomatoid, 10 (37%) were biphasic, and one was reported as epithelioid; 40% (11 cases) showed osteosarcomatous elements only, 19% showed areas of rhabdomyosarcoma only, 19% contained areas of chondrosarcoma only, and 22% exhibited osteochondromatous elements. Immunohistochemical labelling for cytokeratins was present in the majority of cases. Exposure to asbestos was identified in all the 17 cases for which an exposure history was available (63%). Median survival was 6 months after diagnosis, similar to the survival seen in sarcomatoid mesotheliomas. The differential diagnosis includes primary and secondary pleural sarcomas, including osteosarcomas and chondrosarcomas. Immunohistochemical labelling for cytokeratins is helpful in the distinction, but lack of labelling for cytokeratins in a spindle cell/sarcomatoid tumour does not exclude the diagnosis of mesothelioma, irrespective of the presence of heterologous elements. We suggest that if the anatomical distribution conforms to that of mesothelioma, a diagnosis of heterologous mesothelioma should be made in preference to a diagnosis of primary pleural osteosarcoma or chondrosarcoma, regardless of cytokeratin positivity, as for conventional non-heterologous sarcomatoid mesothelioma.

Moran CA, Albores-Saavedra J, Suster S.

Department of Pathology, M D Anderson Cancer Center, Houston, TX 77030, USA. cesarmoran@mdanderson.org

Abstract

Aims: To present eight cases of primary diffuse peritoneal malignant mesothelioma in children <15 years old, with a discussion of the pitfalls of this diagnosis in the paediatric age group.

Methods and Results: The cases were selected based on the following criteria: (i) primary peritoneal neoplasms confined grossly or radiographically to the abdominal cavity; (ii) negative history of previous or another associated malignancy; (iii) histopathological confirmation. All patients (five female, three male) presented clinically with symptoms of abdominal pain, distention and ascites. Grossly, the tumours showed multiple, diffuse peritoneal nodules. Histologically, seven cases corresponded to epithelioid mesotheliomas and one case displayed biphasic (epithelioid and spindle) cellular proliferation. Immunohistochemical studies for cytokeratin (CK) 5/6, calretinin and low-molecular-weight CK (CAM5.2) showed strong cytoplasmic positivity in the neoplastic cells. Three patients were treated by chemotherapy. On clinical follow-up, four patients with epithelioid mesotheliomas were alive and well from 12 to 18 months after initial diagnosis; one patient with a mixed (biphasic epithelioid/sarcomatoid) mesothelioma died of tumour 24 months after diagnosis.

Conclusions: Peritoneal malignant mesothelioma in children is a rare condition that can introduce difficulties in histopathological diagnosis.

Mineo TC, Ambrogi V, Pompeo E, Baldi A, Stella F, Aurea P, Marino M.

Department of Thoracic Surgery, Policlinico Tor Vergata University, Rome, Italy. mineo@med.uniroma2.it

Abstract

Background: The purpose of this study was to examine the prognostic impact of occult disease after extrapleural pneumonectomy for malignant mesothelioma.

Methods: We reviewed the resection margin and node specimens from 41 consecutive patients undergoing extrapleural pneumonectomy for malignant pleural mesothelioma in different institutions between 1985 and 2004. The specimens were reassessed by immunohistochemical staining with anticalretinin and antimesothelin monoclonal antibodies, and results were used to draw Kaplan–Meier survival curves and perform Cox regression analyses.

Results: Histologic examination showed 34 epithelioid, 4 biphasic, and 3 sarcomatoid subtypes. Results of postoperative TNM staging were that 14 patients were in stage I, 6 were in stage II, and 21 were in stage III. One patient died during the early postoperative period. Median survival was 13 months. Survival was affected by nonepithelial histologic type (p = 0.001), TNM stage (p = 0.007), positive resection margins (p = 0.002), and N disease (p = 0.01). Immunohistochemistry revealed occult positive resection margins in 6 patients, not correlated with T stage. Microscopic N disease was discovered in 5 patients, of whom 2 had their nodes retrieved through cervical mediastinoscopy. No correlation with nodal diameter was found. In all patients microscopic N disease could have been accessible through mediastinoscopy. Overall, the presence of occult disease was diagnosed in 5 new patients and influenced survival more than any other variable, both at univariate (p < 0.001) and multivariate Cox regression analysis (p < 0.0001; odds ratio, 5.4; 95% confidence interval, 3 to 15).

Conclusions: In malignant pleural mesothelioma, the presence of occult disease in resection margins and lymph nodes can be identified by immunohistochemistry and significantly influences the prognosis. Cervical mediastinoscopy is useful in all patients considered for radical resection, but all specimens should be processed with immunohistochemical staining.

Takeuchi N, Nakai M, Sato M.

Department of Radiology, Hidaka General Hospital.

Abstract

A man in his 60′s with no apparent history of asbestos exposure was admitted to our hospital with a chief complaint of abdominal fullness. CA125 levels in serum and ascites were very high. Enhanced abdominal CT confirmed a large amount of ascites, inflexible intestinal canal, short mesentery and laminar thickening of the omentum. SPIO-enhanced MRI-T1WI slightly enhanced the thickened omentum. These T1WI images largely matched portal-phase contrast CT images. Furthermore, the thickened omentum was clearly visualized by lowering the signal for the liver and spleen by SPIO and by suppressing the ascites signal by fluid-attenuated inversion recovery (FLAIR). Gascintigraphy confirmed Ga accumulation in the same areas. Chemotherapy was ineffective, and the patient died of liver metastasis in February 2006. Autopsy confirmed biphasic malignant peritoneal mesothelioma. The involvement of asbestos is clear in the onset of malignant peritoneal mesothelioma. Therefore, it is possible that the patient unintentionally inhaled asbestos. Hence, when levels of CA125 in serum and/or ascites are high, it is important to differentiate malignant peritoneal mesothelioma from primaryserous papillary carcinoma of the peritoneum. Here, we experienced a case of biphasic diffused omental mesothelioma. While studies have documented laminar thickening of the omentum by abdominal incision, this is thought to be first case in Japan in which laminar thickening of the omentum was detected on diagnostic imaging. Laminar thickening of the omentum and short mesentery are thought to be characteristic features of diffused peritoneal mesothelioma when subjective symptoms appear. In addition, Gascintigraphy and FDG-PET are useful auxiliary diagnostic tools. In the future, we hope to differentiate epithelial, sarcomatous and biphasic types based on imaging findings.

Kobayashi M, Takeuchi T, Ohtsuki Y.

Department of Respiratory Medicine, Hosogi Hospital, 37 Daizen-cho, Kochi, Kochi 780-8535, Japan. kmakoto@jinseikai-group.or.jp

Abstract

Introduction: The incidence of mesothelioma is estimated to rise sharply worldwide, including Japan, in the next two decades. Molecular and proteomic studies are urgently required to elucidate the pathobiology of malignant mesothelioma. This paper describes the characterization of novel human malignant pleural mesothelioma cell lines representing the sarcomatoid, epithelioid and biphasic subtypes.

Materials and Methods: Established pleural effusion fluid cell lines were observed using phase-contrast microscopy and transmission electron microscopy. The immunoreactivity of the cells was evaluated using immunohistochemistiy, FACS analysis and Western blotting. The expression of SV40 large cell antigen and the EGFR mutation status were also analyzed.

Results: The cell lines had different morphological and immunophenotypic characteristics. All cell lines showed immunophenotypic marker expression of vimentin, mesothelin and N-cadherin, but no expression of CEA or E-cadherin. At the electron microscopic level, a cell surface rich in microvilli confirmed mesothelial origin of the cell lines. Karyotype analyses showed complex abnormalities in all cell lines. Neither EGFR mutations relevant to tyrosine kinase inhibitor responsiveness nor the expression of SV40 large cell antigen was detected in any of the cell lines.

Conclusion: FACS analysis is more sensitive for evaluating mesothelin expression than immunohistochemistry of cut specimens. Irrespective of the expression of EGFR on FACS analysis, no EGFR mutation was detected. These three cell lines may be useful for studying cellular, molecular and genetic aspects of mesothelioma.

Jean M. Seelya, Elsie T. Nguyen, Andrew M. Churgb

• Department of Diagnostic Imaging, The Ottawa Hospital, 1053 Carling Avenue, Ottawa, Ontario K1Y 4E9, Canada
• University of British Columbia, 2211 Wesbrook Mall, Vancouver, BC V6T 1W5, Canada
• University of British Columbia, Vancouver Hospital and Health Sciences Centre, 855 West 12th Avenue, Vancouver, BC V5Z 1M9, Canada

Abstract

Objective: To review the computed tomography (CT) imaging findings of pleural mesothelioma at presentation and to correlate the CT with the histological subtype.

Materials and methods: Pathology reports from 1997 to 2006 were reviewed at two academic institutions to identify patients with proven pleural mesothelioma. Diagnosis was based on histologic findings in specimens obtained by transthoracic needle biopsy, surgical biopsy or resection. All histology slides were reviewed by a lung pathologist. CT scans, available in 92 patients, were reviewed blindly and in random order by two independent radiologists. Kappa analysis was completed to assess inter-observer agreement. Eighty patients in whom there was no significant delay between CT imaging and histological diagnosis were assessed by logistic regression analysis to correlate CT and histologic findings.

Results: Seventy-two of the 92 mesotheliomas were epithelial, 15 sarcomatous, and 5 of mixed histology. All patients (77 male, 15 female, mean age 68 years) had pleural thickening on CT; the thickening was nodular in 79 patients (86%) and mediastinal in 87 (95%). Ipsilateral volume loss was seen in 42 patients (46%). Pleural effusions were present in 80 patients (87%), being large (>2/3 hemithorax) in 19 patients (21%). Atypical features at presentation included bilateral disease in three patients (3%), and spontaneous pneumothoraces in nine patients (10%). Internal mammary lymphadenopathy was observed in 48 patients (52%) and cardiophrenic lymphadenopathy in 42 (46%). Inter-observer agreement was excellent (average kappa = 0.89). Ipsilateral volume loss was associated with sarcomatous or mixed mesothelioma (p = 0.004). Using logistic regression analysis, other CT findings did not correlate with histological subtype.

Conclusions: Ipsilateral volume loss is most frequently associated with sarcomatous or mixed mesothelioma. The remaining imaging findings are not helpful in predicting the histological subtype of malignant mesothelioma.

Keywords: Mesothelioma; CT; Pleura; Malignancy; Pathology