Diffuse Malignant Pleural Mesothelioma Research Articles

Analysis of clinicopathological features of 68 cases of malignant pleural mesothelioma

Objective: To analyze the clinicopathological characteristics of diffuse malignant pleural mesothelioma (MPM), and explore the diagnostic methods in order to improve the early diagnosis rate. Methods: In January 2019 to January 2022, the clinical features, auxiliary examination and immunohistochemical results of 68 cases of MPM were analyzed retrospectively. The pathogenic features, histopathological morphology and the expression of related antibodies including Calretinin (CR), D2-40 and WT-1 were summarized. Results: Among the 68 patients, 40 male (58.82%), 28 female (41.18%), male to female ratio was 1.43%, median age was 58 years old; 50% of patients in Dayao County, epithelial mesothelioma 59 cases (86.76%), occurred in right chest in 39 cases (57.35%), left chest in 25 cases (36.76%), and 4 cases in both sides (5.89%). The most common initial clinical manifestations were pleural effusion (95.59%), chest pain (36.75%), chest tightness and shortness of breath (30.88%). The main imaging findings were pleural effusion in 49 cases (98.00%) and pleural thickening in 46 cases (92.00%). MPM tumor cells often expressed Calretinin, CK5/6, WT1 and D2-40, while TTF-1, NapsinA and CEA, the main markers differentiated from lung adenocarcinoma were negative. Serum CYFRA21-1 and CEA have high value in differential diagnosis of benign and malignant pleural effusions. Conclusion: Diffuse MPM has diverse histological and cytological morphology, which needs to be differentiated from a variety of diseases. Correct diagnosis of diffuse MPM through immunohistochemistry requires the combined application of a group of Mesothelium related antibodies.

Update on Diagnosing and Reporting Malignant Pleural Mesothelioma.

In this review, we summarize current approaches to diagnosis of malignant pleural mesothelioma, focusing on the distinction from benign mesothelial proliferations and other malignant tumors. Current recommendations for reporting histological sub-type and tumor grade are also reviewed. Particular emphasis is placed on immunohistochemical and molecular tools that may help in establishing the diagnosis of mesothelioma with greater confidence. Immunohistochemical stains for BRCA1-associated protein (BAP1) and methylthioadenosine phosphorylase (MTAP) and homozygous deletion of p16 using fluorescence in situ hybridization (FISH) are emphasized as important methods for distinguishing benign from malignant mesothelial proliferations. CONCLUSIONS: Diffuse malignant pleural mesothelioma is a heterogeneous group of aggressive pleural tumors for which histological classification plays an increasingly important role in patient management. Stage and resectability remain key drivers of therapeutic strategies and outcomes. There is an increasingly robust suite of diagnostic tools, including immunohistochemical stains for BAP1 and MTAP and p16 FISH, for differentiating benign from malignant mesothelial proliferations in cytology and tissue specimens.

MS06.05 Transcervical Lymphadenectomies

Introduction: The aim of his study is to analyze the issue of transcervical lympadenectomies for Non-Small-Cell Lung Cancer performed by the techniques of Video-Assisted Mediastinoscopic Lymphadenectomy (VAMLA) and Transcervical Extended Mediastinal Lymphadenectomy (TEMLA). Methods The Pubmed search was performed and there were 27 articles found on VAMLA and 33 articles on TEMLA. After further analysis there were 13 original article on VAMLA and 18 original articles on TEMLA. In the current paper all proven and possible advantages of transcervical lymphadenectomies represented by VAMLA and TEMLA are described. Results The proven advantages of VAMLA and TEMLA: 1. Superior diagnostic value in discovery of the metastatic mediastinal nodes for staging and restaging of NSCLC. 2. bilateral mediastinal lymphadenectomy, more extensive than the techniques of lymphadenectomy used during standard thoracotomy or Video-Assisted Thoracic Surgery (VATS) approaches. Possible advantages include: 1. Improved selection of patients for pulmonary resection for NSCLC 2. Combination of VAMLA/TEMLA with VATS pulmonary resection, 3. Combination of VAMLA/TEMLA with esophegeal resection, 4. Combination of TEMLA and Stereotactic Radiotherapy (SBRT) for advanced NSCLC 5. The use of TEMLA for preoperative staging of mesothelioma, 6. Combination of TEMLA and pulmonary lobectomy through a sole transcevical approach 7. Resection of various metastatic tumors, including thyroid cancer and metastatic mediastinal nodes. 8. Possible impact of VAMLA/TEMLA on improvement of survival for NSCLC patients, which is the most important issue. In case of VAMLA superior survival of patients operated on with the use pulmonary resection with VAMLA in comparison to the pulmonary resection with addition of standard mediastinoscopy. In case of TEMLA no reports on survival has been published, yet Disadvantages of VAMLA/TEMLA include 1. Possible complications, especially the left recurrent nerve palsy 2. Possible delay or elimination of some patients from pulmonary resection due to postoperative complication in case of negative result of VAMLA/TEMLA 3. Scar in the neck (cosmetic) 4. Demanding surgical technique Conclusions 1. Bilateral transcervical lymphadenectomies representd by VAMLA and TEMLA are more extensive than the techniques of lymphadenectomy used during standard thoracotomy or Video-Assisted Thoracic Surgery (VATS) approaches and superior to the other techniques of staging and restaging of NSCLC in regard to the diagnostic value. 2. There are several other possible advantages of TEMLA/VAMLA for the treatment of NSCLC, esophageal cancer, mediastinal tumors and malignant mesothelioma. 3. Possible impact of VAMLA/TEMLA on survival of NSCLC has not been proven, yet. References Hurtgen M, Friedel G, Toomes H et al: Radical video-assisted mediastinoscopic lymphadenectomy (VAMLA) – technique and first results. Eur J Cardiothorac Surg 2002;21:348-51 Zielinski M, Szlubowski A, Kołodziej M, Orzechowski S, Laczynska E, Pankowski J, Jakubiak M, Obrochta A. Comparison of endobronchial ultrasound and/or endoesophageal ultrasound with transcervical extended mediastinal lymphadenectomy for staging and restaging of non-small-cell lung cancer. J Thorac Oncol. 2013 May;8(5):630-6. Zielinski M, Hauer J, Hauer L, Pankowski J, Nabialek T, Szlubowski A. Staging algorithm for diffuse malignant pleural mesothelioma. Interact Cardiovasc Thorac Surg. 2010;10:185-9 Zieliński M, Pankowski J, Hauer L et al: The right upper lobe pulmonary resection performed through the transcervical approach. Eur J Cardiothorac Surg. 2007;32:766-769 Singh AK, Hennon M, Ma SJ, Demmy TL, Picone A, Dexter EU, Nwogu C, Attwood K, Tan W, Hermann GM, Fung-Kee-Fung S, Malhotra HK, Yendamuri S, Gomez-Suescun JA. A pilot study of stereotactic body radiation therapy (SBRT) after surgery for stage III non-small cell lung cancer. BMC Cancer. 2018 Nov 29;18(1):1183. https://doi.org/10.1186/s12885-018-5039-5. Turna A, Demirkaya A, Ozkul S, Oz B, Gurses A, Kaynak K. Video-assisted mediastinoscopic lymphadenectomy is associated with better survival than mediastinoscopy in patients with resected non-small cell lung cancer. J Thorac Cardiovasc Surg. 2013 Oct;146(4):774-80. https://doi.org/10.1016/j.jtcvs.2013.04.036. Epub 2013 Jun 15. Li X, Wang W, Zhou Y, Yang D, Wu J, Zhang B, Wu Z, Tang J. Efficacy comparison of transcervical video-assisted mediastinoscopic lymphadenectomy combined with left transthoracic esophagectomy versus right transthoracic esophagectomy for esophageal cancer treatment. World J Surg Oncol. 2018 Feb 9;16(1):25. https://doi.org/10.1186/s12957-017-1268-3. Call S, Obiols C, Rami-Porta R, Trujilo-Reyes JC, Iglesias M, Saumench R, Gonzalez-Pont G, Serra-Mitjans M, Belda-Sanchís J. Video-Assisted Mediastinoscopic Lymphadenectomy for Staging Non-Small Cell Lung Cancer. Ann Thorac Surg. 2016 Apr;101(4):1326-33. https://doi.org/10.1016/j.athoracsur.2015.10.073. Epub 2016 Jan 21. .Kim HJ, Kim YH, Choi SH, Kim HR, Kim DK, Park SI. Video-assisted mediastinoscopic lymphadenectomy combined with minimally invasive pulmonary resection for left-sided lung cancer: feasibility and clinical impacts on surgical outcomes†. Eur J Cardiothorac Surg. 2016 Jan;49(1):308-13. https://doi.org/10.1093/ejcts/ezv077. Epub 2015 Mar 11 Zielinski M. Transcervical Resection of the Mediastinal Tumors. In Zielinski M, Rami-Porta R (eds). Transcervical Approach in Thoracic Surgery. Springer 2014, pages 141-148.

Diagnostic value of biopsy sampling in predicting histology in patients with diffuse malignant pleural mesothelioma.

The classification of diffuse malignant mesothelioma into epithelioid, biphasic, and sarcomatoid types is based on histologic patterns. The diagnosis is made on biopsies, and because of intratumoral heterogeneity, they may not be representative of the entire tumor. The number and volume of biopsies needed to reach diagnostic accuracy in diffuse malignant mesothelioma and their prognostic value remain unclear. This study examined 759 consecutive patients with pleural diffuse malignant mesothelioma treated by pleurectomy/decortication or extrapleural pneumonectomy for the presence of epithelioid and/or sarcomatoid histology and classified both the presurgery biopsies (core-needle or thoracoscopic) and surgical resection specimens. The number and volume of biopsies were correlated with pre- and postsurgery histologies and overall survival. Diffuse malignant mesothelioma was classified as epithelioid (76%), biphasic (18%), sarcomatoid (5%), or indeterminate (1%) in biopsies and as epithelioid (64%), biphasic (32%), and sarcomatoid (4%) in surgical resection specimens (overall concordance, 80.6%). The positive likelihood ratios were 2.4, 13.6, and 90.1 for biopsies with epithelioid, biphasic, and sarcomatoid histologies, respectively. Concordant histologies between biopsies and resections were associated with a higher number of biopsies (median tissue blocks for concordant histologies vs discordant histologies, 3 vs 2; P<.002) but were less associated with a higher volume (median, 1.2 vs 1.1 cm3 ; P=.06). In a multivariate analysis, overall survival was independently predicted by histology in the resection specimen (P<.0001) but not in the biopsy (P=.09). In contrast to epithelioid histology, sarcomatoid histology in biopsies is highly accurate. Despite intratumoral heterogeneity, the accuracy of histologic classification increases with the number of tissue blocks examined, emphasizing the diagnostic value of extensive sampling by presurgery biopsies.

Molecular characterization of localized pleural mesothelioma.

Localized pleural mesothelioma is a rare solitary circumscribed pleural tumor that is microscopically similar to diffuse malignant pleural mesothelioma. However, the molecular characteristics and nosologic relationship with its diffuse counterpart remain unknown. In a consecutive cohort of 1110 patients with pleural mesotheliomas diagnosedin 2005-2018, we identified six (0.5%) patients diagnosed with localized pleural mesotheliomas. We gathered clinical history, evaluated the histopathology, and in select cases performed karyotypic analysis and targeted next-generation sequencing. The cohort included three women and three men (median age 63; range 28-76), often presenting incidentally during radiologic evaluation for unrelated conditions. Neoadjuvant chemotherapy was administered in two patients. All tumors (median size 5.0 cm; range 2.7-13.5 cm) demonstrated gross circumscription (with microscopic invasion into lung, soft tissue, and/or rib in four cases), mesothelioma histology (four biphasic and two epithelioid types), and mesothelial immunophenotype. Of four patients with at least 6-month follow-up, three were alive (up to 8.9 years). Genomic characterization identified several subgroups: (1) BAP1 mutations with deletions of CDKN2A and NF2 in two tumors; (2) TRAF7 mutations in two tumors, including one harboring trisomies of chromosomes 3, 5, 7, and X; and (3) genomic near-haploidization, characterized by extensive loss of heterozygosity sparing chromosomes 5 and 7. Localized pleural mesotheliomas appear genetically heterogeneous and include BAP1-mutated, TRAF7-mutated, and near-haploid subgroups. While the BAP1-mutated subgroup is similar to diffuse malignant pleural mesotheliomas, the TRAF7-mutated subgroup overlaps genetically with adenomatoid tumors and well-differentiated papillary mesotheliomas, in which recurrent TRAF7 mutations have been described. Genomic near-haploidization, identified recently in a subset of diffuse malignant pleural mesotheliomas, suggests a novel mechanism in the pathogenesis of both localized pleural mesothelioma and diffuse malignant pleural mesothelioma. Our findings describe distinctive genetic features of localized pleural mesothelioma, with both similarities to and differences from diffuse malignant pleural mesothelioma.

Expression of plakophilin 3 in diffuse malignant pleural mesothelioma.

Diffuse malignant pleural mesothelioma (DMPM) is the most common primary malignant pleural neoplasm still posing major diagnostic, prognostic and therapeutic challenges. Plakophilins are structural proteins considered to be important for cell stability and adhesion in both tumor and normal tissues. Plakophilin 3 is a protein present in desmosomes of stratified and simple epithelia of normal tissues with presence in malignant cells of various tumors where it participates in the process of tumorigenesis. The aim of this study was to investigate the expression of plakophilin 3 protein in DMPM, but also to study its prognostic significance and relation to histologically accessible parameters of aggressive growth. Archival samples of tissue with established diagnosis of DMPM and samples of normal pleural tissue were used. Tumor samples were classified into three histological types of DMPM (epithelioid, sarcomatoid and biphasic). Additional subclassification of epithelioid mesotheliomas into nine patterns based on the prevalent histological component of the tumor was then performed. After immunohistochemical staining, cytoplasmic and membrane immunopositivity of tumor cells was assesed by scoring the intensity of the staining from 0 (no staining) to 4 (very strong staining). Prognostic value and expression of plakophilin 3 with consideration to histologically estimated aggression in tumor growth were then statistically analyzed using non- parametric tests. The results demonstrated higher level of plakophilin 3 expression in tumor samples with histologically more aggressive tumor growth, but no significant prognostic value. According to our study, plakophilin 3 appears to be involved in tumor invasion in malignant mesothelioma.

Clinicopathologic and genetic characteristics of young patients with pleural diffuse malignant mesothelioma

Pleural diffuse malignant mesothelioma typically presents during the seventh decade of life and has poor prognosis. Recent epidemiologic studies have shown differences between young and older mesothelioma patients, but the biology of pleural mesothelioma in young patients is poorly understood. We studied the clinicopathologic and genetic characteristics in pleural mesothelioma patients aged 35 years and younger. Thirty-six consecutive pleural mesothelioma patients aged 35 years and younger were compared with 48 older patients. We examined demographic and clinical characteristics, histologic type, growth patterns, mitotic index, and nuclear grade on hematoxylin and eosin-stained slides, BAP1 protein expression by immunohistochemistry, and CDKN2A and NF2 deletions by fluorescence in situ hybridization. Clinicopathologic and cytogenetic results were compared between young and older groups, and correlated with overall survival. Young patients were more frequently women, reported less asbestos exposure, and had a greater frequency of prior therapeutic radiation and family history of breast cancer than older patients (P<0.05 each). There were no histologic differences between young and older patients (all P>0.05). CDKN2A deletion was less prevalent in young patients (P=0.01), loss of BAP1 protein expression less frequent in young patients (P=0.06), and NF2 deletion rates similar between groups (P>0.05 each). Median overall survival was 40 vs 26 months (P=0.10) in young and older patients, respectively, and 47 vs 31 months (P=0.04) when comparing patients with epithelioid histology only. High mitotic index and non-epithelioid histology were the only characteristics associated with a poor overall survival in young patients. Young patients with pleural mesothelioma have an equal sex distribution and are more likely to have a history of mantle radiation, family history of breast cancer, and lower rates of CDKN2A deletion than older patients. Our results suggest that pleural mesothelioma in young patients has distinctive clinical and genetic characteristics, despite some similarities to pleural mesothelioma in older patients.

Association Between Clinicopathological Factors and Genomic Abnormalities Detected by FISH Analysis in Epithelioid Diffuse Malignant Pleural Mesothelioma.

Abnormality of genes including 9p21 is known in malignant mesothelioma and we have examined the frequency of gene deletion and amplification using the fluorescence in situ hybridization (FISH) method. We formerly reported that abnormality of the genes was more common in the sarcomatoid type than epithelioid type. In this study, we compared the clinicopathological factors including nuclear grade (NG) and genomic abnormality in epithelioid malignant pleural mesothelioma (MPM). Using paraffin-embedded tissues of 31 epithelioid MPMs, we investigated the presence of gene abnormalities in the genes 9p21, 1p36, 14q32, 22q12, 5p15, 6p, 8q24, and 7p12 by the FISH method, and compared the results with NG, clinical stage, and prognosis. In the higher NG group of epithelioid MPM, more gene amplifications [in particular 5p15 and 8q24(MYC)] were observed, and clinical stage was more advanced. Cases with the amplification of 7p12(EGFR) tended to exhibit a worse prognosis. The significant correlation between histological differentiation and clinical features such as prognosis was not confirmed. NG status in epithelioid MPM may be related to gene alteration and clinical features.

Small bowel metastasis from pancreatic cancer in a long-term survival patient with synchronous advanced malignant pleural mesothelioma: A case report and literature review

Diffuse malignant pleural mesothelioma (MPM) is an aggressive tumor that originates from the surface of the pleura. Approximately 70% of cases are associated with chronic asbestos exposure. MPM is regarded as an incurable disease, with a median survival of ~2 years following intensive multimodality treatment. Pancreatic cancer is a malignancy also associated with a poor prognosis, with only 2% of patients surviving for 5 years. The majority of patients with pancreatic cancer are diagnosed with an advanced stage of disease and experience a poor response to therapy. The development of synchronous MPM and other types of cancer is rare. The present study describes a patient with synchronous, biphasic MPM and pancreatic adenocarcinoma, who was treated with a multimodal therapeutic approach with stereotactic body radiation therapy. Due to a suspected diagnosis of ‘acute abdomen’, an emergency small intestine resection was performed and a subsequent diagnosis of moderately-differentiated adenocarcinoma was confirmed. During a further immunohistochemical examination, pathologists determined that the small bowel metastasis descended from pancreatic cancer. The onset of bowel metastasis is an event rarely associated with MPM, and has not been previously described in the literature for cases of pancreatic cancer. Therefore, to the best of our knowledge, the present study describes the first case of intestinal metastasis from pancreatic cancer in a long-term survival patient with biphasic MPM.

Clinicopathologic Characteristics of Malignant Mesotheliomas Arising in Patients With a History of Radiation for Hodgkin and Non-Hodgkin Lymphoma

Studies have reported an association between pleural diffuse malignant mesothelioma (PDMM) and chest radiation for lymphoma. The clinicopathologic characteristics of malignant mesotheliomas arising in these patients have not been established. We studied 1,618 consecutive patients diagnosed with pleural PDMM from July 1993 to February 2008 and identified patients with a history of radiation for Hodgkin and non-Hodgkin lymphoma. We evaluated the histology in the surgical resection specimens and compared clinicopathologic features with overall survival. We identified 22 patients who developed PDMM after chest radiation as part of their treatment for lymphoma (mean latency time, 21.4 years; 95% CI, 17.0 to 25.8 years). Asbestos bodies in lymphoma-associated PDMM were lower than in asbestos-associated PDMM (median count, 15 v 325 bodies, respectively; P < .001) and similar to an unexposed control group (median count, 15 v 10 bodies, respectively; P = .6). Seventeen lymphoma-associated PDMMs (77%) were epithelioid and five (23%) were biphasic. Seven PDMMs (32%) had unusual histologies (pleomorphic, myxoid, clear cell, and signet ring cell). Patients with lymphoma-associated PDMM were younger than patients with asbestos-associated PDMM (median age, 45 v 64 years, respectively; P < .001) and had a significantly longer overall survival time (median, 32.5 v 12.7 months, respectively; P = .018). In multivariate analysis, independent favorable predictors for overall survival were history of prior radiation (P = .022), female sex (P < .001), age ≤ 65 years (P = .005), cytoreductive surgery (P < .001), and epithelioid histology (P < .001). Patients with lymphoma-associated PDMM are likely to have unusual histologic features, are significantly younger, and seem to have a longer overall survival compared with patients with asbestos-associated PDMM.

Localized malignant pleural mesothelioma

Localized malignant pleural mesothelioma (LMPM) is a rare tumor; previously only 52 cases have been reported in the English literature. This type of tumor should be distinguished from diffuse malignant pleural mesothelioma, because a good outcome may be obtained by surgical resection. We report a case of LMPM which grew rapidly within 1 year. Surgical resection was performed, and at present, 6 months since the operation, the patient remains free of the disease.

A nuclear grading system is a strong predictor of survival in epitheloid diffuse malignant pleural mesothelioma

Epithelioid mesothelioma is the most prevalent subtype of diffuse malignant pleural mesothelioma in which only staging is prognostic for survival. In this study of epithelioid diffuse malignant pleural mesothelioma, we investigate the prognostic utility of nuclear features. The slides of 232 epithelioid diffuse malignant pleural mesothelioma patients (14 stage I, 54 stage II, 130 stage III, and 34 stage IV) from a single institution were reviewed for the following seven nuclear features: nuclear atypia, nuclear/cytoplasmic ratio, chromatin pattern, intranuclear inclusions, prominence of nucleoli, mitotic count, and atypical mitoses. MIB-1 immunohistochemistry was performed using tissue microarray, and MIB-1 labeling index was recorded as the percentage of positive tumor cells. Median overall survival of all patients was 16 months and correlated with nuclear atypia (P<0.001), chromatin pattern (P=0.031), prominence of nucleoli (P<0.001), mitotic count (P<0.001), and atypical mitoses (P<0.001) by univariate analysis. Multivariate analysis revealed nuclear atypia (P=0.012) and mitotic count (P<0.001) as independent prognostic factors, and these two factors were utilized to create a three-tier nuclear grade score. The resulting nuclear grade stratified patients into three distinct prognostic groups: grade I (n=107, median overall survival=28 months), grade II (n=91, 14 months), and grade III (n=34, 5 months). Not only was nuclear grade an independent predictor of overall survival (P<0.001), but it was also a stronger discriminator of survival than all currently available factors. Furthermore, nuclear grade was associated with time to recurrence (P=0.004) in patients who underwent complete surgical resection (n=159). MIB-1 labeling index correlated with mitotic count (P<0.001) and nuclear atypia (P=0.037) and stratified overall survival (P<0.001) and time to recurrence (P=0.048), confirming the prognostic value of the nuclear grade. Nuclear grading in epithelioid mesothelioma provides a simple, practical, and cost-effective prognostic tool that better stratifies clinical outcome and time to recurrence than currently available clinicopathologic factors.

Asbestos-related Lung Disease

In this work, we describe both benign and malignant asbestos-related diseases and provide an updated review of recent advances in the field. It has long been appreciated that the inhalation of asbestos fibers causes several well-described respiratory diseases including pleural plaques, diffuse pleural thickening, asbestosis, lung cancer, and malignant pleural mesothelioma (MPM). However, despite this knowledge and stricter industrial controls, the incidence of these diseases continues to increase in many parts of the world. In fact, despite the introduction of strict limits early in the 20th century, the mortality rate due to MPM is still increasing in industrialized countries such as the United Kingdom and Australia. In this update we provide an overview of each disease entity while concentrating on the role that newer imaging techniques, including high-resolution computed tomography, magnetic resonance imaging, and positron emission tomography /computed tomography, play in the diagnosis of asbestos-related pleural and parenchymal diseases. As the incidence of MPM continues to increase in many parts of the world, this review also focuses on new approaches to the diagnosis and treatment of this devastating condition. A description of the potential use and limitations of biomarkers in the diagnosis and monitoring of the disease is included along with recent trial data examining novel vaccine-based biological therapies.

Non-Neoplastic and Neoplastic Pleural Endpoints Following Fiber Exposure

Exposure to asbestos fibers is associated with non-neoplastic pleural diseases including plaques, fibrosis, and benign effusions, as well as with diffuse malignant pleural mesothelioma. Translocation and retention of fibers are fundamental processes in understanding the interactions between the dose and dimensions of fibers retained at this anatomic site and the subsequent pathological reactions. The initial interaction of fibers with target cells in the pleura has been studied in cellular models in vitro and in experimental studies in vivo. The proposed biological mechanisms responsible for non-neoplastic and neoplastic pleural diseases and the physical and chemical properties of asbestos fibers relevant to these mechanisms are critically reviewed. Understanding mechanisms of asbestos fiber toxicity may help us anticipate the problems from future exposures both to asbestos and to novel fibrous materials such as nanotubes. Gaps in our understanding have been outlined as guides for future research.

Pleomorphic Epithelioid Diffuse Malignant Pleural Mesothelioma: A Clinicopathological Review and Conceptual Proposal to Reclassify as Biphasic or Sarcomatoid Mesothelioma

In patients with epithelioid diffuse malignant pleural mesothelioma (DMPM), clinical stage is the current primary prognostic factor. We sought to investigate whether histologic subtyping can prognostically stratify patients with epithelioid DMPM. Hematoxylin and eosin-stained slides of 232 patients with epithelioid DMPM (14 stage I, 54 stage II, 130 stage III, and 34 stage IV) from a single institution were reviewed. We classified the tumors into five subtypes, according to the predominant histological pattern: trabecular, tubulopapillary, micropapillary, solid, and pleomorphic (≥10% of tumor). Median overall survival (OS) of all patients with epithelioid DMPM was 16.2 months. Patients with pleomorphic subtype (n = 34) had the worst median OS (8.1 months), followed by solid (n = 89, 13.7 months), micropapillary (n = 20, 15.8 months), tubulopapillary (n = 51, 17.9 months), and trabecular (n = 38, 24.9 months). The pleomorphic subtype was associated with lymphatic and vascular invasion (p < 0.001). The micropapillary subtype was associated with lymphatic invasion (p < 0.001). In univariate analyses, pleomorphic subtype was significantly associated with poor OS (p = 0.003). The pleomorphic subtype showed no significant difference on OS compared with biphasic and sarcomatoid DMPM. In a multivariate analysis, the pleomorphic subtype was an independent predictor of poor OS (p = 0.031). In patients who underwent R1 resection, pleomorphic subtype had the shortest median time to recurrence (13.7 months). Our finding that the pleomorphic subtype is a predictor of aggressive behavior in epithelioid DMPM with no survival difference from biphasic or sarcomatoid DMPM suggests that it may be best regarded as a sarcomatoid pattern rather than a subtype of epithelioid DMPM.

A Rare Cause of Dysphagia: Malignant Pleural Mesothelioma in the Posterior Mediastinum

A 69-year-old man presented to the emergency room with dysphagia and vomiting. A computed tomographic scan revealed a posterior mediastinal mass surrounding the lower portion of the esophagus. Endoscopic examination demonstrated narrowing of the lower esophagus without malignant mucosal lesions. Thoracoscopic biopsies of the mediastinal mass failed to yield a pathologic diagnosis. The hyaluronic acid concentration in the left pleural effusion was remarkably high (755 mg/L), which is a finding strongly suggestive of malignant mesothelioma. Four months after the initial admission, a subcutaneous nodule was found in the left chest wall and a biopsy was taken. The histopathologic and immunohistochemical findings of the biopsy were consistent with the diagnosis of pleural malignant mesothelioma.

Intensity-Modulated Radiation Therapy with Simultaneous Integrated Boost in Unresected Left-Sided Pleural Mesothelioma: A Case Report

A 77-year-old male patient with unresected malignant pleural mesothelioma, clinical stage T3N0M0 according to the New International Staging System for Diffuse Malignant Pleural Mesothelioma, received intensity-modulated radiotherapy (IMRT) with a simultaneous integrated boost (SIB) after 6 cycles of chemotherapy with cisplatin and pemetrexed. SIB-IMRT delivered 40.5 Gy (1.5 Gy/fraction) to the left pleura and 50 Gy (1.85 Gy/fraction) to the sites of macroscopic disease. Radiotherapy was well tolerated. Two months after the end of radiotherapy the patient showed grade 2 lung toxicity (febrile episodes accompanied by dry cough) that was successfully treated with steroid therapy. Local control lasted for 2 years after SIB-IMRT. Then the tumor recurred marginally to the radiation field and the patient underwent chemotherapy with pemetrexed. Three years from the diagnosis, the patient is alive and in good general condition. He only takes prednisone 5 mg/daily for exertional dyspnea. To the best of our knowledge this is the first reported use of SIB-IMRT in unresected malignant pleural mesothelioma. Considering the dosimetric advantages of SIB-IMRT and the clinical results observed in our patient, additional evaluation of this technique seems justified.

A Case of Epithelial-type Diffuse Malignant Pleural Mesothelioma Who Survived with Chemotherapy for 7 Years

背景．びまん性悪性胸膜中皮腫は予後不良の疾患であり，標準的治療も定まっていない．しかし，びまん性悪性胸膜中皮腫は診断が難しい疾患であり，発見された時点で進行した症例が多いのも予後不良の原因と思われる．本症例は胸腔鏡による確定診断後抗癌剤治療を選択し，6年2か月経過後手術を施行した．症例．50歳代，男性．アスベスト曝露歴：あり．2001年春，検診で胸水貯留を指摘され初診医を受診，胸膜針生検で悪性胸膜中皮腫と診断されたが，セカンドオピニオンで中皮腫を否定され2002年秋に当科受診，2003年3月胸腔鏡下胸膜生検を施行し，上皮型悪性胸膜中皮腫（T1bN0M0 stage IB）と診断し化学療法を選択した．診断から6年2か月経過後胸膜肺全摘術を施行した．現在術後1年担癌生存中である．結語．本症例のように化学療法で長期生存がえられることもあり，早期症例の治療法別の効果判定には注意が必要であると思われた．

Three decades of experience in the surgical multi-modality management of pleural mesothelioma

Optimal management of diffuse malignant pleural mesothelioma (DMPM) remains unclear. We report our 30-year surgical experience with DMPM with emphasis on surgical procedure and post-operative adjuvant therapy. During the period of the study, 217 patients with DMPM were referred for surgical opinion. Patients who only had pleural biopsies were excluded (n=78). Consecutive patients who underwent surgical treatment were included (n=139). Surgical options were extra-pleural pneumonectomy (EPP) for Butchart stage I disease in clinically fit patients (n=49) or pleurectomy/decortication in patients who were either not fit for EPP or had advanced disease (Butchart stage II and III) or both (n=90). Post-operative adjuvant therapy included either chemotherapy, radiotherapy, both or none. The median follow-up was 10.0 months. The longest survival (median 26.0 months, IQR: 11.14-40.9 months) occurred in the pleurectomy/decortication group who received both post-operative chemotherapy and radiotherapy (n=24) (p<0.001). EPP whether or not combined with adjuvant therapy provided no significant survival advantage in comparison to pleurectomy/decortication (overall median survival 10.3 months vs 10.1 months, p=0.09). On univariate analysis, pleurectomy/decortication combined with chemotherapy and radiotherapy was the strongest predictor of prolonged survival (Hazard Ratio=3.6). Multivariate analysis with the inclusion of histological type, surgical procedure and type of adjuvant therapy, EPP without adjuvant therapy was an independent risk-factor for decreased survival (Hazard Ratio=9.2). In this series, cytoreductive surgery combined with post-operative adjuvant therapy provided better survival despite either advanced disease or surgically less fit patients. Thus, pleurectomy/decortication may be the procedure of choice, given that neither surgical procedure (EPP or PD) is not curative.

Pathologic Evaluation of Malignant Pleural Mesothelioma

Pathologists play an important role in the surgical management of diffuse malignant pleural mesothelioma, which relies heavily on accurate diagnosis and staging. The pathologist provides crucial input to the determination of many prognostic factors including histologic subtype, extent of local disease progression, resection margins, and nodal status. They consult with the clinical care team at multiple points along the treatment spectrum, preoperatively, intraoperatively, and postoperatively. Finally, they are increasingly called on to guide selection of chemotherapy and measure treatment response.