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Pericardial Mesothelioma, a Disease for Brave Hearts

      In the past decade, there has been a steady, although slow, improvement in the treatment of mesothelioma, the rare tumor of the mesothelial surfaces caused by asbestos exposure. The advances were mostly driven by research in the field of pleural mesothelioma biology and treatment and, at a lesser extent, peritoneal mesothelioma,
      • Janes S.M.
      • Alrifai D.
      • Fennell D.A.
      Perspectives on the treatment of malignant pleural mesothelioma.
      ,
      • Hiltbrunner S.
      • Fleischmann Z.
      • Sokol E.S.
      • Zoche M.
      • Felley-Bosco E.
      • Curioni-Fontecedro A.
      Genomic landscape of pleural and peritoneal mesothelioma tumours [published online ahead of print, 2022 Sep 22]..
      which is the second most frequent. Pericardial mesothelioma is an exceedingly rare entity. Its correlation with asbestos exposure is controversial; indeed, on one hand, some authors exclude any correlation,
      • Mezei G.
      • Chang E.T.
      • Mowat F.S.
      • Moolgavkar S.H.
      Epidemiology of mesothelioma of the pericardium and tunica vaginalis testis.
      and, on the other hand, others report significant association with asbestos exposure,
      • Marinaccio A.
      • Consonni D.
      • Mensi C.
      • et al.
      Association between asbestos exposure and pericardial and tunica vaginalis testis malignant mesothelioma: a case-control study and epidemiological remarks.
      thus leaving the real pathogenic process uncertain.
      According to the most recent epidemiologic data from the Italian Registry on Mesothelioma, one of the most accurate and comprehensive national registries in the world, pericardial mesothelioma has an incidence of 0.049/million/y in men and 0.023/million/year in women,
      • Marinaccio A.
      • Consonni D.
      • Mensi C.
      • et al.
      Association between asbestos exposure and pericardial and tunica vaginalis testis malignant mesothelioma: a case-control study and epidemiological remarks.
      whereas the estimated incidence of pericardial mesothelioma in the United States is 10 to 15 new cases per year.
      • Mezei G.
      • Chang E.T.
      • Mowat F.S.
      • Moolgavkar S.H.
      Epidemiology of mesothelioma of the pericardium and tunica vaginalis testis.
      According to a definition borrowed from the field of sarcoma, pericardial mesothelioma could be defined as “ultra-rare” (i.e., incidence <1/million/y).
      • Stacchiotti S.
      • Frezza A.M.
      • Blay J.Y.
      • et al.
      Ultra-rare sarcomas: a consensus paper from the Connective Tissue Oncology Society community of experts on the incidence threshold and the list of entities.
      The “ultra-rarity” entails major difficulties in conducting adequately powered, prospective studies together with major challenges in making correct diagnosis and in dissecting disease biology.
      Given the complete absence of prospective evidence and specific clinical recommendations in this exceptional presentation, treatment generally follows that of pleural mesothelioma, often with unsatisfactory outcomes.
      The recent article of Offin et al.
      • Offin M.
      • De Silva D.L.
      • Sauter J.L.
      • et al.
      Multimodality therapy in patients with primary pericardial mesothelioma.
      in the Journal of Thoracic Oncology describes the largest retrospective monoinstitutional case series of patients with pericardial mesothelioma ever published to date. The series is composed of 12 patients, eight females and four males, treated in a period of 11 years, with a median age of 51 years, and none of the patients reported asbestos exposure. The median age at diagnosis, lower than that reported for the pleural counterpart, is in line with what was reported in the above-mentioned Italian Registry and Surveillance, Epidemiology, and End Results Program (SEER) database analysis (median age of 61 and 53 y, respectively). This observation along with the lack of asbestos exposure might suggest a distinct biological entity with respect to pleural mesothelioma. Nonetheless, the relative frequency of histotypes (75% epithelioid and 25% nonepithelioid) is superimposable with the larger pleural mesothelioma series. Furthermore, the only Next Generation Sequencing (NGS) analysis reported reveals multiple alterations, including TP53, NF2, and CDKN2A, highly consistent with those described in pleural mesothelioma.
      • Hiltbrunner S.
      • Fleischmann Z.
      • Sokol E.S.
      • Zoche M.
      • Felley-Bosco E.
      • Curioni-Fontecedro A.
      Genomic landscape of pleural and peritoneal mesothelioma tumours [published online ahead of print, 2022 Sep 22]..
      ,
      • Tsao A.S.
      • Pass H.I.
      • Rimner A.
      • Mansfield A.S.
      New era for malignant pleural mesothelioma: updates on therapeutic options.
      Nevertheless, tumor heterogeneity of the epithelioid subtype has been recently discussed,
      • Hiltbrunner S.
      • Fleischmann Z.
      • Sokol E.S.
      • Zoche M.
      • Felley-Bosco E.
      • Curioni-Fontecedro A.
      Genomic landscape of pleural and peritoneal mesothelioma tumours [published online ahead of print, 2022 Sep 22]..
      and the biological and molecular portraits may suggest the optimal treatment according to the clinical phenotype, also in this setting.
      Two main points in the article deserve to be highlighted.
      First, the median overall survival (OS) for the overall cohort was 25.9 months, which is numerically longer than the most recent OS data for pleural mesothelioma
      • Baas P.
      • Daumont M.J.
      • Lacoin L.
      • et al.
      Treatment patterns and outcomes for patients with malignant pleural mesothelioma in England in 2013–2017: a nationwide CAS registry analysis from the I-O Optimise initiative.
      and sharply superior to the median OS of 2 to 6 months previously reported for pericardial mesothelioma.
      • Marinaccio A.
      • Consonni D.
      • Mensi C.
      • et al.
      Association between asbestos exposure and pericardial and tunica vaginalis testis malignant mesothelioma: a case-control study and epidemiological remarks.
      ,
      • Brydges H.
      • Yin K.
      • Balasubramaniyan R.
      • et al.
      Primary pericardial mesothelioma: a population-based propensity score-matched analysis.
      ,
      • McGehee E.
      • Gerber D.E.
      • Reisch J.
      • Dowell J.E.
      Treatment and outcomes of primary pericardial mesothelioma: a contemporary review of 103 published cases.
      Second, the patients with the longest survival were the three who underwent a trimodality treatment (e.g., surgery, adjuvant cisplatin plus pemetrexed, and adjuvant radiation therapy with different radiation therapy strategies): these patients had a far longer median OS than patients treated with systemic therapy only or lost to follow-up (70.3 versus 8.2 mo, hazard ratio = 0.19).
      Although selection bias might underpin this result, we think that this finding is still notable, considering the difficulty of achieving a complete resection in pericardial tumors, even at highly experienced centers. Indeed, in the article by Offin et al.,
      • Offin M.
      • De Silva D.L.
      • Sauter J.L.
      • et al.
      Multimodality therapy in patients with primary pericardial mesothelioma.
      all the patients who underwent surgery had macroscopic residual disease after resection (R2).
      In the present series, trimodality treatment seemed to be associated with the best survival outcomes. This is consonant with published data in pleural mesothelioma
      • Shaikh F.
      • Zauderer M.G.
      • von Reibnitz D.
      • et al.
      Improved outcomes with modern lung-sparing trimodality therapy in patients with malignant pleural mesothelioma.
      ,
      • Thompson A.B.
      • Quinn T.J.
      • Siddiqui Z.A.
      • Almahariq M.F.
      • Grills I.S.
      • Stevens C.W.
      Addition of radiotherapy to surgery and chemotherapy improves survival in localized malignant pleural mesothelioma: a Surveillance, Epidemiology, and End Results (SEER) study.
      and discording with previous retrospective data analysis on pericardial mesothelioma suggesting that only systemic chemotherapy is associated with improved survival.
      • McGehee E.
      • Gerber D.E.
      • Reisch J.
      • Dowell J.E.
      Treatment and outcomes of primary pericardial mesothelioma: a contemporary review of 103 published cases.
      As for pleural mesothelioma, the multidisciplinary team including all the specialists involved in the disease management has a core role in the selection of patients potentially amenable to multimodality treatment; the pericardial involvement adds complexity to the general management thus deserving the expertise of the cardiothoracic surgeon.
      Indeed, in the article by Offin et al.,
      • Offin M.
      • De Silva D.L.
      • Sauter J.L.
      • et al.
      Multimodality therapy in patients with primary pericardial mesothelioma.
      all the patients selected for trimodality therapy had prolonged disease control. Therefore, the multidisciplinary team could aid the selection of patients suitable for more “brave” and aggressive treatment. This issue acquires more and more relevance, considering that the specimen availability may help researchers to depict the main hallmarks of pericardial mesotheliomas.
      As for all the ultra-rare cancers, high-quality evidence can only be built with extensive international collaboration of referral centers. A recent consensus article from the Connective Tissue Oncology Society
      • Stacchiotti S.
      • Maria Frezza A.
      • Demetri G.D.
      • et al.
      Retrospective observational studies in ultra-rare sarcomas: a consensus paper from the Connective Tissue Oncology Society (CTOS) community of experts on the minimum requirements for the evaluation of activity of systemic treatments.
      recommends the collaboration among reference centers for ultra-rare sarcomas, to warrant the conduction of high-quality retrospective studies. In this context, “large” and well-documented retrospective evidence from referral centers, as this case series, may also widen the knowledge of the disease, building the basis for future investigations.
      In conclusion, we think that a multidisciplinary team at the referral centers is the key for an optimal management for this disease. Furthermore, we believe that global collaborative efforts, including the largest number of referral centers, should be done. This will allow the generation of adequate evidence for the definition of clinical recommendations and constitute the basis to support new drug developments for pericardial mesothelioma.

      CRediT Authorship Contribution Statement

      Federica Grosso, Luigi Cerbone, Giulia Pasello: Manuscript review, Editorial drafting.

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        Genomic landscape of pleural and peritoneal mesothelioma tumours [published online ahead of print, 2022 Sep 22]..
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      Linked Article

      • Multimodality Therapy in Patients With Primary Pericardial Mesothelioma
        Journal of Thoracic OncologyVol. 17Issue 12
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          Primary pericardial mesothelioma (PPM) has no accepted standard-of-care treatment options with management and outcomes often extrapolated from diffuse pleural mesothelioma. Disease-specific research is needed to better define PPM. We report our institutional experience with PPM highlighting the potential role for multimodality therapy.
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