Cardiac sarcoidosis: A multimodal approach to reach the diagnosis

Abstract

Cardiac sarcoidosis (CS) is a rare condition involving the pericardium and myocardium most often in the setting of a systemic granulomatous disease. It belongs to myocarditis and more precisely to the granulomatous subtype of myocarditis [ [1] Leone O. Pieroni M. Rapezzi C. Olivotto I. The spectrum of myocarditis: from pathology to the clinics. Virchows Arch. 2019 Sep; 475 (Epub 2019 Jul 11): 279-301https://doi.org/10.1007/s00428-019-02615-831297595 Crossref PubMed Scopus (41) Google Scholar ]. The highlights of CS are the facts that although it is a devastating condition leading to heart failure and arrhythmia [ [2] Miedema J.R. Bonella F. Grunewald J. Spagnolo P. Looking into the future of sarcoidosis: what is next for treatment?. Curr. Opin. Pulm. Med. 2020 Sep; 26: 598-607https://doi.org/10.1097/MCP.000000000000070932657837 Crossref PubMed Scopus (6) Google Scholar ] it is amenable to immunosuppressive treatment [ [3] Terasaki F. Azuma A. Anzai T. Ishizaka N. Ishida Y. Isobe M. et al. Japanese Circulation Society joint working group. JCS 2016 guideline on diagnosis and treatment of cardiac Sarcoidosis - digest version. Circ. J. 2019 Oct 25; 83 (Epub 2019 Oct 9): 2329-2388https://doi.org/10.1253/circj.CJ-19-050831597819 Crossref PubMed Scopus (87) Google Scholar ] under the condition to have a quite early definitive diagnosis and this is the key issue. Indeed the impediments to diagnosis are diverse. First of all cardiac involvement in sarcoidosis is most often subclinical for a long period of time hampering setting-up a diagnostic procedure following guidelines [ [4] Yafasova A. Fosbøl E.L. Schou M. Gustafsson F. Rossing K. Bundgaard H. et al. Long-term adverse cardiac outcomes in patients with sarcoidosis. J. Am. Coll. Cardiol. 2020; 76: 767-777https://doi.org/10.1016/j.jacc.2020.06.03832792073 Crossref PubMed Scopus (27) Google Scholar ]. From autopsy studies it appears that only 12% of myocardial sarcoidosis cases are clinically diagnosed [ [5] Matsui Y. Iwai K. Tachibana T. Fruie T. Shigematsu N. Izumi T. et al. Clinicopathological study of fatal myocardial sarcoidosis. Ann. N. Y. Acad. Sci. 1976; 278: 455-469https://doi.org/10.1111/j.1749-6632.1976.tb47058.x1067031 Crossref PubMed Scopus (305) Google Scholar ] whereas up to 25% of patients with systemic sarcoidosis have cardiac involvement [ [6] Roberts W.C. McAllister Jr., H.A. Ferrans V.J. Sarcoidosis of the heart. A clinicopathologic study of 35 necropsy patients (group 1) and review of 78 previously described necropsy patients (group 11). Am. J. Med. 1977; 63: 86-108https://doi.org/10.1016/0002-9343(77)90121-8327806 Abstract Full Text PDF PubMed Scopus (631) Google Scholar ]. The second pitfall is that the endomyocardial biopsy (EMB) shows a low positive diagnostic yield around 20% [ [7] Uemura A. Morimoto S. Hiramitsu S. Kato Y. Ito T. Hishida H. Histologic diagnostic rate of cardiac sarcoidosis: evaluation of endomyocardial biopsies. Am. Heart J. 1999; 138: 299-302https://doi.org/10.1016/s0002-8703(99)70115-810426842 Crossref PubMed Scopus (0) Google Scholar ] even in sarcoidosis patients with suspected cardiac involvement: interestingly the diagnostic efficiency of biopsies increases to 36.4% in cases with dilated hearts (cardiac failure) whereas it was very low (6.7%) in cases with conduction disturbances and normal left ventricle ejection fraction (LVEF). An EMB is considered as positive if it shows a non-caseating granuloma (Fig. 1A ). An explanation for the low diagnostic rate of EMB is the focal and uneven distribution of granulomatous lesions within the heart [ [5] Matsui Y. Iwai K. Tachibana T. Fruie T. Shigematsu N. Izumi T. et al. Clinicopathological study of fatal myocardial sarcoidosis. Ann. N. Y. Acad. Sci. 1976; 278: 455-469https://doi.org/10.1111/j.1749-6632.1976.tb47058.x1067031 Crossref PubMed Scopus (305) Google Scholar ]. In practice granulomas are mostly constant in the left ventricle free wall and observed in the interventricular septum in about 75% of cases whereas they are present in the right ventricle in less than 50% [ [6] Roberts W.C. McAllister Jr., H.A. Ferrans V.J. Sarcoidosis of the heart. A clinicopathologic study of 35 necropsy patients (group 1) and review of 78 previously described necropsy patients (group 11). Am. J. Med. 1977; 63: 86-108https://doi.org/10.1016/0002-9343(77)90121-8327806 Abstract Full Text PDF PubMed Scopus (631) Google Scholar ]. The development of left ventricle EMB should be an approach to improve diagnostic efficacy of biopsies [ [8] Bhimaraj A. Trachtenberg B. Valderrábano M. Robotically guided left ventricular biopsy to diagnose cardiac sarcoidosis: a multidisciplinary innovation leading to first-in-human case. Circ. Heart Fail. 2018 Mar; 11e004627https://doi.org/10.1161/CIRCHEARTFAILURE.117.00462729519901 Crossref PubMed Scopus (5) Google Scholar ]. Indeed the definitive diagnosis of CS on EMB requires the discovery of granulomas. Nevertheless pathologists should pay attention to less specific changes in EMB when granulomas are absent: combined confluent fibrosis (Fig. 1B), fatty changes and macrophage infiltration have been suggested to make CS likely [ [9] Cha M.J. Seo J.W. Oh S. Park E.A. Lee S.H. Kim M.Y. Park J.Y. Indirect pathological indicators for cardiac sarcoidosis on endomyocardial biopsy. J. Pathol. Transl. Med. 2020 Sep; 54 (Epub 2020 Jul 29): 396-410https://doi.org/10.4132/jptm.2020.06.1032717775 Crossref PubMed Scopus (4) Google Scholar ]. The granuloma-negative biopsy remains a major problem in the diagnostic process of CS.