The 2021 WHO Classification of Tumors of the Heart

The fifth edition of the WHO Classification of Thoracic Tumours1WHO Classification of Tumours Editorial BoardThoracic tumours.5th edition. WHO Classification of Tumours. volume 5. International Agency for Research on Cancer, Lyon, France2021Google Scholar presents an updated classification of cardiac tumors, detailed in Table 1. As in previous iterations, the tumors are stratified into benign and malignant varieties, with a separate section to address hematolymphoid neoplasms of the heart.Table 1ICD-9-O Topographic Coding of Heart Tumors1WHO Classification of Tumours Editorial BoardThoracic tumours.5th edition. WHO Classification of Tumours. volume 5. International Agency for Research on Cancer, Lyon, France2021Google ScholarBenign TumorsMalignant Tumors8820/0Papillary fibroelastoma9120/3Angiosarcoma8840/0Myxoma, NOS8890/3Leiomyosarcoma, NOS8810/0Fibroma, NOS8802/3Pleomorphic sarcoma8900/0Rhabdomyoma, NOS8000/6Neoplasm, metastatic8904/0Adult cellular rhabdomyomaHematolymphoid tumors8850/0Lipoma, NOS9680/3Diffuse large B-cell lymphoma, NOSLipomatous hypertrophy of the atrial septumLipomatous hamartoma of atrioventricular valve9680/3Fibrin-associated diffuse large B-cell lymphomaHamartoma of mature cardiac myocytesMesenchymal cardiac hamartoma9120/0Hemangioma, NOS9122/0Venous hemangioma9131/0Capillary hemangioma9123/0Arteriovenous hemangioma9121/0Cavernous hemangiomaConduction system hamartoma8454/0Cystic tumor of atrioventricular nodeICD-9, International Classification of Diseases, Ninth Revision; NOS, not otherwise specified.Reprinted from WHO Classification of Tumours Editorial Board. Thoracic Tumours. Vol. 5, 5th ed, ICD-O coding of tumours of the heart; page 5, Copyright (2021). Open table in a new tab ICD-9, International Classification of Diseases, Ninth Revision; NOS, not otherwise specified. Reprinted from WHO Classification of Tumours Editorial Board. Thoracic Tumours. Vol. 5, 5th ed, ICD-O coding of tumours of the heart; page 5, Copyright (2021). New to the fifth edition is an extensive collection of online whole slide images that exhibit examples of each of the cardiac entities classified in this volume. In addition, a new online format makes the content even more accessible to clinicians and scientists globally, in the hopes of facilitating adoption. It is only through these common definitions and language that we can hope to better understand these rather uncommon lesions. Advances in our understanding of cardiac tumors were the guiding principle in determining the optimum classification. To reduce redundancy, some mesenchymal entities of the thorax were removed from the site-specific subsections of the book and placed within a general section on the topic. Similarly, syndromic tumors are now discussed separately in a section on genetic tumor syndromes involving the thorax. Here, the changes made in the fifth edition will be summarized. Essential and desirable diagnostic criteria are provided for each entity in Supplementary Table 1. Brief commentaries on the clinical relevance of these changes are provided, with final comments on potential directions for further study in this area. Updates to each of the main categories of cardiac tumors were made in the fifth edition, resulting in some entities being combined with others and some being newly established. Malignant primary cardiac neoplasms have been an area of growing controversy in the past decade. As detailed subsequently, the entities of intimal sarcoma and undifferentiated pleomorphic sarcoma (UPS) have been formally separated, reflecting a better understanding of their biology and a better reflection of their anatomical sites of occurrence. Intimal sarcoma has been relocated to the Lung Section of the Thoracic Volume and the Intimal Sarcoma chapter of the WHO Classification of Soft Tissue and Bone Tumours.2WHO Classification of Tumours Editorial BoardSoft tissue bone tumours.5th edition. WHO Classification of Tumours. volume 3. International Agency for Research on Cancer, Lyon, France2020Google Scholar Although many sarcomas have been described in the heart, only a few are encountered with regularity. Most of the other rare types have been relocated to a specific section on Mesenchymal Tumors of the Thorax or can be found in the Soft Tissue volume. These include rhabdomyosarcoma (embryonal and pleomorphic subtypes), osteosarcoma, dedifferentiated liposarcoma, malignant peripheral nerve sheath tumor, and Ewing sarcoma. There has also been increasing debate on the neoplastic nature of papillary fibroelastomas (PFEs). It is currently the most often excised heart tumor, nearly twice as frequently encountered as cardiac myxoma.3Tamin S.S. Maleszewski J.J. Scott C.G. et al.Prognostic and bioepidemiologic implications of papillary fibroelastomas.J Am Coll Cardiol. 2015; 65: 2420-2429Google Scholar Updates on the biology of these lesions have allowed for their reclassification and an altered bioepidemiologic landscape of cardiac neoplasms. Another reclassification occurred with the lesion formerly referenced as histiocytoid cardiomyopathy, which is now recognized as a primarily tumoral condition, the conduction system hamartoma. Several other hamartomatous lesions (mesenchymal cardiac hamartoma and lipomatous hamartoma of the atrioventricular valves) were also added to the classification because of their distinctive clinical and pathologic presentations. As mentioned previously, a detailed section on thoracic tumor syndromes, including their clinical presentation and molecular genetics, is now present within the text. Specifically, apropos to cardiac neoplasms, is the subsection on Carney complex (CNC), which provides the reader with more detail on the genetic implications of this diagnosis and the contemporary testing or screening strategy. Defined as a malignant neoplasm arising outside of the heart and pericardium, cardiac metastases occur in up to 10% of patients with cancer. Metastases are far more common than primary cardiac tumors and generally portend a poor prognosis. Most encountered are malignant melanoma and supradiaphragmatic epithelial neoplasms, most notably lung and breast carcinomas.4Bussani R. De-Giorgio F. Abbate A. Silvestri F. Cardiac metastases.J Clin Pathol. 2007; 60: 27-34Google Scholar,5García-Riego A. Cuiñas C. Vilanova J.J. Malignant pericardial effusion.Acta Cytol. 2001; 45: 561-566Google Scholar Other reported primary malignancies metastatic to the heart include but are not limited to thyroid, thymic, gastrointestinal, renal, endometrial, ovarian, and urinary bladder. Metastases of nonepithelial tumors may include sarcomas (including angiosarcoma [AS]), mesothelioma, and lymphoma. Radiologic-pathologic correlation studies confirm that metastatic tumors to the heart and pericardium may occur by means of several different mechanisms, including direct extension, hematogenous or lymphatic spread, or transvenous extension.6Schoen F.J. Berger B.M. Guerina N.G. Cardiac effects of noncardiac neoplasms.Cardiol Clin. 1984; 2: 657-670Google Scholar The most common mechanism is metastasis through mediastinal lymphatic channels to the heart, resulting in epicardial deposition of the tumor.7Hancock E.W. Neoplastic pericardial disease.Cardiol Clin. 1990; 8: 673-682Google Scholar The visceral pericardium contains a high density of lymphatic channels draining the pericardial space, which merge at the root of the aorta. A pericardial effusion results when metastatic tumor deposits obstruct the lymphatic system. Acute and chronic pericarditis can be found owing to this impaired lymphatic drainage or direct irritation. Prominent thickening of the pericardium is more often observed in the context of mesothelioma (either metastatic or primary) (Fig. 1) or chronic fibrosing pericarditis. The clinical presentation of cardiac involvement in metastatic disease includes shortness of breath and hypotension which may be out of proportion to radiographic findings in patients with pericardial effusion. Patients may also present with cough, chest pain, or peripheral edema. Metastatic involvement of the heart and pericardium may go unrecognized until autopsy. Impairment of cardiac function occurs in approximately 30% of patients and is usually attributable to pericardial effusion. Cytologic evaluation of pericardial effusion specimens after pericardiocentesis is frequently the initial procedure of choice to diagnose a metastatic malignancy involving the heart, although it has a rather low sensitivity with a false-negative rate approaching 15%.8Dragoescu E.A. Liu L. Pericardial fluid cytology: an analysis of 128 specimens over a 6-year period.Cancer Cytopathol. 2013; 121: 242-251Google Scholar Nevertheless, when tumor cells are detected, it provides an excellent way of differentiating metastatic carcinoma, melanoma, sarcoma, mesothelioma, and reactive processes such as mesothelial hyperplasia, especially with use of adjunct immunohistochemistry and molecular studies. New ancillary studies such as BAP1 and MTAP immunohistochemistry and p16/CDKN2A fluorescence in situ hybridization are excellent for distinguishing malignant mesothelial proliferations from their benign counterparts (Fig. 2A and B).9Chapel D.B. Schulte J.J. Berg K. et al.MTAP immunohistochemistry is an accurate and reproducible surrogate for CDKN2A fluorescence in situ hybridization in diagnosis of malignant pleural mesothelioma.Mod Pathol. 2020; 33: 245-254Google Scholar Most primary cardiac tumors are benign. These benign tumors reflect a broad array of neoplasms and hamartomas that are diagnosed throughout life, ranging from in utero diagnosis to centenarians. The most common among these is the PFE. The classification of this lesion was changed from “growth” to “neoplasm” in the fifth edition, reflecting contemporary understanding that a significant proportion of these tumors harbor canonical oncogenic driver mutations in KRAS.10Wittersheim M. Heydt C. Hoffmann F. Büttner R. KRAS mutation in papillary fibroelastoma: a true cardiac neoplasm?.J Pathol Clin Res. 2017; 3: 100-104Google Scholar,11Bois M.C. Milosevic D. Kipp B.R. Maleszewski J.J. KRAS mutations in papillary fibroelastomas: a study of 50 cases with etiologic and diagnostic implications.Am J Surg Pathol. 2020; 44: 626-632Google Scholar High-resolution imaging has also led to increased detection of these tumors, causing them to usurp the cardiac myxoma as the most common cardiac neoplasm.3Tamin S.S. Maleszewski J.J. Scott C.G. et al.Prognostic and bioepidemiologic implications of papillary fibroelastomas.J Am Coll Cardiol. 2015; 65: 2420-2429Google Scholar PFEs may arise on any endocardial-lined surface, with the aortic valve being most often affected. Damaged endocardial surfaces are also particularly susceptible to PFE development.12Kumar G. Macdonald R.J. Sorajja P. Edwards W.D. Ommen S.R. Klarich K.W. Papillary fibroelastomas in 19 patients with hypertrophic cardiomyopathy undergoing septal myectomy.J Am Soc Echocardiogr. 2010; 23: 595-598Google Scholar These papillary tumors look like sea anemones on both imaging and gross examination (Fig. 3A and B), owing to their avascular, endocardium-lined fronds. Most patients with PFE are asymptomatic, and the PFE is found incidentally during a routine echocardiogram or cardiac computed tomography done for other indications. When symptomatic, the classic presentation is neurologic event (20%–30%), such as stroke or transient ischemic attack, followed by angina and myocardial infarction, sudden death, and rarely pulmonary embolism, retinal embolism, and even more rarely mesenteric ischemia, peripheral emboli, and renal infarction.3Tamin S.S. Maleszewski J.J. Scott C.G. et al.Prognostic and bioepidemiologic implications of papillary fibroelastomas.J Am Coll Cardiol. 2015; 65: 2420-2429Google Scholar Cardiac myxomas are benign neoplasms that most often arise on the septum of the left atrium. They can be lobulated or villiform (Fig. 4A and B) and variable in size and shape. The lesional cell is the myxoma cell, occurring singly or in clusters, embedded in a myxoid matrix typically rich in proteoglycan, collagen, and elastin (Fig. 5). Immunoreactivity with calretinin is found in nearly all cases. Myxomas arising in a non-left atrial site or that are multicentric should always raise the suspicion for CNC, a syndrome resulting from underlying germline mutations in PRKAR1A. PRKAR1A immunostaining provides a useful surrogate to screen for CNC and can help direct future screening of patients with myxoma and their families (Fig. 6).13Maleszewski J.J. Larsen B.T. Kip N.S. et al.PRKAR1A in the development of cardiac myxoma: a study of 110 cases including isolated and syndromic tumors.Am J Surg Pathol. 2014; 38: 1079-1087Google Scholar Although incidental discovery on imaging is possible, nearly 70% of patients with myxoma will present with significant symptoms, such as stroke, peripheral embolization, or myocardial infarction. Obstructive symptoms, leading to heart failure, chest pain unrelated to exercise, palpitations, syncope, and sudden death may occur. Constitutional symptoms are also not infrequent, found in up to a third of patients, and may include fever, weight loss, fatigue, myalgias, arthralgias, and even Raynaud’s phenomena.Figure 5Cardiac myxoma: light microscopy. Myxoma cells are the diagnostic hallmark of cardiac myxoma. These bland, spindle-shaped cells occur both singly and in small clusters.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Figure 6PRKAR1A loss in CNC. Absence of reactivity for PRKAR1A in the myxoma cells is suggestive of the possibility of CNC. Although not a specific finding for CNC, it is a sensitive screen. CNC, Carney complex.View Large Image Figure ViewerDownload Hi-res image Download (PPT) Cardiac rhabdomyoma is the most common pediatric cardiac neoplasm, up to 70% to 90% of which are associated with tuberous sclerosis. It is a benign hamartomatous lesion of striated cardiac myocytes without proliferative activity. They typically arise in multiples and frequently are associated with obstructive symptoms or arrhythmias. Histologically, they consist of enlarged, vacuolated “spider cells” that form circumscribed nodules. Spontaneous regression is common, thus a conservative approach to management is often taken; however, mTOR pathway inhibitors have been found to hasten tumor regression.14Martínez-García A. Michel- Macías C. Cordero- González G. et al.Giant left ventricular rhabdomyoma treated successfully with everolimus: case report and review of literature.Cardiol Young. 2018; 28: 903-909Google Scholar Cardiac fibroma is the second most common pediatric cardiac tumor. Its diagnostic characteristics did not undergo significant revision from the previous classification. These tumors usually arise in the ventricular septum, where they have a large, grossly circumscribed, tan-white, and whorled appearance. Most often, they arise as a single mass with characteristic calcification that can sometimes be found on imaging. Histologically, cardiac fibromas consist of benign fibroblasts admixed with collagen fibers that increase as the lesion ages.15Patel J. Sheppard M.N. Pathological study of primary cardiac and pericardial tumours in a specialist UK Centre: surgical and autopsy series.Cardiovasc Pathol. 2010; 19: 343-352Google Scholar The tumor is frequently associated with an arrhythmic presentation, but it responds favorably to resection with a low rate of tumor recurrence. Cardiac fibromas are associated with germline or somatic PTCH1 mutations, the former of which occur in the setting of Gorlin (nevoid basal cell carcinoma) syndrome. Adult cellular rhabdomyoma is a rare neoplasm that occurs in adults more than 20 years old. In contrast to the more common cardiac rhabdomyoma, adult cellular rhabdomyoma has no known syndromic association and lacks the pathognomonic vacuolated “spider cells” of its pediatric counterpart (though sarcoplasmic vacuolization may be encountered). Instead, it consists of striated muscle cells with histologic resemblance to extracardiac rhabdomyomas.16Burke A.P. Gatto-Weis C. Griego J.E. Ellington K.S. Virmani R. Adult cellular rhabdomyoma of the heart: a report of 3 cases.Hum Pathol. 2002; 33: 1092-1097Google Scholar Grossly, the tumors are circumscribed, tan, homogenous masses that may protrude into adjacent cardiac chambers. Histologically, they seem more cellular than the cardiac rhabdomyoma, with sheet-like growth of ovoid-to-spindled striated myocytes and a prominent vascular background. Immunoreactivity with desmin and myogenin is the rule. Ki-67 staining usually reveals a low proliferation index, generally between 1% and 20%.16Burke A.P. Gatto-Weis C. Griego J.E. Ellington K.S. Virmani R. Adult cellular rhabdomyoma of the heart: a report of 3 cases.Hum Pathol. 2002; 33: 1092-1097Google Scholar The two primary cardiac adipocytic tumors, cardiac lipoma and lipomatous hypertrophy of the atrial septum (LHAS), are now discussed in the same section in recognition of the fact that some cases of LHAS have been found to harbor molecular genetic alterations similar to those found in lipomas.17Bois M.C. Bois J.P. Anavekar N.S. Oliveira A.M. Maleszewski J.J. Benign lipomatous masses of the heart: a comprehensive series of 47 cases with cytogenetic evaluation.Hum Pathol. 2014; 45: 1859-1865Google Scholar Lipomas tend to be epicardial, but they can occur in any layer of the heart. Histologically, a lipoma is an encapsulated mass composed of mature adipocytes; LHAS is instead an unencapsulated collection of fat (including brown fat) and atrial myocytes expanding the atrial septum (Fig. 7) that is rarely itself symptomatic. Lipomatous hamartoma of the atrioventricular valve is a new entity in the fifth edition. These lesions are uncommon, presumably congenital hamartomatous expansions of the mitral and tricuspid valves. Grossly, atrioventricular leaflets seem thickened and billowing, with nodular protuberances (Fig. 8).18Karasu B.B. Yeter E. Yilmazer D. Kiziltepe U. Ulular O. Akdemir R. Primary valvular lipomatous hamartoma: a case report and a collective review of the literature.Cardiovasc Pathol. 2011; 20: 377-380Google Scholar Histologically, they consist of disorganized mature adipose tissue and fibroconnective tissue with thin-walled vasculature. This entity contrasts from cardiac lipoma by its lack of a capsule, causing it to have an infiltrative or expansive appearance on light microscopy. Hamartoma of mature cardiac myocytes is a benign disorganized growth of cardiac myocytes characterized by a poorly defined, pale-gray myocardial mass, usually arising in the ventricular myocardium. Mesenchymal cardiac hamartoma is a newly recognized entity in the fifth edition. In contrast to the aforementioned hamartoma of mature cardiac myocytes, mesenchymal cardiac hamartoma consists of cardiomyocytes and disorganized mature elements native to the myocardium, including the fat, nerve, vasculature, smooth muscle, and collagen.19Bradshaw S.H. Hendry P. Boodhwani M. Dennie C. Veinot J.P. Left ventricular mesenchymal hamartoma, a new hamartoma of the heart.Cardiovasc Pathol. 2011; 20: 307-314Google Scholar Grossly, the lesion forms a discrete tan-pink mass, most often occurring in the ventricular myocardium. Ventricular arrhythmias and sudden death have been documented with these lesions. Cardiac hemangiomas are benign vascular tumors (or vascular malformations) with capillary, cavernous, and arteriovenous types. Their location is variable, but they arise most frequently in the ventricular free walls. Histologically, they are composed of thin-walled vascular spaces, without atypia. Expression of vascular markers (CD31, CD34, and ERG) is found in all cases. Clinically, patients present in the fifth decade and may be asymptomatic or symptomatic with dyspnea, syncope, or angina. Conduction system hamartoma was renamed from its previous designation as “histiocytoid cardiomyopathy,” in recognition of the fact that it is primarily tumoral in presentation rather than cardiomyopathic. Grossly, yellow-tan subendocardial nodules follow the distribution of the conduction system. Histologically, the lesions are composed of large, pale polygonal cells with granular sarcoplasm, ovoid nuclei, and variably prominent nucleoli, which have patchy reactivity with S100 immunohistochemistry. Underlying mutations in the NDUF gene family, encoding components of the oxidative phosphorylation pathway, have been described.20Shehata B.M. Cundiff C.A. Lee K. et al.Exome sequencing of patients with histiocytoid cardiomyopathy reveals a de novo NDUFB11 mutation that plays a role in the pathogenesis of histiocytoid cardiomyopathy.Am J Med Genet A. 2015; 167A: 2114-2121Google Scholar Cardiomegaly is almost always present, including a high rate of arrhythmogenic disorders and sudden death in the young.21Samuel S. Fountain R. Start D. Karpawich P.P. A unique case of sudden cardiac death in an infant.Clin Pediatr (Phila). 2019; 58: 253-256Google Scholar Cystic tumor of the atrioventricular node is a benign, congenital, endodermal developmental rest forming a cystic in the region of the atrioventricular node which (although often <3 mm in size) can result in sudden death. It consists of multiple, variable cysts lined by columnar, transitional, or squamous cells, without cellular atypia. Malignant neoplasms represent the minority (≤10%) of primary cardiac neoplasms, and, excluding tumors of the pericardium (now covered in the section entitled Tumors of the Pleura and Pericardium), fall essentially into two histologic groups—sarcomas and lymphomas. Although a wide variety of sarcomas have been reported to occur primary to the heart, cardiac AS, cardiac UPS, and cardiac leiomyosarcoma (LMS) are the most common, representing approximately three quarters of all cardiac sarcomas. Cardiac AS and UPS each account for approximately a third of cases, with LMS accounting for approximately 10%.22Burke A.P. Cowan D. Virmani R. Primary sarcomas of the heart.Cancer. 1992; 69: 387-395Google Scholar, 23Kim C.H. Dancer J.Y. Coffey D. et al.Clinicopathologic study of 24 patients with primary cardiac sarcomas: a 10-year single institution experience.Hum Pathol. 2008; 39: 933-938Google Scholar, 24Simpson L. Kumar S.K. Okuno S.H. et al.Malignant primary cardiac tumors: review of a single institution experience.Cancer. 2008; 112: 2440-2446Google Scholar As a group, these sarcomas generally present between the fourth and sixth decades of life; however there is a wide age range, including pediatric patients. UPS and LMS occur most often in the left atrium with no sex predilection, whereas AS occurs in the right atrium disproportionately in men.25Randhawa J.S. Budd G.T. Randhawa M. et al.Primary cardiac sarcoma: 25-year Cleveland Clinic experience.Am J Clin Oncol. 2016; 39: 593-599Google Scholar, 26Basso C. Valente M. Poletti A. Casarotto D. Thiene G. Surgical pathology of primary cardiac and pericardial tumors.Eur J Cardio Thorac Surg. 1997; 12: 730-738Google Scholar, 27Zhang C. Huang C. Zhang X. Zhao L. Pan D. Clinical characteristics associated with primary cardiac angiosarcoma outcomes: a surveillance, epidemiology and end result analysis.Eur J Med Res. 2019; 24: 29Google Scholar Patients will often present with chest pain, dyspnea, weight loss, and malaise, which are nonspecific and will delay the diagnosis. These blood vessel-rich tumors may also cause catastrophic hemorrhage with cardiac tamponade (Fig. 9), which is notably devoid of characteristic cytology. Of all the cardiac sarcomas, AS portends the worse prognosis, with a 5-year overall survival of approximately 10%.27Zhang C. Huang C. Zhang X. Zhao L. Pan D. Clinical characteristics associated with primary cardiac angiosarcoma outcomes: a surveillance, epidemiology and end result analysis.Eur J Med Res. 2019; 24: 29Google Scholar The remaining cardiac sarcomas include various differentiated sarcomas which occur rarely in a primary cardiac location and have been condensed into a summative entry entitled Other Sarcomas That May Involve the Heart. Immunohistochemistry remains the mainstay for the classification of differentiated cardiac sarcomas along with hematoxylin and eosin morphology. Cardiac AS typically has immunoreactivity for the endothelial markers (ERG and CD31) and LMS exhibits reactivity with smooth muscle markers (desmin and smooth muscle actin).28Leduc C. Jenkins S.M. Sukov W.R. Rustin J.G. Maleszewski J.J. Cardiac angiosarcoma: histopathologic, immunohistochemical, and cytogenetic analysis of 10 cases.Hum Pathol. 2017; 60: 199-207Google Scholar,29Wang J.G. Cui L. Jiang T. Li Y.J. Wei Z.M. Primary cardiac leiomyosarcoma: an analysis of clinical characteristics and outcome patterns.Asian Cardiovasc Thorac Ann. 2015; 23: 623-630Google Scholar As the name implies, cardiac UPS has no areas of specific tissue differentiation by light microscopic appearance or immunohistochemistry. Epithelioid hemangioendothelioma, which occasionally enters the differential diagnosis, can be distinguished from epithelioid AS by the presence of the CAMTA1-WWTR1 fusion.30Anderson T. Zhang L. Hameed M. Rusch V. Travis W.D. Antonescu C.R. Thoracic epithelioid malignant vascular tumors: a clinicopathologic study of 52 cases with emphasis on pathologic grading and molecular studies of WWTR1-CAMTA1 fusions.Am J Surg Pathol. 2015; 39: 132-139Google Scholar As of yet, there are no diagnostic or prognostic molecular aberrations in the three most common cardiac sarcomas. Cardiac AS typically has complex karyotypes, and point mutations in a variety of genes have been identified, including the well-known tumor suppressor TP53 and oncogene KRAS and less well-known PLCG1 and the MLL/KMT2 family of genes.28Leduc C. Jenkins S.M. Sukov W.R. Rustin J.G. Maleszewski J.J. Cardiac angiosarcoma: histopathologic, immunohistochemical, and cytogenetic analysis of 10 cases.Hum Pathol. 2017; 60: 199-207Google Scholar,31Kunze K. Spieker T. Gamerdinger U. et al.A recurrent activating PLCG1 mutation in cardiac angiosarcomas increases apoptosis resistance and invasiveness of endothelial cells.Cancer Res. 2014; 74: 6173-6183Google Scholar,32Garcia J.M. Gonzalez R. Silva J.M. et al.Mutational status of K-ras and TP53 genes in primary sarcomas of the heart.Br J Cancer. 2000; 82: 1183-1185Google Scholar Recently, recurrent POT1 mutations have been found in cardiac AS in the setting of Li-Fraumeni–like syndrome.33Calvete O. Martinez P. Garcia-Pavia P. et al.A mutation in the POT1 gene is responsible for cardiac angiosarcoma in TP53-negative Li–Fraumeni-like families.Nat Commun. 2015; 6: 8383Google Scholar Although there is no internationally accepted grading specific to cardiac sarcomas, the FNCLCC (Fédération National de Lutte Contre le Cancer) system is often used.34Coindre J.M. Grading of soft tissue sarcomas: review and update.Arch Pathol Lab Med. 2006; 130: 1448-1453Google Scholar Similarly, there is no universally accepted staging system for primary cardiac malignancies; however, the most recent American Joint Committee on Cancer staging manual has included most differentiated sarcomas in their staging system of the abdomen and thoracic visceral organs.35Amin M.B. Edge S.B. STAT!Ref (Online service); Teton Data Systems (Firm)AJCC cancer staging system. American College of Surgeons, Chicago, IL2020Google Scholar An important update in the fifth edition is the recognition of intimal sarcoma as a separate entity from cardiac UPS, with which it has been historically grouped. Intimal sarcoma is distinguished form cardiac UPS by its intraluminal growth and origin within the great vessels. Although it has been reported in other great vessels, those of the pulmonary arterial circulation are most common. As such, it is now termed pulmonary artery intimal sarcoma and is covered in the section entitled, Mesenchymal Tumours Specific to the Lung. Although involvement of the heart can occur in up to 25% of disseminated lymphomas, primary cardiac lymphoma is rare. As a group, it is defined by its primary involvement of the heart and encompasses a variety of T-cell and non–Hodgkin B-cell lymphomas.36Petrich A. Cho S.I. Billett H. Primary cardiac lymphoma: an analysis of presentation, treatment, and outcome patterns.Cancer. 2011; 117: 581-589Google Scholar,37Gowda R.M. Khan I.A. Clinical perspectives of primary cardiac lymphoma.Angiology. 2003; 54: 599-604Google Scholar In contrast to the previous WHO classification that addressed cardiac lymphomas summatively, the new edition focuses on diffuse large B-cell lymphoma (DLBCL), representing greater than or equal to 80% of cardiac lymphomas, along with a specific entry of a rare and recently described subtype, fibrin-associated DLBCL (FA-DLBCL). Cardiac DLBCL occurs most often in men in the sixth and seventh decades of life.36Petrich A. Cho S.I. Billett H. Primary cardiac lymphoma: an analysis of presentation, treatment, and outcome patterns.Cancer. 2011; 117: 581-589Google Scholar,38Chalabreysse L. Berger F. Loire R. Devouassoux G. Cordier J.F. Thivolet-Bejui F. Primary cardiac lymphoma in immunocompetent patients: a report of three cases and review of the literature.Virchows Arch. 2002; 441: 456-461Google Scholar FA-DLBCL is strongly associated with infection of lesional B cells by Epstein-Barr virus and is distinguished from other DLBCL subtypes by its lack of mass formation and tissue infiltration, being almost always restricted to the fibrin within an anatomical space (including around prosthetic devices and tumors such as myxomas). It is usually diagnosed incidentally on histologic examination.39Miller D.V. Firchau D.J. McClure R.F. Kurtin P.J. Feldman A.L. Epstein–Barr virus-associated diffuse large B-cell lymphoma arising on cardiac prostheses.Am J Surg Pathol. 2010; 34: 377-384Google Scholar Other DLBCL subtypes which seem overrepresented in the heart are those associated with Epstein-Barr virus and chronic inflammation.40Bagwan I.N. Desai S. Wotherspoon A. Sheppard M.N. Unusual presentation of primary cardiac lymphoma.Interact Cardiovasc Thorac Surg. 2009; 9: 127-129Google Scholar,41Bonnichsen C.R. Dearani J.A. Maleszewski J.J. Colgan J.P. Williamson E.E. Ammash N.M. Recurrent Ebstein-Barr virus-associated diffuse large B-cell lymphoma in an ascending aorta graft.Circulation. 2013; 128: 1481-1483Google Scholar As a group, the prognosis of cardiac DLBCL is generally poor. FA-DLBCL represents a notable exception and is considered an indolent neoplasm with no directly related deaths reported to date. Although many advances have been made in our understanding of cardiac tumors since the publication of the fourth edition of The WHO Classification of Tumours of the Lung, Pleura, Thymus and Heart, much remains to be understood. As has always been the case, the rarity of these tumors has limited their wholesale study. Nevertheless, advances in molecular technology, which allow interrogation of increasingly smaller samples, including those that have been formalin fixed and paraffin embedded, will undoubtedly facilitate further advances in this field. Specifically, a better understanding of the molecular genetic drivers that underpin the most lethal of these lesions, the cardiac sarcomas, is paramount given the fact that they affect such devastating outcomes on an otherwise relatively young and healthy population. Furthermore, molecular insights into the pathogenesis also afford the opportunity for refinement of classification and nomenclature in these rare neoplasms.42Scicchitano P. Sergi M.C. Cameli M. et al.Primary soft tissue sarcoma of the heart: an emerging. in cardio-oncology.Biomedicines. 2021; 9: 774Google Scholar In addition to malignancies, better understanding of benign lesions such as PFEs is also critically important given their incidence and the potential they have for causing devastating sequelae (e.g., strokes, myocardial infarctions). Fortunately, the need for fresh tissues for such investigative work is being reduced as our technologies are increasingly allowing for interrogation of formalin-fixed, paraffin-embedded specimens.43Talebi A. Thiery J.P. Kerachian M.A. Fusion transcript discovery using RNA sequencing in formalin-fixed paraffin-embedded specimen.Crit Rev Oncol Hematol. 2021; 160: 103303Google Scholar The classification outlined in this fifth edition of the WHO Classification of Thoracic Tumors serves as a common language to level-set investigators around the world. Continued study of these entities will preemptively guide the sixth edition of the classification of these lesions, thus allowing for better care of the patients they afflict. Joseph J. Maleszewski: Conceptualization, Supervision, Writing—original draft, Writing—review and editing, Visualization. Cristina Basso, Melanie C. Bois, Carolyn Glass, Kyle W. Klarich, Charles Leduc, Fabio Tavora: Writing—original draft, Writing—review and editing. Robert F. Padera: Writing—review and editing, Visualization. The authors gratefully acknowledge the support of Dr. William Travis for his helpful comments regarding the content of this manuscript. The authors are also indebted to Dr. Ian Cree and the editorial board and support staff of the International Agency for Research on Cancer for organizing the team of individuals responsible for updating the WHO Classification of Thoracic Tumours group. Download .docx (.02 MB) Help with docx files Supplementary Table 1