Mini Review Aschoff Nodule-Revisited P. CHOPRA, M.D.,* J. NARULA, M.D., and R. TANDON,M.D. Additional Indexing Words: Rheumatic heart disease Myocarditis Left atrial appendage HE true nature of Aschoff nodules is frustratingly elusive. What ex- T actly are Aschoff nodules? Where are they located? Do they represent activity? Where do Aschoff cells come from? There are many other con- troversies that continue to intrigue pathologists and clinicians more than 80 years after the recognition of Aschoff nodules. What is an AschoffNodule? Aschoff nodule as a characteristic and pathognomonic lesion of the rheumatic process has received wide acceptance. The nodule is of variable size and may be round, oval or elongated. It consists of a collection of large cells with an ill-defined, irregular cell margin, abundant pink-blue cytoplasm and prominent vesicular nuclei which may be one, two or multiple in number. A few inflammatory cells, mainly lymphocytes and plasma cells, are also present. The Aschoff nodule may or may not have a central core of eosino- philic, fragmented collagen that is fibrinoid degeneration.1) The Aschoff cell under the electron microscope shows numerous profiles of rough endoplasmic reticulum. Many of these are distended and contain a light electron-dense material. Free ribosomes are increased. Only oc- casional lipid droplets, dense bodies and Golgi apparatus are identifiable. The cell membrane is ruffled and thrown into folds. The nuclei are large, round to ovoid with an irregular nuclear membrane showing occasional in- vaginations.1),2) Aschoff nodules can be identified easily under the scanning electron microscope. They are seen as fairly well defined nodular aggregates, sand- wiched between the endocardium and the myocardium or lying well within the endocardium/myocardium. These cells are closely packed together and From the Departments of Pathology* and Cardiology, All India Institute of Medical Sciences, New Delhi, India. Address for reprints: P. Chopra, M.D., Department of Pathology, All India Institute of Medi- cal Sciences, New Delhi-110029, India. Received for publication July 25, 1988. Accepted November 30, 1988. 479 Jpn. Heart J. J 480 CHOPRA, NARULA, AND TANDON uly 1989 Table I. Endomyocardial Infiltrates (percentages) of Lymphomononuclear Cells in Excised Left Atrial Appendages All values are expressed in percentages as mean•}standard deviation. Abbreviations: Macro= macrophages; TH=T helper-inducer lymphocytes; TS=T suppressor- cytotoxic; n=number of specimens included. are elongated, oblong and often angulated. The surface of the cells is either finely reticulated or relatively smooth and a few blunt projections may be evident on the surface.3) Where do Aschoffcells comefrom? The origin of Aschoff cells has received more than its fair share of at- tention. They have been considered to have arisen from cardiac myocytes, smooth muscle cells, fibroblasts, histiocytes, lymphocytes and endothelial cells. The myogenic origin was proposed because of light microscopic re- semblance and similarity of staining characteristics (with Masson's trichrome and phosphotungstic acid--hematoxylin) between cardiac muscle cells and Aschoff cells.4) Such staining characteristics, we believe, may be nonspecific. Ultra- structural findings refute such a correlation and suggest a similarity with macrophages and fibroblasts.1) Fibroblasts however, do not have multiple nuclei, rarely reach the size of Aschoff cells and have fewer branching proces- ses. Moreover, there is no evidence of fibrillogenesis in the vicinity of As- choff cells.2) The presence of complex branching processes favors (altered) macrophages. Histochemically, Aschoff cells show a strong reaction to nonspecific esterases and acid phosphatase which identify macrophages.1) Our recent immunohistochemical observations confirm that these cells are of macrophage-monocytic origin.5) Aschoff cells showed a consistently posi- tive staining with mouse monoclonal antibodies against macrophages and did not stain with antimyosin antibodies by immunoperoxidase using the avdin- biotin method. Moreover, these cells showed positive staining for HLA-DR (Ia) antigens. A recent case report has also revealed positive staining of Aschoff cells with macrophage antibodies.8) The observations from 50 left atrial appendages excised during closed mitral valvotomies showed (Table I) that one fourth of the cell population in the endomyocardium was comprised of cells of macro-monocytic lineage5) (Table I). Vol.30 No.4 ASCHOFF NODULE-REVISITED 481 What are the characteristicsof Aschoffnodules? The description and consequent controversies regarding the appearance and location of so called Aschoff bodies is rather perplexing. Consider the following: "they are not true Aschoff bodies if not accompanied by myofiber necrosis in myocardium"; "the reports of Aschoff bodies in the surgically excised left auricular appendages are based on an erroneous concept because they are present when clinically the rheumatic process is quiescent"; "rheu- matic subcutaneous nodule and nodules in synovialis should never be con- fused with Aschoff bodies as they are not characteristic"; "experimentally produced cellular accumulations are not true Aschoff bodies".7) What should one look for in the Aschoff bodies then? Aschoff himself could not have been so possessive. Moreover, the interpretations have varied in dif- ferent hands, e.g. rewriting from descriptive to tabular form changes the ideal location from the subendocardial7) to the endocardial region.8) The Aschoff body thus appears to be a sacrosanct entity which, if it does not agree com- pletely with a 'book picture', should not be named an Aschoff body as it is suggested that it is better to err by not diagnosing rather than by mis- diagnosing or overdiagnosing. We would then probably end up with not diagnosing the rheumatic process most of the times. The cell wall and membrane of beta-hemolytic group A streptococci share cross reactivity with human heart antigens9) and the cytotoxic mechan- isms initiated thereof may result in carditis.10)-12) Cytotoxicity is probably effected by the preferential migration of the cytotoxic T lymphocytes.12) The T helper cells may possibly assist transformation of cardiac macro- phages into Aschoff cells. It is conjectural whether these cells can mediate cytotoxicity. The evolution of the Aschoff cells however is peculiar and is limited to rheumatic heart disease. If we extrapolate, it could be a reaction unique to the streptococcal challenge, as some nonspecific perivas- cular nodules have been demonstrated in scarlet fever7) and some Aschoff body-like lesions have been produced in experimental situations.4) Con- version of the cardiac macrophages to Aschoff cells may not be ubiquitous and the histiocytic-macrophage aggregates in acute rheumatic fever appear as characteristic as Aschoff nodules, since they are not encountered in any other type of myocarditis.12) Such a change has been described in acute rheumatic myocarditis13) but has never been considered important as a pos- sible predecessor of the Aschoff nodule or even as a characteristic/pathogno- monic lesion. We have observed them almost universally in endomyocardial biopsies as well as in autopsies of patients with acute rheumatic fever.12) We for all practical purposes, would be satisfied with the connective tissue changes (with or without fibrinoid degeneration) and the macrophage- Jpn. Heart J. J 482 CHOPRA, NARULA, AND TANDON uly 1989 Table II. Frequency of Aschoff Nodules in Chronic Rheumatic Heart Disease Parenthetical figures represent percentages. n=number of specimens included. histiocytic aggregates (closely resembling Aschoff nodules topographically) for the diagnosis of acute rheumatic myocarditis. The additional presence of characteristic Aschoff/Anitschkow cells would of course be reassuring. Thereafter whether the reaction is perivascular or not, be it in the endo- cardium, myocardium or pericardium, either round or otherwise is incon- sequential. However, for the sake of calling it an Aschoff nodule, we would agree that we should not compromise on the appearance of Aschoff cells. Do Aschoffnodules suggest rheumatic activity? Or, are they just the pathognomonic feature of rheumatic heart disease? The answer may be a little circuitous. Aschoff nodules do form during rheumatic fever but they continue to be seen after the disappearance of clini- cal features of activity. The confusion has occurred because of the large number of Aschoff nodules having been demonstrated in chronic rheumatic heart disease in the auricular appendages removed during mitral valvotomy and sent for histologic examination. Aschoff nodules have been reported in 16 to 74% of cases.7) We can recall our eminent pathologist running up the stairs to the operating room after doing frozen sections of a left atrial ap- pendage from our first closed mitral valvotomy to inform the surgeon that he had opened up an active rheumatic patient. Rows of Aschoff nodules in chronic quiescent cases must have baffled pathologists and only thence the Aschoff nodules must have been thought to be an indicator of rheumatic pathology rather than rheumatic activity. Table II demonstrates the frequency of Aschoff nodules in chronic rheumatic heart disease. Myocardial specimens obtained from 208 autop- sies of chronic RHD were compared with 326 left auricular appendages ex- cised during closed mitral commissurotomies. There was no clinical or laboratory evidence of rheumatic activity in any of these