The Many Faces of Cardiac Sarcoidosis

Virian D. Serei, MD, PhD; Billie Fyfe, MD

Disclosures

Am J Clin Pathol. 2020;153(3):294-302. 

In This Article

Microscopic Pathology

Sarcoidosis, whether cardiac or extracardiac, is defined by the presence of nonnecrotizing granulomatous inflammation. The typical sarcoid granuloma is a tight collection of epithelioid macrophages Image 3A and Image 3B that have an elongated shape, finely granular cytoplasm, and an ovoid nucleus.[15,22] Scattered Langhans giant cells, with multiple nuclei linearly arranged towards the periphery of the cell in a semicircular shape, are also characteristic of sarcoid granulomas[15,16,22] Image 3C. Foreign body-type giant cells, with centrally placed and overlapping nuclei, can be found in granulomas in early stage sarcoidosis[15] Image 3D. Intracellular inclusions such as Schaumann bodies and asteroid bodies may be identified but are not specific for sarcoidosis.[15,22] Schaumann bodies are concentric laminations of calcified proteins found within giant cell cytoplasm in up to 88% of sarcoid cases[15,22] Image 3E. Asteroid bodies are less frequently identified in sarcoid giant cells and consist of radiating filamentous arms surrounded by an area of cytoplasmic clearing[15,23] Image 3F. Ultrastructurally, the filamentous arms of asteroid bodies are enveloped by myelinoid membranes associated with calcium.[23] CD4+ T cells are often present within and may form a rim surrounding the granulomas.[15] Although classically without central necrosis, fibrinoid necrosis may be present in up to 20% of cases[22] (Image 2). In these cases it is important to rule out infectious etiology.

Image 3.

A, Mediastinal lymph node showing numerous well-formed nonnecrotizing granulomas (H&E, x40). B, Well-formed nonnecrotizing granuloma composed of a tight cluster of epithelioid macrophages with giant cells of varied morphology (H&E, x200). C, Langhans giant cell within a well-formed granuloma, characterized by multiple nuclei linearly arranged towards the periphery of the cell in a semicircular shape (H&E, x200). D, Foreign body giant cell within a loose cluster of epithelioid macrophages and lymphocytes, characterized by centrally placed and overlapping nuclei (H&E, x200). E, Schaumann body, consisting of calcified concentric laminations within a multinucleated giant cell (H&E, x400). F, Asteroid body, a filamentous structure surrounded by cytoplasmic clearing within a multinucleated giant cell (courtesy of Christine Minerowicz, MD) (H&E, x200).

The microscopic appearance of sarcoid granulomas can vary depending on the stage of the disease. Early granulomas are often a looser association of macrophages with a predominance of lymphocytes[15] (Image 1 and Image 2). Progression of disease is associated with tighter granulomas and less-abundant lymphocytes (Image 2). Further progression of chronic disease can lead to encasement of granulomas in fibrous tissue with eventual replacement of granulomas by dense fibrosis[19] (Image 2 and Image 3). With progression to clinical end-stage heart failure there is considerable fibrosis that correlates with severity of disease[18] (Image 2 and Image 3). The amount of fibrosis is also inversely related to the number of granulomas present in the native heart.[18] Autopsy studies of sudden deaths due to undiagnosed cardiac sarcoidosis have also shown the presence of dense fibrosis with lymphocytic aggregates in a majority of these cases.[16]

Demonstration of nonnecrotizing granulomatous inflammation with exclusion of infectious, autoimmune, and environmental etiologies on endomyocardial biopsy is diagnostic for sarcoidosis.[4,24] However, the sensitivity of endomyocardial biopsy is low, ranging from 20% to 30%.[25] The low sensitivity is thought to be due to sampling error; endomyocardial biopsies are obtained from the right ventricular interventricular septum while sarcoid granulomas more commonly involve the left ventricle.[4] Chronic end-stage cardiac sarcoidosis is characterized by widespread dense fibrosis with little to no granuloma formation[16,18] (Image 1 and Image 2). Sampling these areas may not show granulomatous inflammation and may show nonspecific histologic findings such as areas of myocardial interstitial fibrosis, myocyte necrosis, and inflammation (Image 3). Additionally, when cardiac sarcoidosis presents as ARVC, endomyocardial biopsies may show fibrofatty replacement without evidence of granulomatous inflammation.[6]

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