Giant cell myocarditis (GCM) is a rapidly progressive and frequently fatal disease that mainly affects young to middle-aged previously healthy individuals. Early diagnosis is critical, as recent studies have shown that rapidly instituted cyclosporine-based immunosuppression can reduce inflammation and improve transplant-free survival. Before the 1980s, GCM was mainly a diagnosis made at autopsy. Owing to advancements in diagnostic and therapeutic options, it is now increasingly diagnosed on the basis of endomyocardial biopsies, explanted hearts, or apical wedge sections removed at the time of ventricular assist device placement. Histologic examination remains the gold standard for diagnosis; however, there are many possible etiologies for cardiac giant cells. Having a working knowledge of the clinicopathologic features that distinguish GCM from other giant cell–containing lesions is essential, since such lesions can have widely divergent management and outcome.

Giant cell myocarditis (GCM) was first described in 1905 and is characterized by a mixed myocardial infiltrate with multinucleated giant cells and cardiomyocyte necrosis. In larger autopsy series, the incidence of GCM has been reported to range from 0.007% to 0.051%.13  Given that autopsies are not routinely performed on an unselected population, and patients dying of GCM may not undergo autopsy, it is likely these figures underestimate the true incidence. In the United States in the 1990s, a group of major heart failure referral centers reportedly diagnosed GCM (via autopsy, endomyocardial biopsy, apical wedge resection, or cardiac explantation) an average of once every 21 months.4  Historically, GCM and cardiac sarcoidosis were often conflated, as both presented in similarly aged patients and could result in a myocarditis characterized by giant cells and granulomas. However, it has since been established that the two are distinct clinicopathologic entities with significant differences in presentation, histologic features, and prognosis.4,5 

Giant cell myocarditis generally affects otherwise healthy young and middle-aged adults. In a large multicenter registry of GCM cases (n = 63), patients ranged in age from 16 to 69 years at the time of symptom onset, with an average patient age of 42.6 years.6  It is suspected that the relatively low numbers of reported cases in elderly patients may be attributable to missed diagnoses or possibly a differing degree of GCM severity in this age group. The youngest patient reported to develop GCM was a 6-week-old infant.7  Pediatric cases (defined as age ≤ 19 years at disease onset) comprised 6% (4 of 63) of the multicenter GCM registry.8  While pediatric GCM shows many similarities to adult GCM, one important distinction is that the disease course in children appears to be even more aggressive.7,8  In a review of 15 pediatric GCM cases, all patients either died or required heart transplant.7  Despite being a relatively infrequent cause of myocarditis overall, GCM has been reported to account for approximately 17% of all myocarditis fatalities.9 

Most patients (≥75%) present with rapid-onset congestive heart failure.5,6  Other less common presenting syndromes include ventricular tachycardia (14%–29%), symptoms mimicking acute myocardial infarction (6%–19%), and complete heart block (5%–8%).5,6  The disease course is rapid, with a median time of 3 weeks from symptom onset to hospital presentation.6  While GCM appears to have no sex predilection, approximately 20% of cases occur in patients with an autoimmune disorder such as inflammatory bowel disease, celiac disease, thyroiditis, or rheumatoid arthritis—among others.4,10,11  Some cases of GCM are associated with tumors, most often thymoma and lymphoma.4 

While the etiology of GCM remains to be fully elucidated, evidence suggests that it arises owing to immune dysregulation mediated by T lymphocytes. An experimental animal model has shown that GCM can be induced in certain rats by autoimmunization with cardiac myosin, an intracellular heart protein normally sequestered from immune cells.12  In both human and experimental GCM, the myocardial infiltrate contains many T lymphocytes. Likewise, in both human and experimental animal models, immunosuppressant medications can retard the progression of disease. In the experimental rat model, cyclosporine (an immunosuppressant that inhibits signal transduction in activated T cells) and anti α/β T-cell receptor antibody were both shown to prevent the progression of GCM.13,14  In humans, long-term immunosuppressive regimens can result in partial clinical remission and lengthen transplant-free survival by more than 19 years.11,15 

Overall, the strong association of GCM with autoimmune disorders, as well as tumors of immune cells such as thymoma and lymphoma, would also suggest a process of dysregulated immunity, and recent gene expression profiling of patients with GCM has revealed upregulation of genes involved in the T-cell immune response.16  Other conditions that have been more rarely reported in association with the development of GCM include drug hypersensitivity reaction and infection such as parvovirus B19 (diagnosed via cardiac DNA polymerase chain reaction [PCR]) or coxsackie B2 virus (diagnosed via serology and cardiac immunoblotting).1719  However, electron microscopic studies to date have not identified viral particles in GCM, and no microbiologic agent has been directly identified in cardiac tissue by microscopy, tissue culture, or inoculation in experimental animals.4,20 

Giant cell myocarditis is most commonly diagnosed via endomyocardial biopsy (52%), evaluation of the heart at autopsy (23%) or explantation (21%), or via examination of apical wedge sections removed at the time of ventricular assist device placement (4%).5  On gross examination, cardiomegaly is frequently noted: in one series, the average heart weight in GCM was 476 g with a range of 405 to 580 g.21  Serial sections typically reveal left or biventricular hypertrophy with accompanying dilatation.2,21  The myocardium may appear pale or slightly yellow with geographic white foci of fibrosis.2 

While certain clinical history and noninvasive imaging findings can suggest GCM, microscopic evaluation of the heart muscle is essential to confirm the diagnosis, institute appropriate therapy, guide discussions regarding prognosis, and potentially expedite mechanical circulatory support and/or listing for cardiac transplant. Because GCM usually has diffuse or multifocal involvement of the endocardium, endomyocardial biopsy (EMB) tends to have a higher diagnostic sensitivity in GCM than in cardiac sarcoidosis (35%) or lymphocytic myocarditis (25%).22  If performed soon after the onset of symptoms, the sensitivity of EMB for GCM ranges from 68% to 80%.11,22  False-negative biopsy findings can result from patchy distribution of inflammation, inadequate sampling, or prior therapy effects that obscure the typical histologic changes; thus, the absence of histologic changes on EMB does not completely exclude the possibility of GCM. To minimize false negatives, it is recommended that at minimum 3 to 5 EMB samples measuring 1 to 2 mm3 each be submitted for light microscopy.23,24  Additional samples should be snap-frozen in liquid nitrogen for future viral PCR studies or fixed in 4% glutaraldehyde for transmission electron microscopy, as clinically indicated.23,24 

Microscopically, the classic histopathologic features of GCM are prominent myocyte necrosis associated with a multifocal or diffuse inflammatory cell infiltrate composed of abundant T lymphocytes, multinucleated giant cells, plasma cells, easily identified eosinophils, and occasional neutrophils.2,46,21  The giant cells are CD68+ macrophages, usually present at the border of the active inflammation surrounding the necrotic area. Poorly formed nonnecrotizing granulomas may be seen in GCM but generally, the extent of necrosis appears disproportionate to the granulomatous inflammation.4,5  Variable amounts of granulation tissue or fibrosis may be present (Figure 1, A through C).

Figure 1

Morphologic features of giant cell myocarditis. A, Multifocal serpiginous inflammatory infiltrate. B, The infiltrate is composed of lymphocytes, eosinophils, plasma cells, and prominent multinucleated giant cells. Discrete granulomas are not evident. C, There is extensive myocyte necrosis associated with giant cell infiltrate (hematoxylin-eosin, original magnifications ×4 [A] and ×40 [B and C]).

Figure 1

Morphologic features of giant cell myocarditis. A, Multifocal serpiginous inflammatory infiltrate. B, The infiltrate is composed of lymphocytes, eosinophils, plasma cells, and prominent multinucleated giant cells. Discrete granulomas are not evident. C, There is extensive myocyte necrosis associated with giant cell infiltrate (hematoxylin-eosin, original magnifications ×4 [A] and ×40 [B and C]).

Close modal

Giant cell myocarditis characteristically affects the cardiac ventricles; however, an atrial-predominant form (aGCM) has also been reported.25,26  This distinctive clinicopathologic entity appears histopathologically similar to ventricular GCM (vGCM), but primarily involves the atria and spares the ventricles. The relatively low frequency of diagnosis (0.5%–1.3%) may be attributable to the fact that atrial tissues are not regularly sampled either at postmortem examination or in surgical practice except during atrial ablation procedures.25  As compared to the fulminant clinical course in vGCM, most aGCM cases are indolent and have a more favorable prognosis. The median age of disease onset also appears to be higher, at older than 65 years.25  Atrial fibrillation/flutter is present in nearly all cases, while severe atrial dilatation, mural thrombus formation, and mitral/tricuspid regurgitation are also often seen.

Since giant cells are the key characteristic feature of GCM, the major differential diagnoses include other myocardial lesions containing giant cells such as infectious diseases, systemic granulomatous processes, and foreign body giant cell reaction.4  Foremost among these are cardiac sarcoidosis (CS) and fulminant lymphocytic myocarditis. Unlike GCM, CS is characterized by tight nonnecrotizing granulomas that often have central multinucleated giant cells.5,27  While not specific, giant cell intracytoplasmic inclusions such as Schaumann or asteroid bodies can be supportive of a CS diagnosis. Schaumann bodies are ovoid concentric calcifications reportedly found in 70% to 88% of sarcoidosis cases, whereas asteroid bodies are stellate inclusions within cytoplasmic halos that are found in up to 9% of cases.27  Isolated cardiac sarcoidosis is rare. Pathologists are encouraged to seek out prior testing results such as bilateral hilar lymphadenopathy on thoracic imaging, characteristically elevated serum markers (eg, angiotensin-converting enzyme), and evidence of noncaseating granulomatous inflammation of other tissues—most commonly lymphoid or respiratory. While the fibrosis is more pronounced in CS than in GCM, eosinophils are rare, foci resembling lymphocytic myocarditis are few, and the extent of myocyte necrosis is decreased, appearing proportionate to the degree of granulomatous inflammation (Figure 2, A and B).5,27  While both GCM and CS may present with ventricular tachycardia, presentation with acute-onset heart failure is more commonly seen in GCM, while presentation with heart block is more predictive of CS (Table).5  At least 1 study has found that GCM and CS have distinct gene expression profiles that can be used to distinguish between them; genetic profiling may represent a promising future ancillary testing option.28 

Figure 2

Morphologic features of cardiac sarcoidosis. A, Well-demarcated nonnecrotizing granulomata with centralized multinucleated giant cells. B, Multinucleated giant cell with stellate asteroid body surrounded by rim of cytoplasmic clearing (hematoxylin-eosin, original magnification ×20 [A and B]).

Figure 2

Morphologic features of cardiac sarcoidosis. A, Well-demarcated nonnecrotizing granulomata with centralized multinucleated giant cells. B, Multinucleated giant cell with stellate asteroid body surrounded by rim of cytoplasmic clearing (hematoxylin-eosin, original magnification ×20 [A and B]).

Close modal

Clinicopathologic Features of Giant Cell Myocarditis, Cardiac Sarcoidosis, and Lymphocytic Myocarditis

Clinicopathologic Features of Giant Cell Myocarditis, Cardiac Sarcoidosis, and Lymphocytic Myocarditis
Clinicopathologic Features of Giant Cell Myocarditis, Cardiac Sarcoidosis, and Lymphocytic Myocarditis

Fulminant lymphocytic myocarditis can present similarly to GCM with new-onset heart failure unresponsive to standard therapies such as diuretics, β-adrenergic blocking agents, and angiotensin-converting enzyme inhibitors.29  Histologically, both fulminant lymphocytic myocarditis and GCM show a myocardial lymphocytic infiltrate with associated myocyte necrosis. Criteria for EMB diagnosis of acute myocarditis, as defined by the European Society of Cardiology, require at least 14 infiltrating leukocytes/mm2 with up to 4 monocytes/mm2 and the presence of CD3+ T lymphocytes (at least 7 cells/mm2) in association with myocyte necrosis (Figure 3, A and B).23  While GCM generally has prominent giant cells, it can be misdiagnosed as lymphocytic myocarditis on EMB when giant cells are not seen in the sample, owing to an uneven distribution of cells within the lesion or when an older/treated lesion is sampled. If the imaging studies or other clinical findings are strongly suggestive of GCM, repeated biopsy is helpful. The sensitivity of EMB for detecting GCM reportedly increases from 68% to 93% on repeated biopsy.11  A clinical history of a flulike viral prodrome can be suggestive of lymphocytic myocarditis, as most cases arise owing to infection with a viral agent such as coxsackievirus B, adenovirus, or parvovirus B19 (Table).29 

Figure 3

Morphologic features of fulminant lymphocytic myocarditis. A, Diffuse inflammation with mild myocyte necrosis. The inflammatory infiltrate is composed of many CD3+ T lymphocytes (inset). B, There are some scattered plasma cells and eosinophils (hematoxylin-eosin, original magnifications ×20 [A] and ×40 [B]; CD3, original magnification ×20 [inset A]).

Figure 3

Morphologic features of fulminant lymphocytic myocarditis. A, Diffuse inflammation with mild myocyte necrosis. The inflammatory infiltrate is composed of many CD3+ T lymphocytes (inset). B, There are some scattered plasma cells and eosinophils (hematoxylin-eosin, original magnifications ×20 [A] and ×40 [B]; CD3, original magnification ×20 [inset A]).

Close modal

Other causes of giant cell/granulomatous myocarditis are much rarer in the United States. Infective granulomatous myocarditis arising owing to tuberculosis or fungal organisms generally has significant extracardiac involvement (most commonly of the lungs) and the granulomas are characteristically necrotizing.27  Acute rheumatic heart disease can result in the formation of granulomatous lesions known as Aschoff bodies, which tend to be perivascular in location and may contain enlarged macrophages with nuclear chromatin condensed into a wavy ribbon resembling a caterpillar, that is, Anitschkow cells.4,27  Utilization of the recently revised Jones criteria can aid in the diagnosis of this entity. Foreign body giant cell reaction, vasculitic processes such as giant cell arteritis or Takayasu arteritis, and Wegener granulomatosis would also be included in the histologic differential, though generally, review of the clinical presentations and appropriate diagnostic studies will allow for clear distinction.

In EMB samples obtained for light microscopy, serial sections of paraffin-embedded tissue are sequentially numbered. In many institutions, it is the convention to stain every second or third section with hematoxylin-eosin, and retain the intervening sections for special stains as indicated.24,30  Masson elastic trichrome or Movat pentachrome stains are generally recommended to highlight interstitial fibrosis, myocyte disarray, and necrosis. An iron stain in male and postmenopausal female patients is commonly performed to rule out a potentially treatable iron storage disease.24,30  Congo red staining may be ordered to rule out cardiac amyloidosis, particularly in patients older than 50 years.30  If an inflammatory infiltrate is seen, immunohistochemical staining for T lymphocytes (eg, CD3) and macrophages (eg, CD68) is recommended to better characterize the extent and nature of the infiltrate.23  If granulomatous inflammation is seen, special organism stains such as Gomori methenamine silver or Ziehl–Neelsen are indicated.4,30 

In addition to light microscopic examination, it is suggested that EMB samples be procured for detection of viral genomes.23  While paraffin-embedded tissue can be used for PCR-based assays, the sensitivity and reproducibility of viral genome detection is suboptimal. Snap-freezing the tissue in liquid nitrogen and storing at −80°C, or else storing the tissue at room temperature in an RNA tissue stabilization solution, is preferable.23,24,30  After flash-freezing, submission of tissue for standard histologic processing should be avoided owing to potential ice crystal artifact.24,30  In cases of suspected myocarditis, infiltrative disorders, and cardiotoxic medications (eg, anthracycline), retaining some sample in 2% to 4% glutaraldehyde at room temperature for transmission electron microscopic examination may prove helpful in some cases.24,30  In cases of autopsy or cardiac explantation it is important to sample the heart thoroughly, as myocarditis can be a focal process. In the investigation of sudden cardiac death, the Association for European Cardiovascular Pathology recommends submitting transverse sections of the left ventricular free wall (anterior, lateral, and posterior), interventricular septum (anterior and posterior), right ventricular free wall (anterior, lateral, and posterior), and both atria for histologic examination.31 

Without appropriate immunosuppressive therapy, the median survival from GCM symptom onset to death or transplant is only 3 months.6  With appropriate immunosuppressive therapy, the 5-year survival rate free of transplant ranges from 52% to 72%.11,15  While the optimal immunosuppressive regimen remains to be defined, a combined double- or triple-drug cyclosporine-based therapy reportedly leads to a partial clinical remission in two-thirds of patients.11  Immunosuppression must be continued long term as GCM can recur up to 8 years after diagnosis if immunosuppressive therapy is tapered or terminated.15  Even with long-term immunosuppression, patients remain at risk of developing ventricular arrhythmias and may require implantable cardioverter-defibrillators. Cyclosporine is a known nephrotoxic agent; one GCM series reported episodes of renal failure occurring at a rate of 20% per year in patients receiving cyclosporine-based immunosuppression. For those patients who are unresponsive to immunosuppressive therapy, mechanical circulatory support devices such as extracorporeal membrane oxygenation or ventricular assist devices can act as bridges to recovery or transplant.4,29  Cardiac transplant is an effective therapy, with posttransplant survival rates for patients with GCM being similar to those for patients undergoing cardiac transplant for other reasons.4  Giant cell myocarditis does, however, recur in approximately 25% of transplanted hearts.4,6 

Giant cell myocarditis is a rare, progressive inflammatory myocardial disease with high mortality, affecting a relatively young population. Although much progress has been made during the past decades in understanding the pathophysiology, there are still many deficiencies in our knowledge. Rapid diagnosis is critical, as the management differs from that of other myocardial processes containing giant cells, and early institution of combined cyclosporine-based immunosuppression can dramatically impact the disease course. Promising future directions include the development of serum biomarkers and utilization of gene expression profiling to potentially more rapidly diagnose and monitor GCM progress.

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Author notes

The authors have no relevant financial interest in the products or companies described in this article.