—  SPECIALTY CONFERENCE  —

Cardiovascular Pathology

Case 1 - Giant Cell Myocarditis

Gayle L. Winters
Brigham and Women's Hospital
Boston, MA


Click on each slide thumbnail image for an enlarged view
Clinical Summary
A 51 year-old female nurse presented with a three-week history of fatigue and dyspnea on exertion. The symptoms were progressive and led to significant limitation in her activities of daily living, such that by the day of admission she was unable to climb a single flight of stairs. She also reported occasional burning chest discomfort that did not radiate and had no clear association with exertion, as well as some brief palpitations. Her past medical history (including risk factors for coronary artery disease) was entirely negative and she took no regular medications. She did not smoke or use illicit drugs, consumed alcohol only occasionally, and denied any high-risk sexual behaviors. She had no history of travel outside the US and there were no notable occupational or environmental exposures.

On physical examination, she appeared well. She was afebrile with a blood pressure of 88/60 mm Hg, pulse 90 beats per minute, and respiratory rate 20 breaths per minute. Cardiac examination revealed a regular gallop rhythm with audible left-sided third and fourth heart sounds. Admitting laboratory studies were non-contributory. ECG revealed left axis deviation, poor R wave progression, 2-3 mm ST segment elevations in leads V2, V3, and 2-3 mm ST segment depressions in leads V5 and V6. Emergent left-sided cardiac catheterization revealed a right dominant circulation with clean coronary vessels except for a 20-30% stenosis in the left anterior descending artery. There was global hypokinesis. Transthoracic echocardiography showed a mildly enlarged left ventricle with global hypokinesis and a left ventricular ejection fraction of 15-20%.

The day of admission, the patient became severely hypotensive and developed sustained monomorphic ventricular tachycardia requiring direct-current cardioversion. Urgent right heart catheterization with endomyocardial biopsy was performed (Slide A). She remained hemodynamically unstable and required placement of an intra-aortic balloon pump. Urgent transplant evaluation was undertaken. Two days after her biopsy a Thoratec BiVAD was inserted for cardiogenic shock and recurrent ventricular tachyarrhythmias. Her condition stabilized and she awaited transplantation in the hospital. Approximately two months after her initial presentation, she underwent heart transplantation and her explanted heart became available for examination (Slide B).


Case 1 - Figure 1 -
(Endomyocardial Biopsy): Low power view of four endomyocardial biopsy samples. There is extensive and diffuse replacement of myocardium by an inflammatory process.
Case 1 - Figure 2 -
(Endomyocardial Biopsy): Intermediate power of extensive inflammatory infiltrate containing giant cells. There is extensive myocyte damage.
Case 1 - Figure 3 -
(Endomyocardial Biopsy): High power view showing polymorphous nature of infiltrate, including lymphocytes, histiocytes, plasma cells and eosinophils.



Case 1 - Figure 4 -
(Endomyocardial Biopsy): High power of multinucleated giant cells.
Case 1 - Figure 5 -
(LVAD Core): Intermediate power of diffuse mixed inflammatory infiltrate with multinucleated giant cells and extensive myocyte damage.
Case 1 - Figure 6 -
(LVAD Core): High power of mixed inflammatory infiltrate with multinucleated giant cells and myocyte damage.



Case 1 - Figure 7 -
(Explanted Heart): Four-chamber cut of 310 gm explanted heart with LVAD cannula in left ventricular apex. There is biventricular dilation and a partially organized thrombus in the right atrium. The mitral valve is mildly myxomatous and there is no fusion (post-LVAD) of the aortic valve cusps. The coronary arteries contained only minimal (nonocclusive) atherosclerosis.
Case 1 - Figure 8 -
(Explanted Heart): There is mild mottling of the interventricular septal myocardium (left). Histology of the myocardium (H&E and Trichrome) reveals extensive fibrosis in a non-coronary distribution (right, top and bottom).



Case 1 - Figure 9 -
(Explanted Heart): Scattered giant cells are present within areas of fibrosis.
Case 1 - Figure 10 -
(Explanted Heart): There are multiple foci of residual active inflammation consisting of a mixed infiltrate with giant cells and myocyte damage.


Histologic Findings
The endomyocardial biopsy and the LVAD apical core revealed similar findings and illustrate the acute phase of giant cell myocarditis. There was extensive, diffuse replacement of the myocardium by a mixed inflammatory infiltrate composed of lymphocytes, histiocytes, plasma cells, and eosinophils. Numerous multinucleated giant cells were admixed with the other cells in the inflammatory infiltrate, particularly at the margin of necrotic zones of myocardium, but true granulomas were absent. No organisms or foreign bodies could be demonstrated. There was widespread geographic myocardial necrosis.

The explanted heart obtained approximately two months after the initial biopsy illustrates the healing phase of giant cell myocarditis. Large areas of fibrosis were present, containing a sparser inflammatory infiltrate and occasional giant cells. Active myocyte necrosis was less evident when compared with the acute lesion.

Differential Diagnosis
Myocarditis has been defined as a non-ischemic inflammation of the myocardium characterized by an inflammatory infiltrate and associated myocyte necrosis [1, 2, 3] . Although the cause of myocarditis in a specific case is often idiopathic or unknown, the type of inflammation may provide a clue to the etiology [4, 5] . Lymphocytic myocarditis is most often associated with viral infection (also autoimmunity, polymyositis, sarcoidosis, Lyme disease and drug toxicity). Eosinophilic myocarditis is often the result of drug hypersensitivity (also parasitic infestations, hypereosinophilic syndrome, asthmatic bronchitis, and restrictive cardiomyopathy). Neutrophilic or mixed inflammation is associated with general infection, myocardial infarction, and drug toxicity. Giant cells may be present in giant cell myocarditis and sarcoidosis (also infection, foreign body reaction, rheumatic disease, rheumatoid disease, thymoma, systemic lupus erythematosus, dermatomyositis, thyroiditis, orbital myositis, pernicious anemia, ulcerative colitis, and drug hypersensitivity).

The main differential diagnosis in this case, however, is between giant cell myocarditis and sarcoidosis [5, 6, 7, 8] . The histologic features of cardiac sarcoid are similar to those of extracardiac sarcoid and consist of well-formed non-necrotizing granulomas within the myocardium. Giant cells are usually present in association with the granulomas. Unlike giant cell myocarditis, myocyte necrosis is typically absent and eosinophils are rare. Sarcoid granulomas may involve the endocardium (valves), epicardium, and may surround and extend into the adventitia and media of intramural coronary arteries. In addition, the clinical presentation of giant cell myocarditis is often fulminant cardiac failure whereas sarcoid often presents with ventricular arrhythmias and other conduction disturbances.

Diagnosis: Giant Cell Myocarditis

Discussion

Etiology:
Giant cell myocarditis is a relatively rare condition of unclear etiology. In some patients there appears to be an association with immunologic abnormalities such as active rheumatic disease, thymoma with or without myasthenia gravis [9, 10, 11, 12] , lymphoma [13], systemic lupus erythematosus, dermatomyositis, thyroiditis, orbital myositis [14, 15] , pernicious anemia [16], or ulcerative colitis [17, 18, 19] . In most patients, however, it likely occurs in association with an infective myocarditis, likely viral, in the setting of altered immunity. However, numerous attempts to identify an infective agent have not been successful.

Pathogens have traditionally been identified by growing them in culture from samples of infected tissue or staining the infected tissue with special histochemical and immunoperoxidase stains. These methods, however, do not identify all pathogens. Even molecular methods such as polymerase chain reaction (PCR) require comparisons to known DNA sequences. New methods in molecular diagnostics, in association with the recently completed Human Genome Project, may allow for identification of as yet undetected and possibly novel infectious agents. In order for such techniques to become practical, technology is being developed that allows DNA sequencing to be both faster and cheaper.

DNA sequencing can be carried out on a sample of diseased tissue. Using a technique called "computational subtraction" [20] computers compare the sample DNA with the sequence of DNA derived from the human genome project. When the comparison is done, sequences with similarity to the human genome are subtracted out. The remaining sequences, therefore, are of non-human origin. These non-human sequences include (1) sequences from known pathogenic and commensal organisms, (2) new microbial sequences, (3) sequences representing experimental contamination, and (4) transcripts from unsequenced regions of the human genome. DNA from such organisms as hepatitis B and C viruses, human papillomaviruses, cytomegalovirus, Kaposi's sarcoma herpesvirus, and Epstein-Barr virus have been successfully identified from human tissue using this technique.

While still a research tool, computational subtraction holds great promise for many diseases of unknown origin with proposed infectious etiologies, including rheumatoid arthritis, Type 1 diabetes, atherosclerosis, sarcoidosis, lupus, multiple sclerosis, and some types of cancer. Another potential application is in identifying emerging infectious diseases – such as HIV and Ebola which were unknown until recent decades.

Samples from the patient's left ventricular apical core and explanted heart were submitted for computational subtraction analysis.

Clinical Presentation and Course:
Because giant cell myocarditis is a rare condition, little was known about the natural history or response to therapy. The largest reported series consists of 63 patients from 36 medical centers [21]. The authors found giant cell myocarditis to be a disease of relatively young (mean age 43 years), previously healthy adults with no gender predilection. Patients typically presented within 3 weeks of symptoms and the majority (75%) presented with symptoms of congestive heart failure, followed by ventricular arrhythmias (14%), complete heart block (5%), and symptoms resembling acute myocardial infarction (6%). Nineteen percent of patients had associated autoimmune conditions.

Sustained, refractory ventricular tachycardia developed in half of patients during the course of their illness and, in general, patients had a fulminant course. The rate of death or cardiac transplantation was 89% with a median survival of 5.5 months from the onset of symptoms to the time of death or transplantation. Occasional, prolonged survival, up to 10 years, has been reported [22]. Of note, survival of patients with giant cell myocarditis is significantly worse than those with lymphocytic myocarditis. A comparison of survival between patients with giant cell myocarditis and patients from the Myocarditis Treatment Trial (lymphocytic myocarditis) [23] showed that approximately 50% of patients with lymphocytic myocarditis were alive without cardiac transplant at 5 years vs 10% of patients with giant cell myocarditis.

Role of Endomyocardial Biopsy:
According to the ACC/AHA 2005 Guideline Update for the diagnosis and management of chromic heart failure in the adult, endomyocardial biopsy can be useful in patients presenting with heart failure when a specific diagnosis is suspected that would influence therapy [24]. One study which looked specifically at endomyocardial biopsy for giant cell myocarditis in a referral population compared with the histology of apical cores, explanted hearts or autopsies found a sensitivity of 80-85% [25]. This sensitivity is far higher than in lymphocytic myocarditis which is <10%. It should be noted that the patients with giant cell myocarditis presented relatively early in their disease and had fulminant heart failure. Unlike fulminant lymphocytic myocarditis, patients with fulminant cardiac failure caused by giant cell myocarditis may respond to certain immunosuppressive agents. Therefore, endomyocardial biopsy may be used selectively to distinguish fulminant heart failure caused by giant cell myocarditis from other causes in which prognosis may differ.

Immunosuppressive Therapy and Cardiac Transplantation:
In the series of 63 patients with giant cell myocarditis who did not undergo cardiac transplantation, those treated with corticosteroids and cyclosporine, azathioprine, or both therapies survived longer (average 12 months) as compared with those who received no immunosuppressive therapy (average 3 months). This is, however, non-randomized data. A randomized, open-label giant cell myocarditis treatment trial has recently been completed [26].

In view of the poor prognosis, cardiac transplantation remains the best possibility for long-term survival [27]. Giant cell myocarditis is known to recur in the transplanted heart [28, 29, 30] and was identified by post-transplant endomyocardial biopsy in 26% of patients. Routine anti-T cell immunosuppression for rejection is usually enough to control disease recurrence. When giant cell myocarditis does recur in the allograft, it is usually mild and responds well to a transient increase in immunosuppression. The outcome of patients with giant cell myocarditis who undergo transplantation has clearly been better than that of patients who do not undergo transplantation.

Summary
Giant cell myocarditis is a rare disorder that is distinct from lymphocytic myocarditis both in clinical presentation and prognosis. Treatment must be immediate and aggressive and may be aided by definite diagnosis by endomyocardial biopsy. Immunosuppression and/or early transplantation are viable treatment options. Advances in molecular diagnostic techniques may identify a causative agent allowing for targeted therapy, rather than therapy aimed only at the clinical symptoms.

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