Case 3 -

1. Heart, extensive non-necrotizing granulomatous inflammation and fibrosis consistent with sarcoidosis associated with cardiomegaly (w, 640 gm expected range 302 –526 gm). 2. Lungs, non-necrotizing granulomatous inflammation consistent with sarcoidosis. 3. Non-necrotizing granulomas were also identified in the liver, spleen, kidneys, pancreas, and central nervous system. Henry D. Tazelaar and Marie-Christine Aubry

PDF File (8.8 MB) Clinical History A 35-year-old man was referred from the local prison for further evaluation of his known cardiac and pulmonary problems. He had a history of Hodgkin disease 18 years previously. His recent history began one month prior to admission at which time he collapsed playing basketball. At this time, he was noted to have significant bradycardia and required a permanent pacemaker. An echocardiogram revealed an ejection fraction of 30% and normal coronary arteries. He was discharged, but he returned a few days later with lethargy, chest pain, and shortness of breath. He underwent bronchoscopy, at which time, non-necrotizing granulomas were identified on biopsy, and a diagnosis of sarcoidosis established. He was placed on 60 mg of prednisone and was then referred to Mayo for consultation. At the time of admission, he said he was asymptomatic and felt strong. He was scheduled for a repeat chest x-ray, EKG, and echocardiogram, as well as pulmonary function testing. He returned to the prison and three days later was found unresponsive in the weight room. The paramedics were unable to resuscitate him and he was pronounced dead. The enclosed PDF of the Powerpoint presentation for Case 3 has slides illustrating pertinent features. Discussion Sections of the heart and lungs are submitted for evaluation. The heart sections, taken from the atrioventricular node, show the presence of extensive collagenous fibrosis. At the periphery of the collagenized zones are numerous giant cells admixed with lymphocytes. Non-necrotizing granulomas are present, although they are overshadowed by the extensive fibrosis. At the periphery of the more cellular areas, at the junction with uninvolved myocardium and adjacent to areas of lymphocytic infiltration, myocyte necrosis can be identified. The uninvolved myocardium shows the presence of moderate myocyte hypertrophy. The lungs show more prominent granulomatous inflammation but, even in the lungs, the granulomas are associated with significant collagenous fibrosis. On low power, the granulomas appear randomly distributed; but on closer inspection, many of them are present adjacent to bronchioles, arteries, interlobular septa, and along the pleura. This is a classic lymphangitic pattern. Note that the pulmonary parenchyma away from the areas of granulomatous inflammation is relatively normal. There is no significant interstitial inflammation, no foci of organizing pneumonia, and no isolated giant cells. The features in the heart and lung are very consistent with sarcoidosis. The etiology of sarcoid is still unknown. Despite some recent tantalizing evidence that sarcoid may be related to various infectious agents, including propionibacterium acnes or mycobacterial organisms, these associations have by no means been proven. Furthermore, despite characterization of the cell types involved, the immune mechanisms leading to the formation of the sarcoid granuloma have not been resolved. This patient's history is certainly interesting in that there is a recognized association between malignant disease and sarcoidosis, suggesting that abnormal immune regulatory mechanisms may contribute to the development of sarcoidosis. Cardiac Sarcoidosis The clinical manifestations of sarcoidosis are protean and beyond the scope of this course. The lung is involved in greater than 90% of patients, but it is the presence of cardiac involvement which can be more clinically morbid. Clinical evidence of cardiac involvement is recognized in only 2 – 5% of patients, but the incidence ranges from 20 – 47% in autopsy studies. In Japan, myocardial involvement accounts for up to 70% of sarcoid deaths in contrast to 13 – 50% of sarcoid deaths in the United States. Cardiac involvement may occur at any time during the course of sarcoid, may be the presenting feature, and sometimes occurs with minimal or "absent" systemic disease, raising the possibility that there may be an entity best classified as "isolated non-necrotizing granulomatous myocarditis of idiopathic nature." Sudden death caused by arrhythmias or conduction defects, the most likely cause of death in this patient despite his pacemaker, is the most common cause of death due to cardiac sarcoid. In at least one autopsy series, an antemortem diagnosis of cardiac sarcoidosis was made in only 35% of patients. Other manifestations include intractable heart failure, pericardial effusions, ventricular aneurysms, and papillary muscle dysfunction. In a series of 300 cases of cardiac sarcoidosis, predominant cardiac features were ventricular arrhythmias (45%), bundle branch block (38%), supraventricular arrhythmias (28%), complete heart block (26%), and sudden death (16%) (Fleming). Progressive heart failure due to massive granulomatous infiltrates of the myocardium accounts for at least 25% of deaths due to cardiac sarcoid. Sarcoid can involve the pericardium, myocardium, or endocardium. The left ventricular free wall is the most frequently involved, followed by the basilar ventricular septum, left ventricular papillary muscle, right ventricular free wall, and atrial walls. The myocardial conduction system is particularly vulnerable, resulting in complete obliteration of the sinoatrial node, atrioventricular node, or AV bundle. Involvement of the valves is extremely rare. Myocardial involvement has been described as comprising three basic patterns. Small epithelioid granulomas may be disseminated throughout the myocardium in a relatively random fashion. In more significantly involved hearts, the process may form somewhat linear, interstitial, fingerlike projections; in the third form, the nodules may form expansile conglomerate mass-like lesions. The latter form seems to be present in the current case. At autopsy, the diagnosis of cardiac sarcoidosis may be relatively straightforward. It may be more difficult, however, to arrive at the diagnosis during life. Among 1278 patients to undergo endomyocardial biopsy at Johns Hopkins for diagnosis of congestive heart failure ("dilated cardiomyopathy"), sarcoid was found to be present in 1.3%. Among patients in whom sarcoid is suspected, noncaseating granulomas were found in only 20% of 26 cases in a recent study by Uemura et. al. Thus, the diagnostic rate for sarcoid utilizing endomyocardial biopsy is relatively low, but is certainly higher than that reported for idiopathic lymphocytic myocarditis. The differential diagnosis for cardiac sarcoid on endomyocardial biopsy specimens, EMB (or at autopsy) includes primarily infection and giant cell myocarditis. Infection can generally be excluded by the use of special stains and the clinical setting. Cardiac infections with tuberculosis or fungi diagnosed by EMB are extraordinarily rare. Recently, a case of cat-scratch disease (Bartonella henselae) in which giant cells and well-formed granulomas with central necrosis were identified on EMB, has been reported. More often the challenge is to distinguish cardiac sarcoidosis from giant cell myocarditis (GCM). A recent study by Okura, et. al., confirmed that GCM is clinically and pathologically distinct from cardiac sarcoidosis. A diagnosis of sarcoidosis is favored by the presence of non-necrotizing granulomatous inflammation and fibrosis, while GCM is associated with necrosis, foci resembling lymphocytic myocarditis and tissue eosinophilia. The relative number of giant cells tends to be the same in each disease. Pulmonary Sarcoidosis Involvement of the lung in sarcoid is also manifest by the presence of non-necrotizing granulomas typically present in a lymphangitic distribution. As can be seen in this case, the granulomas are characteristically composed of tightly clustered epithelioid histiocytes and occasionally multi-nucleated giant cells, with few intervening lymphocytes or other inflammatory cells. Hyalinized fibrous tissue may replace portions of granulomas or even entire granulomas. Small foci of central necrosis can be identified in up to 20% of cases and may raise suspicion of infection. Granulomas are typically in the interstitium rather than within airspaces, and as alluded to above, the parenchyma is generally free of significant chronic interstitial inflammation. The granulomas may be scattered individually with little distortion of the underlying architecture or it can form confluent masses. Transbronchial biopsy is the most frequent procedure performed to establish the diagnosis of sarcoidosis. Epithelioid granulomas can be found in 52-97% of patients with suspected or proven sarcoid. The yield is highest in patients with radiographic findings of lung disease, but may often be positive even in their absence. Yield can be improved by increasing the number of samples taken, and increasing the number of histologic levels examined. A number of nonspecific cytoplasmic inclusions may be present within the granulomas or giant cells but should not be confused with inhaled exogenous material. Fragments of clear to lightly golden polarizable crystals most likely represents calcium oxalate and carbonate (breakdown products of cell metabolism). Schaumann bodies are lamellated, blue calcified bodies which bear some resemblance to psammoma bodies; asteroid bodies are eosinophilic star-like arrays of crystallized protein. A granulomatous vasculitis frequently accompanies other changes in sarcoid, especially those with extensive parenchymal involvement. Non-necrotizing granulomas within the intima or media of vessels often compress the lumen, but rarely causes vascular wall necrosis. Table 1 below summarizes histologic features of pulmonary sarcoid or compares them to the findings in infectious granulomas. Table 1: Histologic Features in Transbronchial Biopsy Specimens   Sarcoidosis N=82 Infectious Granulomas N=10 Location of granulomas Airway Parenchyma Blood vessels 92.7% 72.0% 12.2% 50% 70% Necrosis 19.5% 40% Fibrosis (of granulomas) 57.3% 30% Hyalinization 14.6%   Schaumann bodies 69.5% 10% Asteroid bodies 4.9%   Interstitial fibrosis 32.8% 62.5% From Hsu RM, et. al. Arch Pathol Lab Med 1996; 120:364-368 Nodular sarcoid is characterized by the presence of conglomerate nodules of granulomatous inflammation visible radiographically as 4-5 cm in diameter masses. Microscopically, the nodules are composed of masses of granulomas and hyalinized connective tissue. Necrotizing sarcoid angitis and granulomatosis (NSG) bears some histologic resemblance to Wegener's' granulomatosis and sarcoid and suggests that there is a spectrum of conditions between sarcoidosis and Wegener's granulomatosis. The lesions of NSG comprise irregular areas of induration which microscopically consist of confluent aggregates of epithelioid and giant cell granulomas with surrounding fibrosis and chronic inflammation. The granulomas are identical to those seen in sarcoid and tend to follow lymphatic pathways. However, NSG also contains larger areas of coagulative necrosis or necrosis which resembles that seen in Wegener's granulomatosis. Various degrees of vasculitis may be seen involving both arteries and veins. Vessels may also contain discreet granulomas unlike that generally seen in Wegener's granulomatosis. The disease, if it exists, is extraordinarily rare. The differential diagnosis for sarcoidosis includes infection, berylliosis, and hypersensitivity pneumonitis. Routine infections are generally excluded on the basis of negative special stains and cultures. In the study by Hsu et. al., in an urban setting, 89% of transbronchial biopsy specimens with epithelioid granulomas negative for stainable organisms were from patients with sarcoid; only 11% proved to be infectious. A couple of less familiar diseases related to infectious organisms, however, may need to be considered. In elderly women in particular, granulomas may occasionally be identified in biopsy specimens associated with a background of acute and chronic bronchitis, bronchiolitis, and airway dilatation. In such cases, the possibility of infection with MAI associated with bronchiectasis (the so-called Lady Windemere syndrome) ought to be considered. Special stains in such cases are usually negative for the organisms, and a combination of characteristic CT findings and sputum cultures may be necessary to establish the diagnosis. Patients with lung disease related to hot tub exposure may also have non-necrotizing granulomatous inflammation present on a transbronchial or open lung biopsy. In contrast to sarcoid, the granulomas associated with so-called hot tub lung tend to be somewhat less tight in appearance and lack the characteristic cuff of lymphocytes around the epithelioid histiocytes. In addition, the granulomas are often within airspaces and the lumen of bronchioles rather than within the wall, and are usually associated with a patchy chronic interstitial pneumonia with or without areas of organizing pneumonia (bronchiolitis obliterans organizing pneumonia). Berylliosis can look virtually identical to sarcoid, and an appropriate history may be necessary to exclude this diagnosis with certainty. Berylliosis is generally best identified by lymphocyte stimulation tests obtained in bronchoalveolar lavage, although x-ray diffraction can be used to identify the beryllium within tissue. Hypersensitivity pneumonitis (HSP) may be difficult to distinguish from sarcoid, particularly on transbronchial biopsy. On larger transbronchial or surgical biopsies, helpful features can usually be identified. In general, the granulomas of HSP are poorly formed and are rarely as tight and well-developed as those in HSP. HSP is also usually associated with a chronic bronchiolitis, chronic interstitial pneumonia, areas of bronchiolitis obliterans organizing pneumonia, and a more random distribution of the granulomas, sometimes along with scattered isolated giant cells. The inflammatory process in HSP is usually bronchiolocentric and not lymphangitic. Thus, while bronchioles in the immediately surrounding bronchiolar interstitium may be involved in both sarcoid and HSP, it is rare in HSP to see granulomas within the pleura or interlobular septae. Vasculitis is not a feature. The Table 2 below summarizes the distinctions between these entities. Table 2. Granulomatous Lung Disease Differential Diagnosis   HSP NSIP Sarcoid Hot Tub Lung 1. Interstitial pneumonia +-+++ +++ - + 2. Peribronchiolar accentuation of inflammation ++-+++ + _ ++-+++ 3. Granulomatous Inflammation a. well formed b. single giant cells c. lymphangitic d. necrosis +-+++ + +-++ - +-++ _ NA - NA NA +++ +++ - +++ + +++ ++-+++ - - + 4. BOOP +-++ +-++ - +-++ 5. Foam cells +-++ +-++ - - 6. Culture results - - - + MAI References Cardiac Sarcoid Felker GM, et. al. The spectrum of dilated cardiomyopathy. The Johns Hopkins experience with 1278 patients. Medicine, 1999:78 (4):270-83. Flora GS, and Sharma, OP. Myocardial Sarcoidosis: A Review. Sarcoidosis 1989;(6):97-106. Fromm GB. Diagnosis of cardiac sarcoidosis. Chest; 2003; 123:16-17. Iwai K, et. al. Pathological studies on sarcoidosis autopsy. I. Epidemiological features of 320 cases in Japan. Acta Pathol Jpn, 1993. 43(7-8):372-6. Iwai K, et. al. Pathological studies on sarcoidosis autopsy. II. 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