A. Pericardial smear. Examination of the pericardial aspirate can provide useful diagnostic information.

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1 5. PERICARDIUM Heart is encased by the pericardium which has a visceral layer (a) covering the heart and the parietal layer (b). In normal states it is thin, transparent and the myocardium can be seen through it. It shows a lining of flattened to cuboidal mesothelial cells. The normal pericardial cavity contains from 30 to 50 ml of clear fluid. Pericardial diseases. Pericardial disorders include effusions (noninflammatory), inflammatory conditions and tumors. Isolated pericardial disease is unusual, and pericardial lesions typically are associated with pathologic processes elsewhere in the heart or surrounding structures or are secondary to a systemic disorder. As diagnostic tools, pericardial smear (a), biopsy (b) and pericardiectomy (c) are used. A. Pericardial smear. Examination of the pericardial aspirate can provide useful diagnostic information. Pericardial fluid cytology can be helpful in the diagnosis of pericardial tuberculosis and pericardial tumors, in particular mesothelioma. A great deal of difficulty can be encountered in distinguishing reactive mesothelial cells (fig. 5.1 a-up) from cells shed from a mesothelioma (fig. 5.1 b-down) and carcinoma. A final diagnosis in most of the cases rests on a combined evaluation of histological, histochemical and immunocyto-chemical findings (table 5.1) in addition to clinical features of the thickened pericardium. B. Pericardial biopsy. Pericardial biopsy is indicated in cases of myopericarditis, because can be of diagnostic utility. C. Pericardiectomy. Surgically, excised thickened pericardium is evaluated in cases of constrictive pericarditis (fig 5.2). While tuberculosis is encountered in a large majority of cases, non-specific thickening of the pericardium is also observed in a number of cases. The latter diagnosis is given only after extensive sampling of the excised pericardium to exclude tuberculosis.

2 Figure 5.1. (a) Pericardial MHP. (a) Left-up biopsy: Pericardial mesothelial hyperplasia in EVG. Right up-smear: Pericardial effusion aspirate contains groups of reactive mesothelial cells with intercellular windows. The nuclei are small, round and uniform and show only mild variation in size and shape. (b) Pericardial mesothelioma. Left down-biopsy: tubular structures lined by atypical cells. Right down smear: No cohesive tumor cells show hypercromasia of nuclei, variation in size, binucleation, and prominent nucleoli. ICVDI cases. Figure 5.2. Pericardiectomy specimen removed from a case of constrictive pericarditis. Marked pericardial thickening in non-specific chronic pericarditis is seen. CVDI case.

3 Table 5.1. Morphological features and immunohistochemical reactions in mesothelial hyperplasia, mesothelioma and carcinoma Mesothelial hyperplasia Mesothelial hyperplasia Metastatic carcinoma Morphology Cytologic atypia + + Irregular nucleoli /+ + Necrosis of cells +(often) +(often) Intracytoplasmic /+ /+ mucin vacuoles Biphasic growth + Desmoplasia /+ /+ Hyalinised /occasional+ /+ stroma Immunostaining CEA (Most of the cases) +(70 100%) EMA /weak+ +(Strong membrane staining) +(Strong cytoplasmic staining) Leu-M1 (CD15) /occasional+ +(60 100%) Cytokeratin (Low molecular weight) Cytokeratin (High molecular weight) Human milk fat globule-2 /weak+ +(patern is perinuclear) useful in distinguishing sarcoma-tous mesothelioma from sarcoma) +(diffuse or beneath cell membrane) +(more often) (most cases) +(Membranous staining) +(Prominent cytoplasmic staining) (HMFG-2) B72.3 /+ Thrombomodulin + + /+occasional

4 5.1. Pericardial effusion. Pericardial effusion is a collection of large amounts of fluid in pericardial cavity by blocking of the venous blood return to the heart. This may be either inflammatory (exudate) or non-inflammatory (transudate) in nature. According with its appearance, non-inflammatory effusion can be transudate (hydropericardium), blood (haemopericardium), chylous, cholesterol, etc. Hydropericardium and Haemopericardium are the two common types of non-inflammatory effusion. Hydropericardium is an accumulation of clear or straw colored fluid in the pericardial cavity. Common causes include congestive heart failure, and hypoproteinemia. Rheumatic fever, systemic lupus erythematosis are some of the other causes. Hemopericardium. As the name indicates there is a collection of pure blood in the pericardial sac consequent to penetrating injury to the heart, rupture of the heart due to full thickness myocardial infarction, rupture of thoracic aneurysm of aorta into pericardial cavity, extensive tumor metastasis, etc Pericarditis Peicarditis is the inflammation of the pericardium commonly due to infective organisms. Non-infective pericarditis may also occur. There are idiopathic forms, as well. Common types of pericarditis are either acute or chronic forms. Both of them could have an exudative component (effusion). According with its appearance, inflammatory effusion can be serous, fibrinous, purulent, hemorrhagic, etc. Primary pericarditis is uncommon. It most often is due to viral infection, although bacteria, fungi, or parasites may also be involved. In most cases, pericarditis is secondary to cardiac surgery, radiation to the mediastinum, or AMI, or processes involving other thoracic structures (e.g., pneumonia or pleuritis). Uremia is the most common systemic disorder associated with pericarditis. Less common secondary causes include rheumatic fever, systemic lupus erythematosus, and metastatic malignancies (hemorrhagic exudate).

5 5.2.1.Acute pericarditis Fibrinous or serofibrinous pericarditis. There is fibrin deposition on the surface of the pericardium which may or may not be accompanied by effusion. This is seen in a large number of conditions and is not specific of a particular disease. This reaction occurs in acute rheumatic fever (fig left), transmural myocardial infarction and uremia. It is also seen in infections such as bacterial tuberculosis (fig right), viral and other conditions. In acute rheumatic fever, the pericardium characteristically shows fibrinous pericarditis with or without serous effusion. Grossly the pericardium shows fine, granular fibrin deposits on the surface (fig left). The fibrinous exudate has an irregular, shaggy appearance to the pericardial surface (socalled bread and butter pericarditis). Microscopically, the pericardium shows fibrin deposits, histiocytes and lymphocytic infiltration (fig 5.4). Sero-fibrinous pericarditis may either resolve or organize, resulting adhesion of the two layers and obliteration of the pericardial space Purulent or suppurative pericarditis. In acute bacterial pericarditis, the exudate is fibrinopurulent (suppurative), often with areas of frank pus (fig. 5.5). The causal organisms can reach the pericardium either by direct extension from adjacent infective foci or by hematogenous spreading. The pericardium reveals increased vascularity and numerous polymorphs (fig.5.6). The process of healing and organisation may lead to adhesions within the pericardial cavity and cause adhesive or constrictive pericarditis Chronic pericarditis Chronic pericarditis is a sequell of acute pericarditis, resulting by connective organization of the unresolved exudate. In evolution, often, the acute pericarditis is resolved completely (a), can develop a mild fibrosis (adhesive pericarditis) between the two pericardial layers (b), and by diffuse organization can lead to a slow and progressive fibrous thickening (fig. 5.7), and sometimes to pericardial calcification, condition known as constrictive pericarditis (fig. 5.8).

6 Figure 5.3. Left: Fibrinous pericarditis. In acute rheumatic carditis, the external surface of the heart shows fine confluent granularity in large foci over both atria and ventricles (Ercan TH case, 2000); Right: Tuberculous pericarditis. (Darwish Y case, 1998) Figure 5.4. Fibrinous pericarditis. The pericardium shows fibrin deposits, increased vascularity and inflammatory pericardial infiltration. IUMF case.

7 Figure 5.5. Purulent pericarditis: Pus covering the heart. ICVDI case. Figure 5.6. Fibrino-purulent pericarditis. Infiltration of pericardial fat and adjacent myocardium by neutrophils. ICVDI case.

8 Figure-5.7. Chronic nonspecific pericarditis. Left: The pericardium is thickened by dense fibro-collagenous tissue. Right: Hyalin colagenous pericardial thickening with small foci of calcification. ICVDI cases. Figure 5.8. Pericardiectomy specimens removed from a case of constrictive pericarditis. Pericardial thickening in non-specific chronic pericarditis cases. ICVDI. Figure 5.9. Tuberculous pericarditis. Left: Pericardial fibrosis and tuberculous granulomas with giant cells. Right: Pericardial fibrosis, caseous necrosis with peripheral giant cells. ICVDI case.

9 Tuberculous pericarditis. Involvement of the pericardium by tuberculosis continues to be an important cause of constrictive pericarditis. Tuberculous infection of the pericardium is made either by direct spread from pulmonary/tuberculous mediastinal lymph nodes or through a hematogenous spread. Naked eye examination shows marked thickening of both layers of pericardium. Caseation necrosis may be seen. Microscopically, epithelioid cell granulomas with or without necrosis are observed (fig. 5.9). Chronic inflammation, scarring and focal calcification are often encountered. These changes may represent healed tuberculous infection. Healed tuberculous pericardium is a common cause of constrictive pericarditis. Constriction can be successfully relieved by pericardiectomy. Healed pericarditis. Healing of pericarditis leads to obliteration of the pericardial cavity with pericardial adhesions (adhesive pericarditis). Adhesive pericarditis is generally not associated with clinical symptoms. Grossly, in adhesive pericarditis, the pericardium is thickened and is adherent to the surface of the heart. The adhesions had to be cut. Marked thickening of the pericardium may result consequent to tuberculous or suppurative pericarditis, the former being more common. This may produce symptoms and signs of constriction of the pericardium (constrictive pericarditis). Pericardiectomy is indicated to relieve the symptoms. Grossly, in constrictive pericarditis, the heart may be encased within a thickened coat of pericardium which limits its diastolic expansion. Microscopically, abundant collagen or fibrosis of the pericardium is observed. Calcification is often present (fig si 5.8) Tumors of the Pericardium. The most common pericardial tumors are metastases, while primary pericardial tumors are rare Benign tumors include mesothelial cysts (most common), angiomas, lymphangiomas, fibroma (solitary fibrous tumor), teratoma, lipoma, mesothelial papillomas, etc.

10 Solitary fibrous tumour. It is an uncommon, spindle-cell, fibroblastic tumour. Similar tumor names are: benign mesothelioma, fibrous mesothelioma, submesothelial fibroma. Grossly, the tumour tend to be well circumscribed, firm, fleshy or white, although diffuse mesothelial surface involvement has been described. Histological variability is the rule and multiple growth patterns have been described. Most tumours will have a predominant monomorphic spindle cell pattern resembling low-grade fibrosarcoma although broad tumour cell fascicles are rare. Areas of hypercellularity typically alternate with those that are less cellular. The less cellular areas can by myxoid or contain abundant collagen. Typically the nuclei of tumour cells are closely opposed to collagen bundles Primary malignant tumors are generally malignant mesothelioma and various sarcomas. Pericardial Mesothelioma Mesothelioma of the pericardium is rare. Tumor arises from mesothelial cells or demonstrates mesothelial differentiation. Grossly, malignant mesotheliomas (MM) of the pericardium generally present as nodules that fill the pericardial cavity. The heart and great vessels are usually enveloped by the disease process (fig.5.10). The tumor is grey white and firm. Areas of hemorrhage, cystic degeneration and necrosis may be present. Microscopically, pericardial mesotheliomas (fig. 5.11) may be epithelial, sarcomatoid, biphasic or undifferentiated type. Although the majority are of the epithelioid type, forming tubules, papillary structures and cords of infiltrating cells that can incite a desmoplastic response, the sarcomatous variant is also common. Etiologically, mesothelioma has a link with asbestos exposure. This association is weaker for pericardial than for pleural mesotheliomas. Immunohistochemically most mesotheliomas express cytokeratin both in epithelial and sarcomatoid areas in majority of the cases. Epithelial membrane antigen (EMA) is present in the epithelial areas while vimentin is expressed in the spindle cell areas. Mesothelioma can often be difficult to distinguish from mesothelial hyperplasia and adenocarcinoma (table 5.1). Systematic evaluation needs to be done for a definitive diagnosis. Microscopic features such as cytologic atypia, high nuclear cytoplasmic ratio, pleomorphism, mitotic figures, large cytoplasmic vacuoles, necrosis of cells and infiltration favor a diagnosis of mesothelioma rather than hyperplasia (fig. 5.1-b; 5.1-a). Immuno-

11 histochemistry is helpful in that membrane staining is obtained with antibody to EMA and HMFG-2 in mesothelioma cells. Differentiation of mesothelioma from adenocarcinoma can also be extremely challenging. Mesothelioma cells generally have prominent intracytoplasmic vacuoles. There is strong reactivity with alcian blue which is sensitive to hyaluronidase. Immunohistochemistry when judiciously performed aids in the differential diagnosis of mesothelioma. Membrane staining with EMA is observed in mesothelioma cells while carcinoma cells exhibit strong cytoplasmic staining. Adenocarcinoma cells also show strong reaction with CEA Pericardial metastases are the most common pericardial tumors. Almost any tumor can involve the pericardium. Metastasis to the pericardium has been observed from both carcinomas and sarcomas. Lung carcinoma (fig. 5.12), breast carcinoma (fig.5.13), colonic carcinoma (fig. 5.14), malignant melanoma, leukemic infiltration, lymphoma both Hodgkin s and non-hodgkin s can affect the pericardium. Cytological examination of pleural fluid is diagnostic in most cases. The distinction between reactive mesothelial hyperplasia and metastatic carcinoma can be difficult, and is assisted by immunohistochemistry. The presence of carcinoembryonic antigen, berep4, B72.3 antigen, and Leu M1 favour carcinoma over mesothelial hyperplasia. Calretinin and cytokeratin 5/6 reactivity favour the diagnosis of a mesothelial process.

12 Figure Mesothelioma. The tumor encases the heart (Silver MD, 2001) Figure Mesothelioma. Left. Epithelioid type:tubulo-papillary structures; Right. Sarcomatoid type: fusocellular structures are arranged in bundles (Silver MD, 2001)

13 Figure Pericardial metastases. A massive infiltration of the pericardium by carcinoma of the lung (Reynen K, 2004) Figure Pericardial metastases. Histology of epicardial lesion of breast adenocarcinoma. (Reynen K, 2004) Figure Epicardial metastases. Poorly differentiated colon carcinoma (Reynen K, 2004)