CHAPTER 13 CARDIOVASCULAR PATHOLOGY

Non-viral myocarditis

Pericardium

Cysts

Acute purulent pericarditis

Tuberculous pericarditis

Other causes of pericarditis

Tumors

INTRODUCTION

• The heart is often not considered at any length, if at all, in texts on surgical pathology

endomyocardial biopsy for the diagnosis of myocarditis and the occasional rare tumor are the usual specimens described

• This is now changing with the increased prevalence of pediatric cardiac transplantation

protocols for management of transplant patients require repeated endomyocardial biopsies to assess rejection

the procedure itself generates a surgical pathology specimen, the explanted heart

in addition, as a bridge to transplant, a ventricular assist device may be employed with biopsy of diseased myocardium under direct surgical inspection at the time of insertion of the device

• A range of other specimens from the heart may also be submitted in the pediatric age group

specimens removed during surgical procedures to correct congenital defects include:

– short segments of aortic narrowing removed at the time of coarctation repair

– fragments of valves and sub-valvar shelves

tumors

• Vascular samples from, for example, renal artery or small aneurysms or fistulae may also be submitted to any pediatric pathology laboratory

• Close clinicopathological correlation is required to obtain maximum information from the submitted specimen

if lacking or incomplete, it is worth making the effort to obtain the clinical information before assessment of the specimen

DIAGNOSTIC ENDOMYOCARDIAL BIOPSY

• Of necessity, the specimens are small, measuring a couple of millimeters in diameter

• Endomyocardial biopsy is performed most frequently for the assessment of acute cellular rejection following cardiac transplant (see below)

• Endomyocardial biopsy for the assessment of heart muscle disease of uncertain cause usually involves the distinction between myocarditis and dilated cardiomyopathy

• May also be undertaken to:

identify the cause of hypertrophic cardiomyopathy

confirm a suspicion of arrhythmogenic right ventricular cardiomyopathy

• A biopsy sample may also rarely be obtained from the left ventricle under direct inspection at the time of insertion of a left ventricular assist device

this specimen is usually much larger and permits more detailed assessment of the myocardium

CARDIOMYOPATHIES

• Definition: primary heart muscle disease other than ischemic

• Classified into three basic types depending on their pathophysiology

• Cardiomyopathies may also be classified according to their specific pathological features or a combination of pathological and clinical features, or according to their etiology

current WHO classification attempts a mixture of all (Table 13.1)

for descriptions of the macroscopic features see below under examination of the explanted heart

Table 13.1 Simplified classification of pediatric cardiomyopathies (Richardson et al 1996)

Dilated cardiomyopathy

Hypertrophic cardiomyopathy

Restrictive cardiomyopathy

Arrhythmogenic right ventricular cardiomyopathy

Unclassified:

non-compacted myocardium

fibroelastosis

mitochondrial

Histopathological features of cardiomyopathies on biopsy

Dilated cardiomyopathy (Figs 13.1–13.4)

• Myocyte hypertrophy

heart in dilated cardiomyopathy is increased in weight

• Myocytes may be elongated, thin with a wavy cytoplasmic border

indicative of overstretching

• Interstitial fibrosis may be present

• A small amount of lipofuscin can be present in the myocyte cytoplasm in older children

not a feature of younger children

• Endocardial fibroelastic thickening is usually present

• Myocyte necrosis is not a feature

• Inflammatory cell infiltration not usually a prominent feature

scattered lymphocytes may be present

presence of more than a few inflammatory cells suggests myocarditis

• Mast cell numbers are increased in the interstitium

Fig 13.1 Photomicrograph of myocardium of a 2-year-old girl with dilated cardiomyopathy. The myofibers are elongated, stretched and wavy. The nuclei show mild enlargement and hyperchromasia.

Fig 13.2 Photomicrograph of an endomyocardial biopsy from a girl aged 11 years. There is prominent interstitial fibrosis. The myocytes show contraction bands. (Masson-trichrome)

Fig 13.3 Photomicrograph of an endomyocardial biopsy from the same case as Fig 13.2. The myocytes show variation in size, as do their nuclei. There is mild interstitial fibrosis and the endocardium shows mild to moderate, fibroelastic thickening. (Elastic van Gieson)

Fig 13.4 Photomicrograph of myocardium from a 5-year-old boy with dilated cardiomyopathy. Scattered mast cells are evident in a perivascular location. While special staining may be used to demonstrate mast cells, they are usually readily apparent at high-power on H&E staining. Mast cell numbers are increased in the myocardium in dilated cardiomyopathy and in cases of myocarditis. (H&E)

Hypertrophic cardiomyopathy (Figs 13.5, 13.6)

• Myocyte hypertrophy

enlarged, irregular and hyperchromatic myocyte nuclei

• Myofiber disarray

note that myofiber disarray may be present in conditions other than hypertrophic cardiomyopathy (Table 13.2)

• Myofibers may be vacuolated

• In mitochondrial cardiomyopathy, usually in young children, numerous mitochondria may be evident

small pink dots in the cytoplasm on H&E

giant mitochondria may be present

electron microscopy and assessment for mitochondrial oxidative enzymes must be undertaken to confirm the diagnosis

Fig 13.5 Photomicrograph of heart from an 11-year-old boy with hypertrophic cardiomyopathy. There is readily apparent myocyte disarray. Disarray is also usually evident at a macroscopic level where the muscle bundles are whorled, and also at the ultrastructural level where the myofilaments are disorganized.

Fig 13.6 Photomicrograph of a 7-month-old girl with hypertrophic cardiomyopathy due to mitochondrial respiratory chain complex-1 deficiency. Giant mitochondria are visible within the myocyte cytoplasm as rounded homogenous eosinophilic inclusions. (H&E)

Table 13.2 Associations of myocyte disarray

Familial hypertrophic cardiomyopathy

Restrictive cardiomyopathy

Normal heart near the insertion of the septum into the ventricular free walls

Congenital heart disease, particularly hypoplastic left heart

Previous biopsy site on endomyocardial biopsy (see section on post-transplant biopsy)

Adjacent to myocardial scars

Other forms of cardiomyopathy

• Hypertrophic cardiomyopathy histologically mimicking glycogen storage disease may occur with mutations of the PRKAG2 or LAMP2 genes (Arad et al 2005)

these cases associated with atrial and ventricular arrhythmias or atrioventricular block

histologically there are large glycogen-filled vacuoles in the cardiac myocytes

• Some forms of cardiomyopathy with a specific origin such as the cardiomyopathy associated with congenital disorders of glyocosylation do not show specific histological features (Gehrmann et al 2003)

presentation may be either as dilated or hypertrophic cardiomyopathy

endomyocardial biopsy does not permit the specific diagnosis to be made

• Cardiomyopathy associated with mutations in the desmin or associated genes may result in restrictive or dilated cardiomyopathy

eosinophilic inclusions of filaments in the myocytes (Fig 13.8)

Fig 13.8 Photomicrograph of myocardium from a 12-year-old boy with a strong family history of restrictive cardiomyopathy. Many of the myocytes contain rounded brightly eosinophilic homogenous cytoplasmic inclusions that ultrastructurally are composed of aggregated filaments. In longitudinal sections the inclusions are elongated and wavy. (H&E)

VIRAL MYOCARDITIS

• An inflammatory infiltrate of the myocardium with necrosis and/or degeneration of adjacent myocytes, not typical of the ischemic injury associated with coronary artery disease

Histopathological features (Figs 13.9–13.13)

• Myocyte necrosis or damage must also be present for the diagnosis

Fig 13.9 Photomicrograph of an 8-day-old boy with positive PCR for Enterovirus in myocardium. There is a heavy inflammatory cell infiltrate with loss of myocytes. Lymphocytes predominate but eosinophils and neutrophils are also present.

Fig 13.10 Same case as Fig 13.9 stained with anti-CD3 antibody. There are large numbers of positive T-cells in the myocardium.

Fig 13.11 Same case as Fig 13.9 stained with anti-CD79a antibody. There are only scattered B-cells.

Fig 13.12 Same case as Fig 13.9 stained with antibody to CD68. There are large numbers of macrophages in the inflammatory cell infiltrate.

Fig 13.13 Photomicrograph of an 8-year-old girl with Parvovirus B19 myocarditis. There is a lymphocytic infiltrate and the myocytes show disintegration and necrosis.

Differential diagnosis and pitfalls

• Note that myocytes may contain abundant intracytoplasmic lipid

should not be confused with a disorder of fatty acid oxidation (Fig 13.14)

• Histological features do not permit distinction between the various viral causes of myocarditis

Fig 13.14 Same case as Fig 13.9 stained for fat. Note extensive accumulation of lipid droplets in the myocyte cytoplasm. In this context, the finding of abundant cytoplasmic lipid does not indicate a disorder of fatty acid oxidation. (Frozen section stained with Oil-red-O)

NON-VIRAL MYOCARDITIS

Giant cell myocarditis (Laufs et al 2002, Das et al 2006)

• Rare and fulminant myocarditis

• Presents with congestive heart failure, ventricular arrhythmia or heart block

• About one-fifth of cases have associated autoimmune disorders

• Rapidly fatal

• Widespread myocardial necrosis associated with inflammatory infiltrate with multinucleated giant cells (Fig 13.15)

absence of granulomata

inflammatory cell infiltrate includes lymphocytes (largely CD8+ T-cells), histiocytes and eosinophils, and sometimes neutrophils

inflammation involves epicardium, myocardium and endocardium

– giant cells found only in myocardium

• Transplantation the treatment of choice but disease may recur in transplanted heart

Fig 13.15 Photomicrograph of heart from an 8-year-old boy with severe cardiomyopathy. Biopsy at the time of insertion of ventricular assist device. There is giant cell myocarditis. The giant cells are multinucleate and there is a heavy background lymphocytic infiltrate as well as extensive myocyte destruction. Contraction bands are evident in the lower field.

ASSESSMENT OF THE EXPLANTED HEART

CARDIOMYOPATHIES IN THE EXPLANTED HEART

• Explanted hearts submitted for histological examination with or without prior valve harvesting

prior valve harvesting renders assessment more challenging but does not preclude it

• For the assessment of hearts removed for end-stage dilated, restrictive or hypertrophic cardiomyopathy the most useful approach is a simulated 4-chamber cut through the atria and ventricles

provides information regarding relative sizes of the atrial and ventricular cavities

allows demonstration of all the major structures other than the arterial valves (Fig 13.18)

• Histological sampling requires assessment of myocardium from:

both atria and ventricles

interventricular septum

papillary muscles of the mitral valve

– section through the atrioventricular junctions will normally encompass the main right and left coronary arteries together with the coronary sinus

• Electron microscopy required to confirm the presence of large numbers of mitochondria, many abnormal in the mitochondrial cardiomyopathies

Fig 13.18 Macroscopic photograph of an explanted heart cut in a simulated 4-chamber echocardiographic view. Both atria and ventricles are clearly shown. The atrioventricular junctions and valves are well seen, as is the interventricular septum, both muscular and membranous. The posterior wall of the left atrium is not included, nor are the cavo-atrial junctions; these are retained for surgical anastomosis in the patient. The great arteries and arterial valves are not seen in this view but can be inspected and sampled nonetheless.

Fig 13.19 Macroscopic photograph of an explanted heart with dilated cardiomyopathy cut in a simulated echocardiographic parasternal long-axis view. It shows a cannula inserted into the aorta and a cannula inserted into the apex of the left ventricle. The epicardium over the right ventricular wall is thickened and hemorrhagic in keeping with the surgery to insert the cannulae of the left ventricular assist device three and a half months previously.

Fig 13.20 Same case as Fig 13.19, showing the cannula insertion site at the left ventricular apex. There is dense myocardial fibrosis. Dark flecks of dystrophic calcification are seen at the junction with the myocardium. Suture material is evident on the right. Inflammation is minimal in this case.