Gross and Histologic Diagnosis

The pathologic diagnosis of ARVC/D in autopsy hearts or those explanted at the time of cardiac transplantation has been traditionally based upon gross and histologic evidence of transmural fatty or fibrofatty myocardial replacement of the right ventricular free wall. This could be considered a myocardial dystrophy, extending from the epicardium towards the endocardium, sparing only the trabecular myocardium [3-8].

Table 4.1 summarizes the main pathologic features as observed in the original Padua series. At

Gross Explanted Heart

Fig. 4.1 • A 49-year-old woman who was transplanted due to heart failure and refractory ventricular arrhythmias.(a) External view of the native heart specimen obtained at cardiac transplantation:note the yellow appearance of the right side of heart. (b) In vitro spin-echo cardiac magnetic resonance, short axis, shows massive right ventricular dilatation and full-thickness myocardial atrophy with fatty tissue replacement. (c) Panoramic histologic section of the right ventricular free wall shows transmural fibro-fatty replacement (Heidenhain trichrome)

Fig. 4.1 • A 49-year-old woman who was transplanted due to heart failure and refractory ventricular arrhythmias.(a) External view of the native heart specimen obtained at cardiac transplantation:note the yellow appearance of the right side of heart. (b) In vitro spin-echo cardiac magnetic resonance, short axis, shows massive right ventricular dilatation and full-thickness myocardial atrophy with fatty tissue replacement. (c) Panoramic histologic section of the right ventricular free wall shows transmural fibro-fatty replacement (Heidenhain trichrome)

gross examination, the right side of the heart appears yellowish or whitish suggesting fatty or fibro-fatty replacement (Fig. 4.1). Right ventricular aneurysms, whether single or multiple (Figs. 4.2, 4.3) are considered a pathognomonic feature of ARVC/D. The heart weight is almost normal according to sex and age, but right ventricular enlargement, whether mild, moderate or severe, is a constant finding. The right ventricular dystrophic process can be diffuse or segmental, whereas left ventricular involvement may not be seen on gross examination, thus explaining its underestimated prevalence (see below). The ventricular septum may be involved in about 20% of cases

Fig.4.2 • A 17-year-old boy who died suddenly while playing soccer. (a) Basal 12 lead ECG shows inverted T waves in the right precordial leads up to V4. (b) Transverse section of the heart specimen showing extreme thinning of the right ventricular free wall accounting for anterior and posterior (subtricuspid) aneurysms. (c) Panoramic histologic section of the anterior right ventricular free wall shows transmural fibro-fatty replacement (fibro-fatty variant) (Heidenhain trichrome)

Fig.4.2 • A 17-year-old boy who died suddenly while playing soccer. (a) Basal 12 lead ECG shows inverted T waves in the right precordial leads up to V4. (b) Transverse section of the heart specimen showing extreme thinning of the right ventricular free wall accounting for anterior and posterior (subtricuspid) aneurysms. (c) Panoramic histologic section of the anterior right ventricular free wall shows transmural fibro-fatty replacement (fibro-fatty variant) (Heidenhain trichrome)

Subepicardial Fat

Fig. 4.3 • A 40-year-old man, previously asymptomatic, who died suddenly at rest. (a) In vitro spin-echo cardiac magnetic resonance,four-chamber cut,shows increased high intensity signal in both ventricles,either transmural (right) or subepicardial (left). (b) View of the right ventricular inflow with fatty appearance of the lateral wall, subtricuspid aneurysm and endocardial fibrous thickening. (c) View of the postero-lateral left ventricular free wall: note the wave front extension of fat from the epicardium towards the endocardium.(d) Panoramic histologic section of the right ventricular free wall shows transmural fibro-fatty replacement (Heidenhain trichrome).(e) Panoramic histologic section of the left ventricular free wall with fibro-fatty replacement in the outer layer (Heidenhain trichrome)

Fig. 4.3 • A 40-year-old man, previously asymptomatic, who died suddenly at rest. (a) In vitro spin-echo cardiac magnetic resonance,four-chamber cut,shows increased high intensity signal in both ventricles,either transmural (right) or subepicardial (left). (b) View of the right ventricular inflow with fatty appearance of the lateral wall, subtricuspid aneurysm and endocardial fibrous thickening. (c) View of the postero-lateral left ventricular free wall: note the wave front extension of fat from the epicardium towards the endocardium.(d) Panoramic histologic section of the right ventricular free wall shows transmural fibro-fatty replacement (Heidenhain trichrome).(e) Panoramic histologic section of the left ventricular free wall with fibro-fatty replacement in the outer layer (Heidenhain trichrome)

and the left ventricle in nearly half of cases [4, 5] (Table 4.1).

Hearts with end-stage disease and congestive heart failure, obtained either at autopsy or at cardiac transplantation [4, 11], consistently show biventricular involvement. There are usually multiple right ventricular aneurysms and a parchment-like appearance of the free wall. Intracavitary mural thrombi may be present and may be a source of pulmonary embolism. Thickening of the endocardium is a frequent finding, most probably as a result of fine thrombus deposition and organization, usually in conjunction with aneurysms and/or severe dilatation. As a consequence, the trabeculae are shrunk and the intertrabecular spaces appear enlarged, thus explaining the feature of deep fissures at angiography. The

Table 4.1 • Main clinical-pathologic features in 30 ARVC/D cases

M/F

2/1

Age range (mean)

15-65 (28)

Mode of death or failure

Sudden death

24(80%)

Congestive heart failure

6 (20%)

Heart weight range (gr, mean)

270-660 (400)

RV aneurysms (triangle of dysplasia)

15 (50%)*

Inferior

12

Infundibular

8

Apical

6

LV involvement

14 (47%)**

Septal involvement

6 (20%)

Patchy inflammation***

20 (67%)

Note: when considering only the fibro-fatty variant, values are * 78%; ** 78%; and *** 100%; LV left ventricle; RV right ventricle

involvement of the ventricular septum with fibrous scars is rare, and the left ventricle may have fibro-fat-ty or fibrous scars at the mid-outer layers of the free wall. In most severe, long-standing forms, biventricular pump failure may lead to biatrial enlargement, atrial fibrillation, and thrombosis of the atrial appendages.

Based upon the prevalent type of tissue accompanying the progressive myocardial atrophy, two histopathologic variants have been identified, namely fatty and fibro-fatty ARVC/D [3, 4]. In the fatty (or lipomatous) variant, the adipose tissue reaches the endocardium (transmural infiltration) and the wall thickness may be normal or even increased ("pseudo-hypertrophy") (Fig. 4.4). However, a small amount of fibrous tissue, usually focal, is always present. It may be detectable only at higher magnification and can be overlooked with limited histologic sampling.

In the fibro-fatty variant, the wall is thinner, parchment-like, and translucent which accounts for the saccular aneurysms in the so-called triangle of dysplasia, a feature that should be considered pathog-nomonic of the disease.

At histology, in both variants, there is myocyte death and degeneration as well as myocardial substitution by replacement-type fibrosis and fatty tis sue, indicating an injury and repair process (Fig. 4.5). In two thirds of the cases, the fibro-fatty variant shows inflammatory cell infiltrates (CD43, CD45RO, and CD3 positive T-lymphocytes, plus some CD68 positive macrophages) associated with focal my-ocyte necrosis, all features consistent with an inflammatory pathogenesis [4,5,12]. In the setting of sporadic cases, these findings could suggest that ARVC/D is a sequela of myocarditis, like some forms of nonfamilial dilated cardiomyopathy. It is not clear whether the presence of viruses represents a cause and effect relationship or rather that the diseased myocardium is more susceptible to viral infection. Nevertheless, the inflammatory phenomenon may trigger abrupt electrical instability and cause arrhythmic death as well as lead to progression to heart failure and clinically mimic dilated cardiomyopathy [4, 7, 8, 11].

Myocardial apoptosis is another potential mechanism of myocardial cell death and atrophy and subsequent replacement by fatty or fibro-fatty tissue in ARVC/D. Apoptosis was reported both in postmortem specimens [13] and in EMB samples of ARVC/D patients [14]. In the latter report, Valente et al. [14] demonstrated the presence of apoptotic myocyte nuclei in 35% of cases and found a high apoptotic index particularly in those patients with recent

Arvc Histology

Fig.4.4 • A 28-year-old man who died suddenly at rest (fatty variant).(a) Gross view of the right ventricular free wall shows normal wall thickness with whitish appearance. (b) At histology, the almost transmural fatty tissue replacement reaches the endocardium; spots of replacement-type fibrosis are also visible (fatty variant) (Heidenhain trichrome). (c) At higher magnification, myocytolysis and fibro-fatty replacement are visible (haematoxylin-eosin)

Fig.4.4 • A 28-year-old man who died suddenly at rest (fatty variant).(a) Gross view of the right ventricular free wall shows normal wall thickness with whitish appearance. (b) At histology, the almost transmural fatty tissue replacement reaches the endocardium; spots of replacement-type fibrosis are also visible (fatty variant) (Heidenhain trichrome). (c) At higher magnification, myocytolysis and fibro-fatty replacement are visible (haematoxylin-eosin)

Heidenhain Variant

Fig.4.5 • Histologic features of ARVC/D.(a) Contraction band myocyte necrosis and mononuclear inflammatory infiltrates (haematoxylin-eosin). (b) Myocytolisis with early adipocytes and fibroblasts infiltration (haematoxylin-eosin). (c) Mature fibrous tissue and fatty tissue with inflammatory reaction (haematoxylin-eosin). (d) Islands of surviving myocytes are entrapped within fibrous and fatty tissue (Heidenhain trichrome)

Fig.4.5 • Histologic features of ARVC/D.(a) Contraction band myocyte necrosis and mononuclear inflammatory infiltrates (haematoxylin-eosin). (b) Myocytolisis with early adipocytes and fibroblasts infiltration (haematoxylin-eosin). (c) Mature fibrous tissue and fatty tissue with inflammatory reaction (haematoxylin-eosin). (d) Islands of surviving myocytes are entrapped within fibrous and fatty tissue (Heidenhain trichrome)

onset of the disease or with acute bursts of signs or symptoms.

Because inflammation and apoptosis may be triggered by several factors that have been implicated in the etiopathogenesis of ARVC/D, including genetic defects, they could both be regarded as secondary rather than primary disease mechanisms.

The general and forensic pathologist have to be aware that the diagnostic criteria for ARVC/D are not fully established. Lack of appreciation of this may lead to both over- and underdiagnosis. The gross findings for ARVC/D in the right ventricle may be minimal or even absent but the histopathol-ogy can reveal typical ARVC/D findings of fibro-fat-ty replacement, myocyte degeneration, and subepi-cardial involvement in one or even both ventricles [15,16]. Therefore, microscopic findings can be diagnostic in the absence of macroscopic abnormalities. This indicates that both ventricles should be extensively sampled histologically in all cases of sudden cardiac death.

Uhl's anomaly should be distinguished from ARVC/D [17, 18]. While this may be clinically difficult, the morphologic features of these entities are distinct. Uhl's anomaly, as described in the original report in 1952, is defined as "an almost total absence of the myocardium of the right ventricle" [17]. In this parchment-like ventricle, the epicardium is applied directly to endocardium without intervening fat. In contrast, in ARVC/D there is at least a layer of fat and fibrous tissue between the epicardial and endocardial layers. Additional features in differential diagnosis include the lack of family history, infrequency of arrhythmias, and a significantly earlier age of presentation for Uhl's anomaly in infancy.

To recapitulate, the gross and histopathological features of ARVC/D support the use of the term myocardial dystrophy, similar to that used in Duchenne's or Becker's skeletal muscle dystrophies, which are also genetically determined diseases characterized by progressive and acquired muscular atrophy replaced by exuberant fatty and fibrous tissue.

+1 0

Post a comment