Discordance Between Pre and Post Cardiac Transplant Diagnosis

Discordance Between Pre and Post Cardiac Transplant Diagnosis: Implications for Pre- and Postoperative Decision Making Annalisa Angelini, MD,* Giovanni Maria Boffa, MD,† Ugolino Livi, MD,‡ Agata Barchitta, MD,† Dino Casarotto, MD,‡ Gaetano Thiene, MD* Departments of *Pathology, †Cardiology and ‡Cardiovascular Surgery, University Medical School of Padua, Padua, Italy

11 A correct clinical diagnosis in end-stage patients undergoing cardiac transplantation may have important prognostic and therapeutic implications. A retrospective clinico-pathologic study was carried out in 257 patients who had undergone cardiac transplantation at the University of Padua. A discrepancy between clinical and pathological diagnosis was found in 20 cases (8%). Among 126 patients with the clinical diagnosis of dilated cardiomyopathy, seven were found eventually to have ischemic heart disease (IHD), five myocarditis, one arrhythmogenic right ventricular cardiomyopathy (ARVC), and one non-compacted myocardium. Among the 87 patients with clinical diagnosis of IHD, three turned out to be dilated cardiomyopathy and one granulomatous myocarditis. Among the 10 patients with the clinical diagnosis of hypertrophic-restrictive cardiomyopathy, one had ARVC and one had cardiac fibroma. Altogether, only 24.5% underwent endomyocardial biopsy (EMB) and 75% coronary angiography before transplantation. Missed diagnosis of myocarditis occurred in patients in whom EMB was not carried out. EMB and coronary angiography might be indicated routinely in patients with apparent dilated cardiomyopathy, before proceeding to cardiectomy. Cardiovasc Pathol 1999;8:17–23 © 1998 by Elsevier Science Inc.

The role of endomyocardial biopsy (EMB) for the diagnosis of disease that could ultimately lead to cardiac transplant is still rather ill defined. A question that awaits a clear answer is who on the waiting list for transplantation should undergo EMB. The suspicion of nonischemic cardiomyopathy has been so far considered as an indication for EMB (1–13), although even within this group the procedure may have a different diagnostic value (14–22). EMB is considered neither necessary nor to be performed in all the cardiomyopathies, because the histopathological features are often not specific and not present throughout the myocardium; therefore, the biopsy is considered poorly sensitive because of the risk of “sampling error”

(23). Recently, doubts have been advanced even regarding the usefulness of performing EMB in cases of suspected myocarditis (24,25) or acute heart failure (26). In the absence of a consensus on the role of EMB, it is readily understandable why this diagnostic procedure is not included among the routine exams to be performed according to the Guidelines for the Evaluation and Management of Patients with Heart Failure (26). The aim of our study was to evaluate retrospectively the diagnostic procedures carried out at the University of Padua in patients entering the waiting list for and subsequently undergoing cardiac transplantation, in order to see whether the performance of EMB may have improved the diagnostic accuracy and therefore influenced management and outcome.

Manuscript received April 10, 1998; revised July 8, 1998; accepted July 31, 1998. Address for correspondence: Gaetano Thiene, MD, Cardiovascular Pathology, Institute of Pathological Anatomy, Via A. Gabelli, 61, 35121 Padova, Italy. Tel: 139 049-8272283; Fax: 139 049-8272284; E-mail: cardpath@ ux1.unipd.it

Materials and Methods

Cardiovascular Pathology Vol. 8, No. 1, January/February 1999:17–23  1998 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010

We reviewed the clinical and pathologic findings of the 257 orthotopic heart transplants performed at our institution from November 1985 to February 1994.

1054-8807/99/$–see front matter PII S1054-8807(98)00026-X

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Table 1. Cardiac Disease Requiring Transplantation (November 85–February 94) Clinical Diagnosis (%)

Pathological Diagnosis

Cardiac Disease

n

n

(%)

Dilated cardiomyopathy Ischemic heart disease Valvular disease Hypertrophic-restrictive cardiomyopathy Congenital heart disease Arrhythmogenic right ventricular cardiomyopathy Neoplasm Graft failure Active myocarditis Total

126 87 21 10 6

49.0 33.8 8.1 3.9 2.4

115 90 21 8 7

48.8 35.0 8.1 3.1 2.7

1 1 3 2 257

0.4 0.4 1.2 0.8 100

3 2 3 8 257

1.2 0.8 1.2 3.1 100

Indication for transplant was given because of end-stage heart failure, after the following clinical diagnosis had been achieved: dilated cardiomyopathy (126 patients), ischemic heart disease (IHD) (87 patients), valvular heart disease (21 patients), hypertrophic-restrictive cardiomyopathy (10 patients), congenital heart disease (6 patients), arrhythmogenic right ventricular cardiomyopathy (ARVC) (1 patient), neoplasm (1 patient), graft failure (3 patients), active myocarditis (2 patients) (see Table 1).

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The procedures by which clinical diagnosis had been accomplished are indicated in Figure 1. Diagnosis and indication for cardiac transplantation were achieved either at the Department of Cardiology in Padua or elsewhere, our institution being one of the referral centers for cardiac transplantation in northern Italy. Two-dimensional echocardiography was performed in all the patients. Cardiac catheterization was carried out in all but two patients (one baby girl with a cardiac fibroma and an adult male with sudden congestive heart failure). Sixteen patients had only a right heart catheterization and two of them had EMB. Two hundred thirtynine patients had right and left heart catheterization; of them, 202 (79%) had coronary angiography, whereas 37 did not. In the former group 52 patients underwent EMB, in the latter group only 9 patients. Thus, an overall number of 63 patients (24.5%) underwent EMB. The pathological study of all the hearts removed at transplantation consisted of gross and histologic examination. The hearts were fixed in formalin. Three transmural, 3-cm long blocks of ordinary myocardium from left and right ventricles and ventricular septum were obtained from each heart and embedded in paraffin. Sections were stained with hematoxilin and eosin (HE), Azan Mallory, elastic-Van Gieson, congo red. Sections from the coronary arteries were histologically studied when a lesion was found at gross examination through serial transverse cuts. Obstructive atherosclerotic coronary artery disease was diagnosed when at least one major coronary artery pre-

Figure 1. Procedures by which clinical diagnosis was achieved.

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Table 2. Discrepancy Between Clinical and Pathological Diagnosis Clinical Total

Pathological Concordant

Pathological Discordant

126 (100%) 87 (100%) 10 (100%)

112 (88%) 83 (95%) 8 (80%)

14 (12%) 4 (5%) 2 (20%)

Cardiac Disease Dilated cardiomyopathy Ischemic heart disease Hypertrophic-restrictive cardiomyopathy

sented at histology with cross-sectional narrowing .70%. The term “obstructive” plaque, should be considered simply a histologically, high-degree stenosis and not necessarily a “critical lesion” (27). The diagnosis of myocarditis was made by applying the Dallas criteria (28). Immunohistochemical studies were performed in order to characterize the inflammatory infiltrate and in the presence of tumors. The following monoclonal antibodies were used: CD45 (DAKO, diluition 1:20), CD43 (CLONAB, 1:40), CD45RO (DAKO, 1:100), CD20 (DAKO, 1:100), CD68 (DAKO, 1:50), Mac 387 (DAKO, 1:100), Factor VIII-related antigen (DAKO, 1:300), vimentin (DAKO, 1:50), desmin (DAKO, 1:50), alfa-actin (DAKO, 1:50). The avidinbiotin-peroxidase complex was used as detection system.

Statistics Differences between concordant and discordant diagnosis were evaluated by means of Fisher’s exact test. Five percent difference was considered statistically significant.

Results A discordance between clinical and pathological diagnosis emerged in 20 out of 257 cases (8%) (see Tables 2 and 3). Of the 126 patients in whom the clinical diagnosis of dilated cardiomyopathy was achieved, 112 (88%) presented with a concordant pathological diagnosis, while 14 (12%) did not (Table 2). Of these, seven patients turned out to have an ischemic heart disease with proximal obstructive coro-

Table 3. Patients with a Discordant Diagnosis Number

Age

Clinical Diagnosis

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

39 42 39 58 59 68 50 39 42 39 58 59 20 15 49

Dilated cardiomyopathy Dilated cardiomyopathy Dilated cardiomyopathy Dilated cardiomyopathy Dilated cardiomyopathy Dilated cardiomyopathy Dilated cardiomyopathy Dilated cardiomyopathy Dilated cardiomyopathy Dilated cardiomyopathy Dilated cardiomyopathy Dilated cardiomyopathy Dilated cardiomyopathy Dilated cardiomyopathy Ischemic heart disease

16

39

Ischemic heart disease

17

52

Ischemic heart disease

18

54

Ischemic heart disease

19

41

20

40

Hypertrophic-restrictive cardiomyopathy Hypertrophic-restrictive cardiomyopathy

Pathological Diagnosis

Cardiac Catheter

Endomiocardial Biopsy

Coronary Angiography

Ischemic heart disease Ischemic heart disease Ischemic heart disease Ischemic heart disease Ischemic heart disease Ischemic heart disease Ischemic heart disease Myocarditis Myocarditis Myocarditis Myocarditis Myocarditis Arrhythmogenic RV cardiomyopathy Non-compacted myocardium Dilated cardiomyopathy, left ventricular aneurysms Sarcoid myocarditis, left ventricular aneurysm Dilated cardiomyopathy, left ventricular aneurysms Dilated cardiomyopathy, left ventricular aneurysms Arrhythmogenic RV cardiomyopathy

Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes

No No No No No No No No No No No No Yes Yes No

Yes Yes No Yes No No Yes No No No No No Yes Yes Yes

Yes

No

Yes

Yes

No

Yes

Yes

No

Yes

Yes

Yes

Yes

Cardiac fibroma

No

No

No

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Figure 2. Obstructive atherosclerotic lesion of the proximal descending coronary artery in a 68year-old male patient with clinical diagnosis of dilated cardiomyopathy and no pretransplant coronary angiography. (Hematoxylin-eosin, 312.)

nary artery disease, in the setting of mild to moderate myocardial damage (Figure 2), five patients had myocarditis (Figure 3), one had ARVC, and another one a congenital heart disease (non-compacted myocardium). Of the 87 patients with a clinical diagnosis of IHD, 83 (95%) showed a concordant pathological diagnosis, while four (5%) did not.

Of these, the final pathological diagnosis was dilated cardiomyopathy in three and sarcoid myocarditis in one (Figure 4), all with ventricular aneurysms. Of the 10 patients with a clinical diagnosis of hypertrophic-restrictive cardiomyopathy, eight (80%) had a concordant diagnosis while two (20%) did not: one showed ARVC and one had cardiac fibroma.

Figure 3. Lymphocytic myocarditis in a 39-year-old man with a clinical diagnosis of dilated cardiomyopathy, which was put forward in the absence of pre-transplant endomyocardial biopsy. Hematoxylin-eosin, 360.)

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Figure 4. Sarcoid myocarditis in a 39-year-old female patient who was clinically diagnosed as affected by ischemic heart disease, despite the normal coronary angiography, because of the presence of left ventricular aneurysm. Pre-transplant endomyocardial biopsy was not performed. (Hematoxylin-eosin, 360.)

The review of the diagnostic work-up, performed in all the transplanted patients in order to identify possible source of error, led to the following results (Table 4).

Dilated Cardiomyopathy (126 Cases) Among the 112 patients with a concordant pathological diagnosis, right and left cardiac catheterization was performed

in 100 patients (89%) associated with coronary angiography in 80 patients (71%) and with EMB in 45 patients (37%). Eleven patients (10%) underwent right catheterization and EMB was performed only in one of them. One patient was transplanted solely on the basis of echocardiographic evaluation. Of the group of 14 patients with a discordant diagnosis, all had a cardiac catheterization but coronary angiogra-

Table 4. Procedures Performed in the Setting of Concordant and Discordant Diagnosis in Relation to the Different Pathology Concordant Diagnosis

Dilated Cardiomyopathy LRCath Rcath ECHO Total Ischemic Heart Disease LRCath Rcath ECHO Total Hypertrophic-Restrictive Cardiomyopathy LRCath Rcath ECHO Total

100 11 1 112

Discordant Diagnosis

EMB

COR

45 1 – 46 (37.5%)a

80 – – 80 (71%)

14 – – 14

EMB

COR

2 – – 2 (14%)a

6 – – 6 (43%)

82 1 – 83

4 – – 4 (5%)

77 – – 77 (93%)

4 – – 4

1 – – 1

4 – – 4

7 1 – 8

5 1 – 6 (75%)

4 – – 4 (50%)

1 – 1 2

1 – – 1 (50%)

– – – –

Abbreviations: COR 5 coronary angiography; ECHO 5 echocardiogram; EMB 5 endomyocardial biopsy; LRCath 5 left and right catheterization; Rcath 5 right cardiac catheterization. a p 5 0.004.

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phy was performed in 6 (43%) and EMB in two (14%) (p 5 0.004 vs concordant diagnostic group). Of the seven cases with the final pathological diagnosis of IHD, four had a coronary angiography; among the five patients in whom the pathological diagnosis merged into myocarditis, none had undergone EMB (Table 3).

IHD (87 Cases) Among the 83 (95%) patients with a concordant diagnosis, right and left cardiac catheterization was performed in 82 patients (99%) associated with coronary angiography in 77 (93%) and EMB in four (5%). One patient underwent only a right catheterization. Of the four patients with a discordant diagnosis, none had EMB and all underwent coronary angiography (Table 3).

Hypertrophic-Restrictive Cardiomyopathy (10 Cases) Of the eight patients (80%) with a concordant diagnosis, right and left cardiac catheterization was performed in seven (87.5%) associated with coronary angiography in four (50%) and EMB in five (62.5%); only one had right catheterization with EMB. Of the two patients with a discordant diagnosis, both had left and right catheterization with EMB in one disclosing remarkable fibrosis; in this patient the ultimate diagnosis was ARVC, while in the other one, a 42 year old female with final pathological diagnosis of cardiac fibroma of the interventricular septum, disproportional thickening of the ventricular septum had been misinterpreted as asymmetric hypertrophic cardiomyopathy.

Discussion Our results show that in 8% of cardiac transplanted patients at our institution from 1985 to 1994 there was a discordance between the pre-transplant clinical diagnosis and the pathological diagnosis achieved after transplant. An even higher discrepancy was recently reported by Bortman et al. (29). These findings are of utmost importance, taking into consideration the way that an incorrect diagnosis of a hereditary disorder discovered on pathological examination may have implications for the family of the recipient. The highest percentage of discordance was found in the group of dilated cardiomyopathy, and was mainly attributable to misdiagnosed IHD and myocarditis. Interestingly, the pathologic diagnosis of IHD was missed, although a coronary angiography had been performed in four of the seven misdiagnosed patients, because of underestimated coronary artery disease. These patients, because of proximal site of obstructive coronary lesion and presence of enough viable myocardium, might have been potentially amenable to surgical revascularization as an alternative to transplant. Among the five patients with post-transplant diagnosis of myocarditis, none had undergone EMB, which would have increased

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the chance of achieving a correct diagnosis. We do not agree with Davies and Ward (23) who deny the usefulness of performing EMB in myocarditis. If this may be true for focal myocarditis, which is mainly clinically characterized by arrhythmias or could mimic IHD, this is not the case of diffuse involvement of the myocardium, which may lead to cardiac dilatation and end-stage heart failure, as is the case of patients requiring transplantation. The achievement of a correct diagnosis of myocarditis is mandatory, first because of the possibility of an alternative therapeutic option through immunosuppressive therapy, even though the data from the Multicenter Myocarditis Trial did not show demonstrable therapeutic benefit for immunosuppression in cases of active myocarditis (24,25). Moreover, patients with myocarditis have also a high chance of more severe and frequent rejections as well as of recurrence of native disease (30). Other data in favor of pre-transplant cardiac biopsy emerge also from the analysis of our four patients with a clinical diagnosis of IHD. This diagnosis was put forward because of the presence of aneurysms of the left ventricle, despite angiographic evidence of apparently normal coronary arteries or no critical stenosis. These patients were transplanted for medically refractory heart failure, so it would not really matter if they had IHD or not, since transplant would have been the treatment of choice. Nonetheless, the definitive histopathologic diagnosis was dilated cardiomyopathy with left ventricular aneurysms in three cases, and sarcoid myocarditis in the other. In the latter case, a study of other organs would have been also indicated, as sarcoidosis is a systemic disease with secondary localization in the cardiac muscle, and immunosuppression might have constituted an alternative medical therapy to transplantation, even though immunosuppression in sarcoid heart disease entails the risk of promoting aneurysm formation (31). From our experience, it emerges that in patients with heart muscle disease there was an excessive diagnostic discordance that might have been avoided in part by performing EMB. McKenna and Davies (25) think that there are good reasons not to perform cardiac biopsies with conventional histologic staining to diagnose acute myocarditis in patients with heart failure of recent onset. On the other hand, Mason and O’Connel (12) recognized the clinical merit of EMB and, accordingly, we agree with the recommendations of the AHA Scientific Council Special Report on Heart Transplantation (2) which in the setting of nonischemic dilated cardiomyopathy consider EMB an indication to prove or exclude the presence of active lymphocytic myocarditis or to confirm or exclude other potentially reversible causes of heart failure, such as hemochromatosis or conditions that may represent a contraindication to heart transplantation, such as amyloidosis. Thus, our suggestion is that, whenever heart muscle disease is suspected, EMB may be indicated to increase the diagnostic accuracy, to avoid unnecessary orthotopic cardiac transplant, and to obtain a better management of trans-

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planted patients. This aspect is important in the light of the donor shortage and the possible alternative therapeutic options to heart transplantation. If fact, in the cases which turned out to be IHD, a coronary revascularization might have been performed while in the cases diagnosed as myocarditis, immunosuppressive therapy, as well as conservative approaches, such as temporary mechanical ventricular assistance or heterotopic transplantation, might have been attempted to allow the recovery of contractile function. This paper was supported by Veneto Region–Venice, and by MURST– Rome, Italy.

14.

15.

16.

17.

18.

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