Example of student autopsy report
SUMMARY OF CLINICAL
HISTORY:
The patient was a 66 year old hypertensive white male with a
history of orthotopic heart transplantation for severe ischemic heart
disease. His immuno-suppressive regimen
consisted of FK-506, Imuran, and Prednisone.
Endomyocardial biopsies one, two and six months after transplantation
showed no rejection. His
post-transplant course was complicated by recurrent cytomegalovirus (CMV)
enteritis, treated with gancyclovir.
Nine months after transplantation he presented to the hospital with
anorexia and weight loss. CT scan of
the abdomen showed circumferential thickening of the terminal ileum and
duodenum. Endoscopic biopsy showed
polymorphic B cell lymphoma; bone marrow biopsy was negative for lymphoma. He was treated with Rituxan anti-CD20
polyclonal antibody, and the FK-506 was discontinued, with apparent remission
of his lymphoma by CT scan. Three
months later, he had developed clinical signs of heart failure, including
pleural effusion (cytology and cultures negative) and it was felt that
allograft function was declining.
Endomyocardial biopsies eleven and 14 months post-transplant showed mild
to moderate acute cellular rejection.
Fifteen months post-transplant, the patient was admitted to
the SICU at UTMB with complaints of malaise, anorexia, and abdominal pain for
3-4 days. On physical exam, he was
afebrile with systolic blood pressures in the 60’s and heart rates in the 40’s. There was right upper quadrant pain on
palpation. Ultrasound of the
gallbladder showed thickening of the wall and pericholecystic fluid
collection. The clinical impression was
sepsis due to acute cholecystitis. At
23:00 on the same day, the patient became pulseless and cyanotic. CPR was initiated and the patient was
intubated. After 24 hours resuscitation
and IV antibiotics, a laparoscopic cholecystectomy was performed for suspected
acute cholecystitis. Pathology showed
chronic cholecystitis and cultures from the blood and gallbladder were
negative. During the subsequent
hospitalization, the patient’s heart function deteriorated, with EKG revealing
second degree heart block (Mobitz I), low voltage QRS, and T wave inversions
anteriorly. Echocardiogram revealed an
ejection fraction of 25-30%. He
required intermittent intra-aortic balloon pump support and pressors. He developed acute renal insufficiency (BUN
60 mg/dl and creatinine 3.28 mg/dl) thought to be due to cardiogenic
shock. He was re-started on
FK-506. A Hickman catheter was placed
in the right subclavian vein for long term IV access, and he was discharged to
home hospice after his cardiovascular status was stabilized. He died 3 days later. A limited autopsy was performed
approximately 6 hours after death.
DESCRIPTION OF GROSS LESIONS
EXTERNAL EXAMINATION: The body is that of a 66 year old well
developed, well nourished male. There
is no peripheral edema of the extremities.
There is extensive ecchymosis and hemorrhage around the shoulders, the
left inguinal region, and both arms.
There is hemorrhage of the conjunctiva of the right eye. A well healed, 21 cm median sternotomy scar
is seen.
INTERNAL EXAMINATION (BODY CAVITIES)
The right pleural cavity contains 700 cc of clear yellow
fluid. The left pleural cavity is
obliterated by dense fibrous adhesions.
The pericardial sac shows surgical changes and fibrosis. There are 600 cc of clear straw colored
fluid in the peritoneal cavity.
HEART: The patient
is status post orthotopic heart transplant, with intact and unremarkable
surgical anastomoses at the left and right atria, pulmonary trunk, and
aorta. The allograft heart is enlarged
and globular in shape, weighing 600 gm (normal male 270-360 gm). The pericardium is fibrotic and adherent to
the heart. The epicardial fat is firm
diffusely. A section of myocardium is
stained with TTC to identify acute necrosis, but no distinct lesions are
seen. The remaining myocardium is
red-brown with a somewhat mottled appearance.
The endocardium is white, with several petechiae. A thickened, white area of endocardium is
seen in the right ventricle, indicating possible previous biopsy sites. The left ventricle is 1.8 cm thick (normal
1-1.8 cm) and the right ventricle is 0.3 cm thick (normal 0.25-0.3 cm). The valves are normal, with delicate cusps
and leaflets. The foramen ovale is
closed. The coronary circulation is
left dominant. The coronary arteries
reveal only mild atherosclerosis, with a maximum of 30% stenosis by
plaque. There is an occlusive red
thrombus in the right coronary artery, 2.5 cm distal to its ostium; there is no
associated underlying atherosclerotic plaque.
AORTA: There are
severe atherosclerotic changes with ulcerated, calcified plaques in the
abdominal aorta.
LUNGS: The combined
weight of the lungs is 1950 gm (normal male 820 gm). The lung parenchyma is dark red, and foamy fluid exudes from the
cut surface. The bronchi are
normal. Several small peripheral
thromboemboli are found in pulmonary artery branches.
GASTROINTESTINAL SYSTEM: The esophagus has several discrete,
“punched out” appearing oval ulcers, measuring up to 1.5 cm in maximal
dimension. The stomach is grossly
normal, with no evidence of tumor or ulcer.
Two large ulcers with thickened edges are seen in the duodenum, near the
ampulla of Vater. These measure 2.0-2.5
cm in maximal dimension. The pancreas
shows a normal lobular cut surface. A
2.6 cm diameter firm nodule is seen within the wall of the jejunum. A 1.2 cm diameter, irregular ulcer is seen
in the terminal ileum. The large
intestine shows numerous diverticula.
The appendix is present and unremarkable. The liver weighs 1930 gm (normal male 1400-1900 gm) and has a cut
surface with alternating dark and light areas, resembling a nutmeg pattern of
chronic passive congestion. There is no
significant fibrosis grossly. The
gallbladder is surgically absent. A 2.5
cm diameter ill-defined area of induration with central purulent material is
seen in the soft tissue at the surgical site near the porta hepatis.
RETICULOENDOTHELIAL SYSTEM: The spleen is slightly enlarged,
weighing 250 gm (normal 125-195 gm).
The spleen is firm, and cut surface reveals a 0.5x 0.4x 0.3 cm
wedge-shaped pale area of infarction.
Lymph nodes throughout the body are grossly unremarkable.
GENITOURINARY SYSTEM:
The right kidney weighs 150 gm and the left weighs 140 gm
(normal 125-170 gm). There is a 1 cm
diameter white, firm nodule in the left renal cortex. The bladder and ureters are normal. The prostate is not enlarged.
ENDOCRINE SYSTEM:
The adrenal glands have normal conformation and
position. The thyroid gland is not
examined because of limitations of the autopsy.
MICROSCOPIC
DESCRIPTION
HEART AND CORONARY ARTERIES: Within the myocardium, there
are many areas where myocytes have been destroyed and replaced by granulation
tissue. A few areas of wavy fibers are
seen, indicating acute ischemic necrosis.
No lymphocytes are seen in the myocardial interstitium and there is no
acute cellular rejection. No viral
inclusions are seen. Arterioles are
normal. However large epicardial
coronary arteries show marked concentric thickening of the intima by pale
slightly blue staining connective tissue.
A layer of fibrin is seen lining the endothelium. The right coronary artery contains an
occlusive thrombus, with no evidence of fibroblast ingrowth. A few lymphocytes are seen within the media
and intima of the vessels. These
changes indicate severe vascular rejection.
LUNGS: There is a
moderate amount of proteinaceous fluid within alveoli (edema). Alveolar capillaries are markedly
congested. Scattered type II
pneumocytes are enlarged with prominent basophilic nuclear inclusions,
indicating cytomegalovirus (CMV) cytopathic effect.
LIVER: There is
marked centrilobular congestion with sinusoidal dilatation and hepatocyte
atrophy.
SPLEEN: An area of
coagulation necrosis is seen, which is surrounded by hemorrhage. The amount of white pulp is diminished.
SOFT TISSUE AT PORTA HEPATIS: Sections show fibroadipose
tissue with liquefactive necrosis with numerous neutrophils and surrounding
fibrosis (abscess). There are numerous
pseudohyphae, consistent with candida species, seen on silver stained sections.
ESOPHAGUS: There are
numerous ulcers with infiltration of lymphocytes and neutrophils at the
base. Numerous cells with CMV
inclusions are seen in the submucosa.
NODULE IN JEJUNUM: The nodule consists of ectopic pancreatic
tissue that shows chronic inflammation and fibrosis. Numerous CMV-inclusion bearing cells are seen within the ectopic
pancreas.
DUODENUM: Several
deep ulcers are seen, with chronic inflammation (lymphocytes) and numerous CMV
inclusions in fibroblasts at the ulcer bases.
No lymphoma is seen.
ULCER IN ILEUM: Sections show inflammation and CMV
infection.
KIDNEYS: The nodule
in the left kidney is composed of amorphous necrotic debris with surrounding
fibrosis and numerous hemosiderin-laden macrophages. Special stains are negative for bacteria, acid fast bacilli, and
fungi.
CLINICOPATHOLOGIC CORRELATION:
This patient died 18 months after cardiac transplantation
for severe ischemic heart disease.
The autopsy showed severe vascular rejection in the
allograft. This form of rejection is
characterized by vasculitis, endotheliitis, and fibrinoid necrosis of arteries
and arterioles with superimposed thrombosis.
Because of these vascular changes, there were innumerable foci of
ischemic necrosis of varying ages within both ventricles. This led to severe heart dysfunction, with
chronic passive congestion of the lungs and liver. The presenting symptoms and signs of hypotension and right upper
quadrant abdominal pain likely resulted from heart failure with chronic passive
congestion of the liver, rather than sepsis and acute cholecystitis. The cause of death is heart failure due to
acute vascular rejection.
This form of rejection differs from acute cellular
rejection, in which myocytes are attacked by lymphocytes. Endomyocardial biopsy can detect acute
cellular rejection, but not acute vascular rejection, since blood vessels are
not sampled. This could explain the
discrepancy between the patient’s worsening graft function and the appearance
of only mild rejection by biopsy.
Infectious complications may supervene in patients with
immunosuppression post transplantation.
CMV had been a problem for this patient in his post-transplant
course. At autopsy, there was
disseminated CMV infection, involving the lungs, esophagus, duodenum, jejunum,
ileum, and ectopic pancreas within the jejunum. There was no evidence of lymphoma in the gastrointestinal tract
or elsewhere at autopsy. An additional
infection found at autopsy was candida infection of the cholecystectomy
site. This infection likely started
after the cholecystectomy; this opinion is based on the negative surgical
pathology and culture results from the cholecystectomy. Also, the histologic appearance of the
lesion is consistent with the nearly 3 week interval between surgery and
death. A necrotic nodule was found in
the kidney, but the cause of this could not be determined. There were several small peripheral
thromboemboli in the pulmonary vasculature, but these probably did not play a
major role in his demise.
Diverticulosis of the colon was an incidental finding.
In summary, this patient died of heart failure from severe
acute vascular rejection of his cardiac allograft. Contributing factors included disseminated CMV infection. The manner of death is natural.
BASIC SCIENCE QUESTION:
WHAT ARE THE IMMUNOLOGIC MECHANISMS OF VASCULAR REJECTION?
The most typical pattern of rejection in cardiac allografts
is acute cellular rejection, characterized by myocardial infiltration by
lymphocytes; it is this pattern of cellular rejection that is assessed in
endomyocardial biopsies (1). However,
it has been increasingly recognized that in some patients, allograft failure is
due to vascular rejection, characterized histologically by endothelial and
vascular wall inflammation, ultimately leading to accelerated graft
atherosclerosis. This form of rejection
may occur in the absence of acute cellular rejection (2). Whereas acute cellular rejection is believed
to represent T cell-mediated attack against alloantigens on myocytes, vascular
rejection has been associated with deposition of immunoglobulin and complement
in vessel walls, hence it is the hypothesized result of humoral immune attack
against vessel wall structures (2). The
pathogenesis of vascular rejection is not understood, but anti-donor
antibodies, as against HLA antigens, have been implicated (3). This would imply a type II hypersensitivity
mechanism. Binding of antibody to donor
vessel wall (endothelial) antigens would lead to activation of complement by
the classical pathway. Complement
activation in turn leads to lysis of membranes by membrane attack complex
assembly, and to recruitment of inflammatory cells (neutrophils) by
anaphylotoxins C3a and C5a. It is
interesting that an association has been reported between CMV infection and the
development of anti-endothelial antibodies (4). Although these authors did not show a relationship between
anti-endothelial antibodies and vascular rejection, it seems possible that such
antibodies could cause vascular damage by the mechanisms described above. This scenario may well have been important
in this patient’s course.
In addition to evidence suggesting the involvement of
humoral mechanisms in vascular rejection, a recent study of cardiac allografts
from autopsy revealed a pattern of vascular rejection suggestive of T-cell
mediated immune attack directed against smooth muscle cells of the media of
epicardial and intramyocardial arteries (5).
In approximately half the patients studied with vascular rejection, T
cell infiltrates as well as immunoglobulin and complement deposits were
identified in vessel walls. However,
these deposits were seen in the media of the arteries, rather than the intima,
as reported by others. These
observations suggest that vascular smooth muscle cells may be a target for both
humoral and cellular immune mechanisms of rejection. In this study, the presence of vasculitis did not correlate with
the intensity of cellular rejection in the myocardium. These authors suggest that evidence of
medial lymphocytic vasculitis in endomyocardial biopsies is indicative of
diffuse vascular involvement that is likely to involve epicardial vessels, and
may warrant increased immunosuppression, even in the absence of acute cellular
rejection.
In summary, it appears that both humoral and cellular
mechanisms may be involved in the distinct pattern of vascular rejection in
cardiac allografts.
1.
Billingham, ME et
al. A working formulation for
the standardization of nomenclature in the diagnosis of heart and lung
rejection. J Heart Transpl 9:587 (1990)
2.
Hammond, EH et
al. Vascular rejection and its
relationship to allograft coronary artery disease. Journal of Heart and Lung Transplantation. 11:S111-9
(1992).
3.
McCarthy JF, et al.
Vascular rejection and its relationship to allograft coronary artery
disease. Transplant Proc 31:160 (1999)
4.
Toyoda M et
al. Cytomegalovirus infection
induces anti-endothelial cell antibodies in cardiac and renal allograft
recipients. Transplant Immunol 5:104-11 (1997)
5.
Higuchi M et
al. Histological evidence of
concomitant intramyocardial and epicardial vasculitis in necropsied heart
allografts: A possible relationship
with graft coronary arteriosclerosis.
Transplantation 67:1569-1576
(1999).
