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Nonbacterial thrombotic endocarditis in patients with malignant neoplastic diseases
Nonbacterial Thrombotic Endocarditis in Patients with Malignant Neoplastic Diseases
PETER ROSEN, DONALD
M.D.
ARMSTRONG,
M.D.
New York, New York
Seventy-five patients with malignant neoplastic disease and nonbacterial thrombotic endocarditis (NBTE) were studied. The over-all frequency of NBTE was double that observed in other reported autopsy series not limited to patients with cancer. The incidence in autopsy patients with bronchiolar and adenocarcinoma of the lung was twice that of patients with pancreatic and prostatic adenocarcinoma and seven times that of patients with breast cancer. The development of NBTE could not be ascribed to duration of illness or nutritional state. Since 14 patients died of cerebral infarcts and five had major myocardial infarcts resulting from thromboemboli, these and other complications of NBTE should be anticipated particularly in patients with those cancers most often associated with vegetative endocarditis. Although considered an incidental autopsy finding for many years, nonbacterial thrombotic endocarditis (NBTE) is now recognized as a significant cause of morbidity or death [1,4]. NBTE usually develops as a complication of another illness which is often due to a malignant neoplasm. Most recent reports of NBTE describe patients from a general autopsy population and are limited in the number of cancer patients
studied
[3-61
or are
cific types of neoplasms cause emphasis on the
restricted
[2,7,8]. treatment
to patients
with
spe-
This study was initiated beof patients with neoplastic
diseases at Memorial Hospital affords an opportunity to examine clinical and pathologic aspects of NBTE in an unusually large group of patients who were treated for cancer in a single institution. MATERIALS
AND
METHODS
The autopsy records of Memorial Hospital from 1956 through 1971 were reviewed. Vegetative endocarditis was confirmed in 100 or 1.2 per cent of 7,840 autopsies performed during these 16 years. The study includes three patients with NBTE of one valve and infective endocarditis of a second valve, but excludes 25 other patients who From the Department of Pathology and the infectious Disease Service of the Department of Medicine, Memorial Hospital, New York, New York 10021. Requests for reprints should be addressed to Dr. Peter Rosen, Department of Pathology, Memorial Hospital, 444 East 66th Street, New York, New York 10021. Manuscript received May 12, 1972; revised June 13,1972.
had only infective A diagnosis composed inflamed,
endocarditis. of NBTE
was
largely of platelets nonulcerated valve
accepted
when
there
and fibrin on one leaflet. Thrombi
organization were included if microorganisms were by special stains and there was no acute inflammatory Seventy-five well
as the
cases autopsy
January
1973
were protocol,
included
in
were
reviewed
The American
this
was
or more showing
unof
not demonstrated reaction.
study. in each
Journal of Medicine
a vegetation than one evidence
All
slides,
instance.
Volume 54
as Car-
23
NONBACTERIAL
TABLE
I
THROMBOTIC
ENDOCARDITIS-ROSEN,
Age and Sex Distribution Patients with NBTE
ARMSTRONG
of 75
Sex
Aae (Decades)
Male
Female
<20 21-31 31-40 41-50 51-60 61-70 71-80 81+
0 3 1 8 10 8 4 0
0 1 5 7 9 13 5 1
Total
34
41
cinemas
were
classified
by
study
of sections
stained
The majority of adenocarcinemas were characterized by secretion confined to tumor cells or glands. Mutinous adenocarcinomas featuring large pools of extracellular or extraglandular secretion were not found with particular frequency in any organ. Clinical observations are based on the hospital charts and summaries of the clinical records which form part of the autopsy report. with
hematoxylin
and
eosin.
RESULTS
Annual Incidence. The average annual incidence of NBTE in the autopsy population was 0.9 per TABLE II
Classification of Primary Disease and Relative Incidence of NBTE in 75 Patients
Autopsies
with NBTE
Frequency of NBTE
(no.)
(no.)
(%)
Patients Type and Primary Site of Cancer Bronchiolar carcinoma of the lung Adenocarcinoma of the lung Adenocarcinoma of the pancreas Adenocarcinoma of the prostate Epidermoid carcinoma of the cervix or vagina Hodgkin’s disease Adenocarcinoma of the breast
116
9
7.7
112
8
7.1
136
5
3.7
136
4
3.0
308 401
7 5
2.2 1.2
243
14
1.1
NOTE: In the following the number of cases was considered too few to determine incidence. There were three cases each of epidermoid carcinoma.of the urinary bladder and adenocarcinoma of the colon; two cases each of adenocarcinoma of the ovary and stomach, and liver cell carcinoma; and single cases of choriocarcinoma, chronic myelogenous leukemia, renal cell carcinoma, adenocarcinoma of the uterus and cervix, macroglobulinemia, lymphosarcoma, embryonal carcinoma of the testis, malignant melanoma, epidermoid carcinoma of the esophagus and larynx.
24
January
1973
The American Journal of Medicine
cent, ranging from 0.4 per cent in 1956 to 1.7 per cent in 1971. Forty-four per cent of the cases occurred in the first eight years and 70 per cent in the first 12 years. By comparison, 61 per cent of the 26 cases of infective endocarditis developed in the first eight years and 79 per cent in the first 12 years. Age and Sex Distribution. The distribution of patients according to age and sex is presented in Table I. All were adults and two-thirds were 51 years old or more at the time of death. Forty-nine of the 75 patients Primary Disease. (66 per cent) had adenocarcinoma. Hepatocellular, renal ceil and testicular embryonal carcinomas were not included among the adenocarcinomatous neoplasms. Pulmonary adenocarcinoma and bronchiolar carcinoma combined to form the single largest group of cancers by site of origin (17 patients, Table I I). Of these 17 patients 14 were men with an average age of 51 years and three were women with an average age of 42 years. Also presented in Table II is the frequency of certain neoplastic diseases among the 7,840 patients examined at autopsy from 1956 through 1971. The incidence of NBTE in autopsy patients with pulmonary adenocarcinoma (7.1 per cent) and bronchiolar carcinoma (7.7 per cent) was seven times that of patients with adenocarcinoma of the breast and double that of patients with adenocarcinoma of the pancreas. The only groups of patients who did not have adenocarcinoma and yet had an incidence of NBTE of 1 per cent or more were those with epidermoid carcinoma of the cervix or vagina (2.2 per cent) and those with Hodgkin’s disease (1.2 per cent). Duration of Terminal Illness. Thirty-three patients were ill for less than a year and 52 died within two years of the diagnosis of cancer. The patients who survived five years or more included five women with breast cancer, three with cancer of the cervix or vagina and two patients with pulmonary adenocarcinoma. Nutritional State. Fourteen patients were described as obese and 16 as having a good or normal nutritional state at death. In 36 patients (48 per cent) there was evidence of moderate to severe wasting. Information was incomplete in nine (12 per cent). Infections. Twelve episodes of bacteremia during the terminal illness were documented by cultures before death. The bacteria isolated are listed in Table I I I. Included in this group are the three patients with coexistent infective and NBTE. All patients were treated with appropriate antibiotics. In
Volume 54
NONBACTERIAL
two, cultures after initiation of treatment were sterile. The most common infections leading to bacteremia were pneumonia, pyelonephritis and soft tissue abscesses. Blood cultures obtained antemortem in another 10 patients with major infections were sterile. Thrombocytopenia. Thrombocytopenia (less than 60,000 platelets/mm3) was documented in 10 patients. Most of these patients as well as a number of others had varying degrees of pancytopenia related to therapy and the effects of their primary disease. However, the abrupt appearance of thrombocytopenia in four patients was associated clinically with thrombotic or embolic episodes. Murmurs became audible in two of these patients for the first time during their had no cardiac murmurs.
illness.
The other
two
ing the
last
month
of life.
TABLE III
Both
patients
had
ana-
ENOOCAROITIS-ROSEN.
ARMSTRONG
Bacteremia Documeirted by Antemortem Blood Culture in 75 Patients with NBTE Microorganism
Patients(no.)
Staph. aureus coagulase positive* Esch. coli Pr. mirabilis and Alcaligenes faecalis*t Klebsiella Nonhemolytic streptococci Enterococcus
4 4 1 1 1 1
* Includes patients with coexistent infective and nonbacterial endocarditis. ‘f Both bacteria isolated during same episode of bacteremia. tomic evidence of healed involving aortic and mitral imposed NBTE at autopsy. New
Associated Heart Disease. Four patients were said to have a history of rheumatic heart disease although two of them had no valvular lesions other than NBTE. The third patient had changes in the mitral valve consistent with old rheumatic disease and the fourth had healed rheumatic valvulitis of the mitral and aortic valves. Five other patients had lesions consistent with healed rheumatic valvulitis although rheumatic heart disease was not described in their clinical histories. Two also had some degree of aortic valve sclerosis. NBTE was present on the scarred valves. For purposes of this study a heart was considered hypertrophic when its weight was greater than 450 g in men and 350 g in women. Three of six patients with documented systemic hypertension had cardiac hypertrophy, as did an additional 21 patients (8 men and 13 women). Three of this latter group had healed rheumatic valvulitis, and in three severe coronary artery atherosclerosis appeared to be responsible for hypertrophy. Cardiac Murmurs. Heart murmurs were described in 25 patients with NBTE. In 12 the duration of the murmur either was not indicated or was present from two months to several years prior to death without change. These murmurs were most commonly described as soft systolic sounds which were prominent at the left sternal border and were sometimes transmitted to the apex. Two patients with rheumatic heart disease had diastolic murmurs and a patient with hypertension had an aortic systolic murmur. In 3 of these 12 patients congestive heart failure developed terminally. Changes in well documented long-standing cardiac murmurs were observed in two patients dur-
THROMBOTIC
murmurs
were
heard
rheumatic valvulitis valves with superfor the
first
time
in
11 other patients during the last month of life. In three of these, systolic murmurs were heard transiently; in the others they persisted without a recorded change once recognized. All but one of these persistent murmurs were heard during systole. As a group these heart sounds did not differ from those which were present for months or years prior to death in other patients. Three of these patients died of cerebral emboli from NBTE and one of myocardial infarction. Three of the patients with murmurs were severely anemic (hemoglobin 7 g/100 ml or less). Since four other patients with equally severe anemia did not have murmurs there seems to have been no systematic association between anemia and murmurs. Two of the three patients with separate suppurative and nonbacterial thrombotic valvular diseases also had murmurs. These appeared in association with positive blood cultures and presumably were related to the infected lesion. Structural Changes in Valves. Evaluation of altered valve structure in these patients was limited due to the retrospective nature of the study. Those valves which had gross features consistent with healed rheumatic valvulitis or scarring associated with atherosclerosis showed the most severe fibrosis microscopically. Calcification was observed in 10 cases. Some degree of organization was present in one or more vegetations in 25 patients. Usually this consisted only of fibroblastic proliferation in the basal portion of the verruca but in two patients at least half of the thrombus showed evidence of organization. Fibronodular changes in the adjacent or underlying valve substance were found in 37 patients. This was usually accompanied by an increase in the cellularity of the valve. Myocyte-
January 1973
The American Journal of Medicine
Volume 54
25
NONBACTERIAL THROMBOTIC ENDOCARDITIS-ROSEN.
Distribution Involvement
TABLE IV
ARMSTRONG
of Arterial Emboli by Organ in 75 Patients with NBTE Type of Lesion (no. of cases)
Gross Infarct
Organ Involved
36 30 16 13 2 1 1 ... ... 1 1
Spleen Kidney Brain Heart Liver Adrenal gland Pancreas Thyroid gland Pituitary gland Extremities Intestine
Microthrombi Without Gross Infarct
... 2
... 7 1 2 2 1 1
like cells were present in seven of these patients in the valve stroma. Bizarre, giant fibroblasts were observed at the junction of the valve and organizing verruca in four patients. In 44 patients (59 per Distribution of NBTE. cent) the lesion was limited to the mitral valve. In another 21 patients (28 per cent) the mitral thrombus was coexistent with NBTE involving at least one other valve. One woman had quadrivalvular NBTE and this was the only instance in which the pulmonic valve was involved. NBTE was limited to the aortic valve in nine patients (12 per cent). Whether present on one or multiple valves, NBTE usually consisted of two or more verrucae on the involved valve. Solitary vegetations occurred on eight mitral valves, two aortic valves and one tricuspid valve. Sixty-five patients had NBTE of the mitral valve. In 26 both leaflets were involved. Lesions conTABLE V
Cause of Death Due to Brain Lesions in Patients with NBTE Cause
No.
Distribution of cerebral emboli with infarction Right mid-cerebral artery Left mid-cerebral artery Right posterior cerebral artery Left occipital artery Subarachnoid hemorrhage Cerebral metastases with hemorrhage Cerebral metastases Meningitis Arteriosclerotic intracranial hemorrhage Brain not examined Total
26
21
-
January 1973
4 7 2 1 1 1 1 1 1 2
The American
Journal of Medicine
fined to the anterior leaflet were present in eight, and they were limited to the posterior leaflet in another five. In 26 patients, specific distribution was not indicated. The size of mitral lesions varied from 2 to 15 mm in maximum dimension with an average of 6 mm. There was no tendency for larger thrombi to occur more often on either the anterior or posterior mitral leaflet. The average maximal size of 28 aortic valve thrombi was 6.5 mm. In 10 patients each of the three cusps was involved. Distribution of Thrombotic and Emboiic Lesions. Twenty patients had gross evidence of venous thrombosis at the time of autopsy. The order of frequency of the primary sites of adenocarcinoma in this group was approximately the same as in the entire population of the study. No pattern of thrombosis was associated with a particular type of neoplasm. The most frequent sites of thrombosis were the prostatic veins and inferior vena cava, but many other vessels were also involved. Extrapulmonary venous thrombosis was recorded in eight of nine patients with pulmonary emboli and infarction. Seven of 12 patients who had pulmonary microemboli but no infarction had gross thrombosis of major systemic veins elsewhere in the body. Nine of 15 patients found to have thrombophlebitis during life had venous thrombosis of one lower extremity at autopsy. Three other patients had thrombophlebitis of an arm and in two patients migratory involvement of the extremities was observed. Thrombophlebitis was not the initial symptom in any patient, although three were found to have thrombophlebitis at the time a diagnosis of cancer was established. Many of the patients with thrombophlebitis had malignant pulmonary lesions. There were four with adenocarcinoma and two with bronchiolar types of carcinoma. Three of the remaining nine patients had malignant neoplasms other than adenocarcinoma. The distribution of systemic arterial emboli is presented in Table IV. When microthrombi were identified in association with infarction, the lesion was listed as a gross infarct. Cause of Death. In 21 patients death was a direct consequence of cerebral lesions, 14 of which were infarcts resulting from emboli to the brain (Table V). In half of these patients the diagnosis of embolic infarction was suspected clinically and in most it was proved by arteriography. No patient recovered from an episode of cerebral infarction. Only three of these patients had had clinically apparent peripheral venous thrombosis or thrombophlebitis. Other deaths attributable to intracranial
Volume 54
NONBACTERIAL
TABLE VI
Incidence
of NBTE in Selected
Rohner Bryan Rosen,
Robbins
et al. [2] [5] Armstrong
* Includes
unspecified
ARMSTRONG
Autopsy Populations Patients with
Patients with Cancer and NBTE
Total Autopsies (ho.)
(ho.)
(ho.)
Unspecified
General*
18,486
78
27
...
1947-1965
General*
6,459
16
7
...
(78,:8:486) 0.25 (16/6,459)
1950-1967
General*
15,000
63
30
...
0.2 (30/15,000)
1956-1971
Cancer
7,840
75
75
0.96 (75/7,840)
Years
[4]
ENDOCARDITIS-ROSEN.
Type of Patient Population
Reference
MacDonald,
THROMBOTIC
numbers
of cancer
NBTE
Incidence of NBTE (%) Cancer Patients
General Patients
...
patients.
lesions are also listed in Table V. Two patients had definite evidence of a major cerebral lesion but examination of the brain was not permitted. Seven patients died as a result of cardiac disease. Five had major myocardial infarcts resulting from arterial emboli. Smaller areas of infarction were present in 15 others. Review of the clinical records did not implicate the cardiac lesions as a cause of death. Congestive heart failure developed in two patients due to the effects of the vegetation on a valve distorted by rheumatic heart disease. In six patients the immediate cause of death was venous thrombosis. Three deaths were attributable to recent pulmonary emboli. Two patients went into renal failure after thrombosis of the inferior vena cava and renal veins. Extensive liver necrosis developed in one patient after portal vein thrombosis. At the time of death, cancer was no longer confined to the primary site in 68 patients. Four patients had persistent disease locally. Two women who had no residual cancer had been treated by pelvic exenteration for carcinoma of the cervix and died of pyelonephritis. COMMENTS
By comparison with most other institutions, the patient population of Memorial Hospital is unusual because of its emphasis on neoplastic disease. In the data we reviewed, nearly all the autopsies were performed on patients who had been treated for cancer. NBTE was found in 0.96 per cent of the autopsy patients and was not observed in any of the few patients who did not have cancer. We have been unable to find a prior report from a single institution limited to an equally large series of patients with neoplastic disease, but the incidence is more than double that observed in several earlier studies which described general autopsy pop-
ulations (Table VI). None of the investigators cited tabulated the number of autopsies on patients who had cancer separately, but the observations suggest that a third to a half of the cases of NBTE in a general autopsy population occur in patients with malignant neoplastic disease. The relationship of NBTE to suppurative endocarditis has received considerable attention. Angrist [6,9] has emphasized an increased frequency of NBTE and corresponding decline of infective endocarditis since the widespread introduction of antibiotics. Although the period covered by the present investigation falls within the antibiotic era, a similar trend is noted. Fifty-six per cent of the cases of NBTE were observed in the second half of the study by comparison with only 35 per cent of the cases of infective endocarditis. There have been few descriptions of NBTE in children. In their recent review Oppenheimer and Esterly [lo] reported on the frequency with which NBTE is found in children with congenital heart disease. However, in their report 3 of 27 patients had leukemia and no cardiac malformation. Since many children with leukemia and other neoplastic diseases are treated at Memorial Hospital and experience many of the same stresses and physiologic alterations related to therapy for neoplastic disease as adults, it is surprising that none of the patients in the current study fall within the pediatric age group. The emphasis on older patients suggests that factors associated with aging and neoplastic diseases peculiar to older individuals may predispose to the development of NBTE. Bryan [5] summarized 86 cases of NBTE in patients with malignant neoplasms culled from several sources and found that in decreasing order of frequency the three most common sites of neoplasms were the pancreas, stomach and lung. He did not indicate how many of the lung lesions were adenocarcinomas.
January 1973
The American Journal of Medicine
Volume 54
27
NONBACTERIAL
THROMBOTIC
ENDOCARDITIS-ROSEN,
ARMSTRONG
However a number of individual reports have noted an association with pulmonary adenocarcinoma [8,11,12]. Although previously published reports describe various numbers of patients with NBTE who had cancer of a given organ they do not indicate how many patients with each particular cancer were examined at autopsy. The relative incidence of NBTE in patients with different types of cancer has therefore not been evaluated. At this institution the incidence of NBTE was highest in patients with bronchiolar and adenocarcinema of the lung. Although patients with mammary adenocarcinoma form the second largest group with NBTE when classified by primary site, the frequency of NBTE in autopsy patients who died of breast cancer was as low as for patients with Hodgkin’s disease. The frequency of NBTE in women with epidermoid carcinoma of the cervix and vagina was double that of the patients with breast cancer. Undue importance would be attached to NBTE as a complication of mammary
so many of the patients. Although new soft murmurs may seem unimpressive [5], they should not be dismissed as entirely insignificant when they appear in patients with those types of cancer most often associated with NBTE. As one possible manifestation of disseminated intravascular coagulation, NBTE may be associated with the abrupt onset of thrombocytopenia. Four patients in this series had clinical evidence of thromboembolic lesions when thrombocytopenia was first observed. Thrombocytopenia which
ric age group is likely to be a major factor in the rarity of NBTE in children. Some form of heart disease contributed to the development of NBTE in about a third of the patients. In addition to the seven patients with rheumatic valvular scarring, three patients with systemic hypertension and three with severe coronary atherosclerosis had hypertrophied hearts. Cardiac hypertrophy of undetermined etiology was also noted in another 15 cases. Approximately two-thirds of the patients had no associated gross cardiac disease. The presence or absence of murmurs was unrelated to gross cardiac disease except for the few patients with rheumatic valvular lesions in whom the murmur was usually long standing. There was no consistent relationship of murmurs to anemia or obvious heart failure. It is surprising therefore that presumably new murmurs were heard terminally in
persisted for several weeks or months in six other patients was apparently a consequence of therapy or their primary disease. Depressed platelet levels may slow the development of NBTE, but only thrombocytopenia severe enough to be associated with bleeding would seem capable of preventing the initiation vegetative endocarditis. The over-all valvular distribution in this series does not differ significantly from that in other reports [3,4]. Three cases of combined mitral and tricuspid verrucae, and one case of quadrivalvular lesions, are unusual findings although there are no specific features by which these patients are distinguished from the general population of the study. The process by which endocardial vegetations evolve has been studied extensively [6]. The initial platelet and fibrin clot becomes organized first at the base of the lesion, a process observed in 25 of our patients. Ultimately, if healing is uncomplicated, the clot becomes collagenized and incorporated into the valve substance. The organizing clot provides an excellent meshwork for entrapment of microorganisms with the potential for subsequent suppurative endocarditis. In the current study there were seven cases in which postmortem cultures of blood and a vegetation were positive in the same patient. In these cases the vegetations were devoid of inflammatory reaction and very few or no bacteria were seen in sections. In these cases bacteremia was a late event which had resulted in bacterial contamination of the valve without an established infection. Coexistence of nonbacterial and suppurative endocarditis has been described previously [9]. The lesions may be contiguous on the same valve or may occur on separate valves as in the three patients included in this study. In all likelihood thorough study of the vegetations on a given valve would reveal further examples of coexistent lesions. Although almost all of our patients had persistent and often widespread neoplastic disease, 14
28
54
carcinoma in a study based on the number of cases of N BTE alone. Prolonged illness with marked wasting of tissues and starvation is not necessary for the development of NBTE. Many of the patients who died of complications of NBTE or other thrombotic lesions were well nourished despite persisting cancer. Death due to inanition and advanced disease would not have been expected in these patients until months or years later. It is well known that antecedent valvular lesions predispose to the development of NBTE [9]. The absence of ordinary aging changes in the pediat-
January
1973
The American
Journal
of Medicine
Volume
NONBACTERIAL THROMBOTIC ENDOCARDITIS-ROSEN,
died as a consequence of cerebral infarcts and six of complications of major venous thrombosis. In addition, fatal congestive heart failure in two patients with healed rheumatic valvulitis seems to
ARMSTRONG
have been precipitated by superimposed NBTE. Five patients died of major myocardial infarcts resuiting from embolic occlusion of coronary arteries.
REFERENCES 1.
2.
3.
Wooley CF, Baba N, Ryan JM: Nonbacterial thrombotic endocarditis. Clinical recognition. Arch Intern Med (Chicago) 125: 126, 1970. Rohner RF, Prior JT, Sipple JH: Mutinous malignancies, venous thrombosis and terminal endocarditis with emboli. A syndrome. Cancer 19: 1805, 1966. Barry WE, Scarpelli D: Nonbacterial thrombotic endocarditis. A clinicopathologic study. Arch Intern Med (Chicago) 109: 151, 1962.
4.
MacDonald RA, Robbins SL: The significance of nonbacterial thrombotic endocarditis. An autopsy and clinical study of 78 cases. Ann Intern Med 46: 255, 1957.
5.
Bryan CS: Nonbacterial thrombotic endocarditis malignant tumors. Amer J Med 46: 787, 1969.
6.
Angrist A, Oka M, Nakao K: Vegetative Path Annual 2: 155, 1967.
7.
Lafler
CJ. Hinerman
DL: A morphologic
8.
9.
10.
11.
with
endocarditis.
12.
study of pan-
January
1973
creatic carcinoma with reference to multiple thrombi. Cancer 14: 944,196l. Ray-Chaudhuri M: Non-bacterial thrombotic endocarditis in association with mucus secreting adenocarcinomas. Brit J Dis Chest 65: 98. 1971. Angrist A, Marquiss J: The changing morphologic picture of endocarditis since the advent of chemotherapy and antibiotic agents. Amer J Path 30: 39, 1954. Oppenheimer EH, Esterly JR: Nonbacterial thrombotic vegetations. Occurrence in neonate, infant and child and relation to valvular lesions in cardiac defects. Amer J Path 53: 63, 1968. Amromin GD, Wong SK: Degenerative verrucal endocardiosis and myocardial infarction: report of two cases associated with mucus-producing bronchogenic carcinoma. Ann Intern Med 50: 1519, 1959. Hoofer WD: Hypercoagulability and verrucous endocarditis associated with adenocarcinoma of the lung. Ann Thorac Surg 6: 181, 1968.
The American
Journal
of Medicine
Volume
54
29
PETER ROSEN, DONALD
M.D.
ARMSTRONG,
M.D.
New York, New York
Seventy-five patients with malignant neoplastic disease and nonbacterial thrombotic endocarditis (NBTE) were studied. The over-all frequency of NBTE was double that observed in other reported autopsy series not limited to patients with cancer. The incidence in autopsy patients with bronchiolar and adenocarcinoma of the lung was twice that of patients with pancreatic and prostatic adenocarcinoma and seven times that of patients with breast cancer. The development of NBTE could not be ascribed to duration of illness or nutritional state. Since 14 patients died of cerebral infarcts and five had major myocardial infarcts resulting from thromboemboli, these and other complications of NBTE should be anticipated particularly in patients with those cancers most often associated with vegetative endocarditis. Although considered an incidental autopsy finding for many years, nonbacterial thrombotic endocarditis (NBTE) is now recognized as a significant cause of morbidity or death [1,4]. NBTE usually develops as a complication of another illness which is often due to a malignant neoplasm. Most recent reports of NBTE describe patients from a general autopsy population and are limited in the number of cancer patients
studied
[3-61
or are
cific types of neoplasms cause emphasis on the
restricted
[2,7,8]. treatment
to patients
with
spe-
This study was initiated beof patients with neoplastic
diseases at Memorial Hospital affords an opportunity to examine clinical and pathologic aspects of NBTE in an unusually large group of patients who were treated for cancer in a single institution. MATERIALS
AND
METHODS
The autopsy records of Memorial Hospital from 1956 through 1971 were reviewed. Vegetative endocarditis was confirmed in 100 or 1.2 per cent of 7,840 autopsies performed during these 16 years. The study includes three patients with NBTE of one valve and infective endocarditis of a second valve, but excludes 25 other patients who From the Department of Pathology and the infectious Disease Service of the Department of Medicine, Memorial Hospital, New York, New York 10021. Requests for reprints should be addressed to Dr. Peter Rosen, Department of Pathology, Memorial Hospital, 444 East 66th Street, New York, New York 10021. Manuscript received May 12, 1972; revised June 13,1972.
had only infective A diagnosis composed inflamed,
endocarditis. of NBTE
was
largely of platelets nonulcerated valve
accepted
when
there
and fibrin on one leaflet. Thrombi
organization were included if microorganisms were by special stains and there was no acute inflammatory Seventy-five well
as the
cases autopsy
January
1973
were protocol,
included
in
were
reviewed
The American
this
was
or more showing
unof
not demonstrated reaction.
study. in each
Journal of Medicine
a vegetation than one evidence
All
slides,
instance.
Volume 54
as Car-
23
NONBACTERIAL
TABLE
I
THROMBOTIC
ENDOCARDITIS-ROSEN,
Age and Sex Distribution Patients with NBTE
ARMSTRONG
of 75
Sex
Aae (Decades)
Male
Female
<20 21-31 31-40 41-50 51-60 61-70 71-80 81+
0 3 1 8 10 8 4 0
0 1 5 7 9 13 5 1
Total
34
41
cinemas
were
classified
by
study
of sections
stained
The majority of adenocarcinemas were characterized by secretion confined to tumor cells or glands. Mutinous adenocarcinomas featuring large pools of extracellular or extraglandular secretion were not found with particular frequency in any organ. Clinical observations are based on the hospital charts and summaries of the clinical records which form part of the autopsy report. with
hematoxylin
and
eosin.
RESULTS
Annual Incidence. The average annual incidence of NBTE in the autopsy population was 0.9 per TABLE II
Classification of Primary Disease and Relative Incidence of NBTE in 75 Patients
Autopsies
with NBTE
Frequency of NBTE
(no.)
(no.)
(%)
Patients Type and Primary Site of Cancer Bronchiolar carcinoma of the lung Adenocarcinoma of the lung Adenocarcinoma of the pancreas Adenocarcinoma of the prostate Epidermoid carcinoma of the cervix or vagina Hodgkin’s disease Adenocarcinoma of the breast
116
9
7.7
112
8
7.1
136
5
3.7
136
4
3.0
308 401
7 5
2.2 1.2
243
14
1.1
NOTE: In the following the number of cases was considered too few to determine incidence. There were three cases each of epidermoid carcinoma.of the urinary bladder and adenocarcinoma of the colon; two cases each of adenocarcinoma of the ovary and stomach, and liver cell carcinoma; and single cases of choriocarcinoma, chronic myelogenous leukemia, renal cell carcinoma, adenocarcinoma of the uterus and cervix, macroglobulinemia, lymphosarcoma, embryonal carcinoma of the testis, malignant melanoma, epidermoid carcinoma of the esophagus and larynx.
24
January
1973
The American Journal of Medicine
cent, ranging from 0.4 per cent in 1956 to 1.7 per cent in 1971. Forty-four per cent of the cases occurred in the first eight years and 70 per cent in the first 12 years. By comparison, 61 per cent of the 26 cases of infective endocarditis developed in the first eight years and 79 per cent in the first 12 years. Age and Sex Distribution. The distribution of patients according to age and sex is presented in Table I. All were adults and two-thirds were 51 years old or more at the time of death. Forty-nine of the 75 patients Primary Disease. (66 per cent) had adenocarcinoma. Hepatocellular, renal ceil and testicular embryonal carcinomas were not included among the adenocarcinomatous neoplasms. Pulmonary adenocarcinoma and bronchiolar carcinoma combined to form the single largest group of cancers by site of origin (17 patients, Table I I). Of these 17 patients 14 were men with an average age of 51 years and three were women with an average age of 42 years. Also presented in Table II is the frequency of certain neoplastic diseases among the 7,840 patients examined at autopsy from 1956 through 1971. The incidence of NBTE in autopsy patients with pulmonary adenocarcinoma (7.1 per cent) and bronchiolar carcinoma (7.7 per cent) was seven times that of patients with adenocarcinoma of the breast and double that of patients with adenocarcinoma of the pancreas. The only groups of patients who did not have adenocarcinoma and yet had an incidence of NBTE of 1 per cent or more were those with epidermoid carcinoma of the cervix or vagina (2.2 per cent) and those with Hodgkin’s disease (1.2 per cent). Duration of Terminal Illness. Thirty-three patients were ill for less than a year and 52 died within two years of the diagnosis of cancer. The patients who survived five years or more included five women with breast cancer, three with cancer of the cervix or vagina and two patients with pulmonary adenocarcinoma. Nutritional State. Fourteen patients were described as obese and 16 as having a good or normal nutritional state at death. In 36 patients (48 per cent) there was evidence of moderate to severe wasting. Information was incomplete in nine (12 per cent). Infections. Twelve episodes of bacteremia during the terminal illness were documented by cultures before death. The bacteria isolated are listed in Table I I I. Included in this group are the three patients with coexistent infective and NBTE. All patients were treated with appropriate antibiotics. In
Volume 54
NONBACTERIAL
two, cultures after initiation of treatment were sterile. The most common infections leading to bacteremia were pneumonia, pyelonephritis and soft tissue abscesses. Blood cultures obtained antemortem in another 10 patients with major infections were sterile. Thrombocytopenia. Thrombocytopenia (less than 60,000 platelets/mm3) was documented in 10 patients. Most of these patients as well as a number of others had varying degrees of pancytopenia related to therapy and the effects of their primary disease. However, the abrupt appearance of thrombocytopenia in four patients was associated clinically with thrombotic or embolic episodes. Murmurs became audible in two of these patients for the first time during their had no cardiac murmurs.
illness.
The other
two
ing the
last
month
of life.
TABLE III
Both
patients
had
ana-
ENOOCAROITIS-ROSEN.
ARMSTRONG
Bacteremia Documeirted by Antemortem Blood Culture in 75 Patients with NBTE Microorganism
Patients(no.)
Staph. aureus coagulase positive* Esch. coli Pr. mirabilis and Alcaligenes faecalis*t Klebsiella Nonhemolytic streptococci Enterococcus
4 4 1 1 1 1
* Includes patients with coexistent infective and nonbacterial endocarditis. ‘f Both bacteria isolated during same episode of bacteremia. tomic evidence of healed involving aortic and mitral imposed NBTE at autopsy. New
Associated Heart Disease. Four patients were said to have a history of rheumatic heart disease although two of them had no valvular lesions other than NBTE. The third patient had changes in the mitral valve consistent with old rheumatic disease and the fourth had healed rheumatic valvulitis of the mitral and aortic valves. Five other patients had lesions consistent with healed rheumatic valvulitis although rheumatic heart disease was not described in their clinical histories. Two also had some degree of aortic valve sclerosis. NBTE was present on the scarred valves. For purposes of this study a heart was considered hypertrophic when its weight was greater than 450 g in men and 350 g in women. Three of six patients with documented systemic hypertension had cardiac hypertrophy, as did an additional 21 patients (8 men and 13 women). Three of this latter group had healed rheumatic valvulitis, and in three severe coronary artery atherosclerosis appeared to be responsible for hypertrophy. Cardiac Murmurs. Heart murmurs were described in 25 patients with NBTE. In 12 the duration of the murmur either was not indicated or was present from two months to several years prior to death without change. These murmurs were most commonly described as soft systolic sounds which were prominent at the left sternal border and were sometimes transmitted to the apex. Two patients with rheumatic heart disease had diastolic murmurs and a patient with hypertension had an aortic systolic murmur. In 3 of these 12 patients congestive heart failure developed terminally. Changes in well documented long-standing cardiac murmurs were observed in two patients dur-
THROMBOTIC
murmurs
were
heard
rheumatic valvulitis valves with superfor the
first
time
in
11 other patients during the last month of life. In three of these, systolic murmurs were heard transiently; in the others they persisted without a recorded change once recognized. All but one of these persistent murmurs were heard during systole. As a group these heart sounds did not differ from those which were present for months or years prior to death in other patients. Three of these patients died of cerebral emboli from NBTE and one of myocardial infarction. Three of the patients with murmurs were severely anemic (hemoglobin 7 g/100 ml or less). Since four other patients with equally severe anemia did not have murmurs there seems to have been no systematic association between anemia and murmurs. Two of the three patients with separate suppurative and nonbacterial thrombotic valvular diseases also had murmurs. These appeared in association with positive blood cultures and presumably were related to the infected lesion. Structural Changes in Valves. Evaluation of altered valve structure in these patients was limited due to the retrospective nature of the study. Those valves which had gross features consistent with healed rheumatic valvulitis or scarring associated with atherosclerosis showed the most severe fibrosis microscopically. Calcification was observed in 10 cases. Some degree of organization was present in one or more vegetations in 25 patients. Usually this consisted only of fibroblastic proliferation in the basal portion of the verruca but in two patients at least half of the thrombus showed evidence of organization. Fibronodular changes in the adjacent or underlying valve substance were found in 37 patients. This was usually accompanied by an increase in the cellularity of the valve. Myocyte-
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25
NONBACTERIAL THROMBOTIC ENDOCARDITIS-ROSEN.
Distribution Involvement
TABLE IV
ARMSTRONG
of Arterial Emboli by Organ in 75 Patients with NBTE Type of Lesion (no. of cases)
Gross Infarct
Organ Involved
36 30 16 13 2 1 1 ... ... 1 1
Spleen Kidney Brain Heart Liver Adrenal gland Pancreas Thyroid gland Pituitary gland Extremities Intestine
Microthrombi Without Gross Infarct
... 2
... 7 1 2 2 1 1
like cells were present in seven of these patients in the valve stroma. Bizarre, giant fibroblasts were observed at the junction of the valve and organizing verruca in four patients. In 44 patients (59 per Distribution of NBTE. cent) the lesion was limited to the mitral valve. In another 21 patients (28 per cent) the mitral thrombus was coexistent with NBTE involving at least one other valve. One woman had quadrivalvular NBTE and this was the only instance in which the pulmonic valve was involved. NBTE was limited to the aortic valve in nine patients (12 per cent). Whether present on one or multiple valves, NBTE usually consisted of two or more verrucae on the involved valve. Solitary vegetations occurred on eight mitral valves, two aortic valves and one tricuspid valve. Sixty-five patients had NBTE of the mitral valve. In 26 both leaflets were involved. Lesions conTABLE V
Cause of Death Due to Brain Lesions in Patients with NBTE Cause
No.
Distribution of cerebral emboli with infarction Right mid-cerebral artery Left mid-cerebral artery Right posterior cerebral artery Left occipital artery Subarachnoid hemorrhage Cerebral metastases with hemorrhage Cerebral metastases Meningitis Arteriosclerotic intracranial hemorrhage Brain not examined Total
26
21
-
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4 7 2 1 1 1 1 1 1 2
The American
Journal of Medicine
fined to the anterior leaflet were present in eight, and they were limited to the posterior leaflet in another five. In 26 patients, specific distribution was not indicated. The size of mitral lesions varied from 2 to 15 mm in maximum dimension with an average of 6 mm. There was no tendency for larger thrombi to occur more often on either the anterior or posterior mitral leaflet. The average maximal size of 28 aortic valve thrombi was 6.5 mm. In 10 patients each of the three cusps was involved. Distribution of Thrombotic and Emboiic Lesions. Twenty patients had gross evidence of venous thrombosis at the time of autopsy. The order of frequency of the primary sites of adenocarcinoma in this group was approximately the same as in the entire population of the study. No pattern of thrombosis was associated with a particular type of neoplasm. The most frequent sites of thrombosis were the prostatic veins and inferior vena cava, but many other vessels were also involved. Extrapulmonary venous thrombosis was recorded in eight of nine patients with pulmonary emboli and infarction. Seven of 12 patients who had pulmonary microemboli but no infarction had gross thrombosis of major systemic veins elsewhere in the body. Nine of 15 patients found to have thrombophlebitis during life had venous thrombosis of one lower extremity at autopsy. Three other patients had thrombophlebitis of an arm and in two patients migratory involvement of the extremities was observed. Thrombophlebitis was not the initial symptom in any patient, although three were found to have thrombophlebitis at the time a diagnosis of cancer was established. Many of the patients with thrombophlebitis had malignant pulmonary lesions. There were four with adenocarcinoma and two with bronchiolar types of carcinoma. Three of the remaining nine patients had malignant neoplasms other than adenocarcinoma. The distribution of systemic arterial emboli is presented in Table IV. When microthrombi were identified in association with infarction, the lesion was listed as a gross infarct. Cause of Death. In 21 patients death was a direct consequence of cerebral lesions, 14 of which were infarcts resulting from emboli to the brain (Table V). In half of these patients the diagnosis of embolic infarction was suspected clinically and in most it was proved by arteriography. No patient recovered from an episode of cerebral infarction. Only three of these patients had had clinically apparent peripheral venous thrombosis or thrombophlebitis. Other deaths attributable to intracranial
Volume 54
NONBACTERIAL
TABLE VI
Incidence
of NBTE in Selected
Rohner Bryan Rosen,
Robbins
et al. [2] [5] Armstrong
* Includes
unspecified
ARMSTRONG
Autopsy Populations Patients with
Patients with Cancer and NBTE
Total Autopsies (ho.)
(ho.)
(ho.)
Unspecified
General*
18,486
78
27
...
1947-1965
General*
6,459
16
7
...
(78,:8:486) 0.25 (16/6,459)
1950-1967
General*
15,000
63
30
...
0.2 (30/15,000)
1956-1971
Cancer
7,840
75
75
0.96 (75/7,840)
Years
[4]
ENDOCARDITIS-ROSEN.
Type of Patient Population
Reference
MacDonald,
THROMBOTIC
numbers
of cancer
NBTE
Incidence of NBTE (%) Cancer Patients
General Patients
...
patients.
lesions are also listed in Table V. Two patients had definite evidence of a major cerebral lesion but examination of the brain was not permitted. Seven patients died as a result of cardiac disease. Five had major myocardial infarcts resulting from arterial emboli. Smaller areas of infarction were present in 15 others. Review of the clinical records did not implicate the cardiac lesions as a cause of death. Congestive heart failure developed in two patients due to the effects of the vegetation on a valve distorted by rheumatic heart disease. In six patients the immediate cause of death was venous thrombosis. Three deaths were attributable to recent pulmonary emboli. Two patients went into renal failure after thrombosis of the inferior vena cava and renal veins. Extensive liver necrosis developed in one patient after portal vein thrombosis. At the time of death, cancer was no longer confined to the primary site in 68 patients. Four patients had persistent disease locally. Two women who had no residual cancer had been treated by pelvic exenteration for carcinoma of the cervix and died of pyelonephritis. COMMENTS
By comparison with most other institutions, the patient population of Memorial Hospital is unusual because of its emphasis on neoplastic disease. In the data we reviewed, nearly all the autopsies were performed on patients who had been treated for cancer. NBTE was found in 0.96 per cent of the autopsy patients and was not observed in any of the few patients who did not have cancer. We have been unable to find a prior report from a single institution limited to an equally large series of patients with neoplastic disease, but the incidence is more than double that observed in several earlier studies which described general autopsy pop-
ulations (Table VI). None of the investigators cited tabulated the number of autopsies on patients who had cancer separately, but the observations suggest that a third to a half of the cases of NBTE in a general autopsy population occur in patients with malignant neoplastic disease. The relationship of NBTE to suppurative endocarditis has received considerable attention. Angrist [6,9] has emphasized an increased frequency of NBTE and corresponding decline of infective endocarditis since the widespread introduction of antibiotics. Although the period covered by the present investigation falls within the antibiotic era, a similar trend is noted. Fifty-six per cent of the cases of NBTE were observed in the second half of the study by comparison with only 35 per cent of the cases of infective endocarditis. There have been few descriptions of NBTE in children. In their recent review Oppenheimer and Esterly [lo] reported on the frequency with which NBTE is found in children with congenital heart disease. However, in their report 3 of 27 patients had leukemia and no cardiac malformation. Since many children with leukemia and other neoplastic diseases are treated at Memorial Hospital and experience many of the same stresses and physiologic alterations related to therapy for neoplastic disease as adults, it is surprising that none of the patients in the current study fall within the pediatric age group. The emphasis on older patients suggests that factors associated with aging and neoplastic diseases peculiar to older individuals may predispose to the development of NBTE. Bryan [5] summarized 86 cases of NBTE in patients with malignant neoplasms culled from several sources and found that in decreasing order of frequency the three most common sites of neoplasms were the pancreas, stomach and lung. He did not indicate how many of the lung lesions were adenocarcinomas.
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The American Journal of Medicine
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NONBACTERIAL
THROMBOTIC
ENDOCARDITIS-ROSEN,
ARMSTRONG
However a number of individual reports have noted an association with pulmonary adenocarcinoma [8,11,12]. Although previously published reports describe various numbers of patients with NBTE who had cancer of a given organ they do not indicate how many patients with each particular cancer were examined at autopsy. The relative incidence of NBTE in patients with different types of cancer has therefore not been evaluated. At this institution the incidence of NBTE was highest in patients with bronchiolar and adenocarcinema of the lung. Although patients with mammary adenocarcinoma form the second largest group with NBTE when classified by primary site, the frequency of NBTE in autopsy patients who died of breast cancer was as low as for patients with Hodgkin’s disease. The frequency of NBTE in women with epidermoid carcinoma of the cervix and vagina was double that of the patients with breast cancer. Undue importance would be attached to NBTE as a complication of mammary
so many of the patients. Although new soft murmurs may seem unimpressive [5], they should not be dismissed as entirely insignificant when they appear in patients with those types of cancer most often associated with NBTE. As one possible manifestation of disseminated intravascular coagulation, NBTE may be associated with the abrupt onset of thrombocytopenia. Four patients in this series had clinical evidence of thromboembolic lesions when thrombocytopenia was first observed. Thrombocytopenia which
ric age group is likely to be a major factor in the rarity of NBTE in children. Some form of heart disease contributed to the development of NBTE in about a third of the patients. In addition to the seven patients with rheumatic valvular scarring, three patients with systemic hypertension and three with severe coronary atherosclerosis had hypertrophied hearts. Cardiac hypertrophy of undetermined etiology was also noted in another 15 cases. Approximately two-thirds of the patients had no associated gross cardiac disease. The presence or absence of murmurs was unrelated to gross cardiac disease except for the few patients with rheumatic valvular lesions in whom the murmur was usually long standing. There was no consistent relationship of murmurs to anemia or obvious heart failure. It is surprising therefore that presumably new murmurs were heard terminally in
persisted for several weeks or months in six other patients was apparently a consequence of therapy or their primary disease. Depressed platelet levels may slow the development of NBTE, but only thrombocytopenia severe enough to be associated with bleeding would seem capable of preventing the initiation vegetative endocarditis. The over-all valvular distribution in this series does not differ significantly from that in other reports [3,4]. Three cases of combined mitral and tricuspid verrucae, and one case of quadrivalvular lesions, are unusual findings although there are no specific features by which these patients are distinguished from the general population of the study. The process by which endocardial vegetations evolve has been studied extensively [6]. The initial platelet and fibrin clot becomes organized first at the base of the lesion, a process observed in 25 of our patients. Ultimately, if healing is uncomplicated, the clot becomes collagenized and incorporated into the valve substance. The organizing clot provides an excellent meshwork for entrapment of microorganisms with the potential for subsequent suppurative endocarditis. In the current study there were seven cases in which postmortem cultures of blood and a vegetation were positive in the same patient. In these cases the vegetations were devoid of inflammatory reaction and very few or no bacteria were seen in sections. In these cases bacteremia was a late event which had resulted in bacterial contamination of the valve without an established infection. Coexistence of nonbacterial and suppurative endocarditis has been described previously [9]. The lesions may be contiguous on the same valve or may occur on separate valves as in the three patients included in this study. In all likelihood thorough study of the vegetations on a given valve would reveal further examples of coexistent lesions. Although almost all of our patients had persistent and often widespread neoplastic disease, 14
28
54
carcinoma in a study based on the number of cases of N BTE alone. Prolonged illness with marked wasting of tissues and starvation is not necessary for the development of NBTE. Many of the patients who died of complications of NBTE or other thrombotic lesions were well nourished despite persisting cancer. Death due to inanition and advanced disease would not have been expected in these patients until months or years later. It is well known that antecedent valvular lesions predispose to the development of NBTE [9]. The absence of ordinary aging changes in the pediat-
January
1973
The American
Journal
of Medicine
Volume
NONBACTERIAL THROMBOTIC ENDOCARDITIS-ROSEN,
died as a consequence of cerebral infarcts and six of complications of major venous thrombosis. In addition, fatal congestive heart failure in two patients with healed rheumatic valvulitis seems to
ARMSTRONG
have been precipitated by superimposed NBTE. Five patients died of major myocardial infarcts resuiting from embolic occlusion of coronary arteries.
REFERENCES 1.
2.
3.
Wooley CF, Baba N, Ryan JM: Nonbacterial thrombotic endocarditis. Clinical recognition. Arch Intern Med (Chicago) 125: 126, 1970. Rohner RF, Prior JT, Sipple JH: Mutinous malignancies, venous thrombosis and terminal endocarditis with emboli. A syndrome. Cancer 19: 1805, 1966. Barry WE, Scarpelli D: Nonbacterial thrombotic endocarditis. A clinicopathologic study. Arch Intern Med (Chicago) 109: 151, 1962.
4.
MacDonald RA, Robbins SL: The significance of nonbacterial thrombotic endocarditis. An autopsy and clinical study of 78 cases. Ann Intern Med 46: 255, 1957.
5.
Bryan CS: Nonbacterial thrombotic endocarditis malignant tumors. Amer J Med 46: 787, 1969.
6.
Angrist A, Oka M, Nakao K: Vegetative Path Annual 2: 155, 1967.
7.
Lafler
CJ. Hinerman
DL: A morphologic
8.
9.
10.
11.
with
endocarditis.
12.
study of pan-
January
1973
creatic carcinoma with reference to multiple thrombi. Cancer 14: 944,196l. Ray-Chaudhuri M: Non-bacterial thrombotic endocarditis in association with mucus secreting adenocarcinomas. Brit J Dis Chest 65: 98. 1971. Angrist A, Marquiss J: The changing morphologic picture of endocarditis since the advent of chemotherapy and antibiotic agents. Amer J Path 30: 39, 1954. Oppenheimer EH, Esterly JR: Nonbacterial thrombotic vegetations. Occurrence in neonate, infant and child and relation to valvular lesions in cardiac defects. Amer J Path 53: 63, 1968. Amromin GD, Wong SK: Degenerative verrucal endocardiosis and myocardial infarction: report of two cases associated with mucus-producing bronchogenic carcinoma. Ann Intern Med 50: 1519, 1959. Hoofer WD: Hypercoagulability and verrucous endocarditis associated with adenocarcinoma of the lung. Ann Thorac Surg 6: 181, 1968.
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