Candidal Infection of Gastric Ulcers
Histology, Incidence, and Clinical Significance
ANNA-LUISE A. KATZENSTEIN, M.D., AND JOHN MAKSEM, M.D.
Katzenstein, Anna-Luise A., and Maksem, John: Candidal
infection of gastric ulcers: Histology, incidence, and clinical
significance. Am J Clin Pathol 71: 137-141, 1979. Fungal
organisms morphologically resembling Candida were found in
one third of 72 consecutive surgically resected gastric ulcers.
In over half of these cases the organisms were present in
the mycelial form. Large numbers of fungi forming clusters
were found in 13 cases (18%) and were associated with a surprisingly high postoperative mortality, (38.5%). These organisms are most likely one manifestation of debility in otherwise
poor-risk patients rather than a cause of the high morbidity
and mortality in these patients. Although organisms of the
Candida group are probably not directly etiologic in the development of gastric ulcers, it is possible that their presence aggravates and perpetuates gastric ulceration. (Key words: Candidiasis; Ulcer; Stomach.)
Department of Surgical Pathology, Washington University
School of Medicine, St. Louis, Missouri
All slides were stained with hematoxylin and eosin,
Gomori methenamine silver, and Gram stains. The
amounts of both bacteria and fungi were graded as
0 (absent), 1 -I- (rare), 2 + (moderate), and 3 + (marked).
The fungal form, whether yeast or mycelial, or both,
was also recorded. Although cultures were not taken,
the organisms in all cases were morphologically consistent with organisms of the Candida group.
The medical records of all 72 cases were reviewed
with respect to age, sex, race, duration and nature of
symptoms, antibiotic or steroid therapy, fever, associated diseases, and pertinent laboratory studies.
SUPERFICIAL CANDIDAL OVERGROWTH in the
gastrointestinal tract is a relatively common finding at
autopsy, especially in debilitated patients and in patients with underlying malignancy. 2 We unexpectedly,
however, found candidal infection in specimens of surgically resected gastric ulcers from several patients
without known predisposing factors to infection. This
observation prompted us to review all cases of gastric
ulcers resected during a recent 3'/i-year period in order
to assess the incidence and significance of gastric candidiasis in a surgical rather than an autopsy population.
Results
Pathology
Materials and Methods
All gastrectomy specimens coded as gastric ulcers in
the Barnes Hospital Surgical Pathology files between
January 1973 and June 1976 were reviewed. Of 117
cases identified, 45 were eliminated from the study for
various reasons, including duodenal, marginal, or
esophageal location (11), ulceration of a carcinoma or
a lymphoma (6), healed to nonexistent ulcer (19), lack
of medical records (5), and miscellaneous reasons (4).
The 72 remaining cases formed the basis of this study.
Received January 12, 1978; received revised manuscript and accepted for publication March 31, 1978.
Supported in part by PHS Grant #5 T01 CA 05201-08.
Address reprint requests to Dr. Katzenstein: Department of Pathology, Case Western Hospital, Cleveland, Ohio 44118.
All of the ulcers were active; a layer of neutrophils
and fibrin covered the base, which was composed of
granulation tissue or fibrosis. The cases were divided
into the following three groups, depending on the presence and number of fungal organisms;
Group I-no fungi identified. There were 48 ulcers
in which no fungi were found. Clusters of mixed bacteria were present on the surface of the ulcer in six
cases (12.5%).
Group II-scattered isolated fungi. In 11 ulcers rare
yeasts or pseudohyphae were scattered on the surface
of the exudate. The organisms could be seen in the
hematoxylin-and-eosin stain in only one case; the remaining required special stains. There was no invasion
by the fungi into deeper layers of the exudate. Mixed
pseudohyphal and yeast forms were found in six cases,
while only yeasts were found in five. Clusters of mixed
bacteria were present within the superficial layer of
exudate in two cases (18%).
Group Ill-numerous
fungi in clusters. Thirteen
ulcers containing numerous yeasts or pseudohyphae,
0002-9173/79/0200/0137 $00.75 © American Society of Clinical Pathologists
137
138
KATZENSTEIN AND MAKSEM
A.J.C.P. • February 1979
,»^
tew
-it*
S5.-.»*•.« A-4;
TO?*"
*
FIG. 1. Low magnification of a typical gastric ulcer from a patient in Group III showing a thick layer of acute inflammation andfibrincovering
a fibrotic base. Numerous mycelial forms can be seen in the exudate {inset), even without special stains. Hematoxylin and eosin x 150.
Inset x600.
usually arranged in clusters. The organisms were seen
with the hematoxylin-and-eosin stain in ten cases (Fig.
1), while special stains were required for their identification in three cases. A mixture of yeasts and pseudohyphae was present in nine cases, while only yeasts
were found in the remaining four. The organisms were
present within the superficial exudate in most cases, but
they invaded the deep layers of exudate and even the
superficial ulcer bed in four cases (Fig. 2). Clusters of
bacteria were present on the ulcer surface in four
cases (31%).
Clinical Findings
The major clinical findings for the three groups are
summarized in Table 1. As shown in this table, patients
with only scattered isolated fungi in their ulcers (Group
II) had clinical features similar to patients with ulcers
negative for fungi (Group I). Group III, however, differed from the other groups in several respects. There
were twice as many female subjects as male subjects in
Group III, in contrast to an approximately equal sex
ratio in the other two groups. Almost one third of patients in Group III received preoperative antibiotics,
compared to only 8% of Group I and none of Group II.
Preoperative and postoperative fevers and postoperative sepsis were more common in Group III than in the
other groups. Alcoholism and cancer were more frequent in Group III. The mortality of Group III was
greater than that for Groups I and II.
Since there was no significant difference in clinical
features whether fungi were absent (Group I) or whether
rare isolated fungi were found (Group II), these two
groups were combined for statistical comparison with
Group III. Using Fisher's exact test for two-by-two
tables,3 the high incidence of postoperative sepsis and
the high mortality of Group III were found to be statistically significant (P < .01), compared with combined
Groups I and II. The differences in preoperative antibiotic therapy and preoperative fever were highly suggestive but were not statistically significant (P > .05).
Differences in the other features were also not significant.
The relationship of mortality to duration of symptoms
is shown in Table 2. The overall percent mortality was
GASTRIC ULCER CANDIDIASIS
Vol. 71 . No. 2
generally higher for those patients presenting acutely
than for those with more chronic symptoms. Nevertheless, those patients in Group III with an acute or subacute presentation still had a higher mortality than those
patients in the other two groups presenting with similar
acute or subacute symptomatology. The numbers were
too small, however, for statistical significance. The
cause of death in most cases was a combination of
multiple factors including sepsis, pneumonia, pulmonary emboli, renal or hepatic failure. Disseminated
candidiasis was not found in any case.
Table 3 summarizes in detail the clinical feature of
individual patients in Group III. Although four patients
had received preoperative antibiotics, one had received
corticosteroids, four had an underlying malignancy,
and three were alcoholics, it is noteworthy that in five
patients in Group III none of the known predisposing
factors for candidal infection of the gastrointestinal
tract could be identified.
The postoperative courses of five patients in Group
III were complicated by bacterial sepsis. Candida albi-
139
cans, however, was cultured from the blood of only one
patient, and this patient had a central venous pressure
catheter. Yeasts (C. albicans or Candida tropicalis)
were isolated from the urine of four patients, from the
abdominal wounds of two, and from abdominal fluid of
one. In contrast, only one patient in Group II had a positive sputum culture for Candida species, and one patient
in Group I had a positive urine culture. None of the
cultures positive for Candida species were pure cultures;
all had concomitant mixed bacterial growth. In Patient 5
specimens from an endoscopic biopsy two months
before gastric resection contained numerous yeasts and
pseudohyphae.
Discussion
Although the incidence of fungal infection of the
gastrointestinal tract has been estimated to be as low as
1 in 1,000 autopsied patients from general hospitals, the
incidence is much higher from hospitals specializing in
the treatment of immunosuppressed patients.2 In a
series reported from Memorial Hospital, 13% of patients
V
A
FIG. 2. A silver-stained ulcer from a patient in Group III. (Left) Low magnification showing large numbers of mycelia and yeasts with superficial invasion into the ulcer base. Gomori methenamine silver, x 150. (Right) Higher magnification of same case showing typical morphology of
the organisms at the base of the ulcer. Gomori methenamine silver. x350.
A.J.C.P. • February 1979
KATZENSTE1N AND MAKSEM
140
Table I. Comparison of Clinical Features of Patients
in Groups I, II, and III
Males/females (ratio)
Average age (range)
Preoperative antibiotics (%)
Steroids (%)
Preoperative fever (%)
Postoperative fever (%)
Postoperative sepsis
Group I
(N = 48)
Group II
(N = 11)
Group III
(N = 13)
Duration of
Symptoms
Number of Patients
Number of Deaths (%)
22/26 (.85)
57 (23-82)
6/5 (1.2)
53 (35-84)
4/9 (.44)
63 (34-85)
0
1 (9%)
0
3 (27%)
4 (31%)
1 (7.7%)
3 (23%)
8 (62%)
0
5 (38.5%)
2 (18%)
1 (9%)
7 (64%)
8 (62%)
5 (38.5%)
0
Acute
Group I
Group II
Group III
Subacute
Group I
Group II
Group III
Chronic
Group I
Group II
Group III
24
14
2
8
15
9
1
5
29
22
7
0
6(25)
3(21)
0
3 (37.5)
2(13)
0
0
2(40)
1 (3.4)
1 (4.5)
0
0
2 (18%)
1 (9%)
lt(9%)
0
4 (31%)
3 (23%)
0
5 (38.5%)
4
5
2
19
(8.3%)
(10%)
(4.2%)
(40%)
4 (8.3%)
(%)
Duration of symptoms
Acute (<1 wk)
Subacute (1-12 wks)
Chronic (>12 wks)
Underlying diseases
Cancer
Alcoholism
Miscellaneous
Deaths (%)
Table 2. Mortality Rate Percent Related to Duration
of Symptoms in Groups I, II, and III
14 (29%)
9 (19%)
22 (46%)
0
2 (4.2%)
6*(12.5%)
4 (8.3%)
* Includes two chronic renal failure, one diabetes, one dermatomyositis, one systemic
lupus erythematosis. one rheumatoid arthritis.
t Chronic renal failure.
with hematopoietic malignancies and 1.5% of patients
with solid malignancies had gastrointestinal candidiasis
at autopsy.2 The most common sites of involvement
were the stomach and the esophagus. In disseminated
candidiasis, the gastrointestinal tract is considered the
most common portal of entry for the organisms, especially in leukemic patients.9
Ourfindingof organisms morphologically resembling
Candida in 33% of 72 consecutive resected gastric ulcers
is surprisingly high. Although candidal organisms may
be cultured from the alimentary tract of up to 50% of
healthy individuals,6 the presence of large clusters of
organisms, as in our cases, is distinctly unusual. Moreover, in over half of our cases (62.5%) mycelia, which
are considered to represent the pathogenic phase of the
organism7 were present. Invasion into the ulcer bed was
seen in four patients in Group III, although in most
cases the organisms appeared confined to the more
superficial exudate.
Most patients with gastrointestinal candidiasis re-
Table 3. Summary of Clinical Features of Patients in Group III
Patient
Duration
of Symptoms
Preoperative
Antibiotic
Therapy
Preoperative
Steroid
Therapy
Fever
Preoperative
Postoperative
Postoperative
Sepsis
Underlying Disease
Age
Race
Sex
1*
68
White
F
2 Days
Ampicillin
None
None
Present
None
None
2*
70
White
F
Hours
Keflin
Chloramphenical
None
None
None
Present
None
3*
66
Black
F
1 Month
Keflin
None
Present
Present
Present
Miliary tuberculosis,
rectal cancer
4*
34
Black
F
2 Days
None
None
None
Present
None
Thyrotoxicosis
5*
68
White
M
Several
days
Keflex, Ancef,
Kanamycin
None
None
Present
Present
Cancer of the nasopharynx, alcoholism
6
85
White
F
3 Days
None
None
Present
Present
None
None
7
67
White
F
1 Day
None
Prednisone
None
None
None
Cancer of the breast,
Hodgkin's disease
8
47
White
F
2 Months
None
None
None
Present
Present
None
9
10
11
12
13
60
66
59
62
67
Black
White
White
White
White
F
M
M
F
F
6 Weeks
Hours
2 Months
Weeks
Hours
None
None
None
None
None
None
None
None
None
None
None
Present
None
None
None
None
Present
None
Present
None
None
Present
None
Present
None
None
None
Alcoholism
Endometrial cancer
Alcoholism
* Died postoperatively.
Vol. 71 • No. 2
141
GASTRIC ULCER CANDIDIASIS
ported in autopsy series have had one or more factors
predisposing to infection, including previous antibiotic
or corticosteroid therapy, cytotoxic chemotherapy,
radiation, or underlying malignancy.210 Candidal infection of a surgically resected gastric ulcer has been recently reported in a patient with diabetes mellitus, alcoholism, and Laennec's cirrhosis.8 In contrast, no
predisposing factors to infection with Candida could be
identified in five of our 13 patients in Group III with
large numbers of organisms (Table 3). Three cases of
massive yeast overgrowth in stomach remnants following a Billroth I resection have been reported in otherwise
healthy patients.1 Although these patients had no known
predisposing factors to infection, mechanical factors
related to their previous surgery were probably responsible for their candidal infections.
Patients in Group II showed clinical features essentially identical to those in Group I; no effect related
to the presence of isolated fungal elements could be
found in this group. In contrast, patients in Group III
differed in several respects from patients in the other
two groups. The majority of patients in Group III presented acutely, having had ulcer symptoms for less than
one week. Preoperative and postoperative fevers and
postoperative sepsis were more common in Group III
than in the other groups. The most surprising finding,
however, was a significantly higher mortality in Group
III (38.5%). This finding may be partially related to the
acute presentation of many of these patients. However,
even when compared to similar patients in the other
groups who presented as acutely (Table 2), the patients
in Group III still had a higher mortality rate although
this difference was not significant. It is unlikely that the
candidal infection itself directly affected mortality, because disseminated candidiasis was not found in any
case at autopsy. A more plausible explanation is that
the fungi represent a sign of debility in a patient who is
at high risk for multiple complications.
One question raised by this study is what role, if any,
Candida has in the development of gastric ulcers. Candidal infection of gastric ulcers is common in swine, and
may be one factor in the pathogenesis of ulcers in these
animals.4,5 In our patients in Group III, the acute presentation and paucity of pre-existing ulcer symptoms argue
against long-standing candidal infection as a direct
cause of ulceration. However, it is entirely possible that
these organisms may perpetuate and aggravate preexisting ulcers. One way of studying this problem would
be to examine sequential endoscopic biopsies of gastric
ulcers for fungi. The practicality of this approach is
affirmed by the positive endoscopic biopsy in one of our
patients (Patient 5) two months before gastric resection.
It is possible that a trial of oral nonabsorbable antifungal agents may be useful both in eradicating the
organisms and, at the same time, in diminishing symptoms of the ulcer.
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yeasts in resected stomach. Gut 7:244-249, 1966
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4. Kadel WL, Kelley DC, Coles EM: Survey of yeast-like fungi
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5. Kowakzyk T: Etiologic factors of gastric ulcers in swine. Am J
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