GRANULOMATOUS REACTION TO BARIUM SULFATE IN
AND ABOUT A P P E N D I X
REPORT OF A CASE
JOSEPH MENDELOFF, M.D.
Department of Pathology, Veterans Administration Hospital and Emory University,
School of Medicine, Atlanta, Georgia
Exposure to barium sulfate occurs in miners of barium and its salts, workers
in the lithopone industry, and in patients undergoing diagnostic roentgenography
of the gastrointestinal tract. Barium sulfate dust when inhaled leads to a benign
form of pneumoconiosis (baritosis); this occurs primarily in miners and workers
in the lithopone industry. Escape of barium sulfate into the peritoneal cavity
has been reported in patients with peptic ulcers undergoing x-ray studies.
Barium granulomas have been reported in the appendix, sigmoid and peritoneum,
and rectum in patients receiving barium enemas.
KEPORT OP CASE
Clinical Data
A 43-year-old white farmer was admitted with the complaint of a dull aching in the
epigastrium, of 1 day's duration. This was followed by nausea, chill, and fever of 104 F.
He had had episodes of gastric distress during the past 15 years. On admission he was acutely
ill. Tenderness was elicited in the abdomen; this was slight in the right upper quadrant and
maximum in the right flank beneath the rib margin. Blood pressure was 130/SO, temperature
104.4 F., pulse rate 120 per minute. The leukocyte count was 11,150 with a differential count
of 88 neutrophilic polymorphonuclear leukocytes (S5 segmented, 3 bands), 10 lymphocytes,
and 2 monocytes. Urinalysis revealed no abnormal findings.
An acute exacerbation of chronic cholecystitis was regarded the most likely diagnosis
and the patient was treated with fluids, glucose, atropine, and Achromycin. Three days
after admission the clinical symptoms abated and the patient was afebrile.
Diagnostic roentgen studies of the gallbladder, upper gastrointestinal tract and an
intravenous pyelogram did not reveal any abnormal findings. A barium enema performed
2 weeks after admission revealed a retrocecal appendix.
Following those studies it was concluded that the patient had probably had an episode
of appendicitis. Since he was now symptom-free, an elective appendectomy was recommended. The patient was discharged and returned in 28 days. His only complaint during
this period was that of low back pain and several mild episodes of epigastric discomfort.
Examination revealed only some abdominal distention.
Forty-five days after the initial illness, 41 days after the first gastrointestinal series, and
31 days after the barium enema, an appendectomy was performed. The appendix was found
to be retrocecal and retroperitoneal in position. It was bound down by adhesions and the
tip was edematous and indurated. The postoperative course was uneventful.
Pathologic Findings
Grossly, the appendix measured 5.0 cm. in length and ranged from 0.6 to 1.4
cm. in diameter. The external surface was covered with shaggy nodular tissue
Received, October 29, 1955; revision received, November IS; accepted for publication
November 18.
Dr. Mcndelo/T is Chief of Laboratory Service and Assistant Professor of Pathology.
155
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MENDELOFF
Vol. 26
which contributed to the thickness. No point of perforation was demonstrable
grossly.
Microscopically, the architectural pattern of the appendix varied at different
levels. At one level there was complete destruction and replacement of the mucosa and submucosa by a dense cellular granulomatous reaction; to some degree
this process extended into the adjacent muscular coat. The cells comprising this
infiltration were predominantly lymphocytes and macrophages. To a lesser
degree there were smaller numbers of plasma cells and neutrophilic polymorphonuclear leukocytes, and occasional small multinucleated giant cells. Scattered throughout this cellular infiltration were crystals, some lying free and
others within the macrophages. The crystals were fine and granular, or took the
form of small rhomboidal plates. Some had a pale green-yellow tint. There were
some focal collections of lymphocytes and plasma cells in the muscular coat
and in the serosa. The latter also had increased vascularity and increased density of the connective tissue.
At another level only a cresentic half of the muscular coat remained. The
central portion of the appendix was occupied by a cellular granuloma similar to
that described above. Where the muscular coat was absent, the cellular reaction
extended into the periappendiceal fat and mesoappendix. Numerous crystals
were present throughout the granuloma. Nodular infiltrations were present in the
mesoappendix and periappendiceal fat; some of these were close to the appendix
and others were discrete and away from the appendix. In addition to the cellular
reaction mentioned, the latter areas had numerous giant cells of the foreignbody type. Many of the giant cells had crystalline inclusions (Figs. 1 and 2). At
some levels of the rest of the appendix the lumen was obliterated by connective
tissue and only slight components of the mucosa remained. The muscular coat
was thin in some places and hypertrophied in others.
The crystals were anisotropic with polarized light. Solutions of barium sulfate
examined with polarized light revealed crystals which were also anisotropic and
identical in size and shape with those seen in the areas of granulomatous reaction
in and about the appendix. Stains for acid-fast bacilli and fungi did not reveal
the presence of any organisms. Stains for iron revealed the presence of blue
granules in some macrophages.
Diagnosis: Barium sulfate granuloma of appendix.
DISCUSSION
The patient's initial illness was that of acute appendicitis. In view of the
clinical picture and the subsequent demonstration of the retrocecal and retroperitoneal appendix, it can be assumed that a perforation occurred into the mesoappendix, and that "walling off" was successful. This is confirmed by the histologic lesions in the mesoappendix. I t can also be deduced that barium sulfate
used in the diagnostic studies (either the upper gastrointestinal series or the
barium enema) entered the appendix and escaped into the mesoappendix and
adjacent periappendiceal fat. The resulting reaction consisted of chronic nonspecific inflammation and foreign-body granuloma. The nonspecific inflammation
Feb. 1956
157
BAKIUM SULFATE ORANULOATA
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FIG. 1 (upper). Granulomatous reaction, with giant coll containing crystalline
material.
FIG. 2 (lower). Crystalline material within and outside of macrophages and giant
cells. Hematoxylin and eosin. X 500.
is attributed to the escape of appendiceal contents, feces, and bacteria, and the
granulomatous reaction to the escape of barium sulfate. A surprising feature,
in view of the changes found, is the lack of symptoms presented by the patient
between the time of initial improvement and the time of elective appendectomy.
The appendix was removed 41 days after initial exposure to barium and 31
days after the second exposure to barium.
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Vol. 26
Histologic diagnosis was based on the finding of the extra- and intracellular
crystals. Consideration was given to the size, shape, and color of the crystals,
and the results obtained by examination with polarized light. In addition examinations of solutions of barium sulfate revealed crystals with identical characteristics.
Kay 1 ' 4 has reported 3 cases of barium sulfate granuloma. His first case was
one of a duodenal ulcer with perforation into the lesser peritoneal sac, diagnosed
by upper gastrointestinal roentgen studies. A repeat study revealed barium
spilling into the right lumbar gutter, the right upper quadrant, and pelvis. The
patient died of cardiac arrest following operation. At necropsy barium granulomas were found in the capsule of the liver. The time interval between exposure
to barium and the demonstration of the granuloma was 25 days. In the second
case the patient had diarrhea and pain in the right lower quadrant of 4 months'
duration. Studies revealed the presence of a right subdiaphragmatic abscess.
A barium enema did not reveal the presence of any radio-opaque material outside the gastrointestinal tract. The abscess was drained, but subsequently the
patient developed a fecal fistula. Repeat barium enema demonstrated an external colic fistula which had its origin in the ascending colon. At operation a
ruptured retrocecal appendix was found. The appendix had a perforation G.O
cm. from the base and the surface was covered by fibrin and granulation tissue.
Histologically there was chronic periappendicitis and a granulomatous reaction
caused in part by barium. The time interval between administration of barium
and appendectomy was 7 to 60 days. The third patient complained of abdominal
pain, constipation, and the presence of bright red blood in the stools, all of 2
months' duration. Barium enemas had been performed 53 days and 21 days
prior to admission. No abnormalities were found. On admission a small pedunculated "tumor," 1.0 cm. in size, was found on the posterior wall of the rectum,
6.0 cm. above the anal orifice. This was removed and found to consist of a small,
gray, firm nodule covered with mucosa. The time period in this case was between 25 and 42 days from exposure to barium and removal of the lesion. The
histologic findings in all 3 cases were similar. There were numerous amorphous
pale yellow anisotropic crystals set in a stroma of proliferating fibroblasts and
histiocytes. Occasional foreign-body giant cells with intracytoplasmic crystals
were present. There were slight infiltrations of lymphocytes and plasma cells.
The author concluded that barium sulfate produced a minimal fibrous tissue
and inflammatory response.
Kleinsasser and Warshaw 6 reported perforation of the sigmoid that occurred
during a barium enema. The patient had diverticulosis, anal fistulas, and a
rectal stricture. Biopsy of tissue removed 3 hours after the perforation revealed
acute and subacute inflammation at the site of the perforation. Subsequently
the patient had multiple episodes of obstruction and a fecal fistula. At the time
of subsequent operation 4 months later, granulomas and adhesions containing
barium were described in the peritoneum, but no detailed histologic description
of these lesions is included in the case report.
Earlier reports 2 - 7 of escape of barium sulfate are concerned with diagnostic
roentgen studies performed on patients with peptic ulcer. Perforations occurred
Feb. 1956
BARIUM SULFATE GRANULOMA
159
and there was escape into the peritoneal cavity. In most instances prompt surgery corrected both the peritonitis and the rupture and since no further data
were given it is assumed the patients remained well. The one exception is the
first case of Kay mentioned above.
In the report of Pendergrass and Greening6 the patient was a lithopone worker
who was exposed to inhalations of barium sulfate dust over a period of 18 years.
The patient died 12 years later of myocardial infarction. During his life he had
had no respiratory incapacity. He had, however, also been a coal miner and
examination of the lungs revealed anthracosilicosis, silica crystals, and crystals
that resembled barium sulfate. There was no particular tissue reaction to the
latter but proof of the presence of barium sulfate in the lungs was obtained by
chemical analysis, spectrograph!c and x-ray diffraction studies.
Kleinsasser and Warshaw injected barium sulfate, stool, sterile stool, or stool
and barium sulfate into the peritoneum of dogs. They concluded that moderate
amounts of barium produced no serious changes but that the complicating infection was more important. When barium sulfate only was injected all the dogs
survived except one that was listed as having died of other causes. In the remaining dogs, adhesions were encountered in only one and a barium granuloma
was found on the surface of the intestine and peritoneum. The early changes
were acute inflammation, presence of free fluid, and congestion.
Huston and co-workers3 injected barium sulfate suspensions (80 to 90 per
cent) endotracheally into rats, and the animals were sacrificed at intervals varying from 30 minutes to 72 hours; and from 7 to 126 days. At 12 to 24 hours there
was an acute inflammatory reaction. From 48 hours to 15 days there was mononuclear infiltration associated with areas of consolidation containing barium.
The mononuclear cells were packed with particles of barium. During the next
15 to 30 days the mononuclear cells disintegrated and the barium salt was set
free. Tissues studied at 94 to 120 days revealed an occasional small solid area
related to the presence of refractile masses with occasional lymphocytes, monocytes, and giant cells. There was no fibrosis.
It is evidently not correct to regard these lesions as strictly barium sulfate
granulomas. In no instance was the reaction caused by barium sulfate alone.
The conditions under which these granulomas occurred include the escape of
either gastric or fecal contents. These two components certainly elicited severe
inflammatory reactions. However, the barium sulfate did contribute to the
inflammatory reaction by superimposing the presence of both extra- and intracellular anisotropic crystals, macrophages, and giant cells. The lymphocytes,
plasma cells, monocytes, and fibroblasts presented 1 part of the complex inflammatory reaction. No organized granulomatous structures have been described nor were any seen in our patient. There is little doubt that the fecal
components contribute to the tissue reaction.
SUMMARY
A patient with acute appendicitis was given a barium enema and 31 days
later the appendix was removed. A granulomatous reaction to the barium
sulfate was found in and about the appendix. This had formed apparently as a
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result of perforation of the appendix with escape of appendiceal contents including barium sulfate.
STJMMARIO IN INTERLINGUA
Un patiente con appendicitis acute recipeva un clyster a barium e 31 dies plus
tarde le appendice esseva excidite. Esseva constatate in e circa le appendice un
reaction granulomatose al sulfato de barium. Iste reaction habeva apparentemente occurrite como resultato de un perforation del appendice que permitteva
le escappamento de materia intra le appendice, includente sulfato de barium.
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2. ECKMAN, P . F . : Acute perforation of ulcer following barium filling in routine gastrointestinal examination. Surg., Gynec. & Obst., 47: 858-860, 1928.
3. H U S T O N , J . , WALLACH, D . P . J R . , AND C U N N I N G H A M , G. J . : P u l m o n a r y reaction
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