Vol. 334
No. 13
Weekly Clinicopathological Exercises
EUGENE J. MARK, M.D., Associate Editor
WILLIAM F. MCNEELY, M.D., Associate Editor
SALLY H. EBELING, Assistant Editor
CASE 10-1996
A 36-year-old man was admitted to the hospital because of pain in the right lower quadrant of the abdomen and the lumbar region.
There was a two-year history of intermittent pain in
the right lower quadrant and right lumbar region, with
“soreness” of the right testis, which occurred frequently
during urination and less often on defecation. Twentysix months before admission an evaluation elsewhere
led to a diagnosis of prostatitis, but antibiotic therapy
was ineffective.
Five months before admission the patient came to
this hospital. He reported that his brother had hemochromatosis. The physical examination was normal except for tenderness in the right lower quadrant. The
iron-binding capacity was almost totally saturated, and
the ferritin level was 747 mg per liter. Microscopical
examination of a needle-biopsy specimen of the liver
showed moderate periportal parenchymal deposition of
iron without fibrosis, inflammation, or other abnormalities. A chemical analysis revealed 13,378 mg of iron per
gram of liver tissue (normal value, 530). Arrangements
were made for phlebotomies.
A small-bowel follow-through study (Fig. 1) was performed three months before admission. The jejunum
and ileum appeared normal with the exception of the
final 4 cm, which lacked the contours of normal mucosa. The distal portion of the terminal ileum was separated from adjacent bowel loops. Contrast material
flowed through that region into the cecum, but the
cecum appeared incompletely distended. The appendix
was not seen.
Ten weeks before admission a colonoscopic examination, performed 10 to 15 cm into the terminal ileum,
revealed a granular appearance of the distal 2 or 3 cm
of the terminal ileum, with a few small, white submu-
Figure 1. Film from the Small-Bowel Follow-through
The small bowel is normal. The cecum is separated from the terminal ileum, and the medial wall of the cecal pole is incompletely
cosal nodules within the 5-cm portion proximal to the
terminal ileum. The cecum was erythematous, with
edema, superficial erosions, and thick, blunted interhaustral folds about the base of the cecum around the
appendix. The remainder of the colon appeared normal. Microscopical examination of biopsy specimens
of the small bowel disclosed edema and focal eosinophilic infiltration. Examination of a cecal-biopsy specimen from the appendiceal area showed marked acute
and chronic inflammation consistent with ulceration
and granulation tissue, without granulomas. An ultrasonographic examination of the abdomen (Fig. 2)
showed an enlarged hypoechoic appendix (1.2 cm in
diameter). Two focal hyperechogenic areas with posterior shadowing within the appendix were interpreted as appendicoliths. The liver, common hepatic duct,
gallbladder, pancreas, kidneys, and spleen appeared
normal. A computed tomographic (CT) scan of the abdomen and pelvis (Fig. 3), obtained after the oral administration of contrast material, disclosed a tubular
soft-tissue structure that extended medially from the
cecum behind the terminal ileum. The structure was
surrounded by inflammatory changes in the mesentery.
No lymphadenopathy was seen, and the remainder of
the examination was normal. The patient was admitted to the hospital.
The patient did not smoke and consumed little alco-
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March 28, 1996
limeter, and the platelet count was 192,000 per cubic
millimeter. The mean corpuscular volume was 96 mm 3.
The prothrombin and partial-thromboplastin times
were normal, as were the urea nitrogen, creatinine,
and electrolyte concentrations. An electrocardiogram
showed a sinus bradycardia at a rate of 58 and was
within normal limits. A radiograph of the chest was
A diagnostic procedure was performed.
Figure 2. Compression Ultrasonogram Showing a Noncompressible Appendix in Cross-Section.
The appendix is 1.2 cm in diameter. Echogenic foci with posterior acoustic shadowing consistent with appendicoliths are
present in the lumen (arrows).
Figure 3. CT Scan Showing a Thickened Appendix (Arrows) Extending Medially from the Cecum, with Streaking in the Surrounding Mesenteric Fat Consistent with Inflammation.
hol. His bowel functions were normal. His father was
reported to have inflammatory bowel disease.
The temperature was 37.4C, the pulse was 100,
and the respirations were 16. The blood pressure was
145/75 mm Hg.
The physical examination was normal except for
mild tenderness in the right lower quadrant of the abdomen, without guarding or rebound tenderness. The
bowel sounds were normal, as were the genitalia.
The urine was normal. The hematocrit was 39.6
percent, the white-cell count was 5000 per cubic mil-
DR. LESLIE W. OTTINGER*: This otherwise healthy
36-year-old man had experienced pain in the right lower quadrant for two years. The sparse additional history
includes intermittent pain in the right testis, a diagnosis
of hemochromatosis documented by several tests, apparently normal bowel function throughout the illness,
and a family history of hemochromatosis and inflammatory bowel disease. There is no information about
the nature of the pain at its onset, its frequency, its radiation, or whether anything provoked or relieved it,
and except for the pain, there is no mention of intestinal symptoms, even at the onset of the illness. May we
review the radiologic studies?
follow-through examination (Fig. 1), which was performed three months before admission, shows the separation of the distal terminal ileum from the cecum,
which did not distend completely. A compression spot
view shows normal-appearing mucosa in the terminal
ileum with incomplete filling of the cecum, which is
separated from the terminal ileum. These findings are
suggestive of a mass between the cecum and the terminal ileum, probably related to the appendix, which
was not filled on this examination. The CT scan obtained just before admission (Fig. 3) shows a slight
thickening of the posterior wall of the cecum, a normal-appearing terminal ileum, and a tubular soft-tissue density extending medially from the cecum, corresponding to an enlarged appendix. There is stranding
in the periappendiceal fat. These findings are consistent with appendicitis. The compression ultrasonogram of the right lower quadrant (Fig. 2) confirms the
enlargement of the appendix, which appears as a tubular structure. It was 1.2 cm in diameter and noncompressible — features that are characteristic of appendicitis. Two echogenic foci within the lumen show
posterior acoustic shadowing suggestive of appendicoliths. Appendicoliths were not visible on the plain
film but appeared as areas of slightly increased density
on the CT scan. The radiologic findings suggested appendicitis, probably with appendicoliths and surrounding inflammation.
DR. OTTINGER: The basic question in this case is
whether the patient had an inflammatory or infiltrative
*Visiting surgeon, Massachusetts General Hospital; associate professor of surgery, Harvard Medical School.
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Vol. 334
No. 13
process involving primarily the terminal ileum and
cecum, with obstruction and secondary changes in the
appendix, or an appendiceal lesion, with secondary
changes in the terminal ileum and tip of the cecum.
The results of the upper gastrointestinal series and
small-bowel follow-through study are consistent with
either interpretation. The endoscopic findings suggest a
primary process in the mucosa of the terminal ileum
and the cecum, but the findings on the CT scan and ultrasonogram point to the appendix as the primary site
of the disease.
If the disease was a chronic process originating in
the terminal ileum and cecum, it could have been an
infection, such as yersiniosis, amebiasis, tuberculosis,
or giardiasis, or even a typhoid infection. Although the
relative absence of systemic and gastrointestinal symptoms is not consistent with any of those diagnoses,
they merit brief consideration. Yersiniosis is the most
likely infection in a patient with no history suggesting
travel outside New England. Yersinia infections are
caused by either the enterocolitica strain or the pseudotuberculosis strain. They are usually transmitted by
a fecal–oral route and less often by contaminated food
or water. The possibility of yersinia infection in this
patient is particularly interesting. Yersinia strains are
unable to absorb iron directly, not having the protein
necessary to conjugate it, and are thus dependent on
other bacteria or a host as their source of iron.1 Patients who have an excess of iron or hemochromatosis
are said to be subject to rampant yersinia infections.
Yersiniosis usually presents with acute gastroenteritis.
I have seen patients in whom the infection persisted in
a low-grade form in the cecum and terminal ileum for
a long time. Yersinia infection is therefore a possible
diagnosis in this case. Inflammatory bowel disease
and a tumor, particularly a lymphoma, involving the
terminal ileum and cecum are additional considerations, but there is nothing to support these diagnoses.
An appendiceal disease with secondary inflammation
in the ileum and cecum is the alternative possibility.
The patient had a two-year history of a disease without
systemic or gastrointestinal manifestations, and there
were no acute symptoms or signs suggesting acute appendicitis or an acute exacerbation of chronic appendicitis. Chronic obstruction of the appendix must also be
considered. The patient was thought to have two appendicoliths. Appendicoliths almost always occur singly, and when they are associated with appendiceal disease, it is usually acute appendicitis.
Could a tumor have involved the appendix? A mucinous cystadenoma or cystadenocarcinoma would be
the most likely possibility in this case. Mucinous cystadenomas, often called “mucoceles” in the past, are
sometimes associated with myxoglobulosis, a mucocele
with multiple calcified spheres in the appendiceal lumen. The ultrasonographic findings in this case are
not consistent with the presence of calcified spheres. A
mucinous tumor of the appendix may be complicated
by local perforation or periappendiceal inflammation.
However, mucoceles are usually characterized by a much
larger accumulation of mucin within the appendiceal
lumen. The imaging studies in this case suggest that
the appendiceal enlargement was due to a thickening
of the wall rather than an intraluminal accumulation of
Another possibility is chronic appendicitis, which is
probably caused by recurrent appendicitis, but there is
no evidence of recurrence in this case. Other chronic,
low-grade processes involving the wall of the appendix, such as isolated diverticulitis and regional enteritis,
should be considered, but there is also no evidence to
support these diagnoses.
In conclusion, the most logical diagnosis in this
case is a disease with an indolent course that accounts
for the periappendiceal inflammation, with impairment of lymphatic drainage of the testis, resulting in
testicular pain. I favor the diagnosis of a mucinous tumor of the appendix, even though there are few data
to support it.
DR. FIONA M. GRAEME-COOK: Dr. Schapiro, what
was your clinical impression when you saw this patient?
DR. ROBERT H. SCHAPIRO: He was referred to me
for a liver biopsy because of the history of hemochromatosis. He told me incidentally about the episodes of
abdominal discomfort. The most striking aspect of the
colonoscopic examination was the abrupt demarcation
between the area of inflammation that surrounded the
appendiceal orifice for 2 or 3 cm and the rest of the
cecum. On the basis of these observations, I suspected
that the patient had Crohn’s disease of the base of the
cecum and the appendix.
Crohn’s disease of the cecum and appendix.
Mucinous tumor of the appendix.
DR. METIN OZDEMIRLI: The diagnostic procedure
was a laparotomy, which revealed a cecal mass involving the base of the appendix. A right ileocolectomy was
performed. The resected specimen consisted of a 20cm-long segment of the ileum and a 17-cm-long segment of the right colon, with an attached appendix that
was 5 cm long. The abnormal findings were confined to
the cecum surrounding the appendiceal orifice and the
appendix. The cecum had a thickened wall, and its mucosa was congested with petechiae (Fig. 4). The appendix had a diffusely hyperemic serosa with a fibrinous
exudate and was bent into a U shape by soft fibrous adhesions. The diameter ranged from 0.6 cm at the tip to
2 cm at the base. The lumen was filled with soft hemorrhagic material, but no obstruction by a tumor, a foreign body, or parasites was seen. The wall was firm and
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had a maximal thickness of 0.5 cm; no diverticula were
Microscopical examination of the cecum revealed
nonspecific chronic inflammatory changes. The appendix had a thickened wall with transmural lymphoid aggregates, hypertrophy of the muscularis, fibrosis, and
neural hyperplasia (Fig. 5). Crypt abscesses (Fig. 6),
fissures, and erosions were present in the mucosa. Numerous small, noncaseating, sarcoid-like granulomas
were seen throughout the wall, particularly in the submucosa but also in the serosa (Fig. 7). There was acute
serositis with fibrin deposition and fibrous adhesions.
The serositis extended focally into the adjacent ileum.
There were no acute or chronic inflammatory changes
in multiple sections of the ileum and right colon. The
regional lymph nodes were reactive and also contained
sarcoid-like granulomas. Special stains for microorganisms were negative. A diagnosis of granulomatous appendicitis was made.
Chronic granulomatous appendicitis can be either
infectious or noninfectious. Mycobacterium tuberculosis,
schistosoma, and yersinia species are among the wellknown infectious causes. Infection with actinomyces and
campylobacter species, Histoplasma capsulatum, and some
parasites may also result in granulomas. Most of these
infections can be ruled out by special stains for micro-
Figure 4. Close-up View of the Ileocecal Region of the
The cecal mucosa around the appendiceal orifice is congested
with petechiae.
March 28, 1996
Figure 5. Cross Section of the Appendix (Hematoxylin and
Eosin, 35).
The wall is thickened, with transmural lymphoid aggregates and
organisms, cultures, serologic tests, and relevant clinical findings. Yersiniosis of the appendix may be indistinguishable from Crohn’s disease. In general, however,
yersinia infections occur in younger persons and often
present with mesenteric lymphadenitis. On histologic
examination, the inflammation is confined to the mucosa and submucosa, and granulomas characteristically
exhibit central necrosis and contain microabscesses.
Also, serologic tests obtained retrospectively may be
positive for yersiniosis.
Noninfectious forms of granulomatous appendicitis
include those due to foreign material, obstruction, sarcoidosis, and Crohn’s disease, as well as the idiopathic
form. Foreign material can easily be ruled out on the
basis of microscopical findings under polarized light
and the nature of the granulomatous reaction. In rare
cases, obstruction due to tumors such as mucinous neoplasms can elicit a granulomatous reaction, but tumors
should be recognizable on pathological examination.
Sarcoidosis rarely involves the appendix but is always
associated with the involvement of other organs at the
time of diagnosis.
Crohn’s disease can involve the appendix by extension from the terminal ileum or the cecum and present
as acute or subacute appendicitis. About 25 percent of
patients with ileal Crohn’s disease and 50 percent of
those with colonic Crohn’s disease have appendiceal
involvement. However, appendiceal involvement is
rarely the first manifestation of the disease. Approximately 100 cases of Crohn’s disease limited to the appendix have been reported in the English literature.2-7
These cases have usually been classified as primary
Crohn’s disease of the appendix, because the histopathological features are often very similar to those of
colonic Crohn’s disease. These features include a
thickening of the wall, panmural chronic inflammation, mucosal fissures, crypt abscesses, sarcoid-like
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Vol. 334
No. 13
Figure 6. Crypt Abscess (Right) in the Appendiceal Mucosa (Hematoxylin and Eosin, 90).
Figure 7. Noncaseating Sarcoid-like Granuloma (Right) in the
Appendiceal Submucosa (Hematoxylin and Eosin, 150).
granulomas in the wall and regional lymph nodes, and
less commonly, neural hyperplasia and lymphangiectasia.2
In 1990 Ruiz et al.3 reported three cases of presumptive Crohn’s disease limited to the appendix and reviewed 85 cases in the literature. The average age of
the patients was 24 years, and the ratio of male to female patients was 2:1. Eighty-five percent of the patients presented with pain in the right lower quadrant,
27 percent had a palpable mass, and 86 percent had
radiologic evidence of disease. In another study,
marked thickening of the appendiceal wall on radiologic studies strongly suggested the diagnosis of
Crohn’s disease of the appendix.4 In most cases, the
preoperative diagnosis was acute appendicitis (in 68
percent of the cases) or appendiceal abscess (in 27 percent). A simple appendectomy was the surgical procedure performed in 64 percent of the cases. Postoperative complications, which were rare, included pelvic
abscess, wound infection, fistula formation, bowel obstruction, toxic megacolon, and hematoma. No postoperative deaths were reported. A follow-up study (average period, 2.5 years) revealed a recurrence rate of 16
On the basis of the low rate of fistula formation and
recurrence, the evidence suggests that presumptive
Crohn’s disease limited to the appendix comprises two
disorders: unequivocal Crohn’s disease involving the
appendix, which is rare, and idiopathic granulomatous
appendicitis. Dudley and Dean5 addressed this differential diagnosis by studying the comparative clinical
and histopathological features of 10 cases of idiopathic
granulomatous appendicitis and 14 cases of Crohn’s
disease involving the appendix. The histopathological
features of the two disorders overlapped considerably.
They were characterized by a similar degree of acute inflammatory change in the mucosa, transmural lymphoid
aggregates, and fibrosis. However, there were two notable differences. Fistulas were seen only in association
with Crohn’s disease, and there were many more granulomas in the cases of idiopathic granulomatous appendicitis (mean number per case, 144) than in the cases of
Crohn’s disease involving the appendix (mean number,
1). In addition, serosal and lymph-node granulomas
were seen only in the cases of idiopathic granulomatous
The diagnosis of idiopathic granulomatous appendicitis can be made only after careful exclusion of other
forms of appendicitis. One should not make a diagnosis
of Crohn’s disease unless one is certain, since it has
grave implications. In the present case, the most probable diagnosis, based on a combination of clinical and
histopathological findings, is idiopathic granulomatous
DR. MICHAEL B. HODGES: Postoperatively, the patient had obstruction and remained in the hospital for
one month. After he was sent home his condition improved, and he is now asymptomatic.
DR. SCHAPIRO: Are these pathological findings compatible with an infection such as Yersinia enterocolitica?
Was tissue from the surgical specimen cultured? A
stool culture for yersinia was not performed preoperatively.
DR. OZDEMIRLI: Unfortunately, no culture was performed. In most of the reported cases of yersiniosis,
cultures were not done preoperatively, and the diagnosis was made retrospectively by serologic testing.
DR. SCHAPIRO: I am still concerned that this patient
may ultimately prove to have Crohn’s disease, particularly because of the family history. From a practical
standpoint, I have decided not to treat him at the
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present time. There is ongoing controversy in the literature about whether any prophylactic medication can
reduce the frequency of recurrent Crohn’s disease. The
most recent reports suggest that the administration of
5-aminosalicylic acid preparations may be helpful. In
the absence of a specific diagnosis of Crohn’s disease,
however, I shall simply observe the patient and not
be surprised if symptoms recur. He remains well nine
months postoperatively.
Idiopathic granulomatous appendicitis, probable.
? Crohn’s disease of the appendix.
March 28, 1996
1. Cover TL, Aber RC. Yersinia enterocolitica. N Engl J Med 1989;321:16-24.
2. Ariel I, Vinograd I, Hershlag A, et al. Crohn’s disease isolated to the appendix: truths and fallacies. Hum Pathol 1986;17:1116-21.
3. Ruiz V, Unger SW, Morgan J, Wallack MK. Crohn’s disease of the appendix.
Surgery 1990;107:113-7.
4. Agha FP, Ghahremani GG, Panella JS, Kaufman MW. Appendicitis as the
initial manifestation of Crohn’s disease: radiologic features and prognosis.
AJR Am J Roentgenol 1987;149:515-8.
5. Dudley TH Jr, Dean PJ. Idiopathic granulomatous appendicitis, and Crohn’s
disease of the appendix revisited. Hum Pathol 1993;24:595-601.
6. Yang SS, Gibson P, McCaughey RS, Arcari FA, Bernstein J. Primary
Crohn’s disease of the appendix: report of 14 cases and review of the literature. Ann Surg 1979;189:334-9.
7. Timmcke AE. Granulomatous appendicitis: is it Crohn’s disease? Report
of a case and review of the literature. Am J Gastroenterol 1986;81:2837.
1996, Massachusetts Medical Society.
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