Gastrointestinal Involvement in Lymphomatoid Granulomatosis

Report of a Case and Review of the Literature

MARK D. RATTINGER, MD, THADDEUS L. DUNN, MD, C. DAVID CHRISTIAN, JR, MD,
ROBERT M. DONNELL, MD, ROBERT D. COLLINS, MD, J. PATRICK O'LEARY, MD,
AND JOHN M. FLEXNER, MD

Lymphomatoid granulomatosis is a lymphoproliferative process affecting multiple organ systems usually including the lungs. Significant gastrointestinal involvement, however, has rarely been reported.
Pathologic examination reveals a vasocentric polymorphous lymphoid infiltrate. A case of lymphomatoid granulomatosis with gastrointestinal manifestations necessitating aggressive surgical intervention
is reported. The clinical presentation, pathologic features, and various aspects of therapy of lymphomatoid granulomatosis involving the gastrointestinal tract are discussed.
Cancer 51:694-700. 1983.

was originally
described by Liebow et al.' as an angiocentric granulomatous process, usually in the lung, characterized by
a polymorphous lymphoid infiltrate with histopathologic similarity to certain lymphomas and the potential
for evolution into lymphoma. Extrapulmonary disease
was noted in 83% of cases reported by Saldana et al.'
This may involve the central and peripheral nervous
systems, skin, kidneys, liver, spleen, adrenals, and
heart. Gastrointestinal tract involvement, however, is
r a ~ - e ' .particularly
~-~
in autopsied cases. Information regarding the pathologic and clinical features of this unusual complication of lymphomatoid granulomatosis is,
therefore, minimal. A patient with lymphomatoid granulomatosis involving multiple systems, including skin,
lungs, and central nervous system is reported. His course
was marked by life-threatening lower intestinal hemorrhage secondary to lymphomatoid granulomatosis involving the colon and small intestine. The clinical presentation, the pathologic features, and an evaluation of
the various modalities of therapy, including aggressive
surgical procedures, are discussed.
YMPHOMATOID GRANULOMATOSIS

Case Report
A 44-year-old white man was admitted to Vanderbilt University Hospital for evaluation of a persistently tender right
lower quadrant mass. He was well until November of 1977
From the Departments of Medicine, Pathology and Surgery Vanderbilt University Hospital, Nashville, Tennessee.
Address for reprints: Mark D. Rattinger, MD,235 Seminole Avenue, Palm Beach, FL 33480.
Accepted for publication December 7, I98 I .

when he noted multiple skin lesions over the right breast. A

biopsy specimen was interpreted as showing noncaseating xanthogranulomatosis; stains for acid fast organisms and fungi
were negative. Small tender nodules subsequently appeared on
his left arm and biopsy specimens showed nonsuppurative
granulomatous panniculitis. Over the next two years he had
several admissions for abdominal pain, fever, and a right lower
quadrant abdominal mass. Barium enema and intravenous
pyelogram were normal. In September of 1979 a chest x-ray
showed a left lower lobe coin lesion. He underwent thoracotomy and biopsy material revealed a vasocentric granulomatous
process. Stains for acid fast organisms and fungi were again
negative. One month later the patient was found to have a
large tender right lower quadrant mass. Barium enema was
again unremarkable. I n November of I979 a laparotomy was
performed, and a mass lesion involving multiple loops of small
bowel was identified. Biopsy specimens showed a necrotizing
process with granulomatous features and a marked lymphocytic and histiocytic infiltrate. The lesion was not resected and
the patient was referred to Vanderbilt University Hospital.
On admission the patient reported progressive weight loss.
lethargy, chronic abdominal pain, and intermittent fever.
'Temperature was 101.6"F orally. Abdominal exam revealed
a I2 X I2 cni. moderately tender mass in his right lower quadrant. Stool was positive for occult blood. A bone marrow
showcd mild erythroid hyperplasia. Cutaneous anergy was
present. Seven days after admission hematochezia was noted
and signioidoscopy to 18 centimeters was normal. A barium
edema showed displacement of the colon in the right lower
quadrant, and computerized tomographs revealed a large
mass. Sputum, blood, and bone marrow cultures for fungal,
and acid fast organisms were subsequently negative. A diagnosis of lymphomatoid granulomatosis was made upon review
oftissue sections from prior skin, lung, and mesentery biopsies.
Trials of antituberculous and then anti fungal agents were

0008-543></83/02 15/0694 $ I . I5 W American Cancer Society

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GASTROINTESTINAL
LYMPHOMATOID GRANULOMATOSIS

given on the possibility that some components of his illness

were atypical reactions to an infectious process. The patient
was discharged on isoniazid and ethambutol, but was readmitted on January 18, 1980, because of increased abdominal
pain and rectal bleeding. lsoniazid and ethambutol were
stopped and a trial of Amphotericin B was begun. Esophagogastroscopy was normal and colonoscopy was aborted because of bleeding. The patient subsequently developed massive
rectal bleeding requiring multiple transfusions.
Laparotomy was performed in February of 1980. A large
matted mass of distal small intestine was found in the right
lower quadrant. Several firm, white, umbilicated lesions were
identified in the mesentery of the jejunum. These were located
in the mesentery proper and along the mesenteric border of
the intestine. A large bloody inflammatory mass was found in
the right lower quadrant. The bulk of the mass consisted of
multiple loops of small intestine. Due to the possibility of a
remote perforation in one area, damaged small intestine and
right colon were resected without incident. lleocolic and jejunojejunal anastomoses were established. Persistent ileus, fever and abdominal distention prompted a reexploration on the
tenth postoperative day. Although the abdominal cavity was
involved by a purulent peritonitis, no perforation of the intestine was identified and the anastomoses was intact. Pentoneal dialysis catheters were positioned in all quadrants of the
abdomen and peritoneal lavage was carried out for five days.
Bowel function returned and he was discharged from the hospital 24 days after his resection.
The patient was re-admitted on June 27, 1980 with increasing dyspnea on exertion. He had not had further abdominal
complaints and had gained 15 pounds. No fever, chills, or
night sweats had been observed. On physical examination he
appeared to be in far better nutritional status than on his previous admission. His chest x-ray, however, showed multiple
hazy nodules bilaterally (Fig. 1). Pulmonary function tests were
within normal limits. Computerized tomographs did not show
an intra-abdominal mass. Bronchoscopy was performed and
transbronchial biopsy was felt compatible with lymphomatoid
granulomatosis. Stains and cultures for acid fast organisms and
fungi were again negative.
He was given cyclophosphamide 1500 mg/m2 intravenously
(1V) on July 30, 1980. He returned on August 15 with complete
blood counts returning to normal and a chest x-ray showing
dramatic improvement in the nodules. His pulmonary symptoms had diminished and he was without complaints. Because
of prolonged pancytopenia after his initial course of chemotherapy, cyclophosphamide was reduced to 1000 mg/m2. The
patient did well until November of 1980 when he was re-admitted because of neurologic complaints. Physical examination showed weakening in lower extremities and left upgoing
toes. Head computerized tomographs and lumbar puncture
were within normal limits and the patient was consequently
discharged o n BCNU.

Rattinger

121.

695

FIG. I . PA chest x-ray showing bilateral illdefined infiltrates.

tending deep into the subcutaneous fat (Fig. 2). There

was fat necrosis in addition to broad bands of coagulation necrosis. The mixed infiltrate consisted of small

Pathologic Features
Sections Of skin and subcutaneous tissue ( 1977)
showed a well circumscribed inflammatory infiltrate ex-

FIG.2. Dense inflammatory infiltrate, primarily lymphocytes, and

histiocytes. involving subcutaneous adipose tissue.

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CANCERFebruary 15 1983

Vol. 5 1

FIG. 3. Section of lung showing relatively

sharp demarcation between mass and uninvolved lung, with total obliteration of lung
architecture by inflammatory mass.

and large lymphocytes, histiocytes, plasma cells, and

scattered polymorphonuclear leukocytes. Lymphocytes
did not appear to have atypical features and there were
few mitotic figures. Special stains for organisms were
negative.
The mass resected from the small bowel mesentery
( 1979) at initial laparotomy showed similar microscopic
features including fat necrosis and a polymorphous infiltrate with scattered areas of large, more atypical lymphoid cells.
Sections from the resected lung mass (1979) showed
a dense, well circumscribed infiltrate similar to that present in the subcutis and mesentery (Fig. 3). The inflammatory infiltrate was bronchocentric and vasocentric,

and vasculitis involving small and medium size arteries

(Fig. 4) was noted. Large confluent areas of necrosis
surrounded the involved vessels. The infiltrate was
mixed and included large atypical lymphocytes. Mitotic
figures were readily identified.
The small bowel and colon resection (1980) consisted
of a segmental jejunectomy and right colectomy. A large
purulent hematoma filled the mesentery, and was associated with two areas of perforation in the cecum and
ascending colon. Two mass lesions were present. One
was a 2.5 X 2 X 1.5 cm mass in the jejunum and the
other a 4.5 X 4.0 X 3.0 cm mass in the ascending colon.
These were located within the bowel wall without gross
evidence of mucosal ulceration. They were well circum-

FIG.4. Pulmonary vessel with transmural

infiltration of lymphocytes and histiocytes.

No. 4

GASTROINTESTINAL
LYMPHOMATOID
GRANULOMATOSISRattinger et a/.

scribed and extended through the wall into the serosa

and mesenteric fat. They were gray to white with broad
bands of necrotic tissue within their central portion
(Figs. 5 and 6). Microscopic examination showed that
the lesions involved the mesenteric and subserosal fat
with extension into the muscle and submucosa of the
bowel (Fig. 7). There was extensive necrosis of fat and
of smooth muscle. Several arteries were infiltrated by a
dense collection of lymphocytes, histiocytes, and plasma
cells. Areas of coagulation necrosis surrounded some
vessels with luminal occlusion and intense vasculitis
(Fig. 8). High power examination of the infiltrate showed
many atypical cells with large nuclei and prominent
nucleoli (Fig. 9). Mitotic figures were abundant. In contrast to previous biopsy specimens from this patient, the
colonic infiltrate was more dense and appeared more
monomorphous. These features are clearly very suggestive of a lymphoid neoplasm and indicate that an overt
lymphoid neoplasm may have developed in this patient.
However, adjacent lymph nodes did not reveal lymphomatous involvement. Unfortunately, due to contamination and cell death, immunologic studies were not
performed on cell suspensions from the colonic mass.
Therefore, we feel that the diagnosis of malignant lymphoma has not been established in this patient, despite
histopathologic features which were very suggestive.
Discussion

The clinical presentation of lymphomatoid granulomatosis depends on the organ systems involved. Symptoms may be nonspecific such as weight loss, fever, and
malaise, or may be manifestations of specific organ sysA common feature is the eventual
tem inv~lvement.'.~,~

FIG.6. Colonic mass. Tumor involves submucosa and muscle (top) in some areas, but
predominantly involves pericolonic adipose
tissue.

697

FIG.5. Intraoperative appearance of tumor involving wall of small

intestine along mesenteric border.

development of lung involvement in nearly all patients,

who often present with dyspnea or a nonproductive
cough.
Gastrointestinal tract involvement with lymphomatoid granulomatosis is not a common finding at necropsy,and clinically significant bowel lesions, as seen in
this patient, are rare. In Liebow's et af.' original series
of 40 patients, small intestinal lymphomatoid granulomatosis was clinically evident only once and in a subsequent expanded series of 152 patients with pulmonary

698

CANCERFebruary 15 1983

VOl. 5 1

FIG. 7. Small intestine showing dense inflammatory infiltrate in submucosa and muscularis propria.

lymphomatoid granulomatosis. no deaths from gastrointestinal disease were noted. In this later series necrotizing
lesions of small intestine and gallbladder were seen in
four patients during life, and gastrointestinal tract disease was noted in 7% of autopsies.3 In the same series

FIG. 8. Artery in wall of colon showing vasculitis with necrosis of

vessel wall, thrombosis. and coagulation necrosis of surrounding tissue.

hepatic (29%) and pancreatic (7%) lesions were noted

at postmortem. Additional necropsy reports of asymptomatic lymphomatoid granulomatosis involving stomach, mesentery, and pericolic adipose tissue have also
a~peared.',~
Despite the relatively low reported incidence of clinically significant ailmentary disease in the above series,
case report data would suggest that gastrointestinal lymphomatoid granulomatosis may on occasion contribute
significantly to morbidity. Singh and Hellstrom5 described a patient with cutaneous and ultimately fatal
neurologic lymphomatoid granulomatosis which was
preceded by an episode of ischemic colitis treated by
resection. Subsequent review of the colon revealed fibrous intimal thickening of the mesenteric vasculature
which was felt to represent the senescent lesion of lymphomatoid granulomatosis. More recently, a patient has
been reported with exsanguination from oropharyngeal
lymphomatoid granulomatosis, who also had cachexia,
edema, and as cite^.^ Postmortem examination revealed
multiple stricutres of the small intestine and ulceration
of the mucosa with pseudopolyposis and impending
perforation, and histologic examination confirmed lymphomatoid granulomatosis. Hepatic insufficiency has
also been reported. In one patient liver disease occurred
concomitantly with pulmonary manifestations,' and in
another, extensive hepatic involvement followed a protracted course marked by pulmonary, cutaneous, and
neurologic disease." Disease confined solely to the abdomen has been noted with predominantly hepatic lymphomatoid granulomatosis associated with transudative
ascites and pleural effusion."
Evaluation of treatment of lymphomatoid granulostudiesmatosis is hampered by the lack Of
Because of its resemblance to Wegener's granulomatosis

No. 4

GASTROINTESTINAL
LYMPHOMATOID
GRANULOMATOSIS Ratfinger d al.

699

FIG.9. High power view of relatively monomorphous infiltrate of lymphocytes within

wall of vessel shown in Fig. 8. Note large nuclei and prominent nucleoli.

most therapeutic regimens have included corticosteroids

and/or cytotoxic agents. Twenty-two of the 40 patients
reviewed b y Liebow et al. were treated with steroids
alone or in combination with antibiotics. Fourteen of
the 22 eventually died, with survival after onset ranging
from three weeks to 86 months. In some individuals
there was apparent transient improvement while others
showed a progressive course. The other eight patients
remained alive, with follow-up ranging from nine to 97
months. Most of these patients showed resolution of
apparent disease. One had received radiotherapy in conjunction with corticosteroids. McDonald12reported one
patient with skin and lung disease who on 40 mg of
prednisone per day had resolution of his pulmonary lesions. Recurrence followed reduction of his prednisone
dosage to 20 mg per day with resolution again occurring
when dosage was increased. In another patient13 pulmonary lesions resolved after corticosteroid therapy but
central nervous system disease appeared.
Cyclophosphamide has been the most frequently used
cytotoxic agent, often in conjunction with a corticosteroid. Several patientsI4-l6treated with varying regimens
of prednisone and cyclophosphamide have had remission of clinical disease. However, Israel el ul. reviewed
nine patients, eight of whom received cyclophosphamide, chlorambucil, or azathoprine; all died of their
disease. Other
also relate a fatal outcome
despite cytotoxic therapy.
Three patients. received irradiation to pulmonary,
central nervous system, and soft-tissue masses unresponsive to corticosteroids and cytotoxins. All three
showed a good response with marked decrease in size
of local lesions.
In Katzensteins review et ~ 1treatment
, ~
was divided
into four categories: corticosteroids, alone or with later

addition of chemotherapy; corticosteroids and chemotherapy; chemotherapy, alone or with later addition of
corticosteroids; and antibiotics or no therapy. They
found no significant difference in mortality among the
groups with from 24 to 3 1% of patients remaining disease-free at the time of the study (Group I, 24%; Group
I1 24%; Group 111, 3 1%; Group IV, 27%).
Although gastrointestinal involvement has been rarely
seen in lymphomatoid granulomatosis, all of the other
clinical and pathologic features in our case are similar
to the original description. More importantly, the vasocentric lymphoproliferative lesions were typical and
were noted at various times in this patient in skin, lung,
and gastrointestinal tract.
Because of multiple organ system involvement surgery has had only a limited role in treatment of lymphomatoid granulomatosis. However, due to the unusual gastrointestinal lesions aggressive abdominal resection was necessary in our patient. Although he had
recurrence in other organ systems, his gstrointestinal and
nutritional complaints were significantly ameliorated by
surgery. Perforation of the bowel may apparently occur
as a complication of lymphomatoid granulomatosis, and
surgery may be necessary.
Conclusion

Lymphomatoid granulomatosis is a rare and poorly

understood entity with features of lymphoid proliferation and vasculitis. Pulmonary involvement is seen in
most cases and diagnosis is based primarily on pathologic demonstration of a polymorphous lymphoid infiltrate with necrosis and granulomatous features. The
course is variable with asynchronous waxing and waning
of the disease in the various affected organs. N o therapy

CANCERFebruary 15 1983

700

has been consistently useful in this disease, and remission is not unusual. The reported case has been instructional because of the widespread nature of the disease,
the life-threatening aspects, and the apparent response
to a combination of surgical and medical therapy.
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