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Gastro intest inal Invo lvem ent in Lym pho m atoid Granulom atosis
Report
of
a
Case and Review
of
the Li terature
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 usu-
ally including the lungs. Significant gastrointestinal involvement, however, has rarely been reported.
Pathologic examination reveals a vasocentric polymorphous lymphoid infiltrate.
A
case of lymphoma-
toid granulomatosis with gastrointestinal manifestations necessitating aggressive surgical intervention
is
reported. Th e clinical presentation, path ologic features, and various asp ect s
of
therapy of lymphoma-
toid granulomatosis involving the gastrointestinal tract are discussed.
Cancer
51:694-700. 1983.
Y M P H O M A T O I D G R A N U L O M A T O S I S was originally
L escribed by Liebow t al. as an angiocentric gran-
ulomatous process, usually in the lung, characterized by
a polymorphous lymphoid infiltrate with histopatho-
logic 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 ' . ~ - ~articularly in autopsied cases. Information re-
garding the pathologic and clinical features of this un-
usual complication of lymphomatoid granulomatosis is,
therefore, minimal. A patient with lymphomatoid gran-
ulomatosis involving multiple systems, including skin,
lungs, and central nervous system is reported. His course
was marked by life-threatening lower intestinal hem-
orrhage secondary to lymphomatoid granulomatosis in-
volving the colon and small intestine. The clinical pre-
sentation, the pathologic features, and an evaluation
of
the various modalities of therapy, including aggressive
surgical procedures, are discussed.
Case Report
A 44-year-old white man was admitted t o Vanderbilt Uni-
versity 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 Van-
Address
for
reprints: Mark D. Rattinger MD 35 Seminole Av-
Accepted
for
publication December
7, I98
I .
derbilt University Hospital Nashville Tennessee.
enue Palm Beach FL 33480.
when he noted multiple skin lesions over the right breast. A
biopsy specimen was interpreted as showing noncaseating xan-
thogranulomatosis; 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 thoracot-
omy and biopsy material revealeda 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 lympho-
cytic 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 I 2 X I 2 cni. moderately tender mass in his right lower quad-
rant.
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
diag-
nosis 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 .
I
American Cancer Society
694
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No 4 GASTROINTESTINAL
Y
MPHOMATOID
GRANULOMATOSIS
Rattinger 121
695
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 read-
mitted 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. Esophag-
ogastroscopy was normal and colonoscopy was aborted be-
cause of bleeding. The patient subse quently developed massive
rectal bleeding requ iring 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 jejunu m. These were located
in the mesentery proper and along the mesenteric border of
the intestine. A large bloody inflamma tory mass was found i n
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 je-
junojejunal anastomo ses were established. Persistent ileus, fe-
ver and ab dom inal distention prom pted a reexploration
on
the
tenth postoperative day. Although the abdominal cavity was
involved by a purulent peritonitis, no perforation
of
the in-
toneal dialysis catheters were positioned in
all
quadrants of the
abdomen and peritoneal lavage was carried out for
five
days.
Bowel function returned an d he was discharged from th e hos-
pital 2 4 day s after his resection.
Th e patient was re-admitted on Ju ne
27,
1980 with increas-
ing dyspnea on exertion. He had not had further abdominal
complaints and had gained
15
pounds.
N o
fever, chills, or
night sweats had been observed. On physical examination he
appeared to be in far better nutritiona l status than o n his pre-
vious admission. His chest x-ray, however, showed multiple
hazy nod ules bilaterally (Fig. 1 . Pulm onary function tests were
within normal limits. Computerized tomo graphs did not show
an intra-abdominal mass. Bronchoscopy was performed and
transbronchial biopsy was felt compa tible with lymp homato id
granulomatosis. Stains and cultures for acid fast organisms an d
fungi were again negative.
He was given cyclophospham ide
1500
mg/m2 intravenously
(1V)
on July
30,
1980. He returned on August 15 with complete
blood c ounts returning
to
normal and a chest x-ray showing
dram atic impro vem ent in the nodules. His pulmonary symp-
toms had diminished an d he was without complaints. Because
of
prolonged pancytopenia after his initial course
of
chemo-
therapy, cyclophosphamide was reduced t o 1000 mg/m2. Th e
patient did well until November of 1980 when h e was re-ad-
mitted because of neurologic complaints. Physical examina-
tion showed weakening in lower extremities and left upgoing
toes. Head computerized tomo graphs and lum bar puncture
were within normal limits and the patient was consequently
discharged o n BCNU.
FIG. .
PA chest x-ray showing bilateral illdefined infiltrates.
testine was identified and the anastomoses was intact. Pen-
t e n d i n g
deep into
t h e s u b c u t a n e o u s fat
(Fig.
2). T h e r e
w a s f a t
necrosis
in a d d i t i o n to b r o a d
bands
of coagu-
lation
necrosis.
The mixed
inf i l t ra te consisted
of
s m a l l
Pathologic Features
Sections
Of
skin
and
subcutaneous
tissue
1977
showed
a
wel l c i r cum scr ibed in f lam m atory in f i l t ra te
ex-
FIG.2.
Dense inflammatory infiltrate, primarily lymphocytes,
and
histiocytes. involving subcutaneous adipose tissue.
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696
CANCER ebruary 15 1983
Vol. 51
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 in-
filtrate with scattered areas of large, more atypical lym-
phoid cells.
Sections from the resected lung mass (1979) showed
a dense, well circumscribed infiltrate similar to that pres-
ent in the subcutis and mesentery (Fig. 3). The inflam-
matory infiltrate was bronchocentric and vasocentric,
FIG. 3. Section of
lung
showing relatively
sharp demarcation between mass and unin-
volved lung, with total obliteration
of
lung
architecture by inflammatory mass.
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 as-
sociated 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.
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No. 4
GASTROINTESTINALYMPHOMATOIDRANULOMATOSIS
Rattinger
t
a/
697
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 con-
trast to previous biopsy specimens from this patient, the
colonic infiltrate was more dense and appeared more
monomorphous. These features are clearly very sugges-
tive of a lymphoid neoplasm and indicate that an overt
lymphoid neoplasm may have developed in this patient.
However, adjacent lymph nodes did not reveal lym-
phomatous involvement. Unfortunately, due to contam-
ination and cell death, immunologic studies were not
performed on cell suspensions from the colonic mass.
Therefore, we feel that the diagnosis of malignant lym-
phoma has not been established in this patient, despite
histopathologic features which were very suggestive.
Discussion
The clinical presentation of lymphomatoid granulo-
matosis depends on the organ systems involved. Symp-
toms may be nonspecific such as weight loss, fever, and
malaise, or may be manifestations of specific organ sys-
tem inv~lvement.'.~,~common feature is the eventual
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 lymphoma-
toid granulomatosis is not a common finding at nec-
ropsy, 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 granulo-
matosis was clinically evident only once and in a sub-
sequent expanded series of
152
patients with pulmonary
FIG.
6.
Colonic mass. Tumor involves sub-
mucosa and muscle (top) in some areas, but
predominantly involves pericolonic adipose
tissue.
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698
CANCER
ebruary 15
1983
VOl.
5 1
FIG.
7 .
Small intestine showing dense in-
flammatory infiltrate in submucosa and mus-
cularis propria.
lymphomatoid granulomatosis. no deaths from gastroin-
testinal disease were noted. In this later series necrotizing
lesions of small intestine and gallbladder were seen in
four patients during life, and gastrointestinal tract dis-
ease was noted in 7 of autopsies.3 In the same series
hepatic (29%) and pancreatic (7%) lesions were noted
at postmortem. Additional necropsy reports of asymp-
tomatic lymphomatoid granulomatosis involving stom-
ach, mesentery, and pericolic adipose tissue have also
a~peared.',~
Despite the relatively low reported incidence of clin-
ically significant ailmentary disease in the above series,
case report data would suggest that gastrointestinal lym-
phomatoid granulomatosis may on occasion contribute
significantly to morbidity. Singh and Hellstrom5 de-
scribed 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
fi
brous intimal thickening of the mesenteric vasculature
which was felt to represent the senescent lesion of lym-
phomatoid 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 lym-
phomatoid 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 pro-
tracted course marked by pulmonary, cutaneous, and
neurologic disease. Disease confined solely to the ab-
domen has been noted with predominantly hepatic lym-
phomatoid granulomatosis associated with transudative
ascites and pleural effusion.
Evaluation of treatment of lymphomatoid granulo-
matosis is hampered by
the
lack
Of studies-
Because of its resemblance to Wegener's granulomatosis
FIG. 8.
Artery in wall of colon showing vasculitis with necrosis
of
vessel wall, throm bosis. and coagulation nec rosis
of
surrounding tissue.
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No. 4
GASTROINTESTINALYMPHOMATOIDRANULOMATOSIS Ratfinger
d al.
699
FIG. .
High
power view
of
relatively m ono-
morphous infiltrate of lymphocytes within
wall
of
vessel shown in Fig. 8. Note large nu-
clei 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 con-
junction with corticosteroids. McDonald12 reported one
patient with skin and lung disease who on 40 mg of
prednisone per day had resolution of his pulmonary le-
sions. Recurrence followed reduction
of
his prednisone
dosage to 20 mg per day with resolution again occurring
when dosage was increased. In another patient13 pul-
monary 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 corticoste-
roid. Several patientsI4-l6 reated with varying regimens
of prednisone and cyclophosphamide have had remis-
sion of clinical disease. However, Israel
el
ul ” reviewed
nine patients, eight of whom received cyclophospha-
mide, 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 unre-
sponsive to corticosteroids and cytotoxins. All three
showed a good response with marked decrease in size
of
local lesions.
In Katzenstein’s review et
~ 1 ~
reatment was divided
into four categories: corticosteroids, alone or with later
addition of chemotherapy; corticosteroids and chemo-
therapy; 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
31
of patients remaining dis-
ease-free at the time of the study (Group I, 24%; Group
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 va-
socentric 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 sur-
gery has had only a limited role in treatment of lym-
phomatoid granulomatosis. However, due to the
un-
usual gastrointestinal lesions aggressive abdominal re-
section 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.
I
24%; Group 111,
31 ;
Group IV, 27%).
Conclus ion
Lymphomatoid granulomatosis is a rare and poorly
understood entity with features of lymphoid prolifera-
tion and vasculitis. Pulmonary involvement is seen in
most cases and diagnosis is based primarily on patho-
logic demonstration of a polymorphous lymphoid infil-
trate 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
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700 CANCER ebruary
15 1983 V O l .
5 1
has been consistently useful in this disease, and remis-
sion is not unusual. The reported case has been instruc-
tional because of the widespread nature of the disease,
the life-threatening aspects, and the apparent response
to a combination
of
surgical and medical therapy.
REFERENCES
I . Liebow AA Camington CRB Freidman PJ. Lymphomatoid
granulomatosis. IIitm Puihol 1972: 3:457-558.
2. Saldana MJ. Patchefsky AS Israel HI Atkinson GW. Pulmonary
angiitis and granulomatosis: The relationship between histological fea-
tures. organ involvement. and response to treatment.
i im
Puihol
1977: 8:391-409.
3. Katzenstein AA. Camngton CB Liebow AA. Lymphomatoid
granulomatosis: A clinicopathologic study
of
I52 cases. Cuncrr 1979:
4. Gupta S. Gupta OP. Lymphomatoid granulomatosis of the oro
pharynx. Eur Nose. Throuf 1980; 59:152-154.
5 Singh
G.
Hellstrom HR. Lymphomatoid granulomatosis: report
of a case without pulmonary involvement and with ischemic colitis
probably a sequel to granolomatosis. Ifitmun Pufhol 1978; 9:364-366.
6.
Yockey
CC.
Leichter SB Hamptom JR. Lymphomatoid gran-
ulomatosis presenting as fever of unknown origin. JAMA 1977;
237:2633-2634.
7. Saito R. The cytologic manifestation of lymphomatoid granu-
lomatosis in cerebrospinal fluid. c~a y io l 1978; 22:339-343.
8. Mazhar M McShane KL Barrett FA. Lymphomatoid granu-
lomatosis: Report of a case. Rocky Min M ed J 1976; 73:203-204.
43:360-373.
9. Schjilseth SA. Blom GP. Lymphomatoid granulomatosis of the
lung. liver and spleen. Scund
Hu rma fo l
1978; 2 I: 104- 108.
10. Fuller PSB Hafermann DR Byrd RB Jenkins DW.
Use
of
irradiation in lymphomatoid granulomatosis. Chesi 1978: 74:
105-
106.
I
I . Chen KTK. Abdominal form of lymphomatoid granulomato-
sis. Hum Pathol 1977; 8:99-103.
12. MacDonald DM. Lymphomatoid granulomatosis. Proc R o y
13. Bone RC Vernon M Sobonya RE. Rendon H. Lymphomatoid
granulomatosis.
A m
J Med
1978; 65:709-716.
14.
Lee
SC,
Roth LM Brashear RE. Lymphomatoid granuloma-
tosis: Clinicopathologic study of four cases. ancer 1976; 38:846-853.
1 5 .
Minars N. Kay S,Escobar MR. Lymphomatoid granulomatosis
of the skin: A new clinicopathologic entity. Arch Dermafol 1975:
1:493-496.
16. Gibbs AR. Lymphomatoid granulomatosis: A condition with
affinities to Wegener’s granulomatosis and lymphoma.
7horu x 1977:
32:71-79.
17.
Israel HL Patchefsky AS Saldana MJ. Wegener’s granulo-
matosis. lymphomatoid granulomatosis and benign lymphocytic an-
giitis and granulomatosis of lung.
A n n
In tern
M r d
1977: 691-699.
18. Case Records of the Massachusetts General Hospital. NEJM
19. Crissman JD. Midline malignant reticulosis and lymphomatoid
20.
Jauregui HO. Lymphomatoid granulomatosis after immuno-
21. Shank BB Kelley CD Nisce LZ Nori D. Radiation therapy
SOLMrd
1975: 68:452-432.
1976; 294:1052-1056.
granulomatosis. Arch Pufhol L a b M e d 1979; 103561-564.
suppression for pemphigus. Arch Dermufo l 1978: 1141052-1055.
in lymphomatoid granulomatosis.
Cuncer
1978; 42:2572-2580.