gastrointestinal lymphomatoid granulomato

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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



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.



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.



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.



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.



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



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.

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i im

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G.

Hellstrom HR. Lymphomatoid granulomatosis: report

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gastrointestinal lymphomatoid granulomato

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