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8
Five-Year Results of the Treatment of 23 Patients
with Immunoproliferative Small Intestinal Disease
A Turkish Experience
Hakan Akbulut, M.D.1
Irfan Soykan, M.D.2
Fahri Yakaryilmaz, M.D.3
Fikri Icli, M.D.1
Fehmi Aksoy, M.D.4
Serap Haznedaroglu, M.D.3
Safa Yildirim, M.D.3
BACKGROUND. Currently, there is no agreement regarding optimal treatment strategies for immunoproliferative small intestinal disease (IPSID). In this article, the
authors report the treatment outcomes of a group of 23 Turkish patients with
IPSID.
METHODS. Between December 1988 and July 1993, 23 consecutive patients with
1
Department of Medical Oncology, Ibn-i Sina
Hospital, Ankara University School of Medicine,
Sihhiye-Ankara, Turkey.
2
Department of Gastroenterology, Ibn-i Sina
Hospital, Ankara University School of Medicine,
Sihhiye-Ankara, Turkey.
3
Department of Third Internal Medicine, SSK
Hospital, Diskapi-Ankara, Turkey.
4
Department of Pathology, Numune Hospital,
Sihhiye-Ankara, Turkey.
IPSID, including 5 with secretory type, were included in the study. Seven patients
with Stage A disease (according to the criteria of Galien et al.) received tetracycline
(1 g/day, orally) for a median duration of 7 months (range, 6–11 months) initially,
whereas the remaining patients (9 Stage B patients and 7 Stage C patients) received
combination chemotherapy (cyclophosphamide, vincristine, procarbazine, and
prednisolone [COPP regimen]) followed by tetracycline at a dose of 1 g/day for 6
more months in patients with complete response (CR) after the COPP regimen.
RESULTS. The median follow-up was 68 months (range, 38–89 months). As firstline therapy in Stage A patients, tetracycline yielded a 71% CR and 43% disease
free survival (DFS) rate. Eleven of 16 patients (69%) with Stage B or C disease who
received the COPP regimen achieved CR and only 2 patients had a recurrence
(DFS rate of 56%). The 5-year overall survival (OAS) rate for the entire group was
70%, and the 5-year DFS rate for patients with CR was 75%. However, the median
OAS for 3 patients with immunoblastic lymphoma was only 7 months.
CONCLUSIONS. The COPP regimen, with its acceptable toxicity, appears to be a
good alternative as a first-line treatment for patients with Stage B or C IPSID with
low grade lymphoma whereas tetracycline appears to be the initial treatment of
choice for patients with Stage A disease. Cancer 1997;80:8–14.
q 1997 American Cancer Society.
KEYWORDS: lymphoma-mucosa-associated lymphoid tissue type, immunoproliferative small intestinal disease, tetracycline, combination chemotherapy, cyclophosphamide, vincristine, procarbazine, prednisolone.
I
Address for reprints: Hakan Akbulut, M.D., Dept.
of Medical Oncology, Ibn-i Sina Hospital, Ankara
University School of Medicine, Sihhiye-Ankara,
06100 Turkey.
Received December 11, 1996; revision received
February 27, 1997; accepted February 27, 1997.
mmunoproliferative small intestinal disease (IPSID) is a special form
of mucosa-associated lymphoid tissue (MALT) type lymphoma and
remarkably prevalent in the Mediterranean region.1 – 3 Primary extranodal lymphomas, including IPSID, are also more common in Turkey
when compared with Western countries.3,4 It affects adolescents and
young adults and is commonly manifested by chronic diarrhea, weight
loss, abdominal pain, clubbing, and frequent growth retardation.2,5
IPSID usually involves the upper jejunum as well as the distal parts
of the duodenum.1,5,6 Histopathologically, IPSID is characterized with
a dense plasmolymphocytic infiltration of the lamina propria and
mesenteric lymph nodes in its early stages.1,7 In later stages, nodular
mucosal lymphoid infiltrations, so-called follicular lymphoma variant,
q 1997 American Cancer Society
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W: Cancer
Treatment Outcomes in IPSID/Akbulut et al.
and, ultimately, transformation to high grade
lymphoma are observed.1 The geographic variations
in the incidence of the disease, low socioeconomic
status of the affected patients, and improvements in
antibiotics suggest that environmental factors contribute to the pathogenesis.5,6
There is currently no agreement regarding the optimal treatment strategies of the disease. Antibiotics,
different chemotherapeutic regimens, and/or abdominal irradiation have been used.1,2,5,6,8
In this article, the authors report the treatment
outcomes of a group of 23 Turkish patients with IPSID.
PATIENTS AND METHODS
Between December 1988 and July1993, 23 consecutive
patients with IPSID, including 5 with secretory type,
were entered in the study. All the patients underwent
to upper gastrointestinal endoscopy, abdominal computed tomography, small bowel series, and colonoscopy. In addition, bone marrow biopsies in all patients
and fine-needle aspiration biopsies of enlarged abdominal lymph nodes, as well as of the liver and
spleen, when needed, were performed. Laparotomy
was not performed in any of these patients as a staging
procedure. In addition to clinical and immunologic
features, all patients were diagnosed histologically
based on the multiple upper jejunal biopsies taken by
peroral Crosby capsule. All histopathologic examinations were performed by the same pathologist.
Pathologic classification was made according to
the criteria of Galien et al., with some modifications.8
Stage A was characterized by a diffuse, dense, and
apparently benign plasmacytic infiltration of mucosa
and/or lymph nodes, and Stage C by the presence of
low or high grade lymphomas with or without benign
lymphoplasmacytic infiltration. Stage B was intermediate between Stages A and C and characterized by
mixed mature and dystrophic plasma cells infiltrating
the mucosa and villous atrophy. Seven patients were
classified as having Stage A disease, nine as having
Stage B, and seven as having Stage C including three
patients with immunoblastic type lymphoma. Although 7 Stage A patients were given tetracycline (1g/
day orally) for a median duration of 7 months (range,
6 – 11 months), the others were given cyclophosphamide, 600 mg/m2 /day on Days 1 and 8; vincristine,
1.4 mg/m2/day on Days 1 and 8; procarbazine, 100
mg/m2/day orally for 7 days; and prednisolone, 80 mg/
m2/day for 14 days (COPP regimen), with an additional
tetracycline dose of 1 g/day for 6 months given to
patients with a complete response (CR).
Two patients with giardiasis and one patient with
intestinal amebiasis were properly treated before entering the study.
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9
TABLE 1
Patient Characteristics and Treatment Outcomes in 23 Patients with
IPSID
No.
Median age (yrs) (range)
Gender (female/male)
Main symptoms
Chronic diarrhea
Weight loss
Abdominal pain
Main findings
Clubbing
Failure to thrive
Stage
A
B
C
Treatment groups (first-line) (CR—5 year DFS rates)
Tetracycline
COPP { tetracycline
Median follow-up (range) (mos)
5-year OAS ratea
5-year DFS ratea
5-year DFS rateb
25 (12–40)
12/11
23/23
23/23
20/23
7/23
4/23
7
9
7
7 (71–43%)
16 (68–56%)
68 (38–89)
70%
52%
75%
IPSID: immunoproliferative small intestinal disease; CR: complete response; DFS: disease free survival;
OAS: overall survival; COPP: cyclophosphamide, vincristine, procarbazine, and prednisolone.
a
For the entire group.
b
For patients with a complete response.
Response to treatment was assessed using clinical
and histopathologic findings. A CR was considered to
be a full clinical response and histopathologic remission. A partial response (PR) was considered to be a
clinical remission and improvement of histopathologic findings to those of a preceding stage. After treatment, patients were seen at 3-month intervals for 2
years, at 6-month intervals for 3 years, and annually
thereafter. All patients underwent upper gastrointestinal endoscopy at 6-month intervals and peroral jejunal
biopsies annually for 5 years and once every 2 years
thereafter.
Survival analysis was made according to the
Kaplan-Meier method using SPSS 6.0 for Windows
package.9
RESULTS
Patient characteristics are shown in Table 1. The median age of the patients was 25 years (range, 12 – 40).
Although chronic diarrhea, weight loss, and abdominal pain were the main presenting symptoms, the primary clinical findings were clubbing and failure to
thrive (Table 1). One patient with Stage A disease,
three with Stage B disease, and six with Stage C disease
had enlarged mesenteric lymph nodes whereas one
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CANCER July 1, 1997 / Volume 80 / Number 1
FIGURE 2. Endoscopic appearance of the distal part of the duodenum
of a patient with Stage B disese showing diffusely thickened mucosal folds
with small nodules (a cobblestone pattern).
FIGURE 1. A barium study of a patient with Stage A disease with thickened mucosal folds and a coarse mucosal pattern in the upper part of the
jejunum (white arrow).
patient with Stage C disease had enlarged paraaortic
lymph nodes. Barium studies revealed an marked abnormal small intestine pattern in the upper parts of
the small intestine in all patients. The most apparent
findings in patients with Stage A disease were thickened mucosal folds and coarse mucosal pattern (Fig.
1), whereas pseudopolypoid appearance, strictures,
and segmentation were observed in patients with
Stage B or C disease. The intestinal lesions grossly
appeared as diffusely thickened mucosal folds with
small nodules, creating a cobblestone pattern on upper gastrointestinal endoscopy in most of the patients
(Fig. 2). The main histopathologic features in patients
with Stage A disease were a dense mature plasma cell
infiltration of the lamina propria, crypt sparsity, and
a variable degree of villous atrophy (Fig. 3). Although
there were lymphoepithelial lesions comprised of
mainly centrocyte-like cells surrounding epithelial
crypts with some blasts in four patients with Stage C
disease, there was transformation to high grade
lymphoma comprised of immunoblastic cells with
their prominent nucleoli in the other three patients
with Stage C disease (Fig. 4). In patients with Stage B
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disease, a dense plasmacytic infiltration with frankly
dystrophic plasma cells invading the submucosa and
nodular lymphoid infiltrations were the evident features.
Seven patients with Stage A disease initially were
given tetracycline alone for a median duration of 7
months (range, 6 – 11 months). Five of seven patients
receiving tetracycline had a CR and two had a PR.
Partial response in 1 patient persisted for 10 months,
at which time he refused further treatment and was
lost to follow up. At 24 months he presented with Stage
C disease and despite combination chemotherapy
died of progressive disease at 28 months. The other
patient with a PR received six courses of COPP treatment and had a CR. Sixteen patients with Stage B and
C disease received the COPP regimen. Although 11 of
16 patients receiving COPP had a CR, 2 had a PR, and
3 with immunoblastic lymphoma had stable disease.
The CR patients were given six courses of the COPP
regimen. Two patients with PR refused further chemotherapy and were given tetracycline, 1g /day orally, for
a period of 6 months. One was lost to follow up after 24
months and at last follow-up the other had remained
asymptomatic with Stage A disease. Three patients
with immunoblastic lymphoma who had stable disease after receiving the COPP combination were later
given a regimen of bleomycin, 4 mg/m2; doxorubicin,
45 mg/m2; cyclophosphamide, 600 mg/m2; vincristine,
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Treatment Outcomes in IPSID/Akbulut et al.
FIGURE 3. Histologic pattern of the jejunal wall of a patient with Stage
A disease with a dense mature plasma cell infiltration of lamina propria,
crypt sparsity, and villous atrophy.
1 mg/m2 intravenously on Day 1, and methotrexate,
200 mg/m2 orally on Days 8 and 15 (m-BACOD regimen). Two of three patients in this group had a PR
and one developed progressive disease with the mBACOD combination. The median survival of these
patients was 7 months (range, 4 – 13 months). The
symptoms of IPSID were resolved within approximately 2 months of treatment (range, 15 days-4
months) in patients receiving tetracycline and after
the first cycle of the COPP regimen in all patients with
a CR or PR, whereas the histologic remissions were
observed at approximately the fourth month of treatment and after the fourth cycle of COPP regimen.
Two patients in tetracycline group (40%) and 2 in
COPP group (18%) had recurrent disease at 12, 17, 20,
and 36 months, respectively. All patients were given
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11
FIGURE 4. Cytologic pattern of the jejunal wall with a high grade transformation in immunoproliferative small intestinal disease. The large obviously malignant immunoblastic cells (black arrow) are accompanied by a
dense lymphocytic infiltration.
the COPP regimen after recurrence. One patient with
recurrent disease in the COPP group failed to respond
and died of progressive disease at the 24 months. The
others achieved a second CR and remained disease
free at last follow-up.
After a median 68 months of follow-up (range, 38 –
89 months), median overall survival (OAS) and disease
free survival (DFS) for all patients had not yet been
reached. Three of 5 patients receiving antibiotherapy
(60%) and 9 of 11 patients receiving the COPP regimen
(82%), who achieved CR, were disease free. The 5-year
OAS rate for the entire group was 70%. Five-year DFS
rates for the entire group and those with a CR were
52% and 75%, respectively (Table 1) (Fig. 5).
No toxic death was observed. Only five patients
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CANCER July 1, 1997 / Volume 80 / Number 1
FIGURE 5. Overall survival (OAS) curve of the entire group and disease
free survival curve (DFS) of the patients with a complete response.
receiving COPP as a first-line treatment had Grade 2 –
3 hematologic toxicity.
DISCUSSION
In this article, the authors presented the 5-year results
of a prospective study of 23 Turkish patients with IPSID. Although laparotomy was usually recommended
as a staging procedure in earlier reports,5,11 the authors
did not perform laparotomy for staging purposes because of the morbidity and mortality related to this
procedure.14
There is currently no agreement regarding the optimal treatment strategies for IPSID. Antibiotics, different chemotherapeutic regimens, and/or abdominal irradiation have been used.5,6,8 A limited number of reports dealing with IPSID are not adequate to reach a
conclusion regarding the effectiveness of the treatment schedules. The treatment outcomes of nine previous reports, including more than ten patients, are
outlined in Table 2. It has been reported and clearly
established that tetracycline relieves the symptoms of
diarrhea and malabsorption in patients with IPSID.8,13
Although the epidemiologic features of the disease and
good response to antibiotic treatment raised the question of infectious etiology, a specific agent contributing to the pathogenesis of the disease has not yet been
found. Since the first report of IPSID, antibiotics are
considered to be standard treatment for Stage A disease.2,5,11 The average CR rate from 5 previous reports
in which patients were treated with antibiotics was
50% (range, 25 – 70%).11,15,17 – 19 To the authors’ knowledge, the best CR rate with antibiotics reported to date
reached approximately 70% (Table 2).11 In the current
series, 5 of 7 Stage A patients had a CR, but 2 had
recurrent disease at the 12 and 17 months, respectively. Ultimately, it is possible to state that tetracycline, as a first-line treatment, gave a 43% DFS rate in
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patients with Stage A disease, which was comparable
to results from previous reports.5,11,15,17 – 19 CRs were
observed after a median of 7 months of the antibiotic
treatment and the treatment was continued for an additional period of 3 months after CR. However, the
usefulness and duration of maintenance antibiotherapy remain unclear.
Various chemotherapeutic regimens including
single agents such as nitrogen mustard, melphalan,
and chlorambucil and combination chemotherapies
including cyclophosphamide, vincristine, and prednisolone (COP), nitrogen mustard, vincristine, prednisolone, and procarbazine (MOPP), cyclophosphamide,
doxorubicin, vincristine, and prednisolone (CHOP),
bleomycin, doxorubicin, cyclophosphamide, vincristine, and prednisolone (BACOP) with or without abdominal irradiation have been used for Stage B or C
disease.5,10 – 18 Up to 90% CR rates for Stage B or C
disease were reported (Table 2).15 – 19 In the current
study, 16 patients with Stage B or C disease were given
the COPP regimen as a first-line therapy, because of
the low grade potential of the disease observed in the
patients and the reduced tolerability for anthracyclinebased regimens of debilitated and malnourished patients with IPSID. Eleven of 16 patients (69%) had a
CR with a 18% recurrence rate. The poor results in
immunoblastic lymphomas may have been due to the
lack of an anthracycline-based regimen. Furthermore,
two of three unresponsive patients had a PR to the mBACOD regimen as a second-line treatment. Ultimately, a DFS rate of 82% for patients who achieved
a CR was obtained with the COPP regimen as a firstline therapy in patients with Stage B or C disease (median 68 months of follow-up). Unfortunately, a lack of
a standard regimen within each report and the small
number of patients in the previous reports make it
difficult to compare the effectiveness of various chemotherapeutic regimens.
Five deaths due to disease progression were observed in the current study. Treatment toxicities were
in acceptable limits. According to the authors’ results
in patients with Stage A disease (71% CR and 43% DFS
rates) antibiotherapy appears to be the initial treatment of choice and combination chemotherapy
should be considered in resistant or recurrent patients.
Also, results of the COPP regimen in 16 patients with
Stage B or C disease are encouraging. However, this
combination as a first-line treatment failed in three
patients with immunoblastic lymphoma. More aggressive regimens including anthracyclines may be required for IPSID patients in this histopathologic subgroup.
In conclusion, the COPP regimen, with its acceptable toxicity, appears to be a good alternative as a
W: Cancer
Treatment Outcomes in IPSID/Akbulut et al.
13
TABLE 2
Treatment Outcomes of IPSID Patients from Previous Reports including More Than 10 Patients
No.
Stage A/B or C
Treatment schedule
Ramot et al. 1965
Salem et al. 197713
Al-Bahrani et al. 197814
Benisadre et al. 198515
13
25
18a
18
NA
NA
NA
7/11
Omar et al. 198516
33
4/29
Gilinsky et al. 198711
30
11/19
Ben-Ayed et al. 198917
21
6/15
Price 199018
Malik et al. 199519
13
12
NA
6/6
Current study
23
7/16
NR
RT { CC
CPT
Antibiotics
CC
Antibiotics
CC
Antibiotics
CC { RT
Antibiotics
CC
Antibiotics { RT
Antibiotics
CC
Antibiotics
CC
12
Response
(CR rate)
Survival
NR
NR
13/13b
2/4
7/11
NR
8 mos (med. OAS)
NR
NA
NA
8/11
11/19
2/6
9/15
6/13
1/4
5/6
5/7
11/16
24 mos (med. OAS)
14 mos (med. OAS)
OAS rate 67% (at 3 yrs)
OAS rate 29%c
OAS rate 75%c
OAS rate 90% (at 2 yrs)
DFS rate 43%c
DFS rate 56%c
IPSID: immunoproliferative small intestinal disease; NA; not available; NR: not recorded; CR: complete response; RT: radiotherapy; CC: combination chemotherapy; med.: median; OAS: overall survival; CPT:
cyclophosphamide, prednisolone, tetracycline; DFS: disease free survival.
a
Five patients died after staging laparatomy.
b
Complete response plus partial response rate.
c
At 5 years.
first-line treatment for the patients with Stage B or C
disease with low grade lymphoma. However, it is too
early to reach a conclusion regarding the curative effects of antibiotherapy and the COPP regimen, because of the low grade characteristics of non-Hodgkin’s lymphoma observed in most of the IPSID patients. The 5-year DFS rate of 56% (9 of 16 patients)
suggests that patients with Stage B and C disease can
be cured with the COPP combination. To the authors’
knowledge, there has been no report in the literature
on the treatment of IPSID with as many patients receiving a prospective standard treatment protocol and
for as long a duration of follow-up as in the current
study. Therefore, other than being a prospective study,
the current study is valuable with regard to the number of patients and length of the follow-up period.
Because of the rarity of the disease, multicenter trials
are needed for prospective comparative studies to
evaluate the efficacy of the treatment protocols.
4.
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