Prognostic factors in primary gastrointestinal non-Hodgkin's lymphoma. A multivariate analysis,...

Prognostic Factors in Primary Gastrointestinal Non-Hodgkin’s Lymphoma

A Multivariate Analysis, Report of 106 Cases, and Review of the Literature

MOHAMED B. AZAB, MD, MSC, MICHEL HENRY-AMAR, MD, PHlLlPPE ROUGIER, MD, CAROLINE BOGNEL, MD, CHRISTINE THEODORE, MD, PATRICE CARDE, MD, PHlLlPPE LASSER, MD, JEAN-MARC COSSET, MD,

BERNARD CAILLOU, MD, JEAN-PIERRE DROZ, MD, AND MARCEL HAYAT, MD

The authors have reviewed 106 cases of primary gastrointestinal non-Hodgkin’s lymphoma (GI-NHL) treated at the Institut Gustave-Roussy (IGR), France, between 1975 and 1986. The occurrence was 55 in the stomach, 26 in the small intestine, ten ileocecal, seven in the large intestine, and eight patients had multiple involvement. Patients were clinically staged according to the Ann Arbor staging system using the modification of Musshoff for Stage IIE. All histologic material of the 106 patients were reviewed and graded according to the Working Formulation (WF) and the Kiel classifications. Most patients received combination chemotherapy as part or all of their primary treatment program (95 patients, 90%). Seventy five patients (71%) had a multimodality treatment. The overall 5-year survival rate was 60%. Sixteen variables were tested by univariate analyses for prognostic influence on survival. Of these, only clinical stage (P < 0.001), the achievement of initial complete remission (CR) (P < 0.001), erythrocyte sedimentation rate (ESR) (P = 0.01), mesenteric involvement (P = 0.03), and serosal infiltration (P = 0.05) were significant prognostic factors. Important variables were tested by a multivariate analysis using the Cox model taking into account different treatment modalities. Only three variables entered the regression analysis a t a significant level: clinical stage (P = 0.02), surgical resection (P = 0.03), and histologic grade (Kiel) (P = 0.04). When the achievement of initial CR was introduced into the model, it was the most significant variable (P < 0.001) whereas all other variables became nonsignificant except for the histologic grade (Kiel) (P = 0.004). Based on results of the multivariate analyses we propose two prognostic classifications of patients: one at the initial evaluation depending on clinical stage, surgical resectability, and histologic grade (Kiel); the other at the end of primary treatment depending on the achievement or not of CR and the histologic grade.

Cancer 64:1208-1217. 1989.

LTHOUGH PRIMARY gastrointestinal non-Hodglun’s A lymphomas (GI-NHL) have been reported with varying incidence, it is generally agreed that they represent the most frequent extranodal site of NHL as 4% to 18% of all NHL occur in the gastrointestinal (GI) tract.’.’’ They account for 30% or greater of all primary extranodal lymphomas. l 2 - I 4 Review of the literature showed that prognostic factors in primary GI-NHL have been reported with mostly conflicting results (Table 1) .1,227,8,10*15-57

Presented in part at the 13t@ Congress of the European Society for Medical Oncology, Lugano, Switzerland, October 30-November 1.

From the Departments of Medical Oncology, Medical Statistics, Gas- troenterologic Oncology, Histopathology. Surgical Oncology, and Ra- diotherapy, Institut Gustave-Roussy, Villejuif, France.

The authors thank Mrs. Michelle Morrow for typing the manuscript. Address for reprints: Mohamed B. Azab, MD, MSc, Department of

Medicine A, Institut Gustave-Roussy, Rue Camille Desmoulins, 94805 Villejuif Cedex France.

Accepted for publication March 10, 1989.

The number of prospective series is scanty and they

of the reported prognostic factors are interrelated: primary gastric lymphomas tend to be diagnosed in older

at an early stage7J5:1’30 with superficial mural pr~l i ferat ionl~,~~ and low-grade histologic type.” This is in contrast to intestinal lymphomas occurring usually at a younger age6*7327 with important male predom-

and presenting at a more advanced stage7 with deeper GI wall infiltration” and high-grade histologic type.’9,2’ Also, size of the primary tumor is related to stage,24 lymphomas with low-grade histologic type are less likely to infiltrate adjacent structures or have distant lymph node invol~ement ,~~ and high-grade histologic type tumors tend to be associated with more DNA aneu- p10idy.~~

To overcome bias created by interdependence of var- ious prognostic factors, several authors reported their re-

only included a small number of patients.30,33,34,55 M any

1208

No. 6 PROGNOSIS IN GI-NHL - Azab el a/. 1209

TABLE 1. Reported Prognostic Factors in Primary Gastrointestinal Non-Hodgkin’s Lymphoma: Review of the Literature

Prognostic factors for survival

Authors reporting as Authors reporting as nonsignificant

significant (reference nos.) (reference nos.)

1: Age

2: Sex

Worse survival at older age

Male worse than female

3: Site Gastric better than intestinal

4: Clinical stage

5: Histologic type

IE-IIE better than 111-IV; IIlE better than 112E

Rappaport classification: nodular better than diffuse

Kiel classification: Low grade better than high grade Working formulation: low or intermediate better than high grade Lukes and Collins classification: cleaved better than noncleaved cell type

Worse prognosis with larger size 6: Primary tumor size

7: Infiltration of serosa or into adjacent structures

8: Multifocal lesions

9: Mesentenc infiltration

10: Palpable abdominal mass

1 1 : GI perforation

12: Performance status Better survival with Karnofsky >70

Better survival with complete resection

Better survival in patients receiving RT alone or after surgery

Better survival in patients receiving CT

13: Surgery

14: RT

15: CT

16: Achievement of CR

17: DNA aneuploidy Worse prognosis for aneuploid gastric lymphoma

R T radiotherapy; CT: chemotherapy: CR: complete remission; GI:

* Multivariate analysis. gastrointestinal.

sults using multivariate analyses. 15319,21.24,34,45,46 However, many of these studies were carried out over a very long period oftime15.19,24,46 and different treatment modalities were not taken into a c ~ o u n t , ~ ~ , ~ ~ combination chemotherapy was rarely given if any21.24-45.46 and none of them reported the relative death risk attributed to each significant factor. We report here our experience in the treatment of 106 patients with primary GI-NHL the majority of whom (90%) received combination chemotherapy as part or all of their primary treatment program. Based on results of the multivariate analysis of prognostic factors,

15*-18

15.; 16, 19,: 25

1, 7, 10, 17. 19,; 26-29, 301.-32

2, 7, 15*-18, 19,; 21, 22, 24,; 33,t. 35-41

8, 26

2. 16. 19,; 21, 31, 33, 43 21, 30,t 46 47

16, 18. 24, 37. 45,;. 48.

18, 21, 23, 24,* 31, 38,

21, 39

20,22

18

17, 51

34t

49

44, 45, 46,* 49

17, 21,: 21, 33.t 34,$ 37,

7, 18, 37, 41, 43, 56

45.; 46.; 52-54, 557

24, 39. 41, 55t

30.t 33,t 344 35, 40

46

7, 19,* 20, 21,: 22, 23, 24*

7. 20, 2 1 ,* 24*

15,; 21,*, 24,: 33.t 34$

30,t 34$

7, 10, 15,; 17. 19,: 22,

15,: 25, 37, 44, 45; 10, 19,; 35, 46; 39

38, 50

23.42

7

20

34#

7, 24

16, 24, 44, 52, 57

44. 57

46”

t Prospective studies. $ Multivariate analysis in a prospective study.

patients could be classified into different groups with sig- nificantly different prognostic profiles.

Materials and Methods

We reviewed all medical records of patients diagnosed at the Institut Gustave-Roussy (IGR), France, between 1975 and 1986 as having primary GI-NHL. The primary involvement of the GI tract was defined according to the definition of Lewin et a/.” which was also used by other a ~ t h o r s . ~ , ~ , ~ ~ . ~ ~ , ~ ~ ~ ~ ~ . ~ ~ This definition includes patients

1210 CANCER September 15 1989 Vol. 64

presenting with GI symptoms in whom lymphoma was confined to or was clearly predominant within the GI tract.

One hundred seventy-two patients were considered for this study. We had to exclude 66 patients for the following reasons: 24 patients who only had a consultative opinion and did not have their treatment followed at the IGR; 17 patients were found to have a primary retroperitoneal or mesenteric involvement with no identifiable GI lesions; 14 patients for whom no histopathologic material was available for review; four patients were considered as having a secondary GI involvement of NHL upon review of their medical records; three patients had pseudolym- phoma, three patients had primary pancreatic and one patient had a primary liver lymphoma. The remaining 106 patients form the basis of this report.

The initial evaluation for each patient included a complete history and physical examination, complete blood counts, chest roentgenograms, and liver and renal function tests. Almost all patients ( 102 patients) had either abdominal ultrasound, lymphangiogram, abdomen and pelvis computed axial tomography (CAT) scan, or more than one of these at initial presentation. Initial bone marrow trephine biopsy was done in 87 patients, and liver isotopic scan or liver biopsy was available in 61 patients. Histo- pathologic diagnoses were first reached by endoscopic biopsies in 48 patients (45 gastroduodenal and three co- lorectal lymphomas). The remaining 58 patients had their diagnoses only by surgical specimen. All histologic materials were reviewed by two of us (C.B. and B.C.).

Depending on data from the initial evaluation, operative findings and histologic review, patients were staged according to the Ann Arbor staging system5' and were classified according to both the International Working Formulation for clinical usage6' and the Kiel classification.6' Stage IIE patients were further subdivided according to the modification proposed by Musshoff into Stage I1 1 E for perigastric or mesenteric nodal involvement and stage II2E for those with abdominal lymph node involvement not contiguous with the primary GI site.62

Ninety-five patients (90%) were treated with combination chemotherapy: 37 patients as the first-line treatment modality, 27 patients as complementary treatment after incomplete surgical resection, and 3 1 patients as adjuvant therapy after complete resection. Sixty patients (57%) had a regimen of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or CHOP-like regimen in which teniposide (VM-26) was substituted for vincristine (CHVmP) as described in the European Or- ganization for Research and Treatment of Cancer (EORTC) NHL trials.63 Thirty patients received either less-aggressive regimens of cyclophosphamide, vincristine, and prednisone (COP) or COP-like regimens (nine patients) or more aggressive (with at least six cytotoxic

agents) regimens (2 1 patients) depending on whether they had low-grade or high-grade histologic features. Five patients received other variable three-to-four drug regimens containing Adriamycin (doxorubicin).

Eighty-four patients were operated on (79%). Surgical interventions included the following: 18 partial gastrectomies; nine total gastrectomies; ten extended total gastrectomies; 19 intestinal resections, one of them with splenectomy; eight colectomies of whom one was associated with ovariectomy; four terminal ileal resections with right hemicolectomy; one rectosigmoid resection; one resection of anal lymphoma; and one combined partial gastrectomy with intestinal resection. Thirteen operated patients had unresectable primary tumors and only surgical biopsies were performed. No formal staging laparatomy was done. There was only one postoperative mortality from peritonitis after partial gastrectomy.

Radiotherapy (RT) delivered either with a telecobalt unit or a linear accelerator was integrated in the primary treatment program of 29 patients (27%). Doses ranged from 1000 to 4000 cGy with a mean dose of 3300 cGy (Standard Error 1200) distributed with a mean fraction- ation of 18 settings (SE 6). Irradiated fields included the primary tumor site (12 patients), whole abdominal (ten patients), inverted-Y (two patients), a combination of these (three patients), and two patients with high-grade ileocecal lymphoma received prophylactic central nervous system irradiation.

Since most patients received a multimodality primary treatment, responses were evaluated at the end of the whole treatment program. Initial complete remission (CR) was defined as disappearance of all clinical, radiologic, and histologic evidence of disease.

Patients were followed up at regular intervals with clinical, radiologic examinations, and endoscopic biopsies if necessary.

Statistical Analysis

In the analyses, survival status was considered as the end point. Time at risk began at the initiation of first therapy and ended at the date of death, date of last known status, or January 1, 1988, whichever came first. At the time of analysis, the median follow-up for the whole patient population was 47 months. The prognostic value of each of the 15 initial patient characteristics presented in Table 2 plus the value of achieving initial CR were first estimated in a univariate fashion using the log-rank test.64 In a second step, all variables which were found to display a prognostic influence on survival plus age, sex, histologic grade, and treatment type were considered in the proportional hazards regression model described by However, only variables available for all patients were considered in the analysis. Seven patients for whom the

No. 6 PROGNOSIS IN GI-NHL - Azab et al. 121 1

TABLE 2. Initial Patient Characteristics

Small Large Primary site Stomach bowel Ileocecal bowel Multiple

No. of patients

Age ( Y O Range Median

Sex (M/F)

Clinical features (no. [TO]) Systemic symptoms* Presentation with surgical complicationst Abdominal mass

Blood picture HB

Range (9/ 100 ml) Median

Leukocytes Range (X 103/mm3) Median

Range (mm first hr) Median

Clinical stage

ESR

IE IIlE II2E I I I IV

Histologic type WF

LG IG HG uc LG HG uc

Kiel

Mesenteric infiltration Surgical findings*

Tumor size (cm) Range Median

Serosal infiltration

55

18-86 46

1 5 1

4 (7) 10 (18) 2 (4)

4-15.5 11.9

2.7-2 1.9 7.2

1-99 15

19 7

20 3 6

14 26 10 5

26 24

5

0

2-20 9

16

26

11-71 39

4.2: 1

6 (23) 12 (46) 9 (35)

7.1-14.2 11.6

2.8-23 1.15

3-85 35

5 5

10 I 5

3 17 5 1

11 14

1

13

4-25 8 7

10

11-63 21

4: 1

l (10) 4 (40) 5 (50)

9.6-1 4.3 11.5

6.1-9.7 7.0

7-47 23

2 0 6 0 2

2 3 5 0

2 8 0

5

5-20 8 7

7

13-75 50

2.5: 1

2 (28) 4 (57) 2 (28)

7.9-15 12.7

6.6-14.4 9.75

13-134 45

1 2 1 0 3

1 1 5 0

1 6 0

2

2-10 5 2

8

14-79 50

I:1

2 (25) 3 (38) 1(13)

8.1-13.8 11.4

3.2-1 1.5 7.7

21-80 38

1 I 4 1 1

4 3 0 1

6 1 1

2

2-12 8 5

Total

106

1 1-86 41

2: I

15 (14) 33 (31) 19 (18)

4-15.5 11.8

2.7-23 7.25

1-134 24

28 15 41

5 17

24 50 25

7

46 53 7

22

2-25 8

37

HB: hemoglobin; ESR: erythrocyte sedimentation rate; WF: Working Formulation; LG: low grade; IG: intermediate grade; HG: high grade; UC: unclassifiable.

histologic type of lymphoma could not be defined were excluded bringing to 99 the number of patients included in the multivariate model. Relative risks (RR) of death were then calculated for several profiles of patients using the prognostic variables which emerge from the regression analysis at a 0.05 level. The equation used was the following:

RR = exp. (Zi Bi Vi)

where Bi is the coefficient of risk emerging from the analysis corresponding to the variable Vi. The parameter Vi

* Systemic B-symptoms as defined by the Ann Arbor Stagings9

* Only in operated patients in whom this information was available. Hemorrhage, perforation. or occlusion.

is coded 1 when the characteristic is present, otherwise it is coded zero.

Data were analyzed using a specific database management statistical software developed at the IGR.66. For regression analysis, the BMDP-2L program was used.67 Adjusted survival curves were plotted using the Kaplan- Meier method.68

Results

Initial patient characteristics are shown in Table 2. Complete response and the overall 5-year survival rate


TABLE 3. Treatment Response and Survival According to Treatment Modalities

TABLE 5. Cox's Model Analysis: Relative Risk of Death in a Model Testing All Variables Simultaneously

No. of patients in 5-yr survival Treatment modalities CR/no. treated % (SE)

Regression Standard RR of P Factors tested coefficient error death* value

~

Only surgical resection (complete or incomplete) 8/9 63 (17)

Only chemotherapy 8/22 42 (13) Resection + RT 212 2 Alive Resection + CT 32/46 63 (7) RT + CT 11/13 55 (19) Resection + RT + CT 13/14 75 (13)

Total 74/ 106 60 (5)

RT: radiotherapy; CT: chemotherapy; C R complete remission. Overall comparison nonsignificant.

according to primary treatment modalities are shown in Table 3.

There was no overall significant dieerence in survival rate in the different treatment groups by univariate analysis. Significant prognostic factors for survival by univariate analysis are reported in Table 4. It is to be noted that age, sex, primary GI site, initial tumor size, and histologic grade (low versus intermediate versus high grade by the Working Formulation) were all nonsignificant. When the histologic grade by the G e l Classification was analyzed, high-grade tumors tended to do worse but the difl'erence between the 5-year survival rates of low-grade (66%) and high-grade tumors (53%) did not reach statistical significance ( P = 0.13).

Results of the multivariate analysis are given in Table 5. Only three variables entered the regression analysis

TABLE 4. Significant Prognostic Factors by Univariate Analysis

No. of 5-yr survival P Factors patients % (SE) value

Clinical Stage IE HIE I12E Ill + 1v

Initial CR Yes No

ESR* (85 patients) 30 30

Mesenteric involvement Yes No

Serosal infiltration* (49 patients)

Yes No

28 15 41 22

74 32

45 38

22 84

37 12

<0.001 81 (9) 80 (10) 53 (8) 31 ( 1 1 )

<O.OOl 79 (5) 15 (7)

70 (8) =o.o 1

50 (9)

= 0.03 42(11) 64 (6)

=0.05 43 (9) 83111)

CR: complete remission: ESR: erythrocyte sedimentation rate. * Information not available for all patients.

Age (YO Sex (M/F)

Site (gdstric/others)

Mesenteric Inf (yes/no)

Clinical stage IIZE/IE + I I lE Ill + IV/IE + HIE

Histologic type (Gel) (HG/LG)

Surgical resection? (ndyes)

RT (no/yes)

CT (no/yes)

0.0146

0.3052

0.0349

0.659 1

1.0880 1.2765

0.7766

0.8988

0.8008

-0.4360

0.0 102

0.4 I 34

0.4543

0.4582

0.46 18 0.5049

0.3808

0.4146

0.428 1

0.7257

1.01

1.36

I .04

1.93

2.97 3.58

2. I7

2.46

2.23

0.65

NS

NS

NS

NS

=0.02 =O.Ol

=0.04

=0.03

=0.06

NS

HG: high grade; LG: low grade; R T radiotherapy; CT: chemotherapy;

Overall P value < 0.00 1 * RR = Exp (pi) where t Includes complete and incomplete resection.

RR: relative risk; Ink infiltration; Exp:-exponent; NS: nonsignificant.

is the regression coetficient.

model at a significant level. These were clinical stage, histologic grade (Kiel), and surgical resection. It is worth mentioning that when the achievement or not of initial CR was introduced into the model it was the most significant variable ( P < 0.00 1 ; RR of death for no CR = 17) followed by the histologic grade (Kiel) ( P = 0.004; RR for high grade = 3.5) whereas stage and surgical resection lost their significant influence.

Based on results of the multivariate analyses, relative death risks could be attributed to patients according to

TABLE 6. Relative Death Risks as Related to Significant Factors by Multivariate Analysis (Initial Evaluation)

Histologic Clinical Surgical grade No. of

stage resection (Kiel) patients RR*

IE-I1 1 E Yes LG 14 1 .o HG 17 2.17

NO LG 6 2.46 HG 5 5.34

I12E Yes LG 16 2.97 HG 14 6.45

No LG 2 7.29 HG 6 15.85

1I1-1V Yes LG 4 3.58 HG 3 7.79

No LG 4 8.80 HG 8 19.14

LG: low grade; HG: high grade. * Relative death risk (RR) calculated from data of Table 5.

No. 6 PROGNOSIS IN GI-NHL h u b et uf. 1213

TABLE 7. Relative Death Risks as Related to Prognostic Factors by Multivariate Analysis (Posttreatment Evaluation)

Adjusted

Prognostic to grade No. of survival Response Histologic 5-yr

Group treatment (Kiel) patients (YO) RR

A CR LG 34 83 1 .o B HG 37 77 3.48

C‘ No CR LG 12 24 16.58 D’ HG 16 0 58

CR: complete remission; RR: relative risk of death; LG low grade; HG: high grade.

their profile at onset taking into account clinical stage, histologic grade (Gel), and surgical resectability (Table 6). At the end of the primary treatment program and depending on whether or not a complete response was achieved, patients’ relative death risks could be reevalu- ated (Table 7). Consequently, at each evaluation patients with similar prognostic profiles could be grouped together, thus giving us four prognostic groups.

At initial staging the four groups could be synthesized as follows: Group A (14 patients, RR of death = 1 .O, adjusted 5-year survival rate 91%): Clinical Stage (CS) I, I1 1 E, resectable with low-grade histologic features (Kiel); Group B (43 patients, RR of death 2.0-4.99, adjusted 5- year survival 65%): CS I, I1 1 E, resectable high-grade/CS I, I1 1 E unresectable low-grade/CS II2E, 111, IV, resectable low-grade: Group C (28 patients, RR of death 5-9.99, adjusted 5-year survival 48%): CS 1, IllE unresectable high-grade/CS II2E, 111, IV resectable high-grade or unresectable low-grade; and Group D (14 patients, RR of death = 10.0, adjusted 5-year survival 27%): CS II2E, Ill, IV unresectable high-grade.

At posttreatment evaluation the four prognostic groups (A’, B’, C’, D’) are described in Table 7.

Figures 1 and 2 show the adjusted survival curves of these proposed prognostic groups (overall P value < 0.00 I ).

Discussion The GI tract is the most frequent site of extranodal

involvement in NHL,’,1’.14.’6.48 however primary GI-NHL remains relatively rare. 3,6y Non-Hodgkin’s lymphoma is a rather uncommon tumor in the GI tract if compared to other GI malignancies: it represents 1% to 10% of all

bowel and only 0.2% to 0.4% of large bowel malignant turn or^.^',^^

Primary gastric lymphoma is the most common form in western countries accounting for 24% of extranodal lymphoma38 and 35% to 79% of GI-NHL.’5*2’,22,24*27.40,48 However, in the Middle East and Mediterranean countries primary intestinal lymphoma is the most common form

gastric malignancies4- 1 1.14.23.2737.38. , 18% to 24% of all small

p < 0.00 1

0 1 2 3 4 5 6 7 Years from start of treatment

FIG. 1 . Overall survival curves related to the proposed prognostic groups at initial evaluation. Group (A): CS 1-11 1 , LG resectable; Group (B): CS 1-11 I , HG resectable/I-I11 , LG unresectable/II2-1ll-lV, LG resectable; Group (C): CS 1-111, HG unresectable/lI2-IIl-IV, HG resectable or LG unresectable; Group (D): CS I12-Ill-IV, HG unresectable.

accounting for 50% of extranodal and 75% of GI lym- p h ~ m a . ’ ~ This is due to the predominance in these countries of the so-called Mediterranean lymphoma better known as the immunoproliferative small Intestinal disease (IPSID) or alpha heavy chain disease. The distinctive ep- idemiology, clinical aspects, and pathologic and immunologic features of this disease were described else- where.72-74 No patients having IPSID were included in this study.

Prospective series concerning GI-NHL are scanty and they included a small number of patients usually insuf- ficient to provide reliable prognostic analysis.30*33,34~s5 Prognostic data provided in the literature are conflicting for the most part (Table 1).

Only multivariate analyses should be considered since most of the proposed prognostic factors are interdepen- dent. In this study we report a multivariate analysis of prognostic factors in primary GI-NHL from a single in-

50

25 p< 0.00 1

I I . 1

0 1 2 3 4 5 6 7 Years from start of treatment

FIG. 2. Overall survival curves related to the proposed prognosticgroups at the posttreatment evaluation. Group (A’): LG tumors in CR (n = 34); Group (B‘): HG tumors in CR (n = 37); Group (C’): LG tumors with no CR (n = 12); Group (D’): HG tumors with no CR (n = 16).


stitution treated over a relatively short period of time and including 106 evaluable patients in whom most relevant clinical and histologic information were available.

In the current series several factors proved to have a significant influence on survival by univariate analysis (Table 4). Other series have previously pointed out the prognostic value of clinical initial CR,30-33-35940 mesenteric involvement20.2’ and serosal infiltrati~n~’.~~.’~.~~.~~.~~ in primary GI-NHL. Erythrocyte sedimentation rate (ESR) is of prognostic significance in Hodgkin’s disease75; moreover, it is an important biolog- ical marker of tumor bulkiness which is an ominous prognostic sign in nodal NHL.76 Contrary to other series reporting significant prognostic influence of sex,15.16.19,25 initial presentation with perforation, 17s1 pri-

and histologic grade by the Working F o r m ~ l a t i o n , ~ ~ . ~ ~ . ~ ~ these factors were not significant for overall survival in our series; however, tumors with low-grade histologic type by Kiel tended to have a better survival.

Most multivariate analyses in the literature did not re- veal a significant prognostic influence of age.19,2’.24 As for sex, Aozasa et af., using Cox’s model, have insisted on the worse survival of male patients in two report^.'^'.^ They suggested that the marked male predominance in intestinal lesions which have a worse prognosis was the reason behind this finding” since other reports failing to observe a prognostic influence of sex did not have a high male predominance in intestinal lesion^.^." In our series small intestinal and ileocecal lesions showed a higher male predominance (4: 1) than gastric lesions ( 1.5: 1 ) and yet male patients did not have a worse prognosis. However, intestinal lesions did not reflect a worse survival in our patients. This is in contrast to other series reporting a better prognosis of primary gastric lymphoma but in many of these reports gastric NHL was usually diagnosed in a less advanced ~ tage ,~ ,” ,~’ had a lower histologic grade and less multifocal Iesions.I9

Good staging systems should furnish prognostic data for site and extent of disease.77 The Ann Arbor staging system has a confirmed prognostic value in nodal lymphomas particularly when Stage I is compared to other stage^,^'.^^ however it is not well adapted to extranodal lymphomas. In primary GI-NHL the modification proposed by Musshoff6’ to subdivide stage IIE patients according to site of abdominal lymph node involvement has consistently provided relevant prognostic information since most authors have reported a worse survival for Stage II2E as compared to Stage I11 E.2,7.19-24,33 Other authors preferred using the TNM c l a s ~ i f i c a t i o n ~ ~ ~ ~ ~ or a modification of it called the Manchester system.17,52.80 Whatever the staging system used, the initial clinical stage seemed to be an important prognostic f e a t ~ r e . ~ , ~ , ~ ~ , ~ ~ , ~ ~ . ~ ~ . ~ ~ As previously reported in other series, the prognosis of Stage

mary GI site,1.7.10.17.19.30 tumor size, 16.18.24.45.48

I1 1 E patients was much similar to Stage I in our study. Patients with Stages I, lI lE had a better survival than Stage II2E who in turn did better than Stages 111, IV (Ta- bles 4 and 5). This is similar to the experience of Herr- mann et aL7

One of the most debated prognostic factors in primary GI-NHL is the histologic subtype. To date, in extranodal as well as in nodal NHL no single histologic classification has given full satisfaction in terms of prognosis. Several authors in an attempt to improve the prognostic index of existing histologic classifications have suggested different modifications in recent report^.^'-^^ High-grade primary GI-NHL using the Working Formulation was reported to have a worse survival by univariate a r ~ a l y s e s . ~ ” ~ ~ ~ ~ ~ One of these reports failed to confirm these results by a multivariate analysis.46

In concordance with our results, Aozasa et a l l9 were not able to demonstrate a prognostic value of the Working Formulation by multivariate analysis but did show a significant prognostic influence of the histologic grade using the Kiel classification. Several other authors reported a significant prognostic value of histologic grade in primary GI-NHL on the basis of the Kiel classifica-

The Kiel classification was also prognostic and in head and neck primary extra-

nodal lymphoma.88 The reason for nonsignificance of the Working Formulation may be that the diffuse large cell lymphomas recognized as an intermediate-grade tumor by the Working Formulation would behave as a high- grade malignancy and they are classified as such in the Kiel classification under the centroblastic and immuno- blastic subtype^.^^^^' The prognosis of diffuse large cell lymphoma would largely influence any analysis of prognostic factors in primary GI-NHL since this is the predominant histologic type in GI lymphoma^.'^.^^^^',^^

Knowledge of the prognostic factors that characterize a disease is an important prerequisite for planning treatment and designing clinical trials. The best treatment for patients with primary GI-NHL remains uncertain. Most authors still recommend surgical resection as the first-line treatment for primary GI-NHL.16.24,34,38,45.48.52,57 Argu- ments in favor of surgery are large pathology specimens with more reliable histologic typing than endoscopic

, accurate staging and assessment of important prognostic data such as primary tumor size, serosal infiltration, lymph node involvement, and size of residual

unresected tumors responding to primary chemotherapy , and finally the possibility to cure patients

with surgery alone. 18.23,27.44,57

Although some authors have stressed the fact that only complete or radical surgical resection gives the best re- s u l t ~ , ~ ~ . ~ ~ ’ ~ ~ . ~ ~ ~ ~ ~ . ~ ~ - ~ ~ others did not find a worse survival for patients undergoing nonradical surgery or patients with

tion.2. 16.2 I .3 1.33,43

in noda163.78.79.86.87

biopsies21,27,5 1.57.

tUmOr5.20,33.56.57. , avoiding hemorrhage and perforation of

or ~ ~ 6 . 3 4 . 4 0 . 5 7 .

No. 6 PROGNOSIS I N GI-NHL - Azub et uf. 1215

involved margins if postoperative RT or chemotherapy were given.2,23,41,89 This was true in our series since surgical resection (including incomplete resection) was a significant variable by multivariate analysis. Most of our resected patients (62/7 1,879'0) received either RT or chemotherapy or both. It seems here that the debulking procedure is the predominant element. Sheridan et al., in a prospective study of surgery followed by chemotherapy in primary gastric lymphoma showed a better survival in all patients who had surgical resection even those with involved margins and those with an initially advanced Stage IV disease." It is obvious here that for these patients surgery itself was not curative, however it continued to exercise a favorable influence on survival probably due to debulking. It has previously been suggested that the poor response rate and survival of patients with bulky NHL would justify a surgical approach to try to remove the bulk of the disease before chemotherapy is given.76 A retrospective study of patients with abdominal Burkitt's lymphoma has also shown this approach to be of value."

Although surgery remains to date the recommended first-line therapy for primary GI-NHL, several studies have consistently reported an improved survival rate by postoperative RT and/or ~hemotherapy.~~,~~*~'~'~-~~ Other more enthusiastic reports have suggested that RT' or chemotherapy by CHOP9' or CHOP-bleomycin'* can replace surgery as the first-line treatment of GI-NHL. However, these results need to be confirmed and the problem of fatal hemorrhage or perforation of unresected lesions remains to be resolved.

We have taken into account the different treatment modalities in the multivariate proportional hazards model of Cox. The only treatment modality that entered the regression analysis at a significant level was surgical resection ( P = 0.03, RR of death for no surgical resection = 2.5). Radiotherapy had a border line significance (P = 0.06; RR for no RT = 2.2). Chemotherapy was not significant however it is impossible to draw any conclu- sions concerning chemotherapy since most patients (90%) received this treatment modality.

The idea of giving chemotherapy as adjuvant or complementary treatment in primary GI-NHL seems to be most seducing for several reasons. First, it is generally agreed that the predominant histologic subtypes of GI-NHL are the diffuse histiocytic (Rappa- port)7,10~'5~22~24~40,48,54 or the diffuse large cell (Working Form~lation).'~~'~~~~~~'~~'~~~ These are the histologic subtypes in which most progress of chemotherapy has been made in recent years with a consistently reported high cure rate.93-96 The second reason is that about 50% or more of relapses of primary GI-NHL are usually extraabd~minal'~,*~'~~-~~ ho wever in two recent prospective series applying postoperative chemotherapy no distant relapses and one of them reported an excel-

lent actuarial survival rate of 94% in primary gastric lymphoma including advanced Stage IV patients with a median follow-up of 4 1 months.55 Finally, chemotherapy would permit the adoption of less aggressive surgical pro- cedures thus diminishing surgical morbidity and mortal- it^.^' A relatively important postoperative mortality of 5% to 25% has been reported in older series.',18.27,37.38,45,69

Achievement of initial CR is a fundamental step for cure of large cell lymphoma.93 In nodal NHL, patients achieving CR have always been reported to have a much superior survival rate and longer median survival time.76,86794296 The highly favorable impact of initial CR on survival has also been reported in patients with primary GI-NHL30"3-35,40 including the only prospective series using a multivariate analysis of prognostic fact01-s.~~ Indeed, in our series when the achievement of initial CR was introduced into the regression model it was the most significant variable whereas clinical stage and surgical resection became no longer significant. However histologic grade (Kiel) kept a significant influence on survival since some patients with low-grade histologic type continued to survive with the disease whereas high-grade patients all died within the first 2 years if no complete remission was achieved. This is in concordance with the natural history of low-grade nodal NHL.97,98 It is also in agreement with published results in the treatment of GI-NHL reporting death of most or all patients within 2 years if CR was not a ~ h i e v e d . ~ ' * ~ ~ * ~ ~

In this report we propose for the first time a prognostic classification based on results of a multivariate analysis. Two classifications are proposed: the first one at the time of initial evaluation depending on clinical stage, surgical resectability, and histologic grade (Kiel) (Fig. 1). The second classification could be used at the end of the primary treatment program depending on the histologic grade (Kiel) and whether or not an initial CR was achieved (Ta- ble 7, Fig. 2).

In the absence of prospective studies addressing the is- sue of prognostic factors of primary GI-NHL in a sufficient number of patients, prognostic data will continue to be provided by retrospective studies. It is possible that patients with primary GI-NHL could be cured at similar proportions using different programs of single or multimodality treatment according to clinical stage and histologic grade. Only carefully designed prospectively ran- domized clinical trials could precisely appreciate the mer- its and hazards of different treatment programs and provide reliable answers.

REFERENCES

1 . Allen AW, Donaldson G , Sniffen RC et al. Primary malignant lymphoma of the gastrointestinal tract. Ann Surg 1954; 140:428-437.

2. Back H, Gustavsson B, Ridell Bet al. Primary gastrointestinal lymphoma: Incidence, clinical presentation, and surgical approach. J Surg Oncol 1986; 33:234-238.


3. Bush RS, Ash C L Primary lymphoma ofthe gastrointestinal tract. Radiology 1969; 92:1349-1354. 4. Contreary K, Nance FC, Becker WF: Primary lymphoma of the

gastrointestinal tract. Ann Surg 1980; 191593-597. 5. Goffinet DR. Warnke R, Dunnik NR et a/. Clinical and surgical

(laparotmy) evaluation of patients with non-Hodgkin’s lymphomas. Cancer Treat Rep 1977; 6 l:98 1-992.

6 . Hande KR, Fisher RI, DeVita VT ef al. Diffuse histiocytic lymphoma involving the gastrointestinal tract. Cancer 1977; 41:1984-1989. 7. Herrmann R, Panahon AM, Barcos M et al. Gastrointestinal in-

volvement in Non-Hodgkin’s lymphoma. Cancer 1980; 46:2 15-222. 8. Jones SE, Fuks Z, Bull M cf al. Non-Hodgkin’s lymphomas. IV

Clinicopathologic correlation in 405 cases. Cancer 1973; 3 1306-823. 9. Lee YN. Spratt JS. Malignant Lymphoma: Nodal and Extranodal

Diseases. New York: Grune and Stratton, 1974; 229-260. 10. Liang R, Todd D, Chan TK et al. Gastrointestinal lymphoma in

Chinese: A retrospective analysis. IIematol Oncol 1987; 5: 115-126. I 1 . Rosenberg SA, Diamond HD, Jaslowitz B et al. Lymphosarcoma:

A review of 1269 cases. MedLcine 1961; 40:31-84. 12. Aozasa K, Tsujimoto M, Sakurai M ef at. Non-Hodgkin’s lyrn-

phomas in Osaka, Japan. Eur J Cancer Clin Oncol 1985; 2 I :487-492. 13. Boddie AW, Mullins JD. West G et al. Extranodal lymphoma:

Surgical and other therapeutic alternatives. In: Year Book of Surgery. Chicago: Year Book Medical Publishers. 1982; 3-64. 14. Freeman C. Berg JW, Cutler SJ: Occurence and prognosis of ex-

tranodal lymphomas. Cancer 1972; 29:252-260. 15. Aozasa K. Tsujimoto M, Inoue A et al. Primary Gastrointestinal

lymphoma: A clinicopathologic study of 102 patients. Oncology 1985;

16. Dowrkin B, Lightdale CJ, Weingrad DN et al. Primary gastric lymphoma: A review of 50 cases. Dig Dis Sci 1982; 27:986-992. ‘17. Green JA, Dawson AA, Lessells AM et al. Prognostic factors in

Gastrointestinal Lymphoma. Clin Oncol 1981; 7:l 15-131. 18. Shiu MH, Karas M, Nisce L et ul Management ofprimary gastric

lymphoma. Ann Surg 1982; 195: 196-202. 19. Aozasa K, Ueda T, Kuruta A ef ul. Prognostic value of histologic

and clinical factors in 56 patients with Gastrointestinal Lymphomas. Cancer 1988; 61:309-315. 20. Dawson IMP. Cornes JS, Morson BC. Primary malignant lym-

phoid tumours of the intestinal tract: Report of 37 cases with a study of factors influencing prognosis. Br J Surg 196 1; 49:80-89. 2 1 . Dragosics B, Bauer P, Radaszkiewicz T. Primary gastrointestinal

non-Hodgkin’s lymphomas: A retrospective clinicopathologic study of 150 cases. Cancer 1985; 55:1060-1073. 22. Lewin KJ, Ranchod M, Dorfman RF. Lymphomas of the Gas-

trointestinal tract: A study of 117 cases presenting with Gastrointestinal disease. Cancer 1978; 42:693-707. 23. Shimm DS, Dosoretz DE. Anderson T et ul. Primary gastric lym-

phoma: An analysis with emphasis on prognostic factors and radiation therapy. Cancer 1983; 52:2044-2048. 24. Weingrad DN. Decosse JJ, Sherlock P ef al. Primary gastrointes-

tinal lymphoma: A 30-year review. Cancer 1982; 49: 1258-1265. 25. Morgan DR, Holgate CS, Dixon MF el al. Primary small intestinal

lymphoma: A study of 39 cases. J Patliol 1985; I47:2 1 1-22 I . 26. Azzopardi JG, Menzies T. Primary malignant lymphoma of the

alimentary tract. Br J Surg 1960: 47:358-366. 27. Loehr WJ, Mujahed Z, Zahn D et al. Primary lymphoma of the

Gastrointestinal tract: A review of 100 cases. Ann Strrg 1969; 170:232- 238. 28. McGovern VJ. Lymphomas of the gastrointestinal tract. In: Yar-

dey JH, ed. The Gastrointestinal Tract. Baltimore: Williams and Wilkins,

29. Mestel AL. Lymphosarcoma of the small intestine in infancy and childhood. Ann Surg 1959; 149:87-94. 30. Parlier Y, Najman A. Lecompte D of d. A prospective study of

the treatment ofprimary digestive non-Hodgkin’s lymphoma. Gux~isruur~~- ierol Clin Biol 1985; 9:922-928.

3 I . Saraga P, Hurlimann J , Ozzello L. Lymphomas and pseudolym- phomas of the alimentory tract: An immunohistochemical study with clinicopathologic correlations. Hum Path01 1981 ; 12:7 13-722. 32. Usher FC, Dixon CF. Lymphosarcoma of the intestine. Gastro-

enterology 1943; 1 : 160- 178.

42197-103.

t977; 184-205.

33. Herrera A, Solal-Celigny P, Gaulard P et al. Primary lymphomas of the gastrointestinal tract: Results of treatment in a series of 35 cases. Gastroenferol Clin Biol 1984; 8:407-4 13. 34. Steward WP, Hams M, Wagstaff J et al. A prospective study of

the treatment of high-grade histology non-Hodglun’s lymphoma involving the gastrointestinal tract. Bur J Cancer Clin Oncol 1985; 2 1 : 1 195-1200.

35. Boiron M, Gisselbrecht C, Tricot G eta/. Therapeutic indications of non-Hodgkin’s lymphomas localized to the digestive tract. Ann Gas- troenferol Hepatol 1984; 20:33 1-337. 36. Fu YS, Perzin KH. Lymphosarcoma of the small intestine: A

clinicopathological study. Cancer 1972; 29:645-659. 37. Hockey MS, Powell J, Crocker J et al. Primary gastric lymphoma.

Br JSurg 1987; 74:483-487. 38. Lim FE, Hartman AS, Tan EGC ef al. Factors in the prognosis

of gastric lymphoma. Cancer 1977; 39:1715-1720. 39. Nelson DF, Cassady JR. Traggis D el al. The role of radiation

therapy in localized resectable intestinal non-Hodgkin’s lymphoma in children. Cancer 1977; 39:89-97. 40. Rosenfelt F. Rosenberg SA. Diffuse histiocytic lymphoma pre-

senting with gastrointestinal tract lesions: The Standford experience. Cancer 1980 45:2188-2193. 4 I. Shiu MH, Nisce LZ, Pinna A et al. Recent results of multimodal

therapy of gastric lymphoma. Cancer 1986; 58: 1389-1 399. 42. Caraveo J, Trowbridge AA, White RR. Diagnosis and therapy of

primary gastrointestinal lymphomas. Surg Clin North A m 1979; 59377- 883. 43. Filippa DA, Decosse JJ, Lieberman PH et al. Primary lymphoma

of the gastrointestinal tract: Analysis of prognostic factors with emphasis on histologic type. Am J Surg Puthol 1983; 7:363-372. 44. Ravaioli A, Amadori M, Faedi M ef al. Primary gastric lymphoma:

A review of 45 cases. Eur J Cancer Clin Oncol 1986; 22:1461-1465. 45. Rosen CB, Van Heerden JA, Martin JK et a/. Is an aggressive

surgical approach to the patient with gastric lymphoma warranted. Ann

46. Joensuu H, Sijderstrom KO, Klemi PJ et al. Nuclear DNA content and its prognostic value in lymphoma of the stomach. Cancer 1987; 60:

47. Adkins B. Scott HW, Sawyers JL. Gastrointestinal lymphoma and sarcoma: A case for aggressive search and destroy. Ann Surg 1987; 205:625-633. 48. Brady LW, Asbell SO. Malignant lymphoma of the gastrointestinal

tract. Erskine memorial lecture. Radiology 1980; 137:291-298. 49. Joseph JI, Lattes R. Gastric lymphosarcoma: Clinicopathologic

analysis of 71 cases and its relation to disseminated lymphosarcoma. Am J Clin Pathol 1966; 45653-669.

50. In Sook Seo, Binkley WB, Warner TFCS. A combined morphologic and immunologic approach to the diagnosis of gastrointestinal lymphomas: 1. Malignant lymphoma of the stomach. A clinicopathologic study of 22 cases. Cancer 1982; 49:493-501.

5 I . Orlando R 111, Pastuszak W. Preissler PL et al. Gastric lymphoma: A clinicopathologic reappraisal. Am J Surg 1982; 143:450-455. 52. Blackledge G, Bush H, Dodge OG. A study of gastrointestinal

lymphoma. Clin Oncol 1979; 5:209-2 19. 53. Gupta S. Pant GG, Gupta S. A clinicopathologic study of primary

gastrointestinal lymphoma. J Surg Oncol 198 I; 16i49-58. 54. Shepherd FA, Evans WK, Kutas G et ul. chemotherapy following

surgery for Stages IE and IIE non-Hodgkin’s lymphoma of the gastrointestinal tract. J Clin Oncol 1988; 6:253-260.

55. Sheridan WP, Medley G, Brodie GN. Non-Hodglun’s lymphoma of the stomach: A prospective pilot study of surgery plus chemotherapy in early and advanced disease. J Clin Oncol 1985; 3:495-500. 56. Gospodarowicz MK, Bush RS, Brown TC et al. Curability of

gastrointestinal lymphoma with combined surgery and radiation. Inf J Radiat Oncol Biol Phys 1983; 9:3-9.

57. Fleming ID, Mitchell S, Dilawari RA. The role of surgery in the management of gastric lymphoma. Cancer 1982; 49:1I3S-ll4l.

58. Papadimitriou CS, Papacharalampous NX. Kittas C. Primary gastrointestinal malignant lymphomas: A morphologic and immunohistochemical study. Cancer 1985; 55370-879. 59. Carbone PP, Kaplan HS, Musshoff K et al. Report of the com-

mittee on Hodgkin’s disease staging classification. Cancer Res 197 1; 3 1: 1860-186 I.

Sltrg 1987; 2051634-640,

3042-3048.

No. 6 PROGNOSIS IN GI-NHL * Azab et al. 1217

60. The Non-Hodgkin’s lymphoma pathologic classification project: National Cancer Institute sponsored study ofclassification of non-Hodg- kin’s lymphoma: Summary and description of a working formulation for clinical usage. Cancer 1982; 49:2 1 12-2 135.

61. Lennert K, Mohri N, Stein H et al. Malignant lymphomas other than Hodgkin’s disease. Berlin, Heidelberg, New York Springer-Verlag, 1978; 92.

62. Musshoff K. Klinische Stadieneinteilung der Nicht-Hodgkin- Lymphome. Strahlentherapie 1977; 153:218-221.

63. Somers R, Burgers JMV, Qasim M et al. EORTC trial Non- Hodglun’s lymphomas. Eur J Cancer Clin Oncol 1987; 23:283-293.

64. Pet0 R. Pike MC, Armitage P et al. Design and analysis of ran- domized clinical trials requiring prolonged observation of each patient: 11. Analysis and examples. Br J Cancer 1977; 35:l-39.

65. Cox DR. Regression models and life tables (with discussion). J R Stat Soc [B] 1972; 34: 187-220.

66. Wartelle M, Kramar A, Jan P et al. “PICAS”: An interactive statistical database management system. In: Hammond R, McCarthy JL, eds. Proceedings of the Second International Workshop on Statistical Database Management. Los Altos, CA: Laurence Berkeley Laboratory and Statistics Canada, 1983; 124-132.

67. Dixon WJ, Brown MB, Engelman Let al. BMDP Statistical Soft- ware. Berkeley, CA: University of California Press, 1985.

68. Kaplan HS, Meier P. Non-parametric estimation from incomplete observation. Am Stat Assoc J 1958; 53:457-480.

69. Weingrad DN, Decosse JJ. Sherlock P et al. Lymphomas of the Gut. In: Decosse JJ, Sherlock P, eds. Gastrointestinal Cancer 1. The Hague, Boston, London: Martinus Nijhoff Publishers, 198 1; 3 1 1-34 1.

70. Mason GR. Tumors of the duodenum and small intestine. In: Sabiston DC Jr, ed. Davis-Christopher Textbook of Surgery: The Biologic Basis of Modern Surgical Practice. Philadelphia: WB Saunders, 1977;

7 1. Williamson RCN, Welch CE, Malt RA. Adenocarcinoma and lymphoma of the small intestine: Distribution and Etiologic Association. Ann Surg 1983; 197:172-178.

72. Salem P, El-Hashimi L, Anaissie E et al. Primary small intestinal lymphoma in adults: A comparative study of IPSID versus non-IPSID in the Middle East. Cancer 1987; 59:1670-1676.

73. Salem P, Nassar V, Shahid M et al. Mediterranean abdominal lymphoma, or immunoproliferative small intestinal disease: I. Clinical aspects. Cancer 1977; 40:2941-2947.

74. Khojasteh A, Haghshenass M, Haghighi P. Immunoproliferative small intestinal disease: A third world lesion. N Engl J Med 1983; 308:

75. Tubiana M, Henry-Amar M, Burgers MV ef al. Prognostic significance of ESR in clinical Stages 1 and 11 Hodgkin’s disease. J Clin Oncol 1984; 2: 194-200.

76. Cabanillas F, Burke JS. Smith TL et al. Factors predicting for response and survival in adults with advanced non-Hodgkin’s lymphoma. Arch Intern Med 1978; 138:413-418.

77. Rosenberg SA. Validity of Ann Arbor staging classification for the non-Hodgkin’s lymphomas. Cancer Treat Rep 1977; 6 1:1023-1027.

78. Leonard RCF, Cuzick J, Maclennan ICM ef a!. Prognostic factors in non-Hodgkin’s lymphoma: The importance of symptomatic stage as an adjunct to the Kiel histopathological classification. Br J Cancer 1983; 47:9 1 - 102.

969-976.

140 1 - 1 405.

79. Tubiana M, Carde P, Burgers JMV e/ al. Prognostic factors in Non-Hodgkin’s lymphoma. Int J Radiat Oncol Biol Phvs 1986; 12503- 514.

80. Rao AR, Kagan AR, Potyk D et al. Management of gastrointestinal lymphoma. Am J Clin Oncol 1984; 7:213-219.

8 I . Akerman M, Brandt L, Johnson A et al. Mitotic activity in non- Hodgkin’s lymphoma: Relation to the Kiel classification and to prognosis. Br J Cancer 1987; 55:219-223.

82. Stansfeld AG. Diebold J, Noel H et al. Uptated Kiel classification for lymphomas (Letter). Lancet 1988; 1:292-293.

83. Nabholtz JM, Friedman S, Collin F et al. Modification of Kiel and Working Formulation classifications for improved survival prediction in Non-Hodgkin’s lymphoma. J Clrn Oncol 1987; 5:1634-1639.

84. Hall PA, Jass JR, Levison DA ef al. Classification of primary gut lymphomas (Letter). Lancer 1988; 2:958.

85. Isaacson PG, Spencer JO, Wright DH et a/. Classifying primary gut lymphomas (Letter). Lancet 1988; 2:1148-1 149.

86. Brittinger G, Bartels H, Common H ef al. Clinical and prognostic relevance of the Kiel classification of non-Hodglun’s lymphomas: Results of a prospective multicenter study by the Kiel Lymphoma Study Group. Hematol Oncol 1984; 2:269-306.

87. DeWolf-Peeters C, Caillou B, Diebold J et al. Reproducibility and prognostic value of different non-Hodgkin’s lymphoma classifications: Study based on the clinicopathologic relations found in the EORTC trial (20751). Eur J Cancer Clin Oncol 1985; 21579-584.

88. Aozasa K. Nara H, Ikeda H ef al. The influence of histologic type on survival in early extranodal non-Hodgkin’s lymphoma in head and neck. Oncology 1984; 41:164-169.

89. Gray GM. Rosenberg SA, Cooper AD et a/. Lymphomas involving the gastrointestinal tract. Gastroenterology 1982: 82: 143-1 52.

90. Magrath IT, Levanga S, Carswell W ef a/. Surgical reduction of tumor bulk in management of abdominal Burkitt’s lymphoma. Br Med

91. Miller TP, Jones SE. Initial chemotherapy for clinically localized lymphomas of unfavorable histology. Blood 1983; 62:4 13-41 8.

92. Maor MH, Maddux B, Osborne BM et al. Stage IE and IIE non- Hodgkin’s lymphomas of the stomach: Comparison of treatment modalities. Cancer 1984; 54:2330-2337.

93. Coleman M, Gerstein G, Topilow A el ul. Advances in chemotherapy for large cell lymphoma. Senzin Hematol 1987; (Supp1)24:8-20.

94. DeVita VT, Canellos GP, Chabner BA et al. Advanced diffuse histiocytic lymphoma, a potentially curable disease: Results with combination chemotherapy. Lancet 1975; 1:248-250.

95. Ultmann JE. Cure of histiocytic lymphoma. Ann Intern Med 1982;

96. Gaynor ER, Ultmann JE, Golomb HM et al. Treatment of diffise histiocytic lymphoma with COMLA (cyclophosphamide. Oncovin, methotrexate, leucovorin. cytosine arabinoside): A 10-year experience in a single institution. J Clin Oncol 1985; 3:1596-1604.

97. Homing SJ, Rosenberg SA. The natural history of initially un- treated low-grade non-Hodgkin’s lymphomas. N Engl J M e d 1984; 3 I 1: 1471-1475.

98. Rosenberg SA. Kamofsky Memorial Lecture. The low-grade non- Hodgkin’s Lymphomas: Challenges and apportunities. J Clin Oncol1985; 3:299-3 10.

J 1974; 2:308-312.

97~274-275.

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