primary lymphoma of the spleen: clinical features and outcome after splenectomy

Primary Lymphoma of the Spleen

Clinical Features and Outcome After Splenectomy

JOHN KEHOE, MD,* AND DAVID J. STRAUS, MDt

A retrospective review was made of patients with primary splenic non-Hodgkin’s lymphoma (PSL) diagnosed at surgery at Memorial Hospital between 1970 and 1981. Four patients had splenic involvement only (Group I), three patients had splenic and splenic hilar nodal involvement (Group 11), and 14 had involvement of the spleen and other sites including liver (11 patients), bone marrow (eight patients), and distant abdominal lymph nodes (five patients) (Group 111). Three of the seven Group I and I1 patients are alive without disease at 24,42, and 144 months. There was a trend toward a longer survival for the Group I and I1 patients as compared with the Group 111 patients. Patients with truely localized PSL seem to have the same outlook as other Stage I non-Hodgkin’s lymphoma patients.

Cancer 62:1433-1438, 1988.

NVOLVEMENT OF THE SPLEEN is seen in a discrete I number of patients with non-Hodgkin’s lymphoma (NHL). Splenic involvement can be part of a diffuse dis- semination of NHL in which the spleen is one of multiple involved organs or sites. Alternatively, non-Hodgkin’s lymphoma may also originate in the spleen and then spread to other sites. Non-Hodgkin’s lymphoma does not spread in a predictable fashion. Thus, once the disease becomes clinically evident, it may be difficult to appreciate the precise sequence of tumor progression.

Primary splenic lymphoma (PSL) refers to a subset of NHL in which the disease is thought to start in the spleen or the bulk of disease is concentrated in the spleen with additional involvement of hilar lymph nodes. Substantial splenomegaly is a prominent feature of PSL, but significant peripheral adenopathy is absent. Regional lymph node, bone marrow, and liver involvement can be seen. Hypersplenism and various cytopenias can complicate the clinical management. Like other NHL patients with splenic involvement, patients with PSL undergo splenectomy for splenomegaly and/or various cytopenias. Pri- mary splenic lymphoma may also be discovered or con- firmed after splenectomy in a patient with splenomegaly who is suspected to have a hematologic malignancy.

From the *Department of Surgery and the tHematology/Lymphoma Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York.

* Current affiliation: Department of Surgery, Maimonides Medical Center, Brooklyn, New York.

The authors thank Mrs. Dorothy Hemphill, who typed the manuscript. Address for reprints: David J. Straus, MD, Memorial Sloan-Kettering

Accepted for publication February I I , 1988. Cancer Center, 1275 York Avenue, New York, NY 10021.

As a more localized form of NHL, the clinical course of PSL is thought to be more favorable than NHL that originates elsewhere and eventually spreads to the spleen and necessitates splenectomy. In this retrospective review we examine the clinical characteristics and clinical course of PSL.

Materials and Methods

All PSL patients undergoing splenectomy at Memorial Sloan-Kettering Cancer Center from 1970 to 198 1 were reviewed. Splenectomy in these patients was performed for splenomegaly with or without hypersplenism for which a hematologic malignancy was either known or strongly suspected. Patients who had incidental splenectomy or splenectomy for purposes of staging were not considered.

Multiple preoperative factors including age, sex, and race were examined. The course of the patient’s lymphoma was established by watching the interval from the initial diagnosis of lymphoma until the time of splenectomy and the interval from the initial suspicion or dis- covery of splenic involvement until the time of splenectomy. The extent of the patient’s disease was determined by review of initial clinical staging. The histopathologic classification was done according to Rappaport.’ The grouping of primary splenic lymphoma patients was done using a variant of the Ahmann classification scheme.’ In the Ahmann classification Group I disease refers to involvement of the spleen only; Group 11, involvement of the spleen and hilar lymph nodes; and Group 111, involvement of the liver and nodes beyond the hilum. In our variation of this classification we included bone marrow involvement as another indication of Group I11 disease.

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1434 CANCER October I 1988 Vol. 62

TABLE 1. Primary Splenic Lymphoma Patient Characteristics

PSL (n = 21)

Age, yr (median and range) Sex (male/female) Race (whitelother) Histology

Diffuse/nodular/not specified Diffuse well-differentiated Iyrnphocytic Nodular poorly-differentiated Iymphocytic Diffuse poorly-differentiated lymphocytic Diffuse histiocytic Diffuse mixed lymphocytic-histiocytic Atypical

Dx lymphoma -P surgery (median and range, mo) Spleen symp + surgery (median and range, mo) Thrombocytopenia (yes/no) Preop platelet countlpl X 103 (median and range) Anemia (yeslno) Preop HGB g/dl (median and range) Leukopenia (yes/so) Preop leukocytes/pl X 103 (median and range) Lymphangiogram (+/-/unknown) Bone marrow (+/-/unknown) Spleen size (median and range, g)

57 (13-81) 1219 19/2

1 6/41 1 5 4 4 7 0 1 6 (1-48) 3 (1-48) 1714 81 (5-118) 13/8 9.3 (4.5-10.8) 8/13 2.5 (1.4-3.8) 01 1714 911 1/1 1780 (900-6960)

PSL primary splenic lymphoma; symp: symptoms; preop: preoperative; HGB hemoglobin; Dx: diagnosis.

Group I and I1 patients represented truly localized disease and were considered together in our analysis. Preoperative chemotherapy and radiotherapy were also reviewed.

The lowest preoperative platelet count, hemoglobin level, and leukocyte count were recorded. Patients were considered to be thrombocytopenic if the platelet count was less than 120,00O/pl, anemic if the hemoglobin level was below 1 1 g/dl, and leukopenic if the leukocyte count was below 4000 cells/pl.

Splenic weight, the extent and nature of splenic involvement, and the histopathology of the lymphoma were recorded from pathology reports. Operative and pathology reports were examined to determine the presence of tumor in splenic Mar, intraperitoneal and retroperitoneal lymph nodes, and in the liver. Operative mortality and morbidity were recorded. Chemotherapy and radiation therapy in the postoperative period as well as the response to treatment were also reviewed.

Platelet counts, hemoglobin levels, and leukocyte counts were postoperatively followed. The highest platelet count, hemoglobin level, and leukocyte count in the first postoperative month was accepted if it was sustained during that interval after operation. Patients were considered to respond hematologically to splenectomy if (1) they had been thrombocytopenic preoperatively and sustained an increase in their platelet count in the first postoperative month greater than three times their lowest preoperative value; (2) they had been anemic preoperatively and sustained an increase in their hemoglobin to more than 11 g/dl in the first postoperative month; or (3) they had been leukopenic and sustained an increase in their leukocyte

count to more than 4000 cells/pl in the first postoperative month. If splenectomy was performed for more than one hematologic abnormality, each abnormality was initially considered separately. Patients were defined overall as having a hematologic response only if they corrected all hematologic abnormalities after splenectomy. Patients were then observed for recurrence of hematologic abnormalities and the subsequent course of their disease. Sur- vival was determined from the time of splenectomy. Any differences in survival used in this analysis were tested for significance using the Kaplan-Meier curve^.^ All values are expressed as median (range).

Results

Twenty-one patients were eligible for evaluation, and their clinical characteristics are presented in Table 1. In 20 of these 21 patients either lymphoma or another hematologic malignancy (chronic lymphocytic leukemia in three patients or hairy cell leukemia in two patients) was suspected preoperatively. The single patient in whom a hematologic malignancy was not suspected presented with a left upper quadrant mass that was thought to represent a recurrence of a previously resected gastric malignancy. Primary splenic lymphoma was suspected preoperatively in only eight patients. Primary splenic lymphoma patients were generally operated on early in the course of their disease or soon after the appearance of significant symptoms related to disease in the spleen.

There were no abnormal lymphangiograms in PSL patients, but 43% (nine of 21) had positive bone marrow examinations. The majority of PSL patients did, however, present with hematologic abnormalities. Of the 21 PSL patients, 17 had thrombocytopenia, 13 had anemia, and eight had leukopenia. Preoperative platelet counts, hemoglobin levels, and leukocyte counts are shown in Table 1.

Few patients received treatment preoperatively (Table 2). Two received radiation therapy (RT) to the spleen, 650 cGy and 2500 cGy, respectively. Neither responded. One of them, who received chemotherapy postoperatively, did not respond and died of disease 1 month after surgery. The other patient received no additional treatment postoperatively and was alive and without evidence of disease 108 months after splenectomy. Four additional patients received various chemotherapy regimens preoperatively. Two of them showed no response, and two had a partial response. Three of these four patients then received postoperative chemotherapy and their survivals are listed in Table 2.

Six patients received no treatment either preoperatively or postoperatively. Three of them were from Groups I and 11. One died of unrelated causes at 10 months, another died of disease 84 months postoperatively, and the third

No. 1 LYMPHOMA OF THE SPLEEN - Kehoe and Straus 1435

TABLE 2. Treatment of Patients With Primary Splenic Lymphoma

Treatment

Median overall survival from time of splenectomy

Group I + 11 Group Ill (median & range, mo)

Preop XRT only (n = 1) Preop XRT/Postop chemotx (n = 1) Preop chemotx only (n = 1) Pre/Postop chemotx (n = 3) Postop chemotx only (n = 8) No treatment (n = 6 )

1 1 1

1 2 2 6 3 3

- - -

108 1

12 12 (1-42) 18 (3-24) 60 (10-144)

Preop: preoperative; postop: postoperative; XRT: radiation therapy; chemotx: chemotherapy.

was disease-free at 144 months of follow-up. All three Group I11 patients receiving no treatment preoperatively or postoperatively were alive and disease-free at 18 months, 54 months, and 108 months of follow-up. The remaining eight patients received only chemotherapy postoperatively. Two of them were from Groups I and 11. One was alive with disease at 66 months, and the other was disease-free at 24 months of follow-up. The Stage I11 patients did worse-one patient died of unrelated causes at 24 months, and two others died of their disease at 3 and 18 months after surgery. Two patients were alive with disease at 18 months, and the last patient was disease-free at 24 months of follow-up.

Of the PSL patients with thrombocytopenia, 15 of 17 (88%) had correction by splenectomy. Two of the 15 re- sponding patients again developed thrombocytopenia during a later relapse. Nine of 13 PSL patients (69%) with anemia had correction after splenectomy. Two of the re- sponding patients subsequently developed recurrence of anemia during relapse of NHL. Only one of eight PSL patients with leukopenia had no response to splenectomy. Overall, the hematologic abnormalities in 13 of 19 (68%) patients with PSL were corrected with splenectomy.

Follow-up information for all 2 1 patients is presented in Table 3. Median survival was 18 months (1 to 144 months) for patients with PSL. Two- and five-year survival rates were 38% and 24%, respectively.

Surgical grouping of PSL patients is presented in Table 4. Four patients were in Group I, three patients were in Group 11, and 14 patients were in Group 111. A comparison of Group I and 11 patients with Group I11 patients showed no significant difference with respect to age, sex, race, interval from the time of initial diagnosis of lymphoma until splenectomy, interval from the initial suspicion of splenic involvement until the time of splenectomy, histopathologic features, use of preoperative and postoperative chemotherapy and radiotherapy, incidence of various cytopenias, preoperative blood counts, and spleen size. The hematologic abnormalities in all Group I and I1 PSL patients were corrected, while 57% of Stage I11 PSL patients had hematologic abnormalities corrected.

Survival curves and follow-up from the time of surgery comparing Groups I and I1 with Group I11 are presented in Figure 1 and Table 5. Actuarial 2-year survival for Groups I and I1 patients was 7 1 % compared to 2 1 % for Group I11 patients. At 5 years 43% of Groups I and I1 patients were alive compared with 14% of Group I11 patients. This difference, however, is not statistically significant.

Discussion

There has been confusion in the literature as to the proper definition of PSL. DasGupta defined it as disease confined to the spleen or hilar lymph nodes in which no recurrence of disease becomes evident for at least 6 months after splene~tomy.~ Only five patients (Patients 2 through 6, Table 4) fulfilled these conditions. Four of the six had hypersplenism, and all responded favorably to splenectomy. The median survival for these patients was greater than 48 months. There was a trend toward improved survival for this subgroup as compared with the rest of the

TABLE 3. Follow-up of 2 1 Patients With Primary Splenic Lymphoma After Splenectomy

No. of patients Median follow-up in mo (range) Outcome

Dead of disease 1 6 (1-84)

Dead unrelated cause

Alive with disease

Alive disease free

3 12 (10-24)

3 18 (18-66)

8 48 (12-144)

Total 21 18 (1-144)

Percent alive at 2 yr

Percent alive at 5 yr

38

24

1436 CANCER October 1 1988 Vol. 62

TABLE 4. Primary Splenic Lymphoma Surgical Grouping

Patient Hilar Abdominal Follow-up after no. Group BM Liver nodes nodes splenectomy in mo

- - - - DOD 6 - - - DUC 10

I 1

- - - DOD 84 I 2

- - - - ADF 24 3 I

- + - ADF 144 4 I

- - + - AWD 66 5 I1

- + - ADF 42 I1 6

- - - DUC 24 7 I1 +

- + - DOD 12 8 111 +

- + + DOD 1 9 111

10 111 + + + + + ADF 108 - DOD 18

11 111 + + + - - AWD 18

111 + 12

ADF 108 111

14 111 + + 13

+ + + + DOD 1 - ADF 54

I5 111 + + + - - DOD 3

16 111 + - - DUC 12

17 111 + + - ADF 18

18 111 + + - + + + ADF 12

19 111

21 I11 - + AWD 18 111 + 20

- -

-

-

- - -

-

-

-

ADF alive, disease-free; AWF alive with disease; DOD dead of disease; DUD: dead, unknown cause.

PSL patients, but the difference was not statistically significant.

DasGupta's conditions defined early and localized disease and did not adequately account for other PSL patients with more advanced disease or disease discovered later in its course. Also, a built-in survival advantage bias was evident in his patients as disease undetected at splenectomy or immediately recurrent after splenectomy was not considered. Thus, we chose to define PSL as NHL arising primarily in the spleen or as NHL principally confined to the spleen and its local lymph nodes. Disease

may possibly then spread from this area to more distant sites, such as other abdominal lymph nodes, liver, or bone marrow. Peripheral adenopathy is either nonexistent or may represent very late seeding from the spleen. This definition accounts for those frequently encountered patients with obvious disease in the spleen and hilar lymph nodes and small amounts of disease in other abdominal lymph nodes, bone marrow, and liver. Other investigators have also included patients with other abdominal lymph nodes, bone marrow, and liver involvement as still representing PSL.2*5-9 In this study involvement of regional lymph

--- Early ( 7 Pts., 4 Censored) - Late (14 Pts., 7 Censored)

80 cs)

.3 E .- 2 a

FIG. 1. Survival of primary splenic lymphoma patients after splenectomy. Early means patients with splenic involvement with or without splenic hilar nodes only. Late means splenic involvement with involvement of any other sites. - - - - - - - - - - - 40

2ot 0 ' I 1 I I I I

0 24 48 72 96 120 144

Months After S p I e nec to my

No. 7 LYMPHOMA OF THE SPLEEN - Kehoe and Straus 1437

nodes, bone marrow, and liver was seen in patients who had more widespread disease, but in whom we speculated that the NHL started in the spleen before spreading to other sites or in whom the bulk of the disease was found to be in the spleen and splenic hilar lymph nodes.

In our experience between 1958 and 1969, 21.2% of patients with NHL clinically presented with splenic involvement, and splenic lymphoma comprised 2.6% of all Stage I cases.” The percentage of NHL patients undergoing splenectomy who are found to have primary splenic lymphoma has not been reported in the literature. From 1970 to 1981 at our institution 17 patients with disseminated NHL had splenectomies for symptoms related to splenomegaly or hypersplenism in addition to the 2 1 PSL patients. The indication for splenectomy in the latter group was usually for histologic diagnosis, and symptoms and hematologic abnormalities were less severe than in the group with known disseminated NHL. Thus, 55% of patients (2 1 of 38) with NHL had PSL among recent NHL patients undergoing splenectomy in our institution. It is obvious that this group had less advanced disease than the other patients with disseminated NHL who underwent splenectomy .

Some hematologic abnormalities were found in nearly all our PSL patients, although they were sometimes mild. Our high incidence of hematologic abnormalities was similar to that identified by Long, Skarin, and Hyatt, but it was greater than the incidence identified by Ahmann and Nar~ng.’*~-~ Few authors have commented on the hematologic response after splenectomy in PSL patients. Of our PSL patients, 68% had all preoperative hematologic abnormalities corrected. The hematologic response of PSL patients to splenectomy was no different than the he-

100

80 cn c .- 5

FIG. 2. SuMval of all non-Hodglun’s lymphoma ‘5 60 patients following splenectomy: primary splenic lymphoma (PSL) and patients with disseminated lymphoma (non-PSL). 40

20 s

0

TABLE 5 . Primary Splenic Lymphoma: Survival by Group From Date of Surgery

Groups I + 11, Group 111, N = 7 n = 14

n n Median f/u (range)

Outcome in mo in mo Median f/u (range)

Dead of disease 2

(6-84) -

1 Dead unrelated - cause (10)

Alive disease-free 3 42 (24-144)

Percent alive at 2 Yr 71

5 3 (1-18)

2 ( 12,241

5 54 (12-108)

21

Percent alive at 5 Yr 43 14

matologic response of the other 17 NHL patients with disseminated disease requiring splenectomy.

The overall survival from the time of splenectomy was similar for the patients with PSL and those with disseminated NHL in our series (Figure 2). Anecdotal reports have suggested that PSL patients may have a long sur- ~ival.~-’,” Ahmann found a 5-year survival of 31% in 47 of his patients, most of whom were presumed to have PSL.’ It is unfortunate, that Hodgkin’s disease patients were included in the analysis. Long and Aisenberg present a less favorable analysis in 15 patients.’ Narong’s patient had no follow-up beyond 5 years, but 50% of these patients

- - - PSL (21 Pts., 11 Censored) - NONPSL (17 Pts., 7 Censored)

0 24 48 72 96 120 144

Months After Splenectomy

1438 CANCER October I 1988 Vol. 62

died of disease at a median of 24 months after surgery. Five patients were alive with disease at a median of 24 months postoperatively, and four patients were alive and disease-free at a median of 36 months postoperatively.’

The number of patients is too small to draw any definite conclusions. However, it may be that the four of seven patients alive without disease, with splenic involvement, and with or without splenic hilar nodal involvement may have had truly localized disease similar to the 50% to 70% of patients with other Stage I presentations who remain without disease after regional radiation therapy and surgery.12-16 This is in contrast with the patients in Group I11 who have disseminated NHL showing a trend toward a shorter survival.

In his grouping system Ahmann found longer survivals for patients in Group I and 11.’ No statistics accompanied the Ahmann analysis, so the significance of this grouping system is unclear. In our study differences in survival between Group I and I1 versus Group I11 were seen at 2 years, but this disappeared at 5 years. These differences may have been more dramatic if a larger group of patients was analyzed. In addition, bone marrow findings were not even considered in the Ahmann staging system. In a separate analysis of these patients with and without bone marrow involvement, we found a more favorable hematologic response and improved survival in PSL patients without bone marrow than those with bone marrow involvement. However, the difference was not statistically significant, possibly due to the small number of patients (data not shown).

It has been established that there are certain NHL patients with splenic disease who do well and enjoy long term survival after removal of the ~ p l e e n . ~ ~ ~ - ~ ~ ’ W e have been unable to clearly characterize this group of patients and to select them out for more than just a palliative splenectomy. It was our hope that patients with disease confined to the spleen and splenic hilar lymph nodes might have a more favorable prognosis than those in whom the spleen is a site of involvement in association with disseminated NHL. Unfortunately, we did not find that PSL represents a subset of NHL with a unique and different response to splenectomy. Although the numbers are small, our data suggest that patients with localized splenic and splenic hilar nodal disease may have the same prognosis as other patients with Stage I NHL; those with other sites

of involvement have a prognosis similar to other NHL patients with comparably more advanced stages of disease.

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primary lymphoma of the spleen: clinical features and outcome after splenectomy

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