The optimal management of splenic marginal zone lymphoma (SMZL), a rare malignancy of the elderly, is not clearly defined [1, 2]. Splenectomy had been advocated in the past due to its palliative effect on abdominal discomfort, cytopenias, and prolonged remissions, even though most patients have disseminated disease in the bone marrow which subsequently relapses. No prospective studies compared outcomes after surgery or chemotherapy, so the choice of treatment is based on perception of individual benefits and risks. This study analyzed 1,251 cases of SMZL recorded in the Surveillance, Epidemiology, and End Results (SEER) database. Effects of splenectomy on survival outcomes were evaluated after balancing confounders with a propensity score (PS). While 52% of patients underwent spleen removal, no significant impact of the procedure on the risk of lymphoma-related death (LRD) (P = 0.66) or overall survival was detectable. The results strengthen the notion that, with the availability of safe and effective alternatives, splenectomy should no longer be considered the treatment of choice in SMZL.
SMZL is an indolent B-cell lymphoma, introduced as a provisional diagnostic category in the Revised European-American Lymphoma Classification in 1994, and then as a separate subtype in the World Health Organization classification in 2001. Due to its rarity (less than 1% of all non-Hodgkin lymphomas), prognostic factors and treatments are based on retrospective series subject to inherent bias [3, 4]. Several studies from the era when alkylating chemotherapy was the principal therapeutic alternative to splenectomy indicated better survival in patients undergoing surgery [5–7]. This paradigm has been increasingly questioned with excellent outcomes achieved using rituximab alone or in combination with purine analogues [8–11]. Since a randomized trial to answer the question is unlikely to be conducted, I carried out an observational study based on the SEER registry to evaluate previous assertions.
The SEER database contained 1,251 SMZL patients aged 25–96, diagnosed between 1995 and 2009 (Table I). The median age was 68 years, and the median follow-up 37 months, reflecting preponderance of cases diagnosed after 2005. Most patients were Caucasian, residing in metropolitan areas and with disseminated (stage IV) lymphoma. Overall, 52.1% underwent splenectomy and 1.2% radiotherapy as the first course of therapy. There was no available information on alternative management choices (watchful waiting, systemic therapy). Patients undergoing splenectomy were younger, more likely to have B-symptoms or Stage I/II disease. The frequency of splenectomy decreased over the period of study from about 70% in the 1990s to 50% in the late 2000s.
|Variable||Total (% by column)||Group||P-value||Absolute standardized difference|
|No splenectomy (% by row)||Splenectomy (% by row)||Unmatched||Matched|
|Number of patients (%)||1,251 (100)||599 (47.9)||652 (52.1)|
|Mean (SD)||67.3 (12.6)||69.8 (12.7)||65.0 (12.1)||0.397||0.004|
|Median (IQR)||68 (58–77)||72 (60–80)||66 (56–77)||<0.0001|
|Female||670 (53.6)||300 (44.8)||370 (55.2)||0.02||0.135||0.015|
|Male||581 (46.4)||299 (51.5)||282 (48.5)|
|White||1,123 (89.8)||526 (46.8)||597 (53.2)||0.135||0.005|
|Black||60 (4.8)||33 (55.0)||27 (45.0)||0.069||0.007|
|Asian/Native American||51 (4.1)||25 (49.0)||26 (51.0)||0.01||0.01|
|Unrecorded||17 (1.3)||15 (88.2)||2 (11.8)||0.397||0.033|
|Year of diagnosis||0.003|
|1995–2000||108 (8.6)||37 (34.3)||71 (65.7)||0.151||0.025|
|2001–2004||460 (36.8)||213 (46.3)||247 (53.7)||0.048||0.008|
|2005–2009||683 (54.6)||349 (51.1)||334 (48.9)||0.141||0.022|
|ICD-O-3 histology designation||<0.0001|
|9689||866 (69.2)||452 (52.2)||414 (47.8)||0.248||0.023|
|9699||385 (30.8)||147 (38.2)||238 (61.8)|
|Localized (I)||289 (23.1)||81 (28.0)||208 (72.0)||0.394||0.029|
|Regional (II)||81 (6.5)||23 (28.4)||58 (71.6)||0.178||0.008|
|Disseminated (III.IV)||835 (66.8)||467 (55.9)||368 (44.1)||0.434||0.033|
|Unrecorded||46 (3.6)||28 (60.9)||18 (39.1)||0.117||0.033|
|Absent||523 (41.8)||255 (48.8)||268 (51.2)||0.03||0.001|
|Present||287 (22.9)||116 (40.4)||171 (59.6)||0.156||0.033|
|Unrecorded||441 (35.3)||228 (51.7)||213 (48.3)||0.115||0.03|
|No prior malignancy||1,023 (81.8)||505 (49.4)||518 (50.6)||0.028||0.12||0.027|
|Prior malignancy||228 (18.2)||94 (41.2)||134 (58.8)|
|Married||745 (59.6)||336 (45.1)||409 (54.9)||0.137||0.007|
|Widowed||190 (15.2)||94 (49.5)||96 (50.5)||0.027||0.005|
|Other||316 (25.2)||169 (53.5)||147 (46.5)||0.136||0.004|
|East Coast||388 (31.0)||159 (41.0)||229 (59.0)||0.18||0.001|
|Northern Plains||178 (14.2)||80 (44.9)||98 (55.1)||0.047||0.011|
|Pacific Coast||622 (49.7)||333 (53.5)||289 (46.5)||0.227||0|
|South West||63 (5.0)||27 (42.9)||36 (57.1)||0.044||0.015|
|Type of area||0.12|
|Metropolitan||1,100 (87.9)||536 (48.7)||564 (51.3)||0.087||0.042|
|Urban/Rural||151 (12.1)||63 (41.7)||88 (58.3)|
|Percent persons below poverty level|
|Mean (SD)||12.3 (5.2)||12.6 (5.2)||12.0 (5.2)||0.03||0.115||0.042|
|Lymphoma-related death||203 (16.2)||99 (48.8)||104 (51.2)|
|Any death||376 (30.0)||187 (49.7)||189 (50.3)|
|Median follow-up in months (IQR)||37 (15–67)||31 (12–60)||40.5 (17–71)|
Altogether, 203 patients (16.2%) died from lymphoma (54% of all deaths). Other major causes of death included cardiovascular disease (17%), other malignancies (10%), and unspecified events (9%). The 5-year relative survival was 79.8% (95% confidence interval, 95% CI, 75.8–83.1) with no difference by gender (P = 0.62). This correlated with cumulative incidence of LRD, which was 17.4% (95% CI, 15.0–20.0) at 5 years. The Kaplan–Meier estimate of overall survival was 67.8% at 5 years (95% CI 64.7–70.9) with a median survival of 8.6 years (95% CI, 7.8–9.6). In a multivariate Cox model, only age over 65 (hazard ratio, HR, 3.09, 95% CI, 2.23–4.29, P < 0.0001) and the presence of B-symptoms (HR, 1.83, 95% CI, 1.27–2.66, P = 0.001) were significant factors associated with inferior cause-specific outcome. Gender, race, clinical stage, or year of diagnosis were not significant.
The PS analysis successfully balanced all covariates, as evidenced by standardized differences of means (a difference smaller than 0.1 implies adequate balance, Fig. 1). After the adjustment, 1,194 patients were included in the PS-matched cohort. A comparison of cumulative incidence curves indicated no difference between treated and untreated patients in the probability of LRD (P = 0.66) or competing event (P = 0.97, Fig. 2a). Likewise, there was no evident impact of splenectomy in the regression model on the risk of LRD (subhazard ratio, SHR, 1.09, 95% CI, 0.78–1.51, P = 0.63) or on overall survival (HR, 1.03, 95% CI, 0.81–1.30, P = 0.84, Fig. 2b). Consistently null results were also obtained in the subgroup of 568 patients diagnosed before 2005, with a longer median follow-up of 64 months (P = 0.77) as well as inthe unadjusted population using conventional multivariate regression (n = 1,250, SHR 1.00, 95% CI 0.74–1.34, P = 0.99).
As a sensitivity analysis, in an attempt to minimize potentially unobserved treatment indication bias, the author evaluated 203 patients who actually died of SMZL, with a median survival of 17 months. There was similarly no significant effect of splenectomy in this highest-risk subgroup (log-rank test P = 0.16).
The current report, based on the largest cohort of SMZL studied to date, shows no evidence of either beneficial or detrimental impact of splenectomy on survival. The overall survival was lower in this population-derived series than in some prior reports originating from academic centers, but the cause-specific (relative) survival of about 80% at 5 years was similar to larger studies . Splenectomy, while commonly performed in the 1990s, has become diagnostically obsolete in most cases thanks to improved clinical, immunopathologic, and molecular criteria (such as recurrent 7q deletion) [12–15]. Its palliative benefits need to be weighed against surgical morbidity in elderly patients and subsequent risk of sepsis with encapsulated organisms. The operation is often delayed for several weeks to allow appropriate vaccinations. In contrast, rituximab-based chemoimmunotherapy can be initiated immediately and leads to durable improvement in almost all cases (response rate 87–100%, including complete remission in 35–69%) with a reported median time to clinical response of 3 weeks [9, 10]. Some studies suggest that splenectomy may induce potentially unfavorable changes in the lymphomatous bone marrow infiltration, although clinical significance of these findings is unclear [8, 16].
Observational studies can generally only study associations and generate hypotheses, but in rare diseases such as SMZL, in which randomized trials are not practicable, they may represent the only attainable level of evidence. Careful methodology is paramount in order to reduce group imbalance and consider competing events, since many patients die from comorbidities other than lymphoma—a fact frequently unaccounted for in prior literature.
One weakness of the present study is database limitation with regards to some clinical factors that influence eligibility for therapy. Although treatment decisions are typically guided by symptoms, laboratory values (hemoglobin, LDH, albumin) provide prognostic information . Nevertheless, in previous literature they were not significantly different between patients undergoing splenectomy or not [5, 8]. Age and presence of B-symptoms affect cause-specific survival in SMZL, as confirmed by our study, although in this large cohort gender was not of prognostic value, contrary to some smaller studies [15, 17, 18]. PS analysis, while balancing a retrospective cohort akin to a randomized trial, relies on the assumption of ignorable treatment assignment and cannot remove confounding due to unmeasured factors. Indolent lymphomas can be managed with watchful waiting, sometimes for prolonged periods. Comorbidities and extent of malignancy are only approximated by SEER data and patients undergoing splenectomy might fare worse by virtue of symptomatic disease warranting treatment. Conversely, a proportion of patients not needing aggressive therapy may have operations for diagnostic purposes. Additional treatment indication bias could be mitigated by analyzing datasets containing information on all treatment modalities and time to progression. However, previous reports quite uniformly indicate that at least 75% of SMZL patients do require either splenectomy or systemic therapy at diagnosis [3, 5, 8, 19]. Over 90% of the present cohort was diagnosed in the era of availability of efficacious chemoimmunotherapy, the principal therapeutic alternative beyond supportive care, palliative radiation, or interferon (for hepatitis C-associated cases). In an attempt to reduce the indication bias, patients at the extremes of PS were removed from the analysis, a method partly compensating for unmeasured confounding related to medical frailty . The sensitivity analysis conducted in the highest-risk group of patients who died of SMZL demonstrated a consistently negative result. It should be noted that because of the exclusion of cases at high and low extremes of the PS, the results of this study are applicable to patients at average risk, in which splenectomy and systemic therapy might be contemplated as viable alternatives.
In conclusion, this analysis demonstrates lack of association between splenectomy and survival in SMZL. This may alleviate potential concerns when deciding between systemic therapy and surgery. Splenectomy may be considered for palliation or rapid correction of severe cytopenias, but with ongoing diagnostic and therapeutic advances, it should be regarded a historical rather than gold standard, as was the case in hairy cell and chronic lymphoid leukemia. The differential benefits of chemoimmunotherapy and splenectomy with regards to quality of life and remission duration remain to be investigated.