Primary Extranodal Diffuse Large B-Cell Lymphoma In The Rituximab Era: A Single Center, Retrospective Analysis

Abstract

Background: A large proportion of diffuse large B-cell lymphoma originates from extranodal sites. The outcomes of Chinese patients with primary extranodal diffuse large B-cell lymphoma (PE-DLBCL) have been greatly improved.

Methods: Clinical features and outcomes of 197 patients newly diagnosed with PE-DLBCL from January 2015 to December 2020 were analyzed retrospectively.

Results: (1) Gastrointestinal tract (34%) involvement ranked first, followed by central nervous system (CNS) and intraocular (31.5%), nose/nasopharynx (7.1%), breast (5.1%), testis (3.6%) and others. (2) The 3-year overall survival (OS) rate for the entire group was 81%; The 3-year OS rate of PE-DLBCL with CNS and vitreoretinal involvement was 79%. (3) In univariate analysis of PE-DLBCL, Ann Arbor stage, evaluated LDH, IPI>2 and complete remission (CR) were significantly related to survival. The lack of CR was the only independent adverse prognostic factor in OS (p = 0.000; HR = 4.659). (4) Lugano stage and treatment response were independent prognostic factors for primary gastrointestinal DLBCL.

Conclusion: This is a single-center report of PE-DLBCL in China in the past 5 years with a fairly excellent outcome and a large scale. The treatment response of patients is significantly better than before, especially in patients with CNS and vitreoretinal involvement.

Introduction

The malignant lymphomas, which represented a diverse group of diseases, may arise from tissues other than lymph nodes. The definition of extranodal lymphoma is still a controversial issue, especially when both lymph nodes and extranodal sites are involved. Referring to previous studies[1-4], lymphoma is defined to be primarily extranodal if 1) dominant lesion at extranodal sites; 2) only minor or no lymph node involvement. The prevalence of primary extranodal non-Hodgkin’s lymphoma (PE-NHL) varies from country to country and ranging from 8.7 to 48%[5-8]. Diffuse large B-cell lymphoma (DLBCL) was the most common pathological subtype among patients with PE-NHL with a proportion of 71-81.3%[4, 9]. Primary extranodal DLBCL(PE-DLBCL) was originated from nearly every extranodal site of body, especially most common in gastrointestinal (GI) tract, followed by nasopharynx and neck, breast, central nervous system (CNS), skin, bone, thyroid, testis and rarely in other sites[4, 10, 11]. 

PE-DLBCLs are well-recognized heterogeneous Entities. However, the relevant content of research on them are extremely limited. After entering the era of universal affordability of rituximab, the survival of PE-DLBCL had greatly improved. Our center had also made great efforts in standardizing treatment, intensive induction and strengthening central prevention. The main objective of this study is to analyzed the specific clinical characteristics, response to treatments, survival of patients with PE-DLBCLs in a single center of China in new era.

Patients And Methods

Patients

644 patients newly diagnosed with DLBCL between January 2015 to December 2020 at our hospital were included, and 197 patients diagnosed with PE-DLBCL were evaluated. All biopsy specimens were classified by three specialized pathologists according to the WHO classification protocol independently[12]. 

The baseline data, such as sex, age, Ann Arbor stage, performance status, extranodal sites, complete blood count (CBC) and biochemical routine, including liver enzymes, creatinine, serum albumin and the level of lactate dehydrogenase (LDH) were collected. Necessary imaging evaluations such as positron emission tomography/computed tomography (PET/CT) or whole body computed tomography scan (CT) were examined before and after treatment. Patients with lymphoma were staged by the Ann Arbor classification scheme[13] and evaluated according to the International Prognostic Index (IPI) score[14]. PE-DLBCL with CNS or gastrointestinal involvement were evaluated by IELSG score[15] or Lugano classification[16], respectively.

Treatment, response and follow-up

The first-line treatment for patients with PE-DLBCL, except PCNS-DLBCLs, was R-CHOP[17] (rituximab, cyclophosphamide, doxorubicin, vindesine, prednisone) or R-EPOCH regimen[18] for patients with double-protein-expression. The regimen was given every three weeks for 6-8 cycles. MTX[19] (1g/m², total 4 times) was added to some patients as CNS prophylaxis in induction therapy. Local and systemic therapies were applied in patients with primary vitreoretinal DLBCL(PVR-DLBCL): intravitreal methotrexate injections for one year (400ug, total 16 injections) and R2 regimen, which contained 6 cycles of the Lenalidomide (25 mg on day 1-21) and rituximab (375 mg/m² on day 1)[20]. Other PCNS-DLBCLs were treated by high-dose methotrexate (3.5g/m²)-based combined chemotherapy. The regimen was given every three weeks for 6-8 cycles.

The response to treatment was assessed according to the International Working Group criteria[21]. 18 patients were lost to follow-up until the final follow‑up period of December 31, 2021.

Statistical analysis

Outcomes were described by the Progression-free survival (PFS) and Overall survival (OS). PFS was defined from the time of diagnosis to the first disease progression or death for any reason. OS was calculated from the date of diagnosis to the date of last follow-up or death for any reason. The Graph Pad Prisma 9.0 was used to performed the statistical analysis. Univariate analysis and generation of survival curves were performed using Kaplan-Meier and log-rank tests. Differences were evaluated using a two-tailed test; P values < 0.05 were considered statistically significant.

Results

Clinical characteristics

Patients newly diagnosed with PE-DLBCL accounts for 30.6% (197/644) of all DLBCL patients in our study. The median age was 58 (range, 19-91) years and 90 (45.7%) patients were male. Patients with central nervous system, intraocular, bone and thyroid involvement had worse physical status than those with other areas involved. B symptom was less common in patients with CNS (7/48, 14.6%), nose/nasopharynx (1/14, 7.1%), breast (2/10, 20%) or testis (1/7, 14.3%) involvement.

No significant difference was seen in the number of patients whom were classified as clinical stages I-II (122, 61.9%) and III-IV (75, 38.1%). The major involvement sites of patients with PE-DLBCL are presented in Table 1.

The gastrointestinal tract (GIT) constituted the most common site of PE-DLBCL, accounting for 34% of cases (36 stomach, 20 duodenum/jejunum, and 11 colon). Patients with central nervous system and intraocular involvement rank second (62, 31.5%), followed by nose/nasopharynx (14, 7.1%), breast (10, 5.1%), testis (7, 3.6%), bone, skin, thyroid gland [6 patients (3%) each], female genital system (5, 2.5%), liver (4, 2%). Figure 1 shows the site distribution of extra-nodal lymphomas. Subgroups with less than 5 patients were excluded in the subsequent survival analysis.

Figure1. Anatomic Distributions in PE-DLBCL

Table 1. Patient characteristics according to the primary involved site.

Response to treatment and survival

9.1% patients with PE-DLBCL were lost to follow-up in this study. The median follow-up period was 31.8 (range, 0.2-80.8) months. At the last follow-up, 35.6% (69/194) patients had experienced relapse of disease and 19.6% (35/179) patients had been dead. The median PFS and OS were 23.8(range, 0.1-80.8) and 31.8 (range, 0.2-80.8) months, respectively (Figure 2). The 3-year OS rates of patients with primary GI tract, Eye+CNS, nose/ nasopharynx, breast, FGS, bone, thyroid gland, testis and skin involvement were 84%, 79%, 83%, 86%, 100%, 80%, 83%, 100%, 67%, respectively.

A total of 117(59.3%) patients achieved CR and 21(10.6%) achieved PR, leading to a total response rate (RR) of 70.1%. The RR for patients with PCNS-DLBCL and PVR-DLBCL was 67.8%, and nose/ nasopharynx, thyroid gland, testis, breast, GI tract, bone, skin, liver and FGS involvement was 92.9, 83.3, 75, 70, 68.7, 66.7, 57.1, 50 and 33.3%, respectively.

Figure 2. OS and PFS for patients with PE-DLBCL

The proportion of patients undergoing chemotherapy with surgery in PCNS-DLBCL, primary female genital system DLBCL(PFGS-DLBCL), primary breast-DLBCL(PB-DLBCL), primary thyroid gland DLBCL(PT-DLBCL) and primary GI DLBCL (PGI-DLBCL) was 37.5, 40, 60, 66.7 and 28.4%, respectively. There were no significant statistical differences between the clinical outcome in two groups of patients who had and had not undergone surgery both in PCNS-DLBCL and PGI-DLBCL (Figure 3).

Figure 3. OS (a) and PFS(b) of PCNS-DLBCL patients with or without surgery; OS (c) and PFS(d) of PGI-DLBCL patients with or without surgery. 1(9.1%) patient with primary vitreoretinal DLBCL(PVR-DLBCL) was dead during our study period. 64.3% (9/11) patients with PVR-DLBCL achieved CR after first-line therapy and 78.6% (11/14) patients experienced disease relapsed, of which 5 patients had central nervous system relapsed. Complete remission, relapse and mortality rates were 45.8% (22/48),56.2% (27/48) and 20.8% (10/48) for patients with PCNS-DLBCL, respectively. No statistically significant differences in the clinical outcome between two groups of patients (PCNS-DLBCL versus PVR-DLBCL) were observed. (Figure 4) 

Figure 4. OS(a) and PFS(b) between patients with PCNS-DLBCL and PVR-DLBCL

Prognostic factors

Univariate and multivariate analysis results of patients with PE-DLBCL are presented in table 2. According to the univariate results, Ann Arbor stage, evaluated LDH, IPI>2, not received CR and double hit were related to survival significantly. However, in multivariate analysis, failure to achieve CR after first-line therapy was independent predictor of OS and PFS in patients with PE-DLBCL.

Table 2. Risk factors for survival of PE-DLBCL

The univariate and multivariate analysis results of PGI-DLBCL are presented in Table3. According to the univariate results, B symptom, evaluated LDH, IPI>2, Lugano stage, failure to achieve CR and double hit were related to survival of PGI-DLBCL significantly. The independent risk factors for PFS included not received CR and Lugano stage IV in multivariate analysis.

Table 3. Risk factors for survival of PGI-DLBCL

Discussion

To our knowledge, this is a cohort of extranodal lymphomas with fairly good clinical outcomes in the last 5 years. The prognosis of PE-DLBCL is getting better in the era of rituximab.

Different extranodal sites of involvement are related to distinct clinical characteristics. In contrast to previously reported studies[22–24], there are slightly more female patients with PE-DLBCL than male at our center. 38.1% patients with PE-DLBCL were in advanced staged when diagnosed, whereas primary nodal DLBCL were classified as stage III-IV more[22, 25, 26]. Possible because patients will have earlier local symptoms due to tumor mass. In addition, different definition for primary extranodal lymphoma can also lead to this difference[3, 27].

The gastrointestinal tract is the most common site of extranodal involvement, while other sites are rare[4, 28]. However, patients with central nervous system and intraocular involvement also account for a high proportion in our study, partly due to the conduct of clinical trials, which will lead to considerable differences in subsequent analysis.

The patients with PCNS-DLBCL, comparing with the largest descriptive research of China, had a better outcome in our center. Studies have shown that surgical excision for intracranial PCNS-DLBCL does not improve survival[29, 30], and our results are consistent. Systemic chemotherapy combined with intravitreal chemotherapeutic drug injection for patients with primary vitreoretinal DLBCL(PVR-DLBCL) as initial treatment may achieve a relatively better outcome[20]. Lenalidomide[31] had been demonstrated prominent effect on DLBCL, particularly non-GCB subtype. The combination of rituximab and lenalidomide (R2) can lead to good synergistic effect[32]. Recently, the R2 regimen was reported significant activity in relapsed/refractory PVRL and PCNSL patients[33]. Our center began to use R2-MTX regimen as the first choice for standard induction chemotherapy for newly diagnosed PCNS-DLBCL, with ORR of 100% (NCT 04120350). However, despite advances in initial treatment, more than 1/3 of patients relapsed[34] and no uniform treatment guidelines for relapsed and refractory PCNSL (R/R PCNSL). In this study, there was no statistically significant difference in survival between PVR-DLBCL and PCNS-DLBCL, which may be due to the higher relapsed rate of PVR-DLBCL and most of them were associated with central relapsed. In addition, bruton tyrosine kinase (BTK) inhibitors[35] and PD-1 blockade[36] therapy show good antitumor activity in R/R PCNSL. 6 patients with R/R PCNSL and treated by orelabrutinib plus sintilimab achieved PR/CR in this study and are still under follow-up. Patients do have a more promising future as new treatments and monitoring tools increase.

In rituximab era, fewer scholars still believe that surgical treatment can achieve a better prognosis than conservative treatment[37]. Most studies have shown that surgical treatment is playing an increasingly inconspicuous role in the treatment of primary gastrointestinal DLBCL(PGI-DLBCL), while mostly used for definitive diagnosis or clinical emergencies[38, 39]. The data from our study also showed no significant difference in the outcome of patients receiving chemotherapy alone compared with those treated by surgery combined with chemotherapy. The value of probably prognostic factors like gender, LDH levels, B symptoms and International Prognostic Index (IPI) remains controversial[40–42] in patients with PGI-DLBCL. We agreed with previously reported studies that Lugano stage could effectively predict prognosis of PGI-DLBCL[24, 43].

Although univariate analysis showed differences in IPI, LDH, DH, Ann Arbor stage and achieving CR following first-line treatment, achieving CR was indeed identified as factors leading to better survival in our study, which was different from our previous retrospective study[44] and research data of other centers[23]. This can be explained by the selection bias of hospitalized patients and the fact that more alternative immuno-targeted therapies have reduced the differences in outcomes associated with different baseline characteristics. The short follow-up of our study may also be a reason that cannot be ignored. In order to achieve CR in first-line treatment, we took intensive induction therapy in some patients with double-protein-expression, which also proved to have better efficacy. At the same time, it also suggests that we may need a better prognostic integral model for PE-DLBCL in the future[45–47].

Different sites of extranodal involvement are related to widely different clinical outcomes[28, 48]. Comparing the analysis of the largest comprehensive descriptive study in China[49] and SEER database[50], which is based on the anatomical distribution of DLBCL for clinical outcomes, we found that the PE-DCLBL patients in our cohort showed a better prognosis. But this result requires a longer follow-up time to confirm. In our study, primary bone DLBCL and primary thyroid gland DLBCL(PT-DLBCL), consistent with previous reports[51–53], were associated with a better prognosis. Two-thirds of patients with PT-DLBCL underwent total or subtotal thyroidectomy, which had proved to be associated with significantly improved survival[54]. Primary testis DLBCL were related to higher CNS relapsed rate and unfavorable outcome[55, 56]. 4/7 patients in our study used MTX for CNS prophylaxis, which is still controversial[57, 58], only 1/7 of them had central recurrence and all had favorable clinical outcomes.

In summary, our study demonstrated that the different sites of extranodal involvement in patients are accompanied by different clinical features and have different outcomes. The clinical outcome of PE-DLBCL in our center had been greatly improved through standardized treatment, the addition of immune-targeted drugs such as lenalidomide, local plus systemic treatment for PVR-DLBCL in cooperation with ophthalmology, and intravenous MTX prophylaxis for central high-risk groups.

Abbreviations

DLBCL: diffuse large B-cell lymphoma

CNS: central nervous system

PE-DLBCL: primary extranodal diffuse large B-cell lymphoma

GI: gastrointestinal

IPI: International Prognostic Index

PFS: progression-free survival

OS: overall survival

Declarations

Ethics approval and consent to participate

All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975. Informed consent was obtained from all patients for being included in the study.

Consent for publication

Not applicable.

Availability of data and materials

All data generated or analysed during this study are included in this published article [and its supplementary information files].

Competing interests

The authors declare that they have no competing interests.

Funding

Not applicable.

Authors' contributions

JZ analyzed and interpreted the patient data and was a major contributor in writing the manuscript. DBZ and ZW conceived and designed the work that led to the submission, acquired data and had an important role in interpreting the results. YZ, DZ, WW, JR, CW, ZW and ZZ participated in the diagnosis and treatment of patients and provided the clinical data, they also contributed significantly to acquisition and analysis of data, drafting the manuscript and revising it critically. WZ gave final approval of the version to be published. All authors read and approved the final manuscript.

Acknowledgements

Not applicable.

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