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Table of Contents
ORIGINAL ARTICLE - REAL WORLD DATA
Year : 2022  |  Volume : 5  |  Issue : 1  |  Page : 67-74

Clinicopathologic features and outcomes of diffuse large B-cell lymphoma with extranodal involvement: A retrospective analysis


1 Department of Medical Oncology, All India Institute of Medical Sciences, New Delhi, India
2 Department of Radiation Oncology, All India Institute of Medical Sciences, New Delhi, India
3 Department of Laboratory Oncology, All India Institute of Medical Sciences, New Delhi, India
4 Department of Pathology, All India Institute of Medical Sciences, New Delhi, India

Date of Submission26-Aug-2021
Date of Decision02-Aug-2022
Date of Acceptance02-Sep-2022
Date of Web Publication31-Mar-2022

Correspondence Address:
Ajay Gogia
Department of Medical Oncology, IRCH, All India Institute of Medical Sciences, New Delhi - 110 029
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/crst.crst_204_21

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  Abstract 


Background: Extranodal involvement is seen in about 40%–50% of the cases of diffuse large B-cell lymphoma (DLBCL). However, data on the clinicopathological features and outcomes of DLBCL with extranodal involvement, especially in the rituximab era, are scarce from India.
Objectives: In this study, we aimed to assess the clinicopathological features and outcomes of DLBCL with extranodal involvement among Indian patients.
Materials and Methods: This retrospective study was conducted on patients with DLBCL, registered in the Department of Medical Oncology of the All India Institute of Medical Sciences, Delhi, India, between January 2014 and December 2018. Patients with nodal DLBCL aged more than 18 years, with concomitant extranodal disease in any anatomical site were included. All patients were treated with multiagent chemotherapy with or without rituximab.
Results: Median age of the cohort was 50 years (range, 18–86), a male-to-female ratio of 2:1. B-symptoms and bulky disease were seen in 48% and 39% patients, respectively. Bone was the most common site of extranodal involvement observed in 32% patients. Bone marrow involvement was present in 13% patients. Low-risk International Prognostic Index (IPI) was seen in 32% patients and intermediate risk IPI in 38% patients. Cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP)-based treatment was used in 80% of the patients and rituximab (R) was used in 73% of the patients. The objective response rate was 76%, with a complete response rate of 65.5%. After a median follow-up of 26 months, the 3-year progression free survival and overall survival (OS) were 65% and 82.7%, respectively. Involvement of the kidney/adrenal gland and central nervous system, high IPI score, and use of non- R-CHOP regimens were associated with a poor OS on the multivariate analysis.
Conclusions: The bone is the most common site of extranodal involvement in Indian patients with DLBCL. The outcome of extranodal DLBCL depends on the primary site of disease involvement.

Keywords: LMIC, DLBCL, extranodal, rituximab, rituximab-cyclophosphamide, doxorubicin, vincristine, prednisolone


How to cite this article:
Nair SC, Gogia A, Arora S, Kumar L, Sharma A, Biswas A, Gupta R, Mallick S. Clinicopathologic features and outcomes of diffuse large B-cell lymphoma with extranodal involvement: A retrospective analysis. Cancer Res Stat Treat 2022;5:67-74

How to cite this URL:
Nair SC, Gogia A, Arora S, Kumar L, Sharma A, Biswas A, Gupta R, Mallick S. Clinicopathologic features and outcomes of diffuse large B-cell lymphoma with extranodal involvement: A retrospective analysis. Cancer Res Stat Treat [serial online] 2022 [cited 2022 May 21];5:67-74. Available from: https://www.crstonline.com/text.asp?2022/5/1/67/341242




  Introduction Top


Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin's lymphoma (NHL), comprising 25% of all NHL cases in the western population.[1],[2],[3] The incidence of DLBCL in India is higher, ranging from 34% to as high as 60%, depending on the patient population and classification system used.[4],[5],[6] Extranodal involvement is common in DLBCL. It is seen in around 40% of all DLBCL cases according to the data reported from western countries.[7]



According to data from the National Cancer Institute's Surveillance, Epidemiology, and End Results Program (1978–1995), approximately 30% of all lymphomas are extranodal, and almost half of all extranodal NHLs have DLBCL histology. The most common sites for extranodal involvement are the gastrointestinal tract, skin, bone, and brain.[8] The incidence of extranodal presentation is variable across different B-cell histological subtypes, the majority being Burkitt's lymphomas, up to 30%–50% being DLBCLs, and 5%–10% being follicular lymphomas.[8]

Indian data on extranodal DLBCL are scarce. There have been only two studies till date reporting 31% and 36% incidence of extranodal involvement in DLBCL cases, which is comparable to data reported from the western countries.[5],[7] Clinical profile and outcomes of extranodal DLBCL in the rituximab era and prognostic factors affecting the outcomes in our population are currently unknown. Therefore, in this study, we intended to analyze the clinicopathological features and outcomes of DLBCL with extranodal involvement.


  Materials and Methods Top


General study details

This retrospective study was conducted on patients with DLBCL, registered in the Department of Medical Oncology of the All India Institute of Medical Sciences, New Delhi, between January 2014 and December 2018. The hospital caters primarily to patients from Delhi and its neighboring states (including Uttar Pradesh, Haryana, Punjab, Himachal Pradesh, Uttarakhand, Bihar, and Jharkhand). This study was approved by the Institutional Ethics Committee (IECPG-88/28.02.2018) for Postgraduate research, All India Institute of Medical Sciences, Ansari Nagar, Delhi, on Feb 28, 2018 [Supplementary Appendix 1]. A waiver for obtaining written and verbal informed consent was obtained from the ethics committee in view of the retrospective nature of the study. The study was conducted according to the ethical guidelines established by the Declaration of Helsinki and other guidelines like Good Clinical Practice Guidelines and those established by the Indian Council of Medical Research. No funding was required for this study. This study was not registered in a clinical trials registry.



Participants

Patients with nodal DLBCL aged more than 18 years, with concomitant extranodal disease in any anatomical site were included. Patients with isolated extranodal involvement, those with incomplete case records, and those who received no treatment were excluded.

Variables

The primary objectives were to assess the clinical and pathological characteristics of patients with extranodal DLBCL. The secondary objectives included the assessment of the progression free survival (PFS) and overall survival (OS).

PFS was defined as the time from registration to disease relapse, progression, or death from any cause. OS was defined as the time from registration to the time of death due to any cause. Data were censored on December 15, 2019.

Study methodology

Baseline evaluation included history and physical examination, complete blood counts, renal and hepatic function tests, uric acid level, electrolyte level, serum lactate dehydrogenase level, and imaging (either contrast-enhanced computed tomography [CT] or positron emission tomography [PET]/CT) for staging. Clinical staging was done in accordance with the Lugano classification.[9] Any tumor measuring ≥7.5 cm was labeled as bulky disease.[10] Unilateral bone marrow aspiration and biopsy were performed in all patients. Patients were also tested for human immunodeficiency virus and Hepatitis B and C infections. Pre-treatment cardiac function was assessed using multigated acquisition scan or echocardiogram. Immunohistochemistry (IHC) was performed using formalin-fixed paraffin-embedded tissue sections of lymph node excision or core biopsy for the confirmation of diagnosis. Disease was classified as germinal center B-cell like (GCB) or non-GCB-cell-like (non-GCB) type using the Hans algorithm.[11] All patients were treated with multiagent chemotherapy comprising cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP), with or without rituximab. Patients with Stage I/II DLBCL were administered four cycles of chemoimmunotherapy, while those with Stage III/IV disease were administered six cycles. Chemotherapy was followed by involved field radiotherapy (IFRT) to sites of bulky disease in all patients. As per our institutional policy, patients with more than one site of extranodal involvement were administered intrathecal methotrexate with each cycle of chemoimmunotherapy. Responses were defined according to the International Working Group response criteria for malignant lymphoma, preferably using PET/CT, whenever feasible.[12] Common Terminology Criteria for Adverse Events version 5 was used for toxicity assessment. Only Grade 3 or higher toxicities were recorded. The study data were abstracted retrospectively from the medical records and computer database of the hospital.

Statistics

Sample size calculation was not performed as this was an observational study and we included all eligible individuals registered at our department. Descriptive statistics were used for describing demographic and clinical characteristics. Survival was estimated using the Kaplan–Meier method, and log-rank test was used to compare the survivals. The association of study variables with PFS and OS was assessed using the Cox Proportional Hazard regression model. Differences were considered statistically significant if P < 0.05. Data were analyzed using Stata software (StataCorp. 2014. Stata Statistical Software: Release 14. College Station, TX, USA: StataCorp LP).


  Results Top


Between January 2014 and December 2018, a total of 550 patients with DLBCL were registered at the lymphoma/leukemia clinic of our center. Of these, 224 (40.7%) had secondary extranodal lymphoma and were included in the analysis [Figure 1].
Figure 1: Flowchart for patient recruitment

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Baseline characteristics

The baseline characteristics of the patients are given in [Table 1].
Table 1: Baseline characteristics and treatment regimens used in patients with extranodal diffuse B-cell lymphoma

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Treatment

Rituximab-CHOP (R-CHOP) regimen was used in 139 (62%) patients and CHOP in 39 (17%). Other regimens used were R-mini CHOP (modified CHOP) in 15 (6%), rituximab, cyclophosphamide, vincristine, and prednisolone (CVP) in 11 (4.5%), mini CHOP in 3 (1.5%), CVP in 4 (1.5%), and cyclophosphamide, etoposide, vincristine, and prednisolone ± R in 4 (1.5%) patients. A total of 164 (73%) patients received rituximab. Dose modifications of the R-CHOP and CHOP regimens were done in 14 (10%) and 8 (22%) patients, respectively. Older age and poor ECOG performance status were the main reasons for dose modifications. Median number of chemotherapy cycles was 6 (range 1–8). Involved field radiotherapy (IFRT) was used in 62 (28%) patients

Response

PET/CT was used for response assessment in 99 (44.2%) patients. The objective response rate was 166 (74.1%), with complete remission (CR) seen in 142 (63.4%) patients. Primary refractory disease was seen in 37 (16%), and 6 (2.7%) patients died of progressive disease (PD) during treatment. A total of 21 (9.3%) patients were lost to follow up before response assessment. Age >60 years (CR: 56% vs. 70% for age ≤60 years vs. >60 years, respectively; P < 0.001), presence of B-symptoms (CR: 55% vs. 73% for those with and without B-symptoms, respectively; P < 0.001) and poor ECOG PS (3–4) (CR: 57% vs. 71% for ECOG 0–2, respectively; P = 0.004) were associated with inferior CR rates. CR rate for those with Stage I/II disease was 73% and that for those with Stage III/IV disease was 59% (P = 0.003). Low to low-intermediate risk IPI was associated with a CR rate of 73% and high-intermediate to high risk IPI was associated with a CR rate of 52% (P = 0.001). The use of R-CHOP was associated with significantly higher CR rate compared to CHOP or other regimens (76% for R-CHOP vs. 49% for CHOP vs. 47% for others; P < 0.001). The involvement of extranodal sites as a whole was not associated with inferior CR rates; CR rate varied depending on the primary site of involvement. CR rate was significantly lower in cases of central nervous system (CNS) (12.5% vs. 66.5%; P = 0.003) and kidney/adrenal gland involvement (36.4% vs. 67.1%; P < 0.001); it was not significantly different in cases of bone and bone marrow involvement.

Toxicity

Toxicities were assessable in 209 (93.3%) patients. Toxicities of grade ≥3 were noted in 48 (23%) patients. The most common adverse events were neutropenia in 31 (14.8%), anemia in 16 (7.6%), and thrombocytopenia in 5 (2.4%) patients. Other common grade 3/4 toxicities included peripheral neuropathy 8 (3.8%), diarrhea 6 (2.9%), mucositis 5 (2.4%), vomiting 4 (1.9%), and extravasation 2 (1%). Hospitalization for the management of adverse events was required in 18 (8.6%) cases, mostly for febrile neutropenia and gastrointestinal toxicities. Death during initial chemotherapy occurred in 6 (2.9%) patients of which 3 (1. 4%) were due to PD and remaining due to febrile neutropenia.

Survival outcomes

The median follow-up time for survival analysis was 26 months (range, 6–72). A total of 69 events (7 deaths, 31 progressions, and 31 relapses) occurred after initial treatment completion. Of 62 patients who had disease progression or relapse, 49 (21.9%) opted for salvage chemotherapy (using rituximab in combination with either ifosfamide, carboplatin, etoposide, or cisplatin, cytarabine, dexamethasone), and 38 (17%) underwent autologous stem cell transplant. The patients who were ineligible (or unwilling) for transplant were offered palliative chemotherapy with prednisolone, etoposide, procarbazine, and cyclophosphamide and/or best supportive care. Of the 49 patients who underwent salvage chemotherapy, 38 (77.5%) achieved a response (CR, 23 [46.9%]; partial response, 15 [30.6%] and received stem cell transplant, whereas 11 (22.4%) patients failed salvage therapy and received palliative treatment. The median PFS and OS were not reached. The 3-year cumulative PFS was 65% and OS was 82.7%. In total, there were 32 (14%) deaths, of which 6 occurred during initial treatment. The remaining deaths occurred after disease progression or relapse. At the time of final analysis, 132 (59%) patients were alive (118 in CR) and 60 (28%) were lost to follow-up.

Prognostic factors

Univariate and multivariate analyses were performed to identify prognostic factors for PFS and OS [Table 2] and [Table 3]. On multivariate analysis, hypoalbuminemia, involvement of the CNS, or kidney/adrenal gland, high IPI score, and the use of non-rituximab regimens were associated with inferior PFS.
Table 2: Univariate analysis of prognostic factors for progression-free and overall survival in patients with extranodal diffuse large B-cell lymphoma

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Table 3: Multivariate analysis of prognostic factors for progression-free and overall survival

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  Discussion Top


In our retrospective study on patients with DLBCL, 40.7% had secondary extranodal DLBCL. This proportion is much higher than that reported in studies published in the western countries, China, and previous Indian studies [Table 4].[7],[8],[13],[14],[15],[16] This could be due to the higher proportion of patients with bone involvement (32%), which was the most common site of occurrence of extranodal DLBCL in our study population. El-Galaly et al. in their study reported the highest incidence (64%) of extranodal involvement to date. In their study as well, the bone was the most common site of extranodal involvement (29%).[17] The most common mode of presentation of bony lymphomas in our study was pain and swelling in the cheek/jaw or backache with or without paraplegia. Another reason for the high proportion of patients with extranodal lymphoma may be the criteria we used for defining extranodal disease. There is a lack of consensus on the exact definition of extranodal lymphoma; a commonly accepted definition is lymphomas with no or only “minor” nodal involvement associated with a clinically dominant extranodal component.[18],[19] We adopted this definition of extranodal lymphoma for the selection of patients for our study. Another possible reason could be that most of the earlier studies that reported the proportion of extranodal DLBCL were conducted before PET/CT imaging was widely available, and thus, it is likely that they missed out on the cases of primary bony extranodal involvement; however, this needs to be proven prospectively.
Table 4: Studies on extranodal diffuse large B-cell lymphoma

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In our study, the second most common site of extranodal involvement (16.5%) was the gastrointestinal tract This proportion is similar to that reported in western studies.[20],[21],[22],[23] Our study also showed a slightly higher proportion of primary adrenal and renal lymphomas compared to western studies, the reason for which is unclear.[24] Other sites of extranodal involvement in our study were similar to those reported in western data.

The median age (50 years) of our patients with extranodal DLBCL was much lower than that reported in the western studies but comparable to that reported in previous Indian literature.[5],[6],[25] Lower median age is consistent with the pattern for most other malignancies in India and may be the result of the younger population in our country or due to the referral bias of younger patients for treatment at higher centers.[25]

In our study, three factors were found to be independently associated with the PFS and OS, namely involvement of the CNS/kidney/adrenal gland, high IPI, and use of non-rituximab-containing regimens. Low albumin level was additionally found to be associated with inferior event-free survival (EFS) but not OS. Patients with CNS involvement at baseline had a dismal outcome, with only 25% survival at 2 years, which is similar to previous reports.[18],[26],[27] Involvement of the kidney/adrenal gland has been reported to be a poor prognostic factor in previous studies as well.[16],[28],[29] Other sites such as the bone marrow, bone, gastrointestinal tract, lung, liver, testis, ovary, breast, and thyroid gland were not found to be significantly associated with the survival outcomes, but often, the number of cases of these rare subtypes is too small to reach any meaningful conclusions. In a recent analysis, it was found that the CR rate for extranodal sites such as the gastrointestinal tract, bone, testis, and breast was higher than that for nodal DLBCL; additionally, the outcomes for extranodal sites such as the gastrointestinal tract, bone, and breast were better than those of nodal DLBCL.[30] Interestingly, another study has shown that sanctuary sites like the CNS and testis are associated with inferior outcomes, and DLBCLs occurring in these sites are predominantly of the non-GCB subtype.[27]

The cell of origin determined based on the Hans algorithm was found to be prognostic of the outcome in patients with DLBCL as a whole.[9] A recent study of the molecular profile of extranodal lymphomas showed that there is a higher proportion of mutations resulting in the activation of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) pathway in extranodal DLBCL. However, its clinical significance is unknown. Regarding the association between the cell of origin and outcome of patients with extranodal DLBCL, one previous study reported no difference in the outcomes, whereas another reported worse outcomes with the non-GCB subtype.[31],[32] Data for the cell of origin were available for 80% of our patients, with 55% showing the GCB-cell-like subtype and 45% showing the activated B-cell subtype. This is in contrast to western data, in which a higher incidence of non-GCB subtype is reported.[27] Although there was a trend toward more relapses and deaths among those with the non-GCB subtype, it failed to reach statistical significance. This may be because determining the cell of origin was not feasible in around 20% of our patients and the use of IHC instead of fluorescent in situ hybridization or gene expression profiling in our study. Recent studies have shown that digital gene expression tests like Lymph2Cx, which can be performed on formalin-fixed paraffin-embedded tissue sections, demonstrate a concordance rate of >95% with conventional gene expression profiling and that algorithms based on IHC have high false positive and false negative rates, resulting in the loss of prognostic value for IHC-based algorithms.[33],[34],[35]

The role of rituximab-based chemoimmunotherapy in DLBCL is well established but its effects on the outcome of extranodal disease are not clear, although the majority of the studies have shown better outcomes with the incorporation of rituximab.[23],[28],[36],[37] In our study, the use of non-rituximab-based chemotherapy regimens was associated with inferior PFS and OS, thus further strengthening the role of rituximab in extranodal DLBCL. A study by Held et al. showed that the addition of rituximab to the CHOP regimen was associated with inferior EFS but not OS in skeletal DLBCL; however, the sample size of the study was small, and the finding needs prospective validation.[38] Although the proportion of patients treated with rituximab (73%) in our study was greater compared to previous Indian studies, it is still low when compared to the real-world data from the West.[39]

Our study had some drawbacks. PET/CT was used for staging in less than half of the patients, our study had a high lost to follow-up rate, and there was difficulty with accurate radiologic staging and documenting toxicities. In addition, as this was a retrospective analysis, further identification of the cell of origin was not possible in 20% of the cases, which may have affected the outcomes. Nevertheless, ours is one of the largest studies from India on extranodal DLBCL in the rituximab era.


  Conclusions Top


Our study suggests that the bone is the most common site of extranodal involvement and the outcome of extranodal DLBCL depends on the primary site of disease involvement, with involvement of CNS and kidney/adrenal gland being associated with inferior outcomes. High-risk IPI and use of non-rituximab-containing regimens are also associated with inferior outcomes in extranodal DLBCL.

Data sharing statement

Individual de-identified participant data (including data dictionaries) will be shared. Specifically, all the individual participant data collected during the trial will be shared after deidentification.

Additionally, the study protocol will be shared. The data will be shared starting from 3 months after publication, ending 5 years following article publication. The data will be available on request from Dr. Ajay Gogia at [email protected]

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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