Adult Non Hodgkin’s Lymphoma Patients: Experience from a Tertiary Care Cancer Centre in North East India

There is paucity of data on non Hodgkin’s lymphoma (NHL) from our population in North-East India. In this retrospective study, patients were consecutively followed-up to see the clinic-pathological pattern of NHL, various responses, and pattern of relapses to first line treatment with chemotherapy. All patients in the present study received standard regimen of cyclophosphamde, doxorubicin, vincristine, prednisolone (CHOP) with or without rituximab (R-CHOP) as per our institutional protocol as first line therapy. Our study has shown that, in our adult population, the majority of NHL cases present with stage II and stage III disease and extra nodal involvement, B-cell lymphomas and diffuse large cell lymphomas being the most common subtypes. International prognostic index was a significant factor for varied responses to treatment. The majority of relapses after complete remission occurred in the first year.


Introduction
Non-Hodgkin's lymphomas (NHL) are the most varied in terms of pathology, clinical aggressiveness, response to treatment and relapse. There is marked variation in these parameters in patients from different geographic regions (Anderson et al., 1998;Smedby, 2006;Dominik et al., 2007;Bofetta, 2011;Zelenetz et al., 2011). These variations were magnified due to the lack of standard protocol for treatment for most part of the last century. Although now, a routine treatment regimen has been adopted on the basis of histologic and molecular subtypes, chromosomal abnormalities, and risk stratifications (Sengar et al, 2011), such cutting edge facilities are not available in most centers, and treatment heterogeneity still persists. NHL is not a common cancer in this part of the world however; it has been seen to be a common cancer in a hospital based study adjacent to North East India (Hussain et al., 2012). There is paucity of both prospective and retrospective studies on Non Hodgkin's lymphoma from North-eastern part of India, it deserves proper approach. To address these issues, we have tried a retrospective study on patient population from the North-Eastern India. in our hospital from April 2008 to March 2011 were reviewed for this study. For the study, we considered patients who were above 20 years of age because histologic subtypes of NHL below this age group are different and most of them behave differently (Sengar et al., 2011). Only newly diagnosed and immunohistochemistry (IHC) confirmed cases who were treatment naïve were selected for evaluation. Hospital records were retrospectively reviewed for inclusion and exclusion criteria and then evaluated for stage; grades, prognostic index, histology, IHC, treatment regimen, and follow up information. Patients were assigned to one of the four prognostic scores according to the international prognostic index (IPI). Patients were staged according to the modified Ann Arbor Staging system. Histopathological diagnosis in all cases were reviewed and reported by the expert hemato-pathologist as per WHO 2008 classification for hemato-lymphoid neoplasms.
All patients received standard regimen of cyclophosphamde, doxorubicin, vincristine, prednisolone (CHOP) with or without rituximab (R-CHOP) as per institutional protocol as first line therapy. Patients were evaluated after completion of 3 cycles and 6 cycles of chemotherapy. Those who achieved remission were followed up every 3monthly during first year, 6 monthly during 2 nd and 3 rd year and then once yearly. Followup included detailed history, physical examination, complete blood count, serum lactate dehydrogenase, chest radiography and abdominal ultra sonography. Computed Tomogram (CT) scan of the chest, abdomen and pelvis were advised annually or if otherwise indicated for confirmation of relapse. Responses following first line treatment were one of the following complete remission (CR), partial remission (PR), stable disease (SD), and progressive disease (PD). The criteria followed were based on response evaluation criteria for solid tumors as outlined by Eisenhauer et al (2009).

Statistical analysis
Descriptive statistics up-to single decimal place was used and test of independence was done by Chi square test. p<0.05 was considered as significant.

Results
Of the 111 patients analyzed, 73 were male and 38 female with a male: female was 1.9. Age of patients ranged 20-88 years, and the median and mean age were 54 and 51.9 years respectively. The age group distribution is shown on Figure 1.
Ninety patients had B-cell lymphoma (81.1%) and 21 had T-cell (18.9%) lymphoma. Diffuse large cell lymphoma (DLCL) was the most common subtype in 62 (55.8%) patients, followed by follicular lymphoma in 11(9.9%), anaplastic large cell lymphoma 10 (9.0%), Peripheral T-cell lymphoma 8 (7.2%), small lymphocytic lymphoma 8 (7.2%) and marginal zone B-cell lymphomas including MALT lymphomas in 5(4.5%) patients. Out of the 111 patients, 43 patients achieved complete remission (38.7%), 43 patients partial remission (38.7%), 7 patients had disease progression (6.3%), 15 patients stable disease (13.5%). One patient expired after 1st line chemo therapy and 2 patients could not complete 1st line chemo therapy. So, the responses to first line treatment with CHOP with or without rituximab were available in 108 patients. The association of T/B cell and grade with responses to first line treatment was p=0.87 and p=0.732 respectively and that with IPI was p=0.005 ( Table 2).

Pattern of relapses
Out of the 43 patients who achieved complete remission, there were relapses in 20 (46.5%) of patients till the time of analysis. Thirteen (65%) patients relapsed within first year, three (15%) during 2nd year and four patients (20%) during 3 rd year. Out of the 20 patients relapsed after achieving complete remission following

Discussion
Non Hodgkin's lymphoma show considerable variation clinically, biologically and epidemiologically worldwide (Bofetta, 2011). Case-control study from India has shown the risk of NHL to be high in smokers, mutton consumption, and in individuals with exposure to pesticides (Balasubramanium et al., 2013). Recent meta-analyses have shown the association of red meat and processed meat with NHL and a weak association with certain genetic polymorphism (Zhou et al., 2014). In our population most of the cases were seen at 46-60 years age group and males were almost twice affected. Analytic epidemiological studies on NHL will be required to establish additional risk factors for our population. Of primary extra nodal NHL, central nervous system followed by gastrointestinal were common (Padhi et al., 2012). In our present study, spleen followed by stomach was common extra nodal sites of NHL. The distribution of NHL subtypes in India shows important differences with those from the rest of the world. Follicular lymphoma and mantle cell lymphoma are less common in India compared to Europe and the USA. Peripheral T-cell lymphomas and T/NK-cell lymphomas of nasal and nasal types, which are common in many other Asian countries, are also less prevalent. T-cell lymphoblastic lymphoma and anaplastic large T/null cell lymphoma are more prevalent in India (Naresh et al., 2000). In our observation B-cell lymphomas formed 81 % of the NHLs, whereas T-cell lymphomas formed 19 % of the total. This finding is similar to one by Sader-Ghorra et al (2014). DLCL was the most common subtype followed by follicular lymphoma, anaplastic large cell lymphoma, peripheral T-cell lymphoma, and small lymphocytic lymphoma. Low IPI NHL had a favorable prognosis in one recent study ( Mersoytlu et al., 2014). In the present study IPI was significant factor in the initial response to first line chemotherapy (p<0.05), whereas the stage at presentation and grade had no significant impact in the various outcomes (p>0.05).
With the advent of newer therapeutic protocol the outcome of aggressive NHL has improved during the last few decades with 60-80% complete remission; 20-40% relapses which are most commonly occurred during the 2nd -3rd years after completion of treatment (Salles et al., 1994). In our observation 38.7% of the total patients achieved complete remission of which 46.5% subsequently relapsed within 3 years. In our study most of the relapses were detected in sites where lymphoma was diagnosed initially (90%). In a study Elis et al. (2002) observed that 63% relapse occurred in both primary and new nodal sites simultaneously, whereas 23% relapses occurred only at a new site. 65% of relapses occurred within the first year in our study population.
In conclusion, in adult NHL of our population, majority presents at stage II and stage III disease, and with extra nodal presentation, B-cell lymphomas and diffuse large cell lymphoma were the common subtypes.
International prognostic index was a significant factor for varied responses to treatment. Majority of relapses after CR occurred at the first year.