Indian J Hematol Blood Transfus (Apr-June 2016) 32(2):182–185 DOI 10.1007/s12288-015-0610-6
SHORT COMMUNICATION
Nodal Follicular Lymphomas: A Clinicopathological Study from a Tertiary Care Centre in South India Divya Supari1 • Anuradha Ananthamurthy1
Received: 27 February 2015 / Accepted: 19 October 2015 / Published online: 2 November 2015 Ó Indian Society of Haematology & Transfusion Medicine 2015
Abstract The aim of this study was to assess the distribution of nodal follicular lymphomas (FL) among various subtypes of non- Hodgkin lymphoma and to study their clinico-pathological features. Clinical details, histomorphology including grading & patterns and immunoprofile of 44 cases were studied. Majority of the cases were grade 1 (61 %) FL. BCL2 positivity was higher in low grade FLs (97 %). An associated diffuse large B cell lymphoma component was seen in 18 % and was present only in conjunction with grade 3 FL. Majority of our patients (76 %) had a high FLIPI score and belonged to the high risk group. Our study showed that the incidence of FLs is much lower in the Indian population (14.5 %) when compared to western studies and majority were of low grade. Although there was complete initial response to treatment, relapse was common and was much higher in low grade FLs with diffuse areas on histology, Ann Arbor stage III/IV and FLIPI scores of 3–5. Keywords Follicular lymphoma FL Low grade B cell lymphoma FLIPI
Introduction Follicular Lymphoma (FL) is one of the most common B-cell non hodgkin lymphomas (NHL) accounting for 20–40 % in the western population [1, 2]. The incidence is & Divya Supari [email protected] Anuradha Ananthamurthy [email protected] 1
St John’s Medical College, Sarjapur Road, Bangalore 560034, India
123
stated to be much lower in the Asian countries and about 12 % in the Indian population [3]. It is an indolent and clinically heterogeneous disease, with median survival expectations of 8–10 years. Although the disease is sensitive to radio and chemotherapy, many patients relapse several times. [2, 4]. There is very limited literature available on the incidence and pathological profile of FL in the Indian population. This study is an attempt to describe the Clinicopathological profiles of patients with FL seen in this institution.
Materials and Methods Forty-four patients with a diagnosis of a nodal FL in the period between January 2006 and April 2012 were included in this study. Case charts of the patients were retrieved for demographic, clinical, laboratory, treatment and follow up data. Follicular Lymphoma International Prognostic Index (FLIPI) scores based on five clinical parameters namely age, Ann Arbor stage, number of nodal areas, LDH, and hemoglobin level, which differentiates patients into three separate risk groups (low, intermediate and high) were assigned to cases wherever possible. However FLIPI2 analysis could not be done as there was a very high proportion of the patients with missing data of serum b2-microglobulin levels. FLs were graded according to the criteria proposed in the latest 2008 WHO classification of tumors of hematopoietic and lymphoid Tissue [1]. Immunohistochemistry (IHC) was performed with antibodies obtained from commercial source to complete the panel of markers and included CD20 (clone: L26), CD3 (clone: F7.2.38), BCl2 (clone: CL124), CD10 (clone: 56C6) and Ki67 Ag
Indian J Hematol Blood Transfus (Apr-June 2016) 32(2):182–185
(Clone MIB-1). BCL6, CD5 and Cylcin D1 were done in a few cases to rule out other B-cell Lymphomas. Molecular studies were not done in any of our cases. SPSS version 16 was used for the statistical analysis. The categorical data were analyzed using Chi square test. A P value of \0.05 was considered to be statistically significant. However, survival analysis could not be done due to a short duration of follow up.
Table 2 Correlation of BCL2 and CD10 expression with grade IHC marker
Grade 1 and 2
Grade 3
P value
Positive (40/44)
30 (97 %)
10 (77 %)
0.03
Negative (4/44)
1 (3 %)
3 (23 %)
Positive (33/44)
23 (74 %)
10 (77 %)
Negative (11/44)
8 (26 %)
3 (23 %)
BCL2
CD10 0.84
Significant p value is in bold
Results A total of 302 cases of nodal NHL were diagnosed based on histopathology at our hospital, over a 5.4 year period (January 2006–April 2012). Of these, 44 cases (14.5 %) were diagnosed as nodal FL. The patients ranged from 18 to 80 years of age with a median age of 55.5 years. There were 24 males and 20 females, male to female ratio being 1.2:1. Bone marrow involvement was seen in 15 (34 %) cases. Peripheral blood spill was noted in 2 (5 %) cases. There were 4 (9 %) cases in stage I, 5 (11 %) cases in stage II, 17 (39 %) cases in stage III, and 18 (41 %) cases in stage IV. Thus, the majority of patients (79.5 %) presented in advanced stages of III or IV. The findings of histological grading & patterns are summarized in Table 1. Majority of the cases were grade 1 (61 %) FL and the predominant pattern was follicular (56.8 %). An associated diffuse large B cell lymphoma (DLBCL) component (with diffuse areas [25 %) was seen in 8 (18 %) cases of grade 3 FL, among which 6 were grade 3A and 2 were grade 3B. The IHC panel included CD20, CD10, BCL2 and CD3. The expression of BCL2 and CD 10 were correlated with the histological grade (Table 2). The difference in BCL2 positivity between grade 1–2 (low grade) and 3 (high grade) was statistically significant (P = 0.03). Differences in CD10 positivity did not reach statistical significance (grade 1–2, 74 %; grade 3, 77 %, Table 1 Grading and pattern on histopathology Grade (n = 44) Grade 1 (0–5 centroblasts/hpf)
183
27 (61 %)
2 (6–15 centroblasts/hpf)
4 (9 %)
3 ([15 centroblasts/hpf)
13 (30 %)
3A- centrocytes present
11 (25 %)
3B- solid sheets of centroblasts
2 (5 %)
DLBCL ? grade 3 FL
8 (18 %)
Pattern: proportion of follicular component Follicular [75 %
25 (56.8 %)
Follicular and diffuse 25–75 %
17 (38.6 %)
Focal follicular \25 %
2 (4.6 %)
Diffuse 0 %
0
P = 0.84). CD3 was negative in the neoplastic cells in all the cases and stained only the reactive component. Ki 67 showed positivity in 30–60 % of the cells. Ki 67 was also useful in demonstrating the loss of polarity in the neoplastic follicles. Ki 67 was not used for the purpose of grading. Treatment data and follow up were available in 34 cases. Out of 33 cases treated with CHOP chemotherapy, 28 patients received rituximab and 3 of them also received radiotherapy in addition to CHOP. All of the 33 patients achieved complete response (CR). Median follow up period was 44.5 months. Relapse was seen in 7 (16 %) cases, once in 6 (14 %) cases and twice in 1 (2 %) case. FLIPI scores were assigned to 42 cases. Low, intermediate and high risk FL were seen in 2 (5 %), 8 (19 %) and 32 (76 %) cases respectively. The correlation of histological grades, which is also a known prognostic factor, with other prognostic factors are summarized in the Table 3. Except for Ann Arbor Staging, none of the other parameters showed statistically significant correlation with the grades.
Discussion The reported distribution of NHL subtypes in India is different with those from the rest of the world [2]. In a study from India by Naresh et al. [3] which incorporated immunophenotypic studies to investigate the distribution of NHL subtypes, FL was found to constitute about 12.6 % of all NHL. In the current study, incidence of nodal FL is 14.5 % which is slightly higher than the previously published reports. With regard to gender distribution, there was slightly higher incidence in males (M:F ratio-1.2:1) when compared to western countries where FL is seen more in females [5]. We also found that the median age at presentation was 55.5 years, which is similar to the International Working Formulation (IWF) series [6]. It is also interesting that we did not have a single case of pediatric FL in our series and our youngest patient was 18 years of age. Majority (79.5 %) of our patients had high stage
123
184 Table 3 Correlation of various prognostic factors with the grades of FL
Indian J Hematol Blood Transfus (Apr-June 2016) 32(2):182–185
Characterstics
Patients (%)
Grade (%)
Grade 3 (%)
P value
All patients
44 (100 %)
31 (70 %)
13 (30 %)
Age [60 years
17 (39 %)
14 (82 %)
3 (18 %)
0.19
Nodal stations [4
32 (73 %)
21 (66 %)
11 (34 %)
0.45
Hb \12 gm/dl
23/42 (55 %)
14 (61 %)
9 (39 %)
0.35
LDH [ ULN
23/42 (55 %)
14 (61 %)
9 (39 %)
0.35
22 (63 %)
13 (37 %)
0.04 0.54
Ann Arbor stage III–IV
35 (79.5 %)
FLIPI: score (n = 42) Low risk 0–1
2 (5 %)
2 (100 %)
0
Intermediate risk 2
8 (19 %)
6 (75 %)
2 (25 %)
High risk 3–5
32 (76 %)
21 (66 %)
11 (34 %)
Bone marrow involvement
15 (34 %)
10 (67 %)
5 (33 %)
0.96
Significant p value is in bold Hb hemoglobin, LDH lactate dehydrogenase, ULN upper limit of normal, FLIPI Follicular Lymphoma International Prognostic Index
disease (stage III or IV), again similar to the IWF data (73 %) [5]. The latest WHO classification of lymphoid neoplasms recommends pattern of reporting based on the proportion of follicular component [1]. The predominant pattern observed in our case series was follicular pattern (56.8 %) and was in agreement with earlier studies [1]. Majority of our cases were grade 1–2 (70 %) as observed in earlier studies with grade 3 FLs making up only a minority of all FLs (30 %). The WHO classification states that in unselected series, grade 3B constitutes 20–25 % of purely grade 3 FLs [1]. This expected frequency was not seen in the present study. Both the grade 3B cases were not purely follicular but in addition had a DLBCL component, whereas an additional DLBCL component was seen in 55 % (6/11) of grade 3A cases. Immunohistochemistry is the most valuable adjunct to hemotoxylin and eosin (H&E) staining. Recently, evidence has accumulated that FL grade 3, as defined in the REAL and WHO classifications, differs from FL grades 1 and 2 clinically and biologically [1]. FL grade 3 has been reported to express the BCL2 protein in only 50 % of patients which could be due to the mutations in translocated BCL2 genes, which hampers the detection of the protein [1, 7, 8]. The CD10 membrane glycoprotein is found in 70–100 % of patients with grade 1 and 2, but in only 20 % of patients with grade 3 FL [9]. Correlation of BCL2 staining with grade showed statistical significance in our study (p = 0.03). None of our cases exhibited features of In situ Follicular Lymphoma, even focally. Among the grade 3 cases with DLBCL component, expression of the IHC markers was concordant in the follicular and diffuse parts. Treatment of patients with FL is still a matter of controversy because of its potentially long natural history (median survival of 6–12 years), and wide treatment
123
options. High response rates with initial chemotherapy and repeated recurrences with decreasing remission duration are characteristic during the clinical course of patients with FL [4]. Majority of our patients were treated with CHOP and 33 of them achieved CR. Transformation to more aggressive lymphoma is known to occur in 10–60 % of the cases [10, 11], however it was not documented in any of the 34 cases during the follow up. The two best measures of outcome are the FL international prognostic index (FLIPI) and tumor grade. A modified version, of this score, the FLIPI2, evaluates five parameters, with some overlap of the FLIPI [12]. Majority of our cases (76 %) cases had high FLIPI scores and were categorized as high risk group. However we could not correlate the FLIPI scores with survival as we have not done a survival analysis in our study. We also observed that majority of the cases (86 %) with relapse had high FLIPI scores of 3 to 5. In historical series, FL displays an indolent clinical course characterized by a continuous pattern of relapse despite the activity of most proposed treatment with no evidence of cure [13, 14]. We observed relapse in 16 % of our cases. Relapse was high among low grade FLs (6 of 7, 86 %) with diffuse areas on histology (6 of 7, 86 %), patients with higher stages (7 of 7, 100 %) and high FLIPI scores (6 of 7, 86 %). Plancarte et al. [15] observed a high risk of relapse in early stage FLs; in contrast we did not observe relapse in early stage FLs.
Conclusion FL is a type of B-cell NHL that has not been extensively studied in India. The study confirms that incidence of FL is much lower in Indian population when compared to western data and constituted approximately 14.5 % of all our nodal NHLs. The difference in BCL2 positivity
Indian J Hematol Blood Transfus (Apr-June 2016) 32(2):182–185
between grade 1–2 and 3 was statistically significant (P = 0.03). A majority of our patients (76 %) had high FLIPI score and belonged to high risk group. Relapse rate was much higher in low grade cases with diffuse areas on histology, Ann Arbor stage III/IV and FLIPI scores of 3 to 5.
185
8.
9.
Compliance with Ethical Standards Conflict of interest
None of the authors has conflict of interest.
10.
References 11. 1. Harris NL, Swerdlow SH, Jaffe ES, Ott G, Nathwani BN, Jong D et al (2008) Follicular lymphomas. In: Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Vardiman JW (eds) WHO classification of tumours of hematopoietic and lymphoid tissues, 4th edn. International Agency for Research on Cancer (IARC), Lyon, pp 220–226 2. Biagi JJ, Seymour JF (2002) Insights into the molecular pathogenesis of follicular lymphoma arising from analysis of geographic variation. Blood 99:4265–4275 3. Naresh KN, Srinivas V, Soman CS (2000) Distribution of various subtypes of non Hodgkin’s lymphomas in India: a study of 2773 lymphomas using REAL and WHO classifications. Ann Oncol 11(suppl 1):S63–S67 4. Horning SJ, Rosenberg SA (1984) The natural history of initially untreated low grade non-Hodgkin’s lymphomas. N Engl J Med 311:1471–1475 5. Anon (1997) A clinical evaluation of the International Lymphoma Study Group classification of non-Hodgkin’s lymphoma. The non-Hodgkin’s lymphoma classification project. Blood 89:3909–3918 6. Non-Hodgkin’s lymphoma pathologic classification project (1982) National Cancer Institute sponsored study of classifications of non-Hodgkin’s lymphomas: summary and description of a working formulation for clinical usage. Cancer 49:2112–2135 7. Ott G, Katzenberger T, Lohr A et al (2002) Cytomorphologic, immunohistochemical, and cytogenetic profiles of follicular
12.
13.
14.
15.
lymphoma: 2 types of follicular lymphoma grade 3. Blood 99:3806–3812 Karube K, Guo Y, Suzumiya J et al (2007) CD10-MUM1? follicular lymphoma lacks BCL2 gene translocation and shows characteristic biologic and clinical features. Blood 109:3076–3079 Eshoa C, Perkins S, Kampalath B, Shidham V, Juckett M, Chang CC (2001) Decreased CD10 expression in grade III and in interfollicular infiltrates of follicular lymphomas. Am J Clin Pathol 115:862–867 Al-Tourah AJ, Gill KK, Chhanabhai M, Hoskins PJ, Klasa RJ, Savage KJ, Sehn LH, Shenkier TN, Gascoyne RD, Connors JM (2008) Population-based analysis of incidence and outcome of transformed non-Hodgkin’s lymphoma. J Clin Oncol 26:5165–5169 Montoto S, Davies AJ, Matthews J, Calaminici M, Norton AJ, Amess J, Vinnicombe S, Waters R, Rohatiner AZ, Lister TA (2007) Risk and clinical implications of transformation of follicular lymphoma to diffuse large B-cell lymphoma. J Clin Oncol 25:2426–2433 Federico M, Bellei M, Marcheselli L et al (2009) Follicular Lymphoma International Prognostic Index 2: a new prognostic index for follicular lymphoma developed by the International Follicular Lymphoma Prognostic Factor Project. J Clin Oncol 27:4555–4562 Hiddemann W, Kneba M, Dreyling M et al (2005) Frontline therapy with rituximab added to the combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) significantly improves the outcome for patients with advanced-stage follicular lymphoma compared with therapy with CHOP alone: results of a prospective randomized study of the German LowGrade Lymphoma Study Group. Blood 106:3725 McLaughlin P, Grillo-Lopez AJ, Link BK, Levy R et al (1998) Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: half of patients respond to a fourdose treatment program. J Clin Oncol 16:2825–2833 Plancarte F, Lopez-Guillermo A, Arellinas L et al (2006) Follicular lymphoma in early stages: high risk of relapse and usefulness of the Follicular Lymphoma International Prognostic Index to predict the outcome of patients. Eur J Haematol 76:58–63
123
SHORT COMMUNICATION
Nodal Follicular Lymphomas: A Clinicopathological Study from a Tertiary Care Centre in South India Divya Supari1 • Anuradha Ananthamurthy1
Received: 27 February 2015 / Accepted: 19 October 2015 / Published online: 2 November 2015 Ó Indian Society of Haematology & Transfusion Medicine 2015
Abstract The aim of this study was to assess the distribution of nodal follicular lymphomas (FL) among various subtypes of non- Hodgkin lymphoma and to study their clinico-pathological features. Clinical details, histomorphology including grading & patterns and immunoprofile of 44 cases were studied. Majority of the cases were grade 1 (61 %) FL. BCL2 positivity was higher in low grade FLs (97 %). An associated diffuse large B cell lymphoma component was seen in 18 % and was present only in conjunction with grade 3 FL. Majority of our patients (76 %) had a high FLIPI score and belonged to the high risk group. Our study showed that the incidence of FLs is much lower in the Indian population (14.5 %) when compared to western studies and majority were of low grade. Although there was complete initial response to treatment, relapse was common and was much higher in low grade FLs with diffuse areas on histology, Ann Arbor stage III/IV and FLIPI scores of 3–5. Keywords Follicular lymphoma FL Low grade B cell lymphoma FLIPI
Introduction Follicular Lymphoma (FL) is one of the most common B-cell non hodgkin lymphomas (NHL) accounting for 20–40 % in the western population [1, 2]. The incidence is & Divya Supari [email protected] Anuradha Ananthamurthy [email protected] 1
St John’s Medical College, Sarjapur Road, Bangalore 560034, India
123
stated to be much lower in the Asian countries and about 12 % in the Indian population [3]. It is an indolent and clinically heterogeneous disease, with median survival expectations of 8–10 years. Although the disease is sensitive to radio and chemotherapy, many patients relapse several times. [2, 4]. There is very limited literature available on the incidence and pathological profile of FL in the Indian population. This study is an attempt to describe the Clinicopathological profiles of patients with FL seen in this institution.
Materials and Methods Forty-four patients with a diagnosis of a nodal FL in the period between January 2006 and April 2012 were included in this study. Case charts of the patients were retrieved for demographic, clinical, laboratory, treatment and follow up data. Follicular Lymphoma International Prognostic Index (FLIPI) scores based on five clinical parameters namely age, Ann Arbor stage, number of nodal areas, LDH, and hemoglobin level, which differentiates patients into three separate risk groups (low, intermediate and high) were assigned to cases wherever possible. However FLIPI2 analysis could not be done as there was a very high proportion of the patients with missing data of serum b2-microglobulin levels. FLs were graded according to the criteria proposed in the latest 2008 WHO classification of tumors of hematopoietic and lymphoid Tissue [1]. Immunohistochemistry (IHC) was performed with antibodies obtained from commercial source to complete the panel of markers and included CD20 (clone: L26), CD3 (clone: F7.2.38), BCl2 (clone: CL124), CD10 (clone: 56C6) and Ki67 Ag
Indian J Hematol Blood Transfus (Apr-June 2016) 32(2):182–185
(Clone MIB-1). BCL6, CD5 and Cylcin D1 were done in a few cases to rule out other B-cell Lymphomas. Molecular studies were not done in any of our cases. SPSS version 16 was used for the statistical analysis. The categorical data were analyzed using Chi square test. A P value of \0.05 was considered to be statistically significant. However, survival analysis could not be done due to a short duration of follow up.
Table 2 Correlation of BCL2 and CD10 expression with grade IHC marker
Grade 1 and 2
Grade 3
P value
Positive (40/44)
30 (97 %)
10 (77 %)
0.03
Negative (4/44)
1 (3 %)
3 (23 %)
Positive (33/44)
23 (74 %)
10 (77 %)
Negative (11/44)
8 (26 %)
3 (23 %)
BCL2
CD10 0.84
Significant p value is in bold
Results A total of 302 cases of nodal NHL were diagnosed based on histopathology at our hospital, over a 5.4 year period (January 2006–April 2012). Of these, 44 cases (14.5 %) were diagnosed as nodal FL. The patients ranged from 18 to 80 years of age with a median age of 55.5 years. There were 24 males and 20 females, male to female ratio being 1.2:1. Bone marrow involvement was seen in 15 (34 %) cases. Peripheral blood spill was noted in 2 (5 %) cases. There were 4 (9 %) cases in stage I, 5 (11 %) cases in stage II, 17 (39 %) cases in stage III, and 18 (41 %) cases in stage IV. Thus, the majority of patients (79.5 %) presented in advanced stages of III or IV. The findings of histological grading & patterns are summarized in Table 1. Majority of the cases were grade 1 (61 %) FL and the predominant pattern was follicular (56.8 %). An associated diffuse large B cell lymphoma (DLBCL) component (with diffuse areas [25 %) was seen in 8 (18 %) cases of grade 3 FL, among which 6 were grade 3A and 2 were grade 3B. The IHC panel included CD20, CD10, BCL2 and CD3. The expression of BCL2 and CD 10 were correlated with the histological grade (Table 2). The difference in BCL2 positivity between grade 1–2 (low grade) and 3 (high grade) was statistically significant (P = 0.03). Differences in CD10 positivity did not reach statistical significance (grade 1–2, 74 %; grade 3, 77 %, Table 1 Grading and pattern on histopathology Grade (n = 44) Grade 1 (0–5 centroblasts/hpf)
183
27 (61 %)
2 (6–15 centroblasts/hpf)
4 (9 %)
3 ([15 centroblasts/hpf)
13 (30 %)
3A- centrocytes present
11 (25 %)
3B- solid sheets of centroblasts
2 (5 %)
DLBCL ? grade 3 FL
8 (18 %)
Pattern: proportion of follicular component Follicular [75 %
25 (56.8 %)
Follicular and diffuse 25–75 %
17 (38.6 %)
Focal follicular \25 %
2 (4.6 %)
Diffuse 0 %
0
P = 0.84). CD3 was negative in the neoplastic cells in all the cases and stained only the reactive component. Ki 67 showed positivity in 30–60 % of the cells. Ki 67 was also useful in demonstrating the loss of polarity in the neoplastic follicles. Ki 67 was not used for the purpose of grading. Treatment data and follow up were available in 34 cases. Out of 33 cases treated with CHOP chemotherapy, 28 patients received rituximab and 3 of them also received radiotherapy in addition to CHOP. All of the 33 patients achieved complete response (CR). Median follow up period was 44.5 months. Relapse was seen in 7 (16 %) cases, once in 6 (14 %) cases and twice in 1 (2 %) case. FLIPI scores were assigned to 42 cases. Low, intermediate and high risk FL were seen in 2 (5 %), 8 (19 %) and 32 (76 %) cases respectively. The correlation of histological grades, which is also a known prognostic factor, with other prognostic factors are summarized in the Table 3. Except for Ann Arbor Staging, none of the other parameters showed statistically significant correlation with the grades.
Discussion The reported distribution of NHL subtypes in India is different with those from the rest of the world [2]. In a study from India by Naresh et al. [3] which incorporated immunophenotypic studies to investigate the distribution of NHL subtypes, FL was found to constitute about 12.6 % of all NHL. In the current study, incidence of nodal FL is 14.5 % which is slightly higher than the previously published reports. With regard to gender distribution, there was slightly higher incidence in males (M:F ratio-1.2:1) when compared to western countries where FL is seen more in females [5]. We also found that the median age at presentation was 55.5 years, which is similar to the International Working Formulation (IWF) series [6]. It is also interesting that we did not have a single case of pediatric FL in our series and our youngest patient was 18 years of age. Majority (79.5 %) of our patients had high stage
123
184 Table 3 Correlation of various prognostic factors with the grades of FL
Indian J Hematol Blood Transfus (Apr-June 2016) 32(2):182–185
Characterstics
Patients (%)
Grade (%)
Grade 3 (%)
P value
All patients
44 (100 %)
31 (70 %)
13 (30 %)
Age [60 years
17 (39 %)
14 (82 %)
3 (18 %)
0.19
Nodal stations [4
32 (73 %)
21 (66 %)
11 (34 %)
0.45
Hb \12 gm/dl
23/42 (55 %)
14 (61 %)
9 (39 %)
0.35
LDH [ ULN
23/42 (55 %)
14 (61 %)
9 (39 %)
0.35
22 (63 %)
13 (37 %)
0.04 0.54
Ann Arbor stage III–IV
35 (79.5 %)
FLIPI: score (n = 42) Low risk 0–1
2 (5 %)
2 (100 %)
0
Intermediate risk 2
8 (19 %)
6 (75 %)
2 (25 %)
High risk 3–5
32 (76 %)
21 (66 %)
11 (34 %)
Bone marrow involvement
15 (34 %)
10 (67 %)
5 (33 %)
0.96
Significant p value is in bold Hb hemoglobin, LDH lactate dehydrogenase, ULN upper limit of normal, FLIPI Follicular Lymphoma International Prognostic Index
disease (stage III or IV), again similar to the IWF data (73 %) [5]. The latest WHO classification of lymphoid neoplasms recommends pattern of reporting based on the proportion of follicular component [1]. The predominant pattern observed in our case series was follicular pattern (56.8 %) and was in agreement with earlier studies [1]. Majority of our cases were grade 1–2 (70 %) as observed in earlier studies with grade 3 FLs making up only a minority of all FLs (30 %). The WHO classification states that in unselected series, grade 3B constitutes 20–25 % of purely grade 3 FLs [1]. This expected frequency was not seen in the present study. Both the grade 3B cases were not purely follicular but in addition had a DLBCL component, whereas an additional DLBCL component was seen in 55 % (6/11) of grade 3A cases. Immunohistochemistry is the most valuable adjunct to hemotoxylin and eosin (H&E) staining. Recently, evidence has accumulated that FL grade 3, as defined in the REAL and WHO classifications, differs from FL grades 1 and 2 clinically and biologically [1]. FL grade 3 has been reported to express the BCL2 protein in only 50 % of patients which could be due to the mutations in translocated BCL2 genes, which hampers the detection of the protein [1, 7, 8]. The CD10 membrane glycoprotein is found in 70–100 % of patients with grade 1 and 2, but in only 20 % of patients with grade 3 FL [9]. Correlation of BCL2 staining with grade showed statistical significance in our study (p = 0.03). None of our cases exhibited features of In situ Follicular Lymphoma, even focally. Among the grade 3 cases with DLBCL component, expression of the IHC markers was concordant in the follicular and diffuse parts. Treatment of patients with FL is still a matter of controversy because of its potentially long natural history (median survival of 6–12 years), and wide treatment
123
options. High response rates with initial chemotherapy and repeated recurrences with decreasing remission duration are characteristic during the clinical course of patients with FL [4]. Majority of our patients were treated with CHOP and 33 of them achieved CR. Transformation to more aggressive lymphoma is known to occur in 10–60 % of the cases [10, 11], however it was not documented in any of the 34 cases during the follow up. The two best measures of outcome are the FL international prognostic index (FLIPI) and tumor grade. A modified version, of this score, the FLIPI2, evaluates five parameters, with some overlap of the FLIPI [12]. Majority of our cases (76 %) cases had high FLIPI scores and were categorized as high risk group. However we could not correlate the FLIPI scores with survival as we have not done a survival analysis in our study. We also observed that majority of the cases (86 %) with relapse had high FLIPI scores of 3 to 5. In historical series, FL displays an indolent clinical course characterized by a continuous pattern of relapse despite the activity of most proposed treatment with no evidence of cure [13, 14]. We observed relapse in 16 % of our cases. Relapse was high among low grade FLs (6 of 7, 86 %) with diffuse areas on histology (6 of 7, 86 %), patients with higher stages (7 of 7, 100 %) and high FLIPI scores (6 of 7, 86 %). Plancarte et al. [15] observed a high risk of relapse in early stage FLs; in contrast we did not observe relapse in early stage FLs.
Conclusion FL is a type of B-cell NHL that has not been extensively studied in India. The study confirms that incidence of FL is much lower in Indian population when compared to western data and constituted approximately 14.5 % of all our nodal NHLs. The difference in BCL2 positivity
Indian J Hematol Blood Transfus (Apr-June 2016) 32(2):182–185
between grade 1–2 and 3 was statistically significant (P = 0.03). A majority of our patients (76 %) had high FLIPI score and belonged to high risk group. Relapse rate was much higher in low grade cases with diffuse areas on histology, Ann Arbor stage III/IV and FLIPI scores of 3 to 5.
185
8.
9.
Compliance with Ethical Standards Conflict of interest
None of the authors has conflict of interest.
10.
References 11. 1. Harris NL, Swerdlow SH, Jaffe ES, Ott G, Nathwani BN, Jong D et al (2008) Follicular lymphomas. In: Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Vardiman JW (eds) WHO classification of tumours of hematopoietic and lymphoid tissues, 4th edn. International Agency for Research on Cancer (IARC), Lyon, pp 220–226 2. Biagi JJ, Seymour JF (2002) Insights into the molecular pathogenesis of follicular lymphoma arising from analysis of geographic variation. Blood 99:4265–4275 3. Naresh KN, Srinivas V, Soman CS (2000) Distribution of various subtypes of non Hodgkin’s lymphomas in India: a study of 2773 lymphomas using REAL and WHO classifications. Ann Oncol 11(suppl 1):S63–S67 4. Horning SJ, Rosenberg SA (1984) The natural history of initially untreated low grade non-Hodgkin’s lymphomas. N Engl J Med 311:1471–1475 5. Anon (1997) A clinical evaluation of the International Lymphoma Study Group classification of non-Hodgkin’s lymphoma. The non-Hodgkin’s lymphoma classification project. Blood 89:3909–3918 6. Non-Hodgkin’s lymphoma pathologic classification project (1982) National Cancer Institute sponsored study of classifications of non-Hodgkin’s lymphomas: summary and description of a working formulation for clinical usage. Cancer 49:2112–2135 7. Ott G, Katzenberger T, Lohr A et al (2002) Cytomorphologic, immunohistochemical, and cytogenetic profiles of follicular
12.
13.
14.
15.
lymphoma: 2 types of follicular lymphoma grade 3. Blood 99:3806–3812 Karube K, Guo Y, Suzumiya J et al (2007) CD10-MUM1? follicular lymphoma lacks BCL2 gene translocation and shows characteristic biologic and clinical features. Blood 109:3076–3079 Eshoa C, Perkins S, Kampalath B, Shidham V, Juckett M, Chang CC (2001) Decreased CD10 expression in grade III and in interfollicular infiltrates of follicular lymphomas. Am J Clin Pathol 115:862–867 Al-Tourah AJ, Gill KK, Chhanabhai M, Hoskins PJ, Klasa RJ, Savage KJ, Sehn LH, Shenkier TN, Gascoyne RD, Connors JM (2008) Population-based analysis of incidence and outcome of transformed non-Hodgkin’s lymphoma. J Clin Oncol 26:5165–5169 Montoto S, Davies AJ, Matthews J, Calaminici M, Norton AJ, Amess J, Vinnicombe S, Waters R, Rohatiner AZ, Lister TA (2007) Risk and clinical implications of transformation of follicular lymphoma to diffuse large B-cell lymphoma. J Clin Oncol 25:2426–2433 Federico M, Bellei M, Marcheselli L et al (2009) Follicular Lymphoma International Prognostic Index 2: a new prognostic index for follicular lymphoma developed by the International Follicular Lymphoma Prognostic Factor Project. J Clin Oncol 27:4555–4562 Hiddemann W, Kneba M, Dreyling M et al (2005) Frontline therapy with rituximab added to the combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) significantly improves the outcome for patients with advanced-stage follicular lymphoma compared with therapy with CHOP alone: results of a prospective randomized study of the German LowGrade Lymphoma Study Group. Blood 106:3725 McLaughlin P, Grillo-Lopez AJ, Link BK, Levy R et al (1998) Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: half of patients respond to a fourdose treatment program. J Clin Oncol 16:2825–2833 Plancarte F, Lopez-Guillermo A, Arellinas L et al (2006) Follicular lymphoma in early stages: high risk of relapse and usefulness of the Follicular Lymphoma International Prognostic Index to predict the outcome of patients. Eur J Haematol 76:58–63
123
