| Abstract|| |
Follicular Lymphoma (FL) is the second most common B-Non Hodgkin Lymphoma after diffuse large B cell lymphoma (DLBCL). Low grade FL is known for its indolent behavior; however, one subset of FL behave aggressively and may require intensive therapy. One of the diagnostic issues in FL is to identify this subgroup of cases. Proliferation index can have prognostic importance in this subset of cases. We discuss one case of low grade FL with a paradoxically high proliferative index. A 63 year male presented with generalized lymphadenopathy of one year duration, which was gradually increasing in size. On examination, patient had bilateral cervical, axillary and inguinal nodes. Biopsy of the left cervical lymph node was reported as FL - Grade 2, with high proliferative Index (60%). The patient was put on CHOP regimen targeted for high grade lymphomas, and had complete remission. High proliferative index in FL is a poor prognostic factor irrespective of the histologic grade. So, proliferative index should be assessed in all cases of FL as an adjunct to histologic grading.
Keywords: Follicular lymphoma, Grading, Non-hodgkin lymphoma, Proliferative index
|How to cite this article:|
Das S, Basu D, Dubashi B, Jain A. Low grade follicular lymphoma with high proliferation index; diagnostic and management issues. Indian J Pathol Microbiol 2012;55:516-8
|How to cite this URL:|
Das S, Basu D, Dubashi B, Jain A. Low grade follicular lymphoma with high proliferation index; diagnostic and management issues. Indian J Pathol Microbiol [serial online] 2012 [cited 2020 Sep 24];55:516-8. Available from: http://www.ijpmonline.org/text.asp?2012/55/4/516/107795
| Background|| |
Follicular Lymphoma (FL) is a heterogeneous neoplasm composed of follicle centre B cell which usually has at least a partially follicular pattern. In India, it is the second most common B-Non Hodgkin Lymphoma (NHL) subtype after diffuse large B-cell lymphoma (DLBCL) and third most common NHL subtype in this region of the country. ,
One of the main issues in follicular lymphoma is to identify patients with adverse prognosis who might benefit from more intensive treatment or experimental treatment modalities. The World Health Organization (WHO) classification recommends a 3-grade system that is based on the average number of centroblasts (large or small) in 10 neoplastic follicles at (×40) high-power field (HPF) examination (i.e. grade 1, 0-5 centroblasts per HPF; grade 2, 6-15 centroblasts per HPF; and grade 3,>15 centroblasts per HPF). Grade 3 is again subdivided into 3 A and 3B based on the proportion of centrocytes.  However, the major problem in histological grading is the considerable intra- and inter-observer variability. 
In Follicular lymphoma, the germinal centre cells fail to undergo apoptosis, in most cases due to chromosomal rearrangement, t (14;18), which up regulates bcl2 expression. So there is accumulation of cells due to inhibition of apoptosis, and the proliferation index is usually low. Hence, although the proliferative index is known to have prognostic implication in aggressive lymphomas,  its predictive value in follicular lymphoma is less clear. We report one case of low grade follicular lymphoma with a paradoxical high proliferative index and discuss the possible clinical behavior of such cases.
| Case Reports|| |
A 63 year old male presented with complaints of generalized lymphadenopathy of one year duration, which was gradually increasing in size. On examination, patient had bilateral cervical, axillary and inguinal nodes. Liver was enlarged 2 cm below costal margin and spleen was 3 cm below costal margin.
Biopsy of the left cervical lymph node was received and the section was stained with Hematoxylin and Eosin. The lymphnode architecture was completely effaced with cells arranged in predominantly follicular pattern with closely packed follicles [Figure 1]a. No residual germinal centre was identified. All the neoplastic follicles were composed predominantly of small cells with cleaved nuclear contour and scant cytoplasm (centrocytes). The number of centroblasts in all the follicles was in the range of 6 to 8 per HPF and occasional follicle showed increased mitosis [Figure 1]b.
|Figure 1: (a) Lymph node biopsy showing cells arranged in follicular pattern with closely packed follicles (H and E x100), (b) Higher magnification of the same showing centroblasts (6 -8/ HPF), with mitotic figures (H and E x400), (c) The neoplastic cells are positive for CD20 (IHC x100), (d) CD3 has stained the reactive cells (IHC x100). (e) Bcl2 positivity in follicles (IHC x 100), (f) High Ki67 index (60%) in neoplastic cells (IHC x100)|
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Immunohistochemistry was done using marker for CD3, CD20, CD10, BCL2 and Ki 67. The cells were positive for CD20, CD10, BCL2 [Figure 1]c, e and CD3 stained the reactive cells [Figure 1]d. Ki67 labeling index in the follicles was however 60% [Figure 1]f. So, the final diagnosis was given as Follicular Lymphoma - Grade 2, with high Proliferative Index. Bone marrow examination done as a staging protocol, showed no evidence of any infiltration.
The patient was put on CHOP regimen targeted for high grade lymphomas, and had complete remission after 4 months. He is on regular follow up.
| Discussion and Summary|| |
Low grade Follicular lymphoma is usually characterized by relatively long survival and indolent course.  However, some patients with grade 1 and 2 FL have a more rapid course and relatively short survival time, and rare cases are cured with conventional chemotherapy.
It is known that the lymph node may have a mixture of reactive and neoplastic follicles which may confound the interpretation of Ki 67 labeling. Also neoplastic follicles may show gradual transition from low grade to high grade and it is necessary to examine ten representative follicles for grading purpose.  In the present case, the node was completely effaced with neoplastic follicles and the number of centroblasts was in the range of 6-8 per high power field in all the follicles and a diagnosis of FL grade 2 was made.
In their study, Wang et al. found that patients with low proliferative index had a significantly longer disease specific survival than those with a high proliferative index, confirming that proliferative index is an important prognostic factor in Follicular Lymphoma. This is also supported by some of a previous study by Bastion et al. They also demonstrated high proliferative index in 18% cases of grade 1 and 2 Follicular Lymphoma cases. These patients also had a shorter survival. In another study Koster Ad et al. assessed the Proliferation Index in follicles, using Mib-1 immunohistochemical staining in lymph node biopsies from 51 patients with follicular lymphoma who were receiving uniform first-line treatment. The Proliferation Index was significantly associated with both Progression Free Survival and Overall Survival, independently of other risk factors, including the clinically-based International Prognostic Index score.
This subgroup of morphologically low grade lymphoma with a high proliferation index behaves more like grade 3 Follicular lymphoma and DLBCL. Although this is a single case study and needs a larger number of cases for confirmation, we feel that the recommendation by the WHO classification of hematopoietic and lymphoid tissues, 2008 that Ki67 staining is necessary in all cases of Follicular lymphoma is a clinically justifiable adjunct. 
| References|| |
|1.||Kalyan K, Basu D, Soundararaghavan J. Immunohistochemical typig of non - Hodgkin's lymphoma - comparing working formulation and WHO classification. Indian J Pathol Microbiol 2006;49:203-7. |
|2.||Naresh KN, Agarwal B, Sangal BC, Basu D, Kothari AS, Soman CS. Regional variation in the distribution of subtypes of lymphoid neoplasms in India. Leuk Lymphoma 2002;43:1939-43. |
|3.||Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Thiele J, et al. editors. World Health Organization Classification of Tumors of Haematopoietic and Lymphoid tissues. 4 th ed. Lyon: IARC Press; 2008. p. 222-4. |
|4.||Metter GE, Nathwani BN, Burke JS, Winberg CD, Mann RB, Barcos M, et al. Morphological subclassification of follicular lymphoma - variability of diagnoses among hemato-pathologists, a ollaborative Study Between the Repository Centre and Pathology Panel for Lymphoma Clinical-Studies. J Clin Oncol 1985;3:25-38. |
|5.||Miller TP, Grogan TM, Dahlberg S, Spier CM, Braziel RM, Banks PM, et al. Prognostic significance of the Ki-67-associated proliferative antigen in aggressive non-Hodgkin's lymphomas: A prospective Southwest Oncology Group trial. Blood 1994;83:1460-6. |
|6.||Horning SJ. Natural history of and therapy for the indolent non-Hodgkin's lymphomas. Semin Oncol 1993;20(suppl 5):75-88. |
|7.||Wang SA, Wang L, Hochberg EP, Muzikansky A, Harris NL, Hasserjian RP. Low histologic grade follicular lymphoma with high Prolifertion Index. Am J Surg Pathol 2005;29:1490-96. |
|8.||Bastion Y, Berger F, Bryon PA, Felman P, Ffrench M, Coiffier B. Follicular lymphomas: Assessment of prognostic factors in 127 patients followed for 10 years. Ann Oncol 1991;2(suppl 2):123-9. |
|9.||Koster A, Tromp HA, Raemaekers JM, Borm GF, Hebada K, MacKenzie MA, et al. The prognostic significance of the intra-follicular tumor cell proliferative rate in follicular lymphoma. Haematologica 2007;92:184-90. |
Department of Pathology, JIPMER, Puducherry
Source of Support: None, Conflict of Interest: None