1.

Definisi

Follicular lymphoma (FL) is a low-grade non-Hodgkin lymphoma (NHL) with

follicular-like growth derived from B cells (Wei Zhang et al, 2022). Follicular

lymphoma (FL) is one of the most common type of indolent non- Hodgkin’s

lymphoma. It originates from germinal center B cells and has characteristic

translocation t(11,14) involving immunoglobulin heavy chain gene (chromosome

14q32) and Bcl2 gene (chromosome 18q21) in 90% of patients (Gopila Gupta and

Vikas Garg, 2021)

Follicular lymphoma (FL) is the second most common type of non-Hodgkin

lymphoma (NHL) and accounts for almost 30% of all lymphomas. It is number one

among clinically indolent non-Hodgkin lymphomas. FL is a slow-growing B cell

lymphoproliferative disorder, and survival is calculated in years (Kaseb et al., 2022).

Follicular lymphoma (FL) is generally an indolent B cell lymphoproliferative

disorder of transformed follicular center B cells. Follicular lymphoma is characterized

by diffuse lymphadenopathy, bone marrow involvement, and splenomegaly (Jacobsen

and Freedman, 2019).

2. Etiologi

Follicular lymphoma originates from germinal/follicular center B cells. Most cases of

FL show at (14;18) (q32;q21), which leads to an overexpression of BCL2, an anti-

apoptotic protein. About 5% of follicular lymphoma have BCL-6 deregulating

mutations. BCL-6 is required for germinal center formation. BCL-6 related protein is
 a repressor of transcription and modulates the interleukin-4 response of B-cells. Other

upregulated genes thought to play a role in follicular lymphoma are associated with

p21, p16, and G1 arrest. Similarly, regulatory proteins (p120, p16, CKD10, p21),

transcription factors (Id-2 and PAX5), and cell-cell interaction (TNF, IL4RA, and

IL2RG) related genes are also upregulated. Adhesion related genes MRP14 and

MRP8 are downregulated (Kaseb et al., 2022).

3. Epidemiologi

Follicular lymphoma (FL) is one of the most common forms of indolent

lymphoma constituting 20–25% of all non-Hodgkin’s lymphoma (NHL) in the United

States and Europe. However, it is less common in the African and Asian population

accounting for 10% of all NHL. There is no known risk factor for follicular

lymphoma. It is a disease of the elderly with a median age of 65 years, and the young

are only rarely affected [6]. It is an indolent disease that typically manifests as

asymptomatic adenopathy. Involvement of the bone marrow is frequent, occurring in

up to 80% of cases. B symptoms and high serum lactate dehydrogenase (LDH) levels

are observed in approximately 20% of patients. Extranodal involvement is less

prevalent, occurring in about 10% of cases (Gopila Gupta and Vikas Garg, 2021)

Follicular lymphoma biasanya memiliki perjalanan penyakit yang lambat yang

pada dasarnya tetap tidak berubah selama bertahun-tahun. Namun, setiap tahun 2-

3% kasus FL berkembang menjadi bentuk yang sangat agresif yang sering disebut

stadium 3B FL, menjadi limfoma sel B besar yang menyebar secara agresif, atau ke

jenis kanker sel B agresif lainnya. Ini mengubah limfoma folikel (t-FL) pada dasarnya
 tidak dapat disembuhkan. Namun, kemajuan terbaru dalam pengobatan t-FL

(misalnya penambahan standar kemoterapi agen) telah meningkatkan waktu bertahan

hidup secara keseluruhan. Rejimen yang lebih baru ini juga dapat menunda

transformasi FL menjadi t-FL. Kemajuan tambahan dalam memahami FL dapat

mengarah pada perbaikan lebih lanjut dalam mengobati penyakit.

4. Patogenesis

The characteristic hallmark, present in up to 90% of FL, is the t(14;18)

(q32;q21) translocation, an error occurring in the maturing B cell where the

immunoglobulin heavy chain gene is juxtaposed to the anti-apoptotic gene B cell

lymphoma/leukemia 2 (BCL2) leading to an overexpression of the latter. The process

is initiated in the bone marrow and followed by migration of affected cells to

germinal centers in lymph nodes where secondary events occur.29 The same t(14;18)

translocation can be found in approximately 1 per 105 of peripheral blood B cells in

healthy individuals with a large inter individual variation but often increasing with

age. It is also thought to be present in 2-3% of reactive lymph nodes. For a lymphoma

to occur, a number of additional genetic alterations; mutations in chromatin modifiers

among others, as well as certain interactions of the B cell with the microenvironment

are needed. Due to its complexify the pathogenesis remains poorly understood

(Figure 1).

Several of the most frequently mutated genes (CREBBP, EZH2, KMT2D,

MEF2B) may cause a maturation arrest at the proliferative stage of the cell,

preventing it from differentiating into a memory or plasma cell. Like for normal B
 cells signaling downstream of the B cell receptor seems crucial for FL cell survival

and retention of immunoglobulin expression is mandatory. The surface

immunoglobulin is known to provide both a low-level tonic signal, perhaps from

environmental autoantigens with interaction facilitated by mannosylation of the

immunoglobulin binding-sites, as well as a true antigen-mediated signal, and their

relative importance in FL cell survival is unclear. Several studies have focused on FL

with versus without the classical BCL2 breakpoint. found that the BCL2 protein was

expressed also in the majority of breakpointnegative cases, indicating that a

mechanism other than t(14;18) leads to BCL2 expression. It is still unknown which

events in the FL pathogenesis may compensate for the lack of BCL2 protein in

t(14;18) negative cases.

5. Klasifikasi

 Follicular lymphoma grades 1 to 3a is considered a low-grade :

  Non-Hodgkin lymphomas are divided into the following stages :

- Stage I: Single lymph node group or single extra lymphatic organ involved

without lymph node involvement.

- Stage II: Two or more lymph node regions involved on the same side of the

diaphragm with or without the involvement of an extra lymphatic

organ.

- Stage III: Lymph nodes on both sides of the diaphragm involved.

- Stage IV: One or more extra lymphoid organs diffusely involved with or

without lymph node involvement (Kaseb et al., 2022).

6. Manifestasi Klinis

Clinical presentation of FL is most commonly that of enlarged lymph

nodes, frequently in the neck or abdomen. FL is a localized disease in about 10% to

20% of cases. The vast majority of FLs present with widespread nodal involvement

(~80%) and advanced stage disease (stages III–IV) at the time of diagnosis. Some

cases follow a chronic relapsing course. A subset progresses rapidly and transforms to

aggressive lymphomas such as diffuse large B-cell lymphomas, double-hit large B-

cell lymphomas, and lymphoblastic leukemia/lymphoma. FL can also relapse as

classic Hodgkin lymphoma, which is clonally related to the antecedent FL and with
 Hodgkin lymphoma cells also harboring the t(14;18) (q32;q21) translocation. Most

patients with FL are mainly asymptomatic. Symptomatic presentations may include

fatigue, fever or night sweats, weight loss, or recurrent infections (Chapman and

Mahsa, 2022).

7. Diagnosis Banding

Follicular lymphoma is differentiated from other types of lymphomas based on

nodular pattern, absence of tangible body macrophages, monoclonal cells, and

immunophenotyping (i-e, CD10, BCL-2, BCL-6). Following are the differential

diagnosis of follicular lymphoma : (Kaseb et al., 2022).

- Follicular colonization by other low-grade lymphomas

- Mantle cell lymphoma with a diffuse pattern

- Marginal zone B cell lymphoma

- Peripheral T cell lymphoma

- Reactive hyperplasia

- Small lymphocytic lymphoma/ chronic lymphocytic leukemia (SLL / CLL)

8. Penatalaksanaan

The management of follicular lymphoma depends on the disease stage.

Options available for the treatment of follicular lymphoma include radiation (RT),

immunochemotherapy (Rituximab plus chemotherapy), Bundamustine with

immunotherapy, R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine,

prednisone), immunochemotherapy plus RT, CVP. (cyclophosphamide, vincristine,

 and prednisolone), single-agent rituximab, and observation until progression. The

choice of regimen depends on the stage of the disease, preference of physician, and

preference of the patient. In stage 1 lymphomas, radiation therapy is preferred in

grades 1, 2, and 3a lymphomas. In contrast, patients with grade 3b follicular

lymphoma are treated with aggressive regimens (such as R-CHOP) used for other

aggressive lymphomas (e.g., diffuse large B cell lymphoma). Treatment of stage II-IV

follicular lymphoma is mainly focused on the improvement of life, alleviation of

symptoms, and reversal of cytopenias. Asymptomatic patients are mostly observed

closely without any intervention. Anti-CD20 antibodies (obinutuzumab, rituximab)

are combined with chemotherapy regimens for the treatment of symptomatic

advanced follicular lymphomas. Autologous hematopoietic stem cell transplantation

is the preferred management for recurrent/relapsed patients or patients who have

undergone a transformation to higher grade lymphoma. Patients with advanced,

relapsed, or refractory disease are encouraged to take part in clinical trials of new

therapies like CAR-T cell therapy (chimeric antigen receptor T cells) .

9. Komplikasi

Follicular lymphoma complications include BM suppression, organ dysfunction, and

adverse effects related to high dose chemotherapy.

10. Prognosis

Age, stage, nodal burden, LDH, hemoglobin, and β2-microglobulin have

been recognized as important prognostic factors. Various prognostic models have

been developed based on these factors (Table 2), including FLIPI (follicular

lymphoma international prognostic index), FLIPI 2, and PRIMA-PI (Primary

Rituximab and Maintenance study prognostic index). FLIPI is a widely used tool

developed in the pre-rituximab era, but it has been validated in several prospective

trials in patients receiving rituximab [27–29]. PRIMA-PI incorporates only two

parameters, serum 2-microglobulin levels, and bone marrow involvement, however it

has not been prospectively validated [30]. POD24 (progression within 24 months of

therapy) has recently been found as a key prognostic and predictive marker [31, 32].

It may be used method for predicting relapse and aid in therapy selection.