Follicular Lymphoma

Etiology

FL originates from germinal or follicular center B-cells. Most cases of FL show at the translocation (14;18)(q32;q21), which leads to an overexpression of B-cell lymphoma 2 (BCL2), an antiapoptotic protein. About 5% of FLs 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 (IL-4) response of B-cells.[3] 

Other upregulated genes thought to play a role in FL are associated with p21, p16, and G1 arrest. Similarly, regulatory proteins (p120, p16, CKD10, p21), transcription factors (inhibitor of DNA-binding 2 [Id2] and paired box 5 [PAX5]), and cell-cell interaction–related genes (tumor necrosis factor [TNF], IL-4 receptor α [IL4RA], and IL-2 receptor subunit gamma [IL2RG]) are also upregulated. Adhesion-related genes, such as myeloid-related protein (MRP)14 and MRP8, are downregulated in FL.[4]

Epidemiology

FL is the second most common form of NHL in the US, with an estimated incidence of 6 new cases per 100,000 persons per year.[5] The rate of FL is higher in Caucasians than in Asians and African Americans.

FL is typically found in the US and Europe but less so in the rest of the world. It is a disease of older adults (median age 55 years) and relatively uncommon in children; rarely is FL diagnosed in patients under 20 years of age. Exposure to pesticides and herbicides has been established as a risk factor.[2]

Histopathology

Morphological assessment of a lymph node excisional biopsy is crucial for diagnosing FL. Lymph nodes will show variable-sized, closely packed follicles containing small cleaved cells without nucleoli (centrocytes) and larger noncleaved cells with moderate cytoplasm, open chromatin, and multiple nucleoli (centroblasts). The morphology will also show minimal apoptotic cells or tingible body macrophages. The mantle zones are typically absent, and necrosis is rare. Usually, there is interfollicular involvement or capsular infiltration. Different patterns include diffuse, floral, and incipient.

There are 4 FL variants:

1. In situ follicular neoplasia (formerly called FL in situ)
2. Duodenal-type FL
3. Testicular FL 
4. Diffuse variant of FL

In 2017, the World Health Organization (WHO) Classification of Lymphoid Neoplasms distinguished pediatric FL from FL, categorizing pediatric FL as an independent entity.[2][6]

FL typically involves the paratrabecular areas of the bone marrow. Centroblasts are enlarged, rapidly dividing B-cells in a lymphoid follicle. Per WHO Classification, the grading of FL is based on the percentage of centroblasts.

• Grade 1: Follicular small cleaved cell lymphoma; 0 to 5 centroblasts per high power field (HPF)
• Grade 2: Follicular mixed-cell lymphoma; 6 to 15 centroblasts per HPF
• Grade 3: Follicular large cell lymphoma; more than 15 centroblasts per HPF
  • Grade 3A: Centrocytes present
  • Grade 3B: Solid sheets of centroblasts

It is clinically important to differentiate grades 1 and 2 from grade 3. If areas of diffuse large B-cell lymphoma exist with FL, the exact percentage of diffuse large B-cell lymphoma (DLBCL) should be reported. Immunohistochemistry (IHC) is useful in confirming the FL diagnosis. Positive stains supporting FL include clusters of differentiation (CD)10, CD19, CD20 (strong), CD79a, BCL2 within follicles, and BCL6. Variable stains include CD30, CD11c, CD23, CD25, CD43 and surface immunoglobulin. Negative stains include T-cell markers such as CD5 (although mixed T-cells are often present) and cyclin D1.[2][6][7]

History and Physical

FL typically presents with generalized painless lymphadenopathy, which is waxing and waning in nature. FL commonly involves axillary, cervical, femoral, and inguinal lymph nodes; rarely, it may present with an asymptomatic large mediastinal mass. Only 20% of patients with FL experience B symptoms (night sweats, fever, weight loss). Increased serum lactate dehydrogenase (LDH) is also seen in 20% of the patients. Usually, FL only involves bone marrow and lymphoid organs.[8][9] In children, FL majorly affects lymphoid tissues (tonsils and lymph nodes) of the head and neck.[2]

The disease is usually indolent with a favorable prognosis. Marrow involvement occurs in most cases (>50%), with the paratrabecular pattern of infiltration being the most common. In some cases, lymphocytosis with atypical forms shows deeply cleft nuclei. Spleen infiltration presents as lymphocyte aggregates in the white pulp.

There are some subtypes of FL, such as double-hit follicular lymphoma (myelocytomatosis [MYC] and BCL2 translocations) and low-grade FL with a high proliferation index, that present with low-grade morphology and a relatively aggressive course; more research on these and other rare subtypes is underway.[10][11] 

Transformation of FL to different aggressive forms of NHL, such as DLBCL, Burkitt and Burkitt-like lymphoma, high-grade B-cell lymphoma (not otherwise specified or with double- or triple-hit genetics), and B-cell acute lymphoblastic leukemia (B-ALL) occurs and is associated with an unfavorable outcome. Transformation of FL can be suspected clinically when there are rapidly enlarging disproportionate masses, B symptoms, and abnormal laboratory tests (such as elevated serum LDH or calcium).[1][2][5]

Evaluation

Evaluation of FL should include history, physical examination, laboratory studies (complete blood count with differential, routine chemistries, and LDH), and imaging (including CT, MRI, and whole-body combined fluorodeoxyglucose positron emission tomography with computed tomography [FDG PET/CT]). Diagnosis of FL usually requires a lymph node morphological assessment and flow cytometry; sometimes, genetic testing is incorporated to confirm the diagnosis.

Peripheral blood smear rarely shows atypical lymphocytes that have scant cytoplasm and deeply cleaved nucleus [12]. Effacement of nodal architecture with CD20+ CD10+ BCL2+ cells (small- to medium-sized cells) supports FL diagnosis. In some cases, it is hard to differentiate FL from reactive hyperplasia. For these cases, the assessment of CD10 will be helpful since the expression of the stain supports FL. Bone marrow biopsy should be performed before the initiation of therapy to confirm staging.

Genetics is a useful tool for assessing FL as most cases will show clonally rearranged immunoglobulin genes. Further, most cases will show at translocation (14;18)(q32;q21). The translocation affects the immunoglobulin heavy chain (IgH) and BCL2 and leads to an overexpression of BCL2, which prevents cells in the follicular center from undergoing apoptosis. BCL2 is sensitive but not specific for FL and can be present in other forms of NHL, such as DLBCL [13]. After the achievement of remission, follow-up of patients should be planned every 3 months during the first year and then every 3 to 6 months [1].

Treatment / Management

The management of FL depends on the disease stage. Options available for the treatment of FL include:

• Radiotherapy (RT)
• Immunochemotherapy (rituximab plus chemotherapy)
• Bundamustine with immunotherapy
• Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP)
• Immunochemotherapy plus RT
• Cyclophosphamide, vincristine, and prednisolone (CVP)
• Single-agent rituximab
• Observation until progression

The choice of regimen depends on the disease stage, the physician's preference, and the patient's preference. In stage I lymphomas, RT is preferred in grades 1, 2, and 3A. In contrast, patients with grade 3B FL are treated with aggressive regimens such as R-CHOP that are used for other aggressive lymphomas (eg, DLBCL).

Treatment of stage II, III, and IV FL mainly focuses on improving quality of life, alleviation of symptoms, and reversing cytopenias. Asymptomatic patients are mainly observed closely without any intervention. Anti-CD20 antibodies (obinutuzumab, rituximab) are combined with chemotherapy regimens for the treatment of symptomatic advanced FLs.

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 participate in clinical trials of new therapies like chimeric antigen receptor (CAR) T-cell therapy).[1][13][14]

Differential Diagnosis

FL is differentiated from other types of lymphomas based on nodular pattern, absence of tangible body macrophages, monoclonal cells, and immunophenotyping (ie, CD10, BCL-2, BCL-6). The differential diagnosis of FL include:[15][16][17][18]

• 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)

Radiation Oncology

RT continues to play a critical role in the treatment of FL. In low-grade (grades 1, 2, and indolent 3A) stage I and contiguous stage II disease, it may be considered the sole curative treatment modality.[19] In more advanced cases, palliative RT is utilized to alleviate pain or prevent impending end-organ damage. Despite declining utilization in the setting of lymphomas, a large National Cancer Database (NCDB) retrospective analysis suggests that the use of RT in treating early-stage FL is associated with improved overall survival at 5- and 10-year follow-up on multivariate analysis.[20]

Simulation

The use of the immobilization technique is dependent on the area to be treated. For example, involvement of the head and neck region would require a thermoplastic mask mold.[21] Motion management is encouraged for tumors of the thoracic cavity or close to the diaphragm.[21] Once appropriate immobilization is completed, a 3- to 5-mm slice CT scan of the region of interest is performed. A contrast-enhanced CT is ideal for better anatomic delineation of the tumor versus the vasculature.[21] However, this may not be possible in many departments. Functional imaging with FDG-PET is strongly encouraged.

Treatment Delivery 

Three-dimensional conformal treatment delivery is most commonly utilized. However, other techniques such as intensity-modulated radiation therapy (IMRT) or even proton therapy may be considered in patients who fail to meet initial dose constraints, re-irradiation cases, or younger patients where normal tissue sparing is critical. 

Target Delineation

Involved site RT (ISRT) is the dominant conceptual framework for target delineation in lymphoma. It assumes chemotherapy eliminates microscopic regional disease and, as a result, treats a significantly smaller volume than its predecessor, involved field RT (IFRT).

Prechemotherapy functional imaging with FDG-PET imaging is critical as it helps determine the extent of the disease and the response to treatment. A prechemotherapy gross target volume (GTV) should be outlined first using the PET as a guide. The postchemotherapy GTV should also be outlined.

Ideally, the clinical target volume (CTV) should encompass both the pre- and postchemotherapy GTV, but should be excluded from normal structures such as the lung, heart, great vessels, etc.[21][22] However, modifications are necessary in the context of early-stage FL since these patients are not being treated with chemotherapy. Therefore, the CTV is typically much more generous and encompasses uninvolved adjacent nodal groups within the nodal compartment.[21][22]

An internal target volume (ITV) may be needed, especially to account for motion. The planning target volume (PTV) is an expansion of the CTV, taking into account daily set-up uncertainty, which is a function of treatment location and immobilization technique.[22] If the involved nodes are more than 5 cm apart, they may be treated with separate fields.[22] 

Dosing 

In the definitive setting, early-stage low-grade FLs can be treated at a dose of 24 to 30 Gy in 1.5 to 2.0 Gy/fraction. Dose de-escalation trials suggest equivalent local failure, progression-free survival, and overall survival in patients with indolent NHL receiving 24 Gy versus 40 to 45 Gy.[23] More recently, more dramatic dose de-escalation trials have been attempted.

The Follicular Radiotherapy Trial (FoRT), a noninferiority trial, compared 4 Gy in 2 fractions to 24 Gy in 12 fractions for follicular and marginal zone lymphomas.[24] The findings suggest inferior 5-year progression-free survival in the 4-Gy arm (70% vs 90%).[24] However, the authors imply that 4 Gy in 2 fractions ("Boom-Boom") may be an effective palliative regimen, which is accepted in the National Comprehensive Cancer Network (NCCN) guidelines.[24]

Table. Commonly accepted dose and volume constraints

Modified from Wirth et al 2020.[25] 

Outcomes 

Long-term outcomes for stage I and II FLs treated with RT alone are excellent, with a 97% complete response rate.[26] Fifteen-year overall survival and progression-free survival for a patient treated with radiotherapy alone are 57% and 46%, respectively.[26] An NCDB analysis reviewing the management of early-stage FL showed a 14% improvement in 10-year overall survival (54% vs 68%) in patients who received RT with or without chemotherapy versus those who received chemotherapy alone or observation.[20] Other retrospective reviews have suggested similar improvements in disease-specific survival and overall survival in patients given upfront RT.[27]

PET/CT staged patients with stage I FL appear to have better outcomes than those staged without it. This may suggest that many so-called early-stage patients treated in the pre-PET staging era may have had more extensive disease than previously thought.[28] 

In the palliative setting, short-course RT with Boom-Boom has shown a high overall response rate of 88%.[29] This regimen has several advantages, including a low incidence of toxicity, fewer treatment visits, high response rates, and ease of retreatment in the event of recurring pain/symptoms. 

Relapsed FL

Approximately 30% of patients who have received definitive radiotherapy for early-stage indolent FL will relapse within 5 years.[30] In the vast majority of cases, relapse occurs outside of the previous treatment field.[30] Local relapse occurs in <10% of cases but may be amenable to re-irradiation with acceptable toxicity.[30][31] 

Toxicity

Late toxicities are the most concerning aspect of RT treatment; their development depends on the treatment location, field size, and dose. Prior to the widespread use of chemotherapy for lymphoma, RT was the definitive treatment modality. At that time, the doses were far higher, and treatment fields were more comprehensive using mantle and inverted Y fields. Although these treatments produced long-term survivors, they did so at the cost of several late toxicities, including secondary malignancies, cardiomyopathies, valvulopathies, restrictive pulmonary disease, bowel obstructions, infertility, and endocrine deficiencies.  

The introduction of chemotherapy and a concerted effort on the part of radiation oncologists to reduce the field size and dose of radiation has helped to reduce late toxicity. However, these issues persist. In a randomized dose de-escalation trial for indolent lymphomas, the most common late toxicities included xerostomia (13%), telangiectasias (14%), alopecia (9%), bowel toxicity (2%), and bladder toxicity (1%).[23] 

The risk of secondary malignancies, specifically solid tumors, increases linearly with dose.[32] Radiation is associated with a 1.5- to 15-fold increase in secondary malignancy risk.[32] Cardiovascular complications such as conduction abnormalities, pericardial disease, valvulopathies, and coronary atherosclerosis are possible with treatment directed to the thorax. In a large multivariate analysis, the hazard ratio for radiation was 1.015 per Gy for the development of cardiovascular disease.[32]

Staging

NHLs 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 [33]

Prognosis

The prognosis and risk assessment of FL are determined based on the Follicular Lymphoma International Prognostic Index (FLIP)2 study risk factors, including:

• Beta 2 microglobulin greater than the upper limit of normal
• Bone marrow involvement
• Hemoglobin <12g/dL
• The diameter of the largest involved node greater than 6 cm
• Age over 60 years

The 5-year progression-free survival based on these risk factors is:

• Low risk (0 risk factors): 80%
• Intermediate risk (1-2 risk factors): 51%
• High risk (3-5 risk factors): 19%[1][2][1][34][35]

Complications

FL complications include bone marrow suppression, organ dysfunction, and adverse effects related to high-dose chemotherapy.