Follicular lymphoma

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Sowminya Arikapudi, M.B,B.S. [2]

Follicular lymphoma is defined as a lymphoma of follicle center B-cells (centrocytes and centroblasts). It is a type of non Hodgkin’s lymphoma. Follicular lymphoma is caused by translocation between the chromosomes 14 and 18 that results in the overexpression of the BCL-2 gene. The progression to follicular lymphoma involves the microRNAs (miRNAs).On microscopic histopathological analysis, centrocytes and centroblasts are the characteristic findings of follicular lymphoma. Follicular lymphoma may be classified according to WHO criteria into 3 subtypes: low grade follicular lymphoma, high grade follicular lymphoma and diffuse large B cell lymphoma. The prevalence of follicular lymphoma increases with age. Women are more commonly affected with follicular lymphoma than men. The prognosis is generally poor and the 5-year survival rate is approximately 72-77%. The most common symptoms of follicular lymphoma include fever, weight loss, night sweats, skin rash, painless swelling in the neck, axilla, groin, thorax, and abdomen, and chest pain, abdominal pain, and bone pain. Common physical examination findings of follicular lymphoma include fever, rash, splenomegaly, peripheral lymphadenopathy, central lymphadenopathy, chest tenderness, abdominal tenderness, and bone tenderness. Laboratory tests for the diagnosis of follicular lymphoma include lymph node biopsy, complete blood count (CBC), blood chemistry studies, cytogenetics studies, flow cytometry, immunohistochemistry, FISH, genetic testing, and immunophenotyping. CT, MRI, and PET may be helpful in the diagnosis and assessing the spread of follicular lymphoma. Other diagnostic studies for the diagnosis of follicular lymphoma include bone marrow aspiration and biopsy, laparoscopy, and laparotomy. The optimal therapy for follicular lymphoma depends on the stage at diagnosis, age, and prognostic scores. The predominant therapy for follicular lymphoma is chemotherapy. Adjunctive hematopoietic stem cell transplantation, and radioimmunotherapy may be required.

Follicular lymphoma may be classified according to WHO criteria into 3 subtypes: low grade follicular lymphoma, high grade follicular lymphoma and diffuse large B cell lymphoma. Three variants of follicular lymphoma include pediatric follicular lymphoma, primary intestinal follicular lymphoma, and other extranodal follicular lymphoma.

Genes involved in the pathogenesis of follicular lymphoma include BCL-2 and BCL-6. The most common cause is reciprocal translocation t(14;18)(q32;q21). The progression to follicular lymphoma involves microRNAs (miRNAs). On microscopic histopathological analysis, centrocytes, centroblasts along with various non-neoplastic cells including T cells, follicular dendritic cells, and macrophages are the characteristic findings of follicular lymphoma.

Follicular lymphoma may be caused by translocation between chromosome 14 and 18 that results in the overexpression of the BCL-2 gene.

Follicular lymphoma must be differentiated from other diseases such as diffuse large B cell lymphoma, Mucosa-Associated Lymphatic Tissue lymphoma (MALT), small cell lymphocytic lymphoma, and mantle cell lymphoma (MCL).

The prevalence of follicular lymphoma increases with age. Women are more commonly affected with follicular lymphoma than men.

Screening for follicular lymphoma is not recommended.

The Prognosis is generally poor and the 5 year survival rate is approximately 72-77%.

According to the Lugano classification, there are four stages of follicular lymphoma based on the number of nodes and extranodal involvement.

The most common symptoms of follicular lymphoma include fever, weight loss, night sweats, skin rash, painless swelling in the neck,under arm, groin, thorax, and abdomen, and chest pain, abdominal pain, and bone pain.

Common physical examination findings of follicular lymphoma include fever, rash, splenomegaly, peripheral lymphadenopathy, central lymphadenopathy, chest tenderness, abdominal tenderness, and bone tenderness.

Laboratory tests for the diagnosis of follicular lymphoma include complete blood count (CBC), blood chemistry studies, cytogenetics studies, flow cytometry, immunohistochemistry, FISH, genetic testing, and immunophenotyping.

CT scan may be helpful in the diagnosis of follicular lymphoma.

MRI may be helpful in the diagnosis of follicular lymphoma.

There are no ultrasound findings associated with follicular lymphoma.

Lymph node or extranodal tissue biopsy is diagnostic of follicular lymphoma.

PET scan may be helpful in the diagnosis of follicular lymphoma.

Other diagnostic studies for the diagnosis of follicular lymphoma include bone marrow aspiration and biopsy, laparoscopy, and laparotomy.

The optimal therapy for follicular lymphoma depends on the stage at diagnosis, age, and prognostic scores. The predominant therapy for follicular lymphoma is chemotherapy. Adjunctive hematopoietic stem cell transplantation, and radioimmunotherapy may be required.

Surgical intervention is not recommended for the management of follicular lymphoma.

Follicular lymphoma was described in 1925 by Brill and Symmers.

• Follicular lymphoma was first described in 1925 by Brill and Symmers^[1].
• It was earlier known as Brill – Symmers disease after the authors of the original papers.
• Most of its clinical features were described by the early 1940s.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sowminya Arikapudi, M.B,B.S. [2]

According to the World Health Organization (WHO), follicular lymphoma may be classified into 3 subtypes: low-grade follicular lymphoma, high-grade follicular lymphoma, and diffuse large B cell lymphoma. Three variants of follicular lymphoma include pediatric follicular lymphoma, primary intestinal follicular lymphoma, and other extranodal follicular lymphoma.

The World Health Organization (WHO) classifies follicular lymphoma as follows:^[1][2]

• Grades 1 and 2 also known as low-grade follicular lymphoma
• Grade 3A as high-grade follicular lymphoma
• Grade 3B as diffuse large B cell lymphoma

Follicular lymphoma has 3 variants that include the following:^[3][4]

A. Pediatric follicular lymphoma

• Involves cervical lymph nodes, other peripheral lymph nodes, or Waldeyer’s ring
• Patients typically have early-stage disease
• Lacks bcl-2 protein expression and t(14;18)

B. Primary intestinal follicular lymphoma

• Occurs most commonly in the small intestine, and frequently involves the duodenum.

• Duodenal follicular lymphoma

• Found in the second portion of the duodenum
• Present as multiple polyps
• Diagnosis is most often an incidental finding
• Most patients have localized disease
• Prognosis is excellent even without treatment

C. Other extranodal follicular lymphomas

• Usually have localized extranodal disease.
• Systemic relapses are rare.
• Testicular follicular lymphoma are reported with increased frequency in children, but also are reported in adults.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sowminya Arikapudi, M.B,B.S. [2]

Genes involved in the pathogenesis of follicular lymphoma include BCL-2 and BCL-6. The most common cause is reciprocal translocation t(14;18)(q32;q21). The progression to follicular lymphoma involves microRNAs (miRNAs). On microscopic histopathological analysis, centrocytes, centroblasts along with various non-neoplastic cells including T cells, follicular dendritic cells, and macrophages are the characteristic findings of follicular lymphoma.

• Follicular helper T cells (Tfh) are specialized helper T-cells that are predominantly located in germinal centers along with B-cells.^[1][2]

• Follicular lymphoma is the second most common non-Hodgkin lymphoma.^[3].
• The disease is characterized by the clonal proliferation of neoplastic lymphoid cells that share morphological, immunophenotypic and molecular genetic attributes of germinal center B-cells.
• The development of follicular lymphoma tumors in adults is dependent upon the overexpression of B-cell leukemia/lymphoma 2 (BCL-2) located on chromosome band 18q21.
• BCL-2 is an oncogene that blocks programmed cell death (apoptosis). As such, overexpression results in prolonged cell survival.
• These tumors contain a mixture of neoplastic centrocytes and centroblasts along with various non-neoplastic cells including T-cells, follicular dendritic cells, and macrophages.
• Follicular lymphoma can be designated as low grade (1 and 2) or higher grade (3A and 3B) disease, depending on the number of centroblasts per high-power field.

• The most common cause is reciprocal translocation between (14;18)(q32;q21) in 80-85% of cases.^[4]

• This somatic rearrangement is initiated within the bone marrow during B-cell lymphopoiesis and results from immunoglobulin heavy chain gene (IGH) rearrangement.
• The t(14;18) translocation leads to placement of the B cell lymphoma 2 (BCL2) gene under the influence of transcriptional enhancers associated with IGH, resulting in overexpression of anti-apoptotic BCL2 leading to increased cell survival and uncontrolled cell proliferation in germinal centers.^[5][6][7]
• BCL2, along with other anti-apoptotic proteins, inhibits apoptosis by binding and neutralizing activated pro-apoptotic proteins including the mitochondrial outer membrane permeabilizers BAX and BAK, as well as the intracellular stress sensors which activate BAX and BAK.
• Mutations in chromatin-modifying genes occur, affecting histone methyltransferases, histone acetyltransferases or histone linker proteins.
• These mutations act to promote increased proliferation of B cells.
• Genes encoding components of vacuolar H+-ATPase, or RRAGC, a guanine nucleotide binding protein, regulate the mTOR activation.
• Mutations in these genes upregulate mTOR (mammalian target of rapamycin) signaling in FL cells. These mutations are found in approximately 15 to 20 percent of cases.
• Upregulated mTOR directs many cellular processes including growth, differentiation, survival, and adhesion or cellular migration, and resulting in follicular lymphoma development.
• KMT2D, CREBBP, EZH2, EP300, HIST1H1E, KMT2C, ARID1A, and SMARCA4 are some of the other genomes which undergo mutations in very few cases.
• The tumor microenvironment comprised of T cells and dendritic cells may influence the development and progression of Follicular lymphoma.
• Communication between the tumor cells and the microenvironment involves chemokines, chemokine receptors, and adhesion molecules, the balance of which determines whether there is tumor cell growth promotion or inhibition.
• MicroRNA expression- short non-coding RNAs named microRNAs (miRNAs) have important functions in follicular lymphoma biology.^[8]
• In malignant B cells, miRNAs participate in pathways fundamental to B cell development like:
  • B cell receptor (BCR) signaling
  • B cell migration/adhesion, cell-cell interactions in immune complexes.
  • The production and class-switching of immunoglobulins.^[9]

• miRNAs influence B cell maturation, generation of pre marginal zone, follicular, B1, plasma and memory B cells.^[9]
• It is positive for the B-cell markers CD10, CD19, CD22, and usually CD20.^[10]

• A translocation between chromosome 14 and 18 results in the overexpression of the BCL-2 gene.^[11][12]
• The BCL-2 gene is normally found on chromosome 18, and the translocation moves the gene near to the site of the immunoglobulin heavy chain enhancer element on chromosome 14.
• Translocations of BCL6 at 3q27 can also be involved.^[13]

The tumor is composed of follicles containing a mixture of the following^[14]:

• Centrocytes (small cleaved cells without nucleoli)
• Centroblasts (larger noncleaved cells with moderate cytoplasm, open chromatin, and multiple nucleoli)
• These follicles are surrounded by non-malignant cells, mostly T-cells.

Within the follicles, centrocytes typically predominate; centroblasts are usually scarce.

According to the WHO criteria, the disease is morphologically graded into:^[15]

• Grade 1 (<5 centroblasts per high-power field (hpf))
• Grade 2 (6–15 centroblasts/hpf)
• Grade 3 (>15 centroblasts/hpf)

• Grade 3A (centrocytes still present)
• Grade 3B (the follicles consist almost entirely of centroblasts)

The WHO 2008 update provided the following grading for follicular lymphoma:

• Grades 1 and 2 now as low-grade follicular lymphoma
• Grade 3A as high-grade follicular lymphoma
• Grade 3B as diffuse large B Cell lymphoma

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sowminya Arikapudi, M.B,B.S. [2]

Follicular lymphoma may be caused by a translocation between chromosome 14 and 18 that results in the overexpression of the BCL-2 gene.

• A translocation between chromosome 14 and 18 results in the overexpression of the BCL-2 gene.^[1]
• As the bcl-2 protein is normally involved in preventing apoptosis, cells with overexpression of this protein are basically immortal.
• The BCL-2 gene is normally found on chromosome 18, and the translocation moves the gene near to the site of the immunoglobulin heavy chain enhancer element on chromosome 14.
• Translocations of BCL6 at 3q27 may also be involved.^[2]

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sowminya Arikapudi, M.B,B.S. [2]

Follicular lymphoma must be differentiated from diffuse large B cell lymphoma, Mucosa-Associated Lymphatic Tissue lymphoma (MALT), small cell lymphocytic lymphoma, and mantle cell lymphoma (MCL).

Follicular lymphoma must be differentiated from:

• Diffuse large B cell lymphoma
• Mucosa-Associated Lymphatic Tissue lymphoma (MALT)
• Small cell lymphocytic lymphoma
• Mantle cell lymphoma (MCL)

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Sowminya Arikapudi, M.B,B.S. [2]

The prevalence of follicular lymphoma increases with age.

• The incidence of follicular lymphoma around the world is 3.18 cases per 100,000 people.^[1][2]

• The prevalence of follicular lymphoma increases with age.
• The median age at diagnosis of follicular lymphoma is 60 years.

• The incidence in Whites is more than twice that in Black and Asian populations.
• It is less common in Central and South America.

• Follicular lymphoma has no sex predilection^[2].

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sowminya Arikapudi, M.B,B.S. [2]

The risk factors include viruses, certain chemicals such as hair dyes and immunodeficiency states.

Risk factors for follicular lymphoma include^[1][2]:

• Viruses:
  • Epstein-Barr virus (EBV)
  • Human T-cell lymphotropic virus (HTLV) type I,
  • Herpesvirus-associated with Kaposi sarcoma (ie, human herpesvirus [HHV]-8 )
  • Hepatitis B and C viruses
• Chemicals:
  • Defoliants (eg, Agent Orange)
  • Hair dyes

• Immunodeficiency states:
  • Congenital immunodeficiencies
  • Infection with the human immunodeficiency virus (HIV). Most lymphomas associated with HIV are intermediate-grade or high-grade lymphomas.
  • Patients who have been on immunosuppressant drugs after organ transplantation. Most of these lymphomas are diffuse or high-grade lymphomas.
  • Autoimmune diseases

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Sowminya Arikapudi, M.B,B.S. [2]

Screening for follicular lymphoma is not recommended.

Screening for follicular lymphoma is not recommended.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sowminya Arikapudi, M.B,B.S. [2]

Follicular lymphoma presents in the age group of 60-65 with systemic symptoms of fever, weight loss, anorexia, night sweats and other organ dependent symptoms based on the metastatic spread of the lymphoma. Complications arise from the systemic effects of the lymphoma and metastasis. The prognosis is evaluated from follicular lymphoma international prognostic index which divides patients into 3 groups.

• Follicular lymphoma presents in older age group people of age 60-65^[1][2][3][4].
• Patients may present with complaints of:
  • Unexplained fever
  • Weight loss
  • Painless and progressive adenopathy
  • Night sweats
  • Nerve lesions
  • Constant fatigue
  • Itchy skin
  • Reddened patches on the skin
  • Cough
  • Shortness of breath
• Organ-related symptoms develop depending on the metastatic spread of the lymphoma.
• Patients may have a history of:
  • Viral disease (HIV, HBV, HCV or EBV)
  • Autoimmune diseases
  • Immunocompromised state

• Skin reactions
• Bone marrow suppression
• Secondary cancers
• Gastric obstruction
• Urethral obstruction
• Renal failure
• Infertility
• Heart disease (Heart failure, valvular defects, pericarditis)
• Lung disease (Pleural effusion, lung mass)
• Mediastinal mass
• Immune system deficiency

• Follicular Lymphoma International Prognostic Index (FLIPI) is used for the evaluation of prognosis.^[5][6]

• It includes the following:

• • Age >60 years
  • Bone marrow involvement
  • Hemoglobin level <12.0 g/dl
  • Greatest diameter of the largest involved node >6 cm
  • Elevated serum β-2 microglobulin level
• The FLIPI divides patients into 3 groups:
  • Low (0-1 risk factor)
  • Intermediate (2 risk factors)
  • High (≥ 3 risk factors)
• The 10-year mortality of low group is 96%.
• The 10-year mortality of intermediate group is 71%.
• The 10-year mortality of high group is 37%.