Follicular Lymphoma
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Follicular lymphoma (FL) is a
cancer Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal bl ...
that involves certain types of
white blood cell White blood cells, also called leukocytes or leucocytes, are the cells of the immune system that are involved in protecting the body against both infectious disease and foreign invaders. All white blood cells are produced and derived from mult ...
s known as
lymphocyte A lymphocyte is a type of white blood cell (leukocyte) in the immune system of most vertebrates. Lymphocytes include natural killer cells (which function in cell-mediated, cytotoxic innate immunity), T cells (for cell-mediated, cytotoxic ad ...
s. The cancer originates from the uncontrolled division of specific types of B-cells known as centrocytes and centroblasts. These cells normally occupy the follicles (nodular swirls of various types of lymphocytes) in the germinal centers of lymphoid tissues such as
lymph nodes A lymph node, or lymph gland, is a kidney-shaped organ of the lymphatic system and the adaptive immune system. A large number of lymph nodes are linked throughout the body by the lymphatic vessels. They are major sites of lymphocytes that incl ...
. The cancerous cells in FL typically form follicular or follicle-like structures (see adjacent Figure) in the tissues they invade. These structures are usually the dominant
histological Histology, also known as microscopic anatomy or microanatomy, is the branch of biology which studies the microscopic anatomy of biological tissues. Histology is the microscopic counterpart to gross anatomy, which looks at larger structures vis ...
feature of this cancer. There are several synonymous and obsolete terms for FL such as CB/CC lymphoma (centroblastic and centrocytic lymphoma), nodular lymphoma, Brill-Symmers Disease, and the subtype designation, follicular large-cell lymphoma. In the US and Europe, this disease is the second most common form of
non-Hodgkin's lymphoma Non-Hodgkin lymphoma (NHL), also known as non-Hodgkin's lymphoma, is a group of blood cancers that includes all types of lymphomas except Hodgkin lymphomas. Symptoms include enlarged lymph nodes, fever, night sweats, weight loss, and tiredness. ...
s, exceeded only by diffuse large B-cell lymphoma. FL accounts for 10-20% of non-Hodgkin's lymphomas with ~15,000 new cases of it being newly diagnosed each year in the US and Europe. Recent studies indicate that FL is similarly prevalent in Japan. FL is a broad and extremely complex clinical entity with a wide range of manifestations which have not yet been fully systematized. It is commonly preceded by a benign precancerous disorder in which abnormal centrocytes and/or centroblasts accumulate in lymphoid tissue. They may then circulate in the blood to cause an asymptomatic condition termed ''in situ'' lymphoid neoplasia of the follicular lymphoma type (i.e. ISFL). A small percentage of these cases progress to FL. Most commonly, however, FL presents as a swelling of lymph nodes in the neck, armpits, and/or groin. Less often, it presents as a
gastrointestinal tract The gastrointestinal tract (GI tract, digestive tract, alimentary canal) is the tract or passageway of the digestive system that leads from the mouth to the anus. The GI tract contains all the major organs of the digestive system, in humans a ...
cancer, a cancer in children involving lymphoid tissues of the head and neck area (e.g. tonsils), or one or more masses in non-lymphoid tissues such as the
testes A testicle or testis (plural testes) is the male reproductive gland or gonad in all bilaterians, including humans. It is homologous to the female ovary. The functions of the testes are to produce both sperm and androgens, primarily testostero ...
. FL typically has a slow disease course which persists essentially unchanged for years. However, each year 2-3% of FL cases progress to a highly aggressive form often termed stage 3B FL, to an aggressive diffuse large B-cell lymphoma, or to another type of aggressive B-cell cancer. These transformed follicular lymphomas (t-FL) are essentially incurable. However, recent advancements in the treatment of t-FL (e.g. the addition to standard
chemotherapy Chemotherapy (often abbreviated to chemo and sometimes CTX or CTx) is a type of cancer treatment that uses one or more anti-cancer drugs (chemotherapeutic agents or alkylating agents) as part of a standardized chemotherapy regimen. Chemothe ...
of agents such as rituximab) have improved overall survival times. These newer regimens may also delay the transformation of FL to t-FL. Additional advances in understanding FL may lead to further improvements in treating the disease.


Pathophysiology


Genomic alterations

The serial progressions of ''in situ'' FL to FL and FL to t-FL appear to involve the accumulation of increasing numbers of genomic alterations (i.e.
chromosome abnormalities A chromosomal abnormality, chromosomal anomaly, chromosomal aberration, chromosomal mutation, or chromosomal disorder, is a missing, extra, or irregular portion of chromosomal DNA. These can occur in the form of numerical abnormalities, where ther ...
and gene mutations) in the formative B-cell precursors to these disorders. At least some of these alterations appear to cause the over-expression or under-expression of the products of genes that regulate these cells' susceptibility to develop further genomic alterations, to survive, to proliferate, and/or to spread to other tissues. In consequence, multiple B-cell clones that exhibit increasing genomic alterations and malignant behaviors populate the disorder. No single genomic alteration seems responsible for the development of each of the spectrum of FL disorders. Rather, interactions between multiple genomic alterations appear to underlie this serial progression.


''In situ'' follicular lymphoma

In situ follicular lymphoma is an accumulation of monoclonal B cells (i.e. cells descendent from a single ancestral cell) in the germinal centers of lymphoid tissue. These cells commonly bear a pathological genomic abnormality, i.e. a
translocation Translocation may refer to: * Chromosomal translocation, a chromosome abnormality caused by rearrangement of parts ** Robertsonian translocation, a chromosomal rearrangement in pairs 13, 14, 15, 21, and 22 ** Nonreciprocal translocation, transfer ...
between position 32 on the long (i.e. "q") arm of chromosome 14 and position 21 on chromosome 18's q arm. This translocation juxtaposes the '' B-cell lymphoma 2'' (''BCL2'') gene on chromosome 18 at position q21.33 near to the '' immunoglobulin heavy chain locus'' (''IGH@'') on chromosome 14 at position q21. In consequence, ''BCL2'' overexpresses its product, BCL2 apoptosis regulator (i.e. Bcl2). Bcl2 functions to inhibit
programmed cell death Programmed cell death (PCD; sometimes referred to as cellular suicide) is the death of a cell (biology), cell as a result of events inside of a cell, such as apoptosis or autophagy. PCD is carried out in a biological process, which usually confers ...
thereby prolonging cell survival. The overexpression of Bcl2 in the B-cells of ISFL is thought to be a critical factor in their pathological accumulation and subsequent malignant progression. Small numbers (e.g. 1 in 100,000) of circulating nucleated blood cells bearing this t(14:18)q32:q21) translocation are found in 50-67% of otherwise healthy individuals. The prevalence of this finding increases with age and years of tobacco smoking. Since most individuals with this translocation in their blood cells do not develop ISFL, the t(14:18)(q32:q21) translocation, while prolonging cell survival, must be just one step in the development of ISFN. This translocation is proposed to occur during the early development of immature
bone marrow Bone marrow is a semi-solid tissue found within the spongy (also known as cancellous) portions of bones. In birds and mammals, bone marrow is the primary site of new blood cell production (or haematopoiesis). It is composed of hematopoieti ...
B-cells (i.e. pre-B-cells/pro-B-cells) after which these cells circulate freely and in rare cases accumulate and mature to centrocytes and/or centroblasts in the germinal centers of lymphoid follicles to form ISFL. The mechanism favoring this localization and further accumulation is unclear. Individuals with ISFL progress to FL at a rate of 2-3%/year for at least the first 10 years following diagnosis. This progression likely involves the acquisition of genomic aberrations besides the t(14:18)q32:q21) translocation in the ISFL B-cells. Suspect
mutations In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, mitosi ...
include those in the following genes: 1) '' EZH2'' (encodes polycomb repressive complex 2 family protein which is involved in maintaining the transcriptional repressive state of various genes and is found in up to 27% of FL cases); 2) '' CREBBP'' (encodes CREB-binding protein which contributes to the activation of various genes); 3) '' TNFSF14'' (encodes tumor necrosis factor superfamily member 14, a member of the
tumor necrosis factor superfamily The tumor necrosis factor (TNF) superfamily is a protein superfamily of type II transmembrane proteins containing TNF homology domain and forming trimers. Members of this superfamily can be released from the cell membrane by extracellular pr ...
which may function as a co-stimulatory factor for the activation of lymphoid cells); and 4) ''
KMT2D Histone-lysine N-methyltransferase 2D (KMT2D), also known as MLL4 and sometimes MLL2 in humans and Mll4 in mice, is a major mammalian histone H3 lysine 4 (H3K4) mono- methyltransferase. It is part of a family of six Set1-like H3K4 methyltransfera ...
'' (encodes histone-lysine N-methyltransferase 2D, a
histone methyltransferase Histone methyltransferases (HMT) are histone-modifying enzymes (e.g., histone-lysine N-methyltransferases and histone-arginine N-methyltransferases), that catalyze the transfer of one, two, or three methyl groups to lysine and arginine residue ...
which regulates the expression of various genes). ISFL may also acquire numerous
copy-number variation Copy number variation (CNV) is a phenomenon in which sections of the genome are repeated and the number of repeats in the genome varies between individuals. Copy number variation is a type of structural variation: specifically, it is a type of d ...
s (i.e. duplications and deletions of a portion of a chromosome along with any of the genes contained therein) that may contribute to FL. In all cases, the number of genetic abnormalities acquired in the B-cells of ISFL are much less than those in FL.


Follicular lymphoma

The genomic alterations found in FL include 1) the t(14:18)(q32:q21.3) translocation (85-90% of cases); 2) 1p36 deletions (i.e. deletions in the q arm of chromosome 1 at position 36, 0-70% of cases that lead to lose of '' TNFAIP3'' (encodes tumor necrosis factor, alpha-induced protein 3 which inhibits the activation of
NF-κB Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is a protein complex that controls transcription of DNA, cytokine production and cell survival. NF-κB is found in almost all animal cell types and is involved in cellular ...
, blocks cell death due to apoptosis, and regulates lymphocyte-based immune responses through its
ubiquitin ligase A ubiquitin ligase (also called an E3 ubiquitin ligase) is a protein that recruits an E2 ubiquitin-conjugating enzyme that has been loaded with ubiquitin, recognizes a protein substrate, and assists or directly catalyzes the transfer of ubiquiti ...
activity); 3) mutations in '' PRDM1'' (encodes the PR domain zinc finger protein which promotes the maturation and proliferation of B-cells); and 4) the same mutations seen in ISFL including ''KMT2D'' (85-90% of cases), ''CREEBP'' (40-65% of cases), ''BCL2'' (40-65% of cases), and ''EZH2'' (20-30% of cases) as well as other mutations such as those in the histone-modifying gene ''
HIST1H1E Histone H1.4 is a protein that in humans is encoded by the ''HIST1H1E'' gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' ...
'' (20-30% of cases), the '' RRAGC'' gene (~17% of cases) which regulates cell growth, survival, death, and proliferation, and, in ≤15% of cases several other genes including '' MEF2B,
STAT6 Signal transducer and activator of transcription 6 (STAT6) is a transcription factor that belongs to the Signal Transducer and Activator of Transcription (STAT) family of proteins. The proteins of STAT family transmit signals from a receptor co ...
,
EP300 Histone acetyltransferase p300 also known as p300 HAT or E1A-associated protein p300 (where E1A = adenovirus early region 1A) also known as EP300 or p300 is an enzyme that, in humans, is encoded by the ''EP300'' gene. It functions as histone ac ...
, ARID1A,
SLC22A2 Solute carrier family 22 member 2 (also termed ''OCT2'' or ''organic cation transporter-2'') is a protein that in humans is encoded by the ''SLC22A2'' gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to de ...
, CARD11,
FOXO1 Forkhead box protein O1 (FOXO1), also known as forkhead in rhabdomyosarcoma (FKHR), is a protein that in humans is encoded by the ''FOXO1'' gene. FOXO1 is a transcription factor that plays important roles in regulation of gluconeogenesis and glyco ...
, GNA12, B2M'' (i.e. the gene for
beta-2 microglobulin β2 microglobulin (B2M) is a component of MHC class I molecules. MHC class I molecules have α1, α2, and α3 proteins which are present on all nucleated cells (excluding red blood cells). In humans, the β2 microglobulin protein is encoded by ...
), and '' SGK1''. Except for the t(14:18)(q32:q21.3) translocation and ''EZH2'' mutations which lead to gains in the expression and function, respectively, of their products, the genetic alterations generally lead to a loss in the production or function of the cited genes products. However, the exact roles, if any, of these genomic abnormalities in promoting the progression of ISFL to FL are unclear.


Transformed follicular lymphoma

The transformation of FL to a more aggressive state or other type of aggressive lymphoma is associated with: 1) primarily gene-activating mutations in ''CREEBP, KMT2D, STAT6, CARD11'' (encoding a guanylate kinase which interacts with BCL10 and activates
NF-κB Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is a protein complex that controls transcription of DNA, cytokine production and cell survival. NF-κB is found in almost all animal cell types and is involved in cellular ...
to regulate cell survival); 2) changes in the expression of diverse genes; 3) the overproduction of various cell-activating
cytokine Cytokines are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are peptides and cannot cross the lipid bilayer of cells to enter the cytoplasm. Cytokines have been shown to be involved in a ...
s and '' CD79B'' (encoding the Ig-beta protein component of the
B-cell receptor The B cell receptor (BCR) is a transmembrane protein on the surface of a B cell. A B cell receptor is composed of a membrane-bound immunoglobulin molecule and a signal transduction moiety. The former forms a type 1 transmembrane receptor prote ...
); 4) gene-inactivating mutations in ''TNFAIP3, CD58'' (encoding the
cell adhesion molecule Cell adhesion molecules (CAMs) are a subset of cell surface proteins that are involved in the binding of cells with other cells or with the extracellular matrix (ECM), in a process called cell adhesion. In essence, CAMs help cells stick to each ...
, lymphocyte function-associated antigen 3, that is involved in activating
T-cell A T cell is a type of lymphocyte. T cells are one of the important white blood cells of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell ...
s), ''
CDKN2A CDKN2A, also known as cyclin-dependent kinase inhibitor 2A, is a gene which in humans is located at chromosome 9, band p21.3. It is ubiquitously expressed in many tissues and cell types. The gene codes for two proteins, including the INK4 family ...
'' (encoding p16INK4a and p14arf
tumor suppressor A tumor suppressor gene (TSG), or anti-oncogene, is a gene that regulates a cell during cell division and replication. If the cell grows uncontrollably, it will result in cancer. When a tumor suppressor gene is mutated, it results in a loss or re ...
proteins) or '' CDKN2B'' (encoding cyclin dependent kinase inhibitor 2B multiple tumor suppressor 2) (inactivation of either CDKN2 gene causes
genome instability Genome instability (also genetic instability or genomic instability) refers to a high frequency of mutations within the genome of a cellular lineage. These mutations can include changes in nucleic acid sequences, chromosomal rearrangements or aneup ...
, i.e. increased frequency of other gene mutations), and ''
TNFRSF4 Tumor necrosis factor receptor superfamily, member 4 (TNFRSF4), also known as CD134 and OX40 receptor, is a member of the TNFR-superfamily of receptors which is not constitutively expressed on resting naïve T cells, unlike CD28. OX40 is a seconda ...
'' (encoding one type of
tumor necrosis factor receptor The tumor necrosis factor receptor superfamily (TNFRSF) is a protein superfamily of cytokine receptors characterized by the ability to bind tumor necrosis factors (TNFs) via an extracellular cysteine-rich domain. With the exception of nerve growt ...
); and 5) gene-activating or -inactivating mutations in, or other causes for the under- or over-expression of, ''
c-MYC ''Myc'' is a family of regulator genes and proto-oncogenes that code for transcription factors. The ''Myc'' family consists of three related human genes: ''c-myc'' ( MYC), ''l-myc'' ( MYCL), and ''n-myc'' ( MYCN). ''c-myc'' (also sometimes re ...
'' ((encoding the c-Myc proto-
oncogene An oncogene is a gene that has the potential to cause cancer. In tumor cells, these genes are often mutated, or expressed at high levels.
transcription factor In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription of genetic information from DNA to messenger RNA, by binding to a specific DNA sequence. The fu ...
that regulates the expression of diverse genes many of which promote cell proliferation).


Tumor environment

The non-neoplastic immune and
stromal cell Stromal cells, or mesenchymal stromal cells, are differentiating cells found in abundance within bone marrow but can also be seen all around the body. Stromal cells can become connective tissue cells of any organ, for example in the uterine muco ...
s as well as the
extracellular matrix In biology, the extracellular matrix (ECM), also called intercellular matrix, is a three-dimensional network consisting of extracellular macromolecules and minerals, such as collagen, enzymes, glycoproteins and hydroxyapatite that provide struc ...
in tissues may enable neoplastic follicular cells to survive, proliferate, and avoid surveillance by the immune system. For example, laboratory studies show that: 1)
follicular dendritic cells Follicular dendritic cells (FDC) are cells of the immune system found in primary and secondary lymph follicles (lymph nodes) of the B cell areas of the lymphoid tissue. Unlike dendritic cells (DC), FDCs are not derived from the bone-marrow hem ...
, fibroblastic reticular cells, and T helper cells provide growth and survival signals to neoplastic follicular B-cells; 2) neoplastic follicular B-cells recruit
regulatory T cell The regulatory T cells (Tregs or Treg cells), formerly known as suppressor T cells, are a subpopulation of T cells that modulate the immune system, maintain tolerance to self-antigens, and prevent autoimmune disease. Treg cells are immunos ...
s that act to suppress immune responses to them; 3) the
cytotoxic T-cells A cytotoxic T cell (also known as TC, cytotoxic T lymphocyte, CTL, T-killer cell, cytolytic T cell, CD8+ T-cell or killer T cell) is a T lymphocyte (a type of white blood cell) that kills cancer cells, cells that are infected by intracellular pa ...
which normally kill neoplastic cells become dysfunctional in the presence of neoplastic follicular cells that are embedded in this multicellular environment; and 4)
bone marrow Bone marrow is a semi-solid tissue found within the spongy (also known as cancellous) portions of bones. In birds and mammals, bone marrow is the primary site of new blood cell production (or haematopoiesis). It is composed of hematopoieti ...
stromal cells Stromal cells, or mesenchymal stromal cells, are differentiating cells found in abundance within bone marrow but can also be seen all around the body. Stromal cells can become connective tissue cells of any organ, for example in the uterine mucos ...
directly support the growth of neoplastic follicular cells. Reduced levels of immune-infiltration has been shown to be strongly associated with early progression of disease.


Presentation and course


In situ follicular lymphoma

FL is commonly preceded by but uncommonly progresses to ISFL, an asymptomatic disorder that usually is discovered in tissues which are biopsied for other reasons. FL lymphoma may be diagnosed in the uncommon cases in which individuals with ISFL are found to have FL on follow-up examinations. Similarly, individuals with >1 in 10,000 circulating lymphocytes containing the t(14:18)q32:q21) translocation are at increased but still small risk of developing FL and being diagnosed as having FL on follow up examinations.


Follicular lymphoma

FL commonly presents as an otherwise asymptomatic enlargement of lymph nodes in the neck, armpit, groin, femoral canal, or other sites in individuals (median age 65) without a known history of ISFL or abnormal numbers of circulating t(14:18)q32:q21-conatianing lymphocytes. These enlargements may have been present for months to years and during this time waxed and waned in size. Less commonly, FL presents as extra-nodal masses in the skin, thyroid gland, salivary gland, breast, testicles.
spleen The spleen is an organ found in almost all vertebrates. Similar in structure to a large lymph node, it acts primarily as a blood filter. The word spleen comes .
, liver, and/or lung. Regardless of the type of presentation, FL is usually (~80% of cases) at an advanced stage at diagnosis as indicated by involvement of the bone marrow (50% to 70% of cases), multiple lymph nodes in different parts of the body, and/or other tissues. A minority (<33%) of FL patients present with B symptoms, i.e. recurrent unexplained
fever Fever, also referred to as pyrexia, is defined as having a temperature above the normal range due to an increase in the body's temperature set point. There is not a single agreed-upon upper limit for normal temperature with sources using val ...
s, recurrent night sweats, and/or
weight loss Weight loss, in the context of medicine, health, or physical fitness, refers to a reduction of the total body mass, by a mean loss of fluid, body fat (adipose tissue), or lean mass (namely bone mineral deposits, muscle, tendon, and other con ...
≥10% in the past 6 months. Generally, the disease has an indolent and prolonged course with a median life expectancy of 15–20 years: a large percentage of patients die from other causes than their FL disease. However, each year, including the early years after diagnosis, some 2-3% of FL cases transform to t-FL; Median survival has been ~4.5 years after the onset of this transformation. There are less common subtypes of FL that differ not only in their presentation but also in their
histopathology Histopathology (compound of three Greek words: ''histos'' "tissue", πάθος ''pathos'' "suffering", and -λογία '' -logia'' "study of") refers to the microscopic examination of tissue in order to study the manifestations of disease. Sp ...
, genetic abnormalities, and course. These subtypes, which are now (i.e. primary gastrointestinal tract FL) or may in the future (pediatric-type FL) be considered distinctive diseases, are:


Duodenal-type follicular lymphoma

Duodenal-type follicular lymphoma (DFL) was initially considered to be a type of Primary gastrointestinal tract (GI tract) follicular lymphoma (PGTFL), i.e. a follicular lymphoma in which GI tract lesions were prominent parts of the disease. However, a subset of PGTFL cases had lesions that were localized to the
duodenum The duodenum is the first section of the small intestine in most higher vertebrates, including mammals, reptiles, and birds. In fish, the divisions of the small intestine are not as clear, and the terms anterior intestine or proximal intestine ...
and other parts of the
small intestine The small intestine or small bowel is an organ in the gastrointestinal tract where most of the absorption of nutrients from food takes place. It lies between the stomach and large intestine, and receives bile and pancreatic juice through t ...
usually without involving other parts of the GI tract or tissues outside of the GI tract. This contrasts with the other cases of PGTFL which were
systemic disease A systemic disease is one that affects a number of organs and tissues, or affects the body as a whole. Examples * Mastocytosis, including mast cell activation syndrome and eosinophilic esophagitis * Chronic fatigue syndrome * Systemic va ...
s involving a wide range of GI tract and non-GI tract tissues. Consequently, the World Health Organization (2017) removed the localized disease from the primary gastrointestinal tract follicular lymphoma category, reclassified it as a distinct disease entity, and termed it duodenal-type follicular lymphoma. DFL is most often an
asymptomatic In medicine, any disease is classified asymptomatic if a patient tests as carrier for a disease or infection but experiences no symptoms. Whenever a medical condition fails to show noticeable symptoms after a diagnosis it might be considered as ...
disease that is diagnosed on
endoscopic An endoscopy is a procedure used in medicine to look inside the body. The endoscopy procedure uses an endoscope to examine the interior of a hollow organ or cavity of the body. Unlike many other medical imaging techniques, endoscopes are inser ...
examination of the GI tract conducted for other reasons. Less commonly, it presents with vague abdominal symptoms. In one review of former studies, the lesions in 85% of primary duodenal follicular lymphoma were located not only in the duodenum but also other sites in the intestine (i.e.
jejunum The jejunum is the second part of the small intestine in humans and most higher vertebrates, including mammals, reptiles, and birds. Its lining is specialised for the absorption by enterocytes of small nutrient molecules which have been previou ...
and/or
ileum The ileum () is the final section of the small intestine in most higher vertebrates, including mammals, reptiles, and birds. In fish, the divisions of the small intestine are not as clear and the terms posterior intestine or distal intestine m ...
), with rare cases having lesions in the rectum or cecum PDF is an indolent disease that may spontaneously remit and relapse but only rarely progresses to a more aggressive form. A watch-and-wait strategy has been a generally recommended method for the initial treatment of the disease.


Primary gastrointestinal tract follicular lymphoma

PGTFL is a follicular lymphoma (which as currently defined excludes cases of duodenal-type follicular lymphoma) that has a prominent component of GI tract involvement. The disease may present with signs and symptoms typical of the common type of follicular lymphoma. For example, enlargement of lymph nodes in the neck, armpit, groin, femoral canal, and/or other areas, and/or signs and symptoms of GI tract disease due to lesions in the stomach, small intestine, large intestine or rectum may be seen. These signs and symptoms may include abdominal pain,
bowel obstruction Bowel obstruction, also known as intestinal obstruction, is a mechanical or functional obstruction of the intestines which prevents the normal movement of the products of digestion. Either the small bowel or large bowel may be affected. Signs ...
, persistent nausea and vomiting, hematochezia (i.e. passage of fresh blood usually on
feces Feces ( or faeces), known colloquially and in slang as poo and poop, are the solid or semi-solid remains of food that was not digested in the small intestine, and has been broken down by bacteria in the large intestine. Feces contain a rela ...
through the rectum), or
melena Melena or melaena refers to the dark black, tarry feces that are associated with upper gastrointestinal bleeding. The black color and characteristic strong odor are caused by hemoglobin in the blood being altered by digestive enzymes and intes ...
(i.e. passage of tarry feces containing blood that has been digested in the stomach or upper intestine). PGTFL is generally treated like cases of common follicular lymphoma: depending on the severity of the disease and its symptoms, patients are treated with
watchful waiting Watchful waiting (also watch and wait or WAW) is an approach to a medical problem in which time is allowed to pass before medical intervention or therapy is used. During this time, repeated testing may be performed. Related terms include ''expe ...
, surgery, chemotherapy, radiation,
immunotherapy Immunotherapy or biological therapy is the treatment of disease by activating or suppressing the immune system. Immunotherapies designed to elicit or amplify an immune response are classified as ''activation immunotherapies,'' while immunotherap ...
plus
radiotherapy Radiation therapy or radiotherapy, often abbreviated RT, RTx, or XRT, is a therapy using ionizing radiation, generally provided as part of cancer treatment to control or kill malignant cells and normally delivered by a linear accelerator. Ra ...
, or combinations of these modalities.


Predominantly diffuse follicular lymphoma with 1p36 deletion

Predominantly diffuse follicular lymphoma with 1p36 deletion is a rare subtype of FL in which involved lymph nodes show infiltrations of centrocytes and centoblasts that generally do not form the nodular, swirling patterns characteristic of most types of FL. In addition, these cells lack the t(14:18)(q32:q21.3) translocation commonly found in other FL types but, similar to many FL cases, have a deletion in the terminal part of the short (i.e. "p") arm of chromosome 1 that encodes the ''TNFRSF14'' gene (see pathophysiology section). Predominantly diffuse follicular lymphoma with 1p36 deletion usually presents with bulky enlargements of inguinal (i.e. groin) lymph nodes but may present with enlargements of the axillary (i.e. armpit) or cervical (i.e., neck) lymph nodes. In rare cases, there may be involvement of the
bone marrow Bone marrow is a semi-solid tissue found within the spongy (also known as cancellous) portions of bones. In birds and mammals, bone marrow is the primary site of new blood cell production (or haematopoiesis). It is composed of hematopoieti ...
. In spite of the evidence of bulky and disseminated disease, predominantly diffuse follicular lymphoma with 1p36 deletion appears to be an indolent disorder that may require long-term observation rather than overtreatment.


Pediatric-type follicular lymphoma

Pediatric-type follicular lymphoma (PTFL) was initially reported to occur in children ages 1–17 years old (median age ~13-14) but more recently has been reported to occur in adults. The disorder was recently defined by the World Health Organization (2016) as a distinct entity that occurs mostly in males and involves swollen lymph nodes in the head (including tonsils and adenoids), neck, or, rarely, axillary, or inguinal areas, or non-lymphoid tissues. Currently, however, patients who had exhibited or are exhibiting involvement of areas or tissues outside of the head, neck, armpit, or groin areas are now regarded as far more likely to have a newly and provisionally defined disease, large B-cell lymphoma with IRF4 rearrangement. The lesions in PTFL consists of infiltrates containing rapidly proliferating centrocytes and centroblasts that lack the t(14:18)(q32:q21.3) translocation but nonetheless often overexpress the ''BCL2'' gene. These cells may show a
loss of heterozygosity Loss of heterozygosity (LOH) is a type of genetic abnormality in diploid organisms in which one copy of an entire gene and its surrounding chromosomal region are lost. Since diploid cells have two copies of their genes, one from each parent, a sing ...
at 1p36 (20-50% of cases) that results in decreased expression of the ''TNFRSF14'' gene (see Pathophysiology section) as well as mutations in the '' IRF8'' (10-50% of cases), which contributes to the development and function of B cells, and the ''
MAP2K1 Dual specificity mitogen-activated protein kinase kinase 1 is an enzyme that in humans is encoded by the ''MAP2K1'' gene. Function The protein encoded by this gene is a member of the dual-specificity protein kinase family that acts as a mito ...
'' gene (10-40% of cases), which regulates activation of the ERK cell signaling pathway. More than 2 dozen other genes have been reported to be mutated in rare cases of PTFL but in general the genetic abnormalities found in this disorder are fewer and less complex than those in other types of FL. PTFL has an indolent, relapsing and remitting course with a 5-year survival rate of >95%. Patients diagnosed with PTFL have been treated with chemotherapy, surgery, and combinations of these treatments. In general, these patients did well (100% survival with <5% of cases relapsing regardless of treatment modality). More recently, 36 patients have been treated with surgical resection alone followed by observation; all these patients survived with only one having a relapse. Thus, PTFL appears to be a highly indolent type of FL in which multiple studies have reported overall and progression-free survival rates of 100% and >90%, respectively, for >2 years and an estimated probability of 5-year event-free survival rate of ~96%. The therapeutic regimens versus follow-up observations that best treat this disorder in children, adolescents, and adults (adults may require different treatments than children and adolescents) requires further study.


Primary follicular lymphoma of the testis

Primary follicular lymphoma of the testis (PFLT), also termed testicular follicular lymphoma, was classified as a distinct form of FL by the World Health Organization in 2016. It is an extremely rare disease that has been recognized as occurring primarily in children and adolescents but also has been reported in 5 adults. PFLT differs from cases of typical follicular lymphoma that involve the testis in that it more often occurs in children and adolescents; involves malignant B-cells that do have the t(14:18)q32:q21) translocation; and presents with disease that is strictly limited to the testis. While similar to pediatric-type follicular lymphoma in not involving cells that bear the t(14:18)q32:q21) translocation, PFLT differs from the former disease in that it is limited to the testis and involves malignant cells that do not express Bcl2. PFTL is an extremely indolent disease which is manifested by lesions that exhibit a typical FL histology or, more commonly, a mixed FL-diffuse large cell lymphoma histology. It usually involves a 2-4 centimeter lesion in a single testicle. Patients have been treated with removal of the involved testes followed by various standard anti-lymphoma chemotherapy regimens to attain excellent results, i.e. 100% completed remissions with no recurrence of disease in 15 child and adolescent patients observed for 4–96 months. No cases of primary follicular lymphoma of the testis have been reported to progress to t-FL. Surgery followed by less strenuous or even no chemotherapy may prove to be the optimal treatment for this disease.


Transformed follicular lymphoma

FL progresses at a rate of 2-3% per year for at least the first 10 years after diagnosis to a more aggressive form, principally diffuse large B-cell lymphoma (~93% of cases) or Burkitt-like lymphoma (~7% of cases) or in rare cases exhibit the
histology Histology, also known as microscopic anatomy or microanatomy, is the branch of biology which studies the microscopic anatomy of biological tissues. Histology is the microscopic counterpart to gross anatomy, which looks at larger structures vi ...
resembling precursor B-cell lymphoblastic leukemia,
plasmablastic lymphoma Plasmablastic lymphoma (PBL) is a type of large B-cell lymphoma recognized by the World Health Organization (WHO) in 2017 as belonging to a subgroup of lymphomas termed lymphoid neoplasms with plasmablastic differentiation. The other lymphoid neop ...
, the high grade subtype of
B-cell lymphoma The B-cell lymphomas are types of lymphoma affecting B cells. Lymphomas are "blood cancers" in the lymph nodes. They develop more frequently in older adults and in immunocompromised individuals. B-cell lymphomas include both Hodgkin's lymphoma ...
,
Hodgkin lymphoma Hodgkin lymphoma (HL) is a type of lymphoma, in which cancer originates from a specific type of white blood cell called lymphocytes, where multinucleated Reed–Sternberg cells (RS cells) are present in the patient's lymph nodes. The condition ...
of the B-cell type, chronic lymphocytic leukemia/small cell lymphcytic lymphoma, or histiocytic sarcoma. t-FL is almost always diagnosed in patients being followed for FL. These FL patients present with the: fast growth of lymph nodes; formation of extra-nodal lesions in extra-nodal sites such as the
central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all p ...
, liver or bone; the onset of B-symptoms (i.e. fever,
night sweats Night sweats, also referred to as nocturnal hyperhidrosis (Hyperhidrosis - a medical term for excessive sweating + nocturnal - night), is the repeated occurrence of excessive sweating during sleep. The person may or may not also perspire exces ...
, weight loss); development of
hypercalcemia Hypercalcemia, also spelled hypercalcaemia, is a high calcium (Ca2+) level in the blood serum. The normal range is 2.1–2.6  mmol/L (8.8–10.7 mg/dL, 4.3–5.2 mEq/L), with levels greater than 2.6 mmol/L defined as hypercalce ...
(i.e. high serum levels of calcium); and/or sudden rises in serum levels of the enzyme
lactate dehydrogenase Lactate dehydrogenase (LDH or LD) is an enzyme found in nearly all living cells. LDH catalyzes the conversion of lactate to pyruvate and back, as it converts NAD+ to NADH and back. A dehydrogenase is an enzyme that transfers a hydride from one ...
. A minority of t-FL patients present without a history of FL. These patients generally present with advanced, bulky disease that may be accompanied by extra-nodal lesions and B-symptoms. Typically, all the various forms of t-FL are aggressive, rapidly progressive diseases with overall media survival times in treated patients of ~4.5 years. The transformation of FL to DLBCL is in over 70% of cases associated with the gain of MYC activity by genetic or non-genetic mechanisms.


Diagnosis

The diagnosis of FL depends on examining involved tissues for
histological Histology, also known as microscopic anatomy or microanatomy, is the branch of biology which studies the microscopic anatomy of biological tissues. Histology is the microscopic counterpart to gross anatomy, which looks at larger structures vis ...
,
immunological Immunology is a branch of medicineImmunology for Medical Students, Roderick Nairn, Matthew Helbert, Mosby, 2007 and biology that covers the medical study of immune systems in humans, animals, plants and sapient species. In such we can see there ...
, and
chromosomal A chromosome is a long DNA molecule with part or all of the genetic material of an organism. In most chromosomes the very long thin DNA fibers are coated with packaging proteins; in eukaryotic cells the most important of these proteins are ...
abnormalities that are indicative of the disease. FL usually involves enlarged lymph nodes populated by abnormal follicles (see adjacent picture) that when examined histologically contain a mixture of centrocytes or centroblast surrounded by non-malignant cells, mostly T-cells. The centrocytes, which typically outnumber centroblasts, are small to medium-sized B-cell lymphocytes that characteristically exhibit cleaved nuclei; the centropblasts are larger B-cell lymphocytes without cleaved nuclei. Rare cases of FL may show lesions that contain tissue infiltrations dominated by B-cells with features of precursor (i.e. "blast") cells,
monocytes Monocytes are a type of leukocyte or white blood cell. They are the largest type of leukocyte in blood and can differentiate into macrophages and conventional dendritic cells. As a part of the vertebrate innate immune system monocytes also infl ...
, or malignant mantle cells such as those found in
mantle cell lymphoma Mantle cell lymphoma (MCL) is a type of non-Hodgkin's lymphoma (NHL), comprising about 6% of NHL cases. There are only about 15,000 patients presently in the United States with mantle cell lymphoma. It is named for the mantle zone of the lymph ...
. Immunochemical analyses reveal that these cells generally express B-cell surface markers including the CD10 (60% of cases), CD20,
CD19 B-lymphocyte antigen CD19, also known as CD19 molecule ( Cluster of Differentiation 19), B-Lymphocyte Surface Antigen B4, T-Cell Surface Antigen Leu-12 and CVID3 is a transmembrane protein that in humans is encoded by the gene ''CD19''. In humans, ...
,
CD22 CD22, or cluster of differentiation-22, is a molecule belonging to the SIGLEC family of lectins. It is found on the surface of mature B cells and to a lesser extent on some immature B cells. Generally speaking, CD22 is a regulatory molecule that ...
, and CD79 but not CD5,
CD11c CD11c, also known as Integrin, alpha X (complement component 3 receptor 4 subunit) (ITGAX), is a gene that encodes for CD11c . CD11c is an integrin alpha X chain protein. Integrins are heterodimeric integral membrane proteins composed of an alph ...
, or CD23 cell surface proteins; genomic analyses reveal that these cells contain t(14:18)(q32:q21.3) translocation (85-90% of cases), 1p36 deletions (60-70% of cases), and with far less frequency the other genomic abnormalities listed in the above sections on Pathophysiology and Presentation and course. None of these protein markers or genomic abnormalities are diagnostic for FL, e.g. the t(14:18)(q32:q21.3) translocation is found in 30% of diffuse large B-cell lymphoma and in a small number of reactive benign lymph nodes. Rather, the diagnosis is made by a combination of histological, immunological, and genomic abnormalities. According to
World Health Organization The World Health Organization (WHO) is a specialized agency of the United Nations responsible for international public health. The WHO Constitution states its main objective as "the attainment by all peoples of the highest possible level o ...
(WHO) criteria, differences in the microscopically determined morphology of these tissues can be used to diagnose and categorized FL into the following 3 Grades with grade 3 having A and B subtypes: *Grade 1: follicles have <5 centroblasts per high-power field (hpf). *Grade 2: follicles have 6 to 15 centroblasts per hpf. *Grade 3: follicles have >15 centroblasts per hpf. **Grade 3A: Grade 3 in which the follicles contain predominantly centrocytes. **Grade 3B: Grade 3 in which the follicles consist almost entirely of centroblasts. Grades 1 and 2 are regarded as low grade FL; Grade 3A is usually also regarded as low grade FL although some studies have regarded it as high grade FL; and Grade 3B is regarded as a highly aggressive FL in the t-FL category. In addition to grade 3B disease, histologic examinations may reveal other evidence of t-FL such as histologic findings consistent with FL and diffuse large cell lymphoma in the same tissue (referred to as composite lymphomas) or in separate tissues (referred to as (discordant lymphomas) or histologic findings similar to those found in Burkitt lymphoma, precursor B-cell lymphoblastic leukemia, plasmablastic lymphoma, the high grade subtype of B-cell lymphoma, Hodgkin lymphoma of the B-cell type, chronic lymphocytic leukemia/small cell lymphocytic lymphoma, or histiocytic sarcoma. Other findings indicating the presence of this transformation include rapid growth in size of lymph nodes, recently acquired or new B symptoms, recent development of FL lesions in non-nodal tissue, rapid rises in serum
lactate dehydrogenase Lactate dehydrogenase (LDH or LD) is an enzyme found in nearly all living cells. LDH catalyzes the conversion of lactate to pyruvate and back, as it converts NAD+ to NADH and back. A dehydrogenase is an enzyme that transfers a hydride from one ...
levels, and the presence of high levels of serum calcium.


Differential diagnosis

FL may be confused with marginal zone B-cell lymphoma,
mantle cell lymphoma Mantle cell lymphoma (MCL) is a type of non-Hodgkin's lymphoma (NHL), comprising about 6% of NHL cases. There are only about 15,000 patients presently in the United States with mantle cell lymphoma. It is named for the mantle zone of the lymph ...
, and the small lymphocytic lymphoma variant of
chronic lymphocytic leukemia Chronic lymphocytic leukemia (CLL) is a type of cancer in which the bone marrow makes too many lymphocytes (a type of white blood cell). Early on, there are typically no symptoms. Later, non-painful lymph node swelling, feeling tired, fever, n ...
. The malignant cells in marginal zone B-cell lymphoma may form follicular structures but commonly proliferate in the
marginal zone The marginal zone is the region at the interface between the non-lymphoid red pulp and the lymphoid white-pulp of the spleen. (Some sources consider it to be the part of red pulp which borders on the white pulp, while other sources consider it t ...
rather than germinal center of lymphoid tissues. These malignant cells often show features of
monocytes Monocytes are a type of leukocyte or white blood cell. They are the largest type of leukocyte in blood and can differentiate into macrophages and conventional dendritic cells. As a part of the vertebrate innate immune system monocytes also infl ...
or plasma cells. Mantle cell lymphomas show monotonous, medium-sized lymphocytes, monocytes, and atrophied germinal centers; unlike FL, the malignant lymphocytes in this disease are positive for
Cyclin D1 Cyclin D1 is a protein that in humans is encoded by the ''CCND1'' gene. Gene expression The CCND1 gene encodes the cyclin D1 protein. The human CCND1 gene is located on the long arm of chromosome 11 (band 11q13). It is 13,388 base pairs lon ...
by immunohistochemistry staining. Small lymphocytic lymphomas are composed of nodular structures with small- to medium-sized malignant cells surrounding immature lymphocytes and immunoblasts. The malignant cells in this disease, unlike FL, stain positive for CD5 and CD23.


Treatment and prognosis

FL is typically a slowly growing lymphoma with an overall median life expectancy for treated patients of 10–15 years with many cases of it waxing and waning in the size of their lesions and rare cases of it remitting spontaneously. These considerations favor the use of observation over intervention in patients whose particular form of FL has a favorable prognosis or who are intolerant to aggressive treatments. However, most cases of FL have a less favorable prognosis at some stage of their disease and will therefore require intervention. There is little consensus regarding the guidelines to be used to define the prognosis and treatment for FL at its presentation or during its course.. Currently used indicators for this include the disease's: 1) histology; 2) subtype; 3) predicted indolence and potential for transformation; and 4) extent of disease as measured by clinical examinations,
bone marrow biopsy Bone marrow examination refers to the pathologic analysis of samples of bone marrow obtained by bone marrow biopsy (often called trephine biopsy) and bone marrow aspiration. Bone marrow examination is used in the diagnosis of a number of conditi ...
to determine bone marrow involvement, and PET/CT imaging of the chest, abdomen, pelvis, and any areas outside of these regions if physical examination suggests involvement. Some suggested guidelines using these parameters to indicate the prognosis and need for treatment in FL include: *The WHO criteria using histological grade (see previous section): Patients with Grades 1, 2, and 3A disease are predicted to have the same low risk prognosis that is seen in cases of typical FL while patients with grade 3B disease are predicted to have the high risk prognosis typical of t-FL. *The Follicular Lymphoma International Prognostic Index (FLIPI): FLIPI uses the following criteria: age ≥60 years; Ann Arbor disease stage III (i.e. lesions located both above and below the
thoracic diaphragm The thoracic diaphragm, or simply the diaphragm ( grc, διάφραγμα, diáphragma, partition), is a sheet of internal skeletal muscle in humans and other mammals that extends across the bottom of the thoracic cavity. The diaphragm is the ...
) or IV (i.e. disseminated lesions involving one or more non-lymphatic organs); blood hemoglobin <12 gram/deciliter; serum lactose dehydrogenase level above normal; and involvement of >4 lymph nodes. Patients positive for 0–1, 2, or ≥3 of these factors are classified as in low, intermediate, and high risk group, respectively, and after treatment with regimens that include rituximab have 2 year predicted progression free survivals of 84, 72, and 65%, respectively, and overall survivals of 98, 94, and 87%, respectively. *The FLIP2 index. This modification of FLIP1 uses age ≥60; blood hemoglobin <12 gram/deciliter; serum lactose dehydrogenase level above normal; serum beta-2 microglobulin level above normal; ≥1 lymph node with a diameter >6 centimeters; and bone marrow involvement. The predicted percentage of therapy-treated patients with progression free survival at 5 years for individuals positive for 0, 1–2, and ≥3 of these factors are 80, 51, and 19%, respectively. *CT/PET imaging: This method measures total body tumor volume as detected by tissue uptake of radioactive fludeoxyglucose (F18). Progression free and overall survival at 5 years for patients with estimated tumor volumes above versus below 510 cubic centimeters are reported to be 32.7 and 84.8% versus 65.1 and 94.7%, respectively. *Lugano staging: this method classifies Stage I disease as involving a single lymphatic region or extra-lymphatic site; Stage II disease as involving ≥2 lymphatic sites or 1 lymphatic site plus 1 extralympatic site with all lesions being on the same side of the diaphragm; Stage III disease as involving ≥2 lymphatic regions that are on opposite sides of the diaphragm; and Stage IV disease as disseminated lesions that are found to be in ≥1 non-lymphatic organs. *Response-based prognosis: FL patients whose disease progresses within 24 months of initiating treatment with chemotherapy and immunotherapy versus patients whose disease does not progress within 24 months are predicted to have 5 year survival rates of 50-74% versus ~90%, respectively. The prognosis and treatment for the specific presentations of typical FL cases (see above sections for the prognoses and treatment recommendations for primary gastrointestinal tract FL, predominantly diffuse FL with 1p36 deletion, pediatric-type FL, and primary FL of the testis) that are in common use are as follows:


In situ follicular lymphoma

ISFL is a benign condition that may be reevaluated periodically to detect the rare cases of it which progress to FL; otherwise ISFL is not treated.


Localized follicular lymphoma

In 10-20% of cases, FL appears limited to single radiation field, does not involve the bone marrow, and is therefore regarded as localized early-stage FL. In these cases, which are sometimes classified as
Ann Arbor Anne, alternatively spelled Ann, is a form of the Latin female given name Anna. This in turn is a representation of the Hebrew Hannah, which means 'favour' or 'grace'. Related names include Annie. Anne is sometimes used as a male name in the ...
stage I (i.e. disease limited to a single restricted region) or stage II (i.e. disease restricted to two sites that are on the same side of the diaphragm), radiation therapy achieves 10 year overall survival rates of 60-80% and median overall survival times of 19 years. It seems likely that many of the relapses in these cases are due to undetected disease outside of the radiation field at the time of radiation treatment. The use of PET/CT imaging is strongly recommended to insure that the FL is localized. In any case, the excellent results achieved with radiation therapy strongly support its use in localized disease. The use of an immunotherapeutic agent such as Rituximab alone or in combination with a chemotherapeutic regimen such as CVP (i.e.
cyclophosphamide Cyclophosphamide (CP), also known as cytophosphane among other names, is a medication used as chemotherapy and to immunosuppressant, suppress the immune system. As chemotherapy it is used to treat lymphoma, multiple myeloma, leukemia, ovarian can ...
,
vincristine Vincristine, also known as leurocristine and marketed under the brand name Oncovin among others, is a chemotherapy medication used to treat a number of types of cancer. This includes acute lymphocytic leukemia, acute myeloid leukemia, Hodgkin' ...
,
prednisone Prednisone is a glucocorticoid medication mostly used to suppress the immune system and decrease inflammation in conditions such as asthma, COPD, and rheumatologic diseases. It is also used to treat high blood calcium due to cancer and adren ...
and rituximab) in cases of localized, early-stage disease may be appropriate choices for some of these early-stage patients. However, the latter approach is recommended for cases of localized disease in which the disease extends beyond a single field: 56% of patients treated in this manner had progression-free survival at 10 years while patients treated with other regimens had progression free survivals of 41%. Nonetheless, overall survival did not differ between the two groups.


Asymptomatic follicular lymphoma

Patients with asymptomatic but not localized low grade FL, gastrointestinal tract FL, and pediatric-type follicular lymphoma have been served by careful follow-up without therapeutic intervention. Even high grade, aggressive, relapsed, or transformed FL may also be served with observation in patients who are asymptomatic. Findings in asymptomatic patients who have been recommended as triggers for starting treatment include one or more of the following: tumor size ≥7 cm in diameter; involvement of ≥3 nodes in 3 distinct areas, each of which is ≥3 cm in diameter; organ compression; presence of
ascites Ascites is the abnormal build-up of fluid in the abdomen. Technically, it is more than 25 ml of fluid in the peritoneal cavity, although volumes greater than one liter may occur. Symptoms may include increased abdominal size, increased weight, a ...
or
pleural effusion A pleural effusion is accumulation of excessive fluid in the pleural space, the potential space that surrounds each lung. Under normal conditions, pleural fluid is secreted by the parietal pleural capillaries at a rate of 0.6 millilitre per ...
(i.e. build-up of fluid in the abdominal or
pleural The pleural cavity, pleural space, or interpleural space is the potential space between the pleurae of the pleural sac that surrounds each lung. A small amount of serous pleural fluid is maintained in the pleural cavity to enable lubrication ...
cavities); poor performance status due to the disease; elevated levels of serum lactose dehydrogenase or
beta-2 microglobulin β2 microglobulin (B2M) is a component of MHC class I molecules. MHC class I molecules have α1, α2, and α3 proteins which are present on all nucleated cells (excluding red blood cells). In humans, the β2 microglobulin protein is encoded by ...
; presence of localized bone lesions; kidney involvement; reduced levels of circulating blood platelets or any of the various types of
white blood cells White blood cells, also called leukocytes or leucocytes, are the cells of the immune system that are involved in protecting the body against both infectious disease and foreign invaders. All white blood cells are produced and derived from mult ...
; onset of significant
pruritus Itch (also known as pruritus) is a sensation that causes the desire or reflex to scratch. Itch has resisted many attempts to be classified as any one type of sensory experience. Itch has many similarities to pain, and while both are unpleasant ...
(i.e. itching sensation) or other B symptoms; and enlargement (i.e. ≥50% increase in size over a period of at least 6 months) of lymph nodes, spleen, or other follicular lymphoma-infiltrated organs or tissues.


Symptomatic follicular lymphoma

Symptomatic FL requires treatments directed at relieving symptoms by reducing the load of tumor cells. Various
chemotherapeutic Chemotherapy (often abbreviated to chemo and sometimes CTX or CTx) is a type of cancer treatment that uses one or more anti-cancer drugs (chemotherapeutic agents or alkylating agents) as part of a standardized chemotherapy regimen. Chemothe ...
regimens have been used for this including combinations of
alkylating antineoplastic agent An alkylating antineoplastic agent is an alkylating agent used in cancer treatment that attaches an alkyl group (CnH2n+1) to DNA. The alkyl group is attached to the guanine base of DNA, at the number 7 nitrogen atom of the purine ring. Since ca ...
s,
nucleoside analogue Nucleoside analogues are nucleosides which contain a nucleic acid analogue and a sugar. Nucleotide analogs are nucleotides which contain a nucleic acid analogue, a sugar, and a phosphate group with one to three phosphates. Nucleoside and nucl ...
s, and/or
anthracycline Anthracyclines are a class of drugs used in cancer chemotherapy that are extracted from ''Streptomyces'' bacterium. These compounds are used to treat many cancers, including leukemias, lymphomas, breast, stomach, uterine, ovarian, bladder ...
s. Two commonly used chemotherapeutic regimens are CVP (see Localized FL section) and
CHOP Chop, CHOP, Chops, or CHOPS may refer to: Art *Embouchure, in music, a synonym for chops (and later, more broadly, musical skill or ability) *CHOPS, an Asian-American hip hop producer, rapper and member of rap group Mountain Brothers * ''Chops'' ...
(i.e. CVP plus the anthracycline adriamycin). Newer agents used to treat FL include
monoclonal antibodies A monoclonal antibody (mAb, more rarely called moAb) is an antibody produced from a cell Lineage made by cloning a unique white blood cell. All subsequent antibodies derived this way trace back to a unique parent cell. Monoclonal antibodies ...
such as rituximab, obinutuzumab,
galiximab Galiximab is a monoclonal antibody designed for the treatment of B-cell lymphoma. , it is undergoing Phase III clinical trials. The drug is a chimeric antibody from ''Macaca irus'' and ''Homo sapiens Humans (''Homo sapiens'') are the most ...
,
inotuzumab ozogamicin Inotuzumab ozogamicin, sold under the brand name Besponsa, is an antibody-drug conjugate medication used to treat relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL). The medication consists of a humanized monoclonal antib ...
, or epratuzumab and immunomodulators such as
lenalidomide Lenalidomide, sold under the trade name Revlimid among others, is a medication used to treat multiple myeloma, smoldering myeloma, and myelodysplastic syndromes (MDS). For multiple myeloma, it is used after at least one other treatment and gene ...
and
interferon Interferons (IFNs, ) are a group of signaling proteins made and released by host cells in response to the presence of several viruses. In a typical scenario, a virus-infected cell will release interferons causing nearby cells to heighten t ...
. The latter medications have been used in combination or alone to treat symptomatic FL. Most such regimens add rituximab (a monoclonal antibody which binds and thereby kills the CD20 cell surface protein on B cells) with CVP or CHOP regimens (termed R-CVP and R-CHOP regimens). The R-CHOP regimen appears superior to the R-CVP regimen with, for example, one study finding 8-year progression-free survival rates of 57% versus 46% for the two respective regimens. More recently, FL patients have been treated with other regimens including: 1) rituximab combined with the chemotherapeutic
alkylating agent Alkylation is the transfer of an alkyl group from one molecule to another. The alkyl group may be transferred as an alkyl carbocation, a free radical, a carbanion, or a carbene (or their equivalents). Alkylating agents are reagents for effecting ...
bendamustine; 2) rituximab combined with the chemotherapeutic agent fludarabine and the inhibitor of Type II topoisomerase, mitoxantrone; and 3) rituximab combined with another immunotherapeutic agent such as
galiximab Galiximab is a monoclonal antibody designed for the treatment of B-cell lymphoma. , it is undergoing Phase III clinical trials. The drug is a chimeric antibody from ''Macaca irus'' and ''Homo sapiens Humans (''Homo sapiens'') are the most ...
, epratuzumab (monoclonal antibodies directed respectively against the
CD80 The Cluster of differentiation 80 (also CD80 and B7-1) is a B7, type I membrane protein in the immunoglobulin superfamily, with an extracellular immunoglobulin constant-like domain and a variable-like domain required for receptor binding. It is cl ...
or
CD22 CD22, or cluster of differentiation-22, is a molecule belonging to the SIGLEC family of lectins. It is found on the surface of mature B cells and to a lesser extent on some immature B cells. Generally speaking, CD22 is a regulatory molecule that ...
cell surface proteins on immune cells including B cells), or the immunomodulating medication,
lenalidomide Lenalidomide, sold under the trade name Revlimid among others, is a medication used to treat multiple myeloma, smoldering myeloma, and myelodysplastic syndromes (MDS). For multiple myeloma, it is used after at least one other treatment and gene ...
. While it is too soon to judge the long-term results of the latter regimens, the regimens have shown similar results when analyzed based on poor treatment responses (~10-20% poor responses). Bendamustine with rituximab may be preferable to R-CHOP or R-CVP for treating low-grade (i.e. Grades 1, 2, and possibly 3A) FL; R-CHOP may be preferred in FL that has high-risk characteristics (e.g. high levels of Beta-2 macroglobulin or bone marrow involvement). The combination of lenalidomide with rituximab has shown good potential in treating indolent cases of FL. Studies indicate that maintenance therapy with rituximab following successful induction therapy prolongs progression-free survival; for example one study found progression-free survival after 6 years of treatment was 59.2% in patients treated with rituximab maintenance and 42.7% without this maintenance; however, overall survival at 6 years was similar in the two groups, 87.4% and 88.7%, respectively. Another study found that prolonged maintenance with rituximab did not have any benefits over an eight-month maintenance period. Finally, surgery and radiation are additional therapies that can be used to relieve symptoms caused by bulky t-FL disease or to treat lesions in patients who cannot withstand other types of treatment.


Transformed follicular lymphoma

Early studies on treating t-FL with various purely chemotherapy regimens gave poor results with median overall survival times of 1–2 years. However, the addition of rituximab to the regimens such as CVP and CHOP as part of induction and maintenance therapies (i.e. R-CVP and R-CHOP) greatly improved overall 5 year survival to rates of 73%. The R-CHOP regimen is a good option for treating such cases. However, these regimens need not be started in people with FL who are asymptomatic and have low tumor burdens: the outcomes in such patients show no difference between early versus delayed treatment. Some recent studies found that the use of rituximab in combination with bendamustine (i.e. the RB regimen) provided better results than R-CHOP: progression-free survival times in one study were 69.5 months for RB and 31.2 months for R-CHOP. Similar results were obtained when RB was compared to R-CVP. These studies also found no overall survival time benefit between the RB and R-CHOP regimens. Other recently examined regimens include 1) the use of obinutuzumab instead of rituximab in the R-CHOP and R-CVP regiments to attain progression-free survival rates at 3 years of 80% for the obinutuzumab-chemotherapy regimen versus 73% for the rituximab-chemotherapy regimen and 2) the combination of rituximab with lenalidomide (no chemotherapy agent) versus various chemotherapy plus immunotherapy (principally rituximab) to achieve similar complete remission and 3 year progression-free survival rates but with rituximab plus lenalidomide causing less toxicity (i.e. severe
neutropenia Neutropenia is an abnormally low concentration of neutrophils (a type of white blood cell) in the blood. Neutrophils make up the majority of circulating white blood cells and serve as the primary defense against infections by destroying bacteri ...
). Many of these studies did use rituximab maintenance therapy after induction therapy.


Prevention

Several studies, while not conclusive, suggest that the early treatment of low risk FL reduces the incidence of the disease progressing to t-FL. The treatments used in these studies include chemotherapy, radiation therapy, and immunotherapy combinations plus rituximab maintenance therapy.


Relapsed follicular lymphoma

Patients who relapse after initial therapy for FL may be followed closely without therapy if asymptomatic. When treatment is required, patients may be treated with the initial treatment regimen when such treatment led to a remission that lasted for at least one year; otherwise an alternative regimen is used. The regimens commonly used in relapsed lymphoma include R-CHOP, R-CVP, RFM (i.e. rituximab, fludarabine, and mitoxantrone), and RB (Bendamustine plus rituximab). Patients who have early treatment failure (e.g. within 1–2 years of initial treatment) or multiple relapses have also been treated with either
autologous Autotransplantation is the organ transplantation, transplantation of Organ (anatomy), organs, Biological tissue, tissues, or even particular proteins from one part of the body to another in the same person (''wikt:auto-, auto-'' meaning "self" ...
(i.e. stem cells taken from patient) or allogeneic (i.e. stem cells taken from a donor) stem cell bone marrow transplantation. While studies are inconclusive, autologous stem cell bone marrow transplantation appears to prolong survival in early treatment failure patients who are healthy enough to withstand this therapy. Unfit patients may benefit from initial treatment with obinutuzumab plus bendamustine followed by maintenance treatment with obinutuzumab (if they have not been treated previously with obinutuzumab). Other mostly experimental treatments currently under study in patients with multiple treatment failures include: 1) Phosphoinositide 3-kinase inhibitors such as copanlisib, duvelisib, and idelalisib which block the
phosphoinositide 3-kinase Phosphoinositide 3-kinases (PI3Ks), also called phosphatidylinositol 3-kinases, are a family of enzymes involved in cellular functions such as cell growth, proliferation, differentiation, motility, survival and intracellular trafficking, which i ...
signaling pathway that promotes the survival, proliferation, and other potentially malignant behaviors of cells; 2) infusion of
tisagenlecleucel Tisagenlecleucel, sold under the brand name Kymriah, is a CAR T cells medication for the treatment of B-cell acute lymphoblastic leukemia (ALL) which uses the body's own T cells to fight cancer ( adoptive cell transfer). Serious side effects o ...
chimeric antigen receptor T cell In biology, chimeric antigen receptors (CARs)—also known as chimeric immunoreceptors, chimeric T cell receptors or artificial T cell receptors—are receptor proteins that have been engineered to give T cells the new ability to target a specifi ...
s (i.e. CAR T cells) (i.e. T cells that have been isolated from patients, engineered to express a receptor for the
CD19 B-lymphocyte antigen CD19, also known as CD19 molecule ( Cluster of Differentiation 19), B-Lymphocyte Surface Antigen B4, T-Cell Surface Antigen Leu-12 and CVID3 is a transmembrane protein that in humans is encoded by the gene ''CD19''. In humans, ...
protein on, and thereby kill, T cells, and then infused back into the donor patient); 3) Bruon's tyrosine kinase inhibitor, ibrutinib, to block the B-cell maturating actions of this kianase; 4) BCL inhibitor venetoclax to block Bcl2's action in promoting B-cell survival and proliferation; 5) histone deacetylase inhibitors
abexinostat Abexinostat (INN, formerly PCI-24781) is an experimental drug candidate for cancer treatment. It was developed by Pharmacyclics and licensed to Xynomic. and is in Phase II clinical trials for B-cell lymphoma. Pre-clinical study suggests the po ...
and tazemetostat to modify the expression of various genes; and 6)
Checkpoint inhibitor Checkpoint inhibitor therapy is a form of cancer immunotherapy. The therapy targets immune checkpoints, key regulators of the immune system that when stimulated can dampen the immune response to an immunologic stimulus. Some cancers can protect t ...
s
nivolumab Nivolumab, sold under the brand name Opdivo, is a medication used to treat a number of types of cancer. This includes melanoma, lung cancer, malignant pleural mesothelioma, renal cell carcinoma, Hodgkin lymphoma, head and neck cancer, urothe ...
,
pidilizumab Pidilizumab (formerly CT-011) is a monoclonal antibody being developed by Medivation for the treatment of cancer and infectious diseases. Pidilizumab was originally thought to bind to the PD-1 immune checkpoint molecule, however, recent evidence su ...
, and
pembrolizumab Pembrolizumab, sold under the brand name Keytruda, is a humanized antibody used in cancer immunotherapy that treats melanoma, lung cancer, head and neck cancer, Hodgkin lymphoma, stomach cancer, cervical cancer, and certain types of breast ...
to promote the immune system's ability to suppress cancer cell growth. In preliminary studies on FL patients who were known or thought to be refractor to more conventional therapies these drugs, when combined with more conventional drugs, particularly rituximab, produced promising results. Phosphoionsitide 3-kinase inhibitors produced overall response rates of 10–12.5 months in 42-59%; tisagenlecleuce cells produced an overall progression-free response rate of 70% after a follow-up of 28 months; phosphoinositide 3-kinase inhibitors produced overall response rates of ~40% and complete response rates of 1-20%; Bruton's tyrosine kinase inhibitor produced overall and complete response rates of 38% and 18%, respectively; the Bcl inhibitor produce overall and complete response rates of 33% and 14%, respectively; histone deacetylase inhibitors produce overall response rates of 35%-71%; and checkpoint inhibitors produce overall response rates of 40%-80% and complete response rates of 10-60%.


See also

*
List of hematologic conditions :''This is an incomplete list, which may never be able to satisfy certain standards for completion.'' There are many conditions of or affecting the human hematologic system—the biological system that includes plasma, platelets, leukocytes, and ...
* large-cell lymphoma * ''In situ'' follicular lymphoma


References


External links


Follicular large cell lymphoma
entry in the public domain NCI Dictionary of Cancer Terms {{DEFAULTSORT:Follicular Lymphoma Non-Hodgkin lymphoma