Pediatric-type follicular lymphoma

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Pediatric-type follicular lymphoma
Other namesPediatric follicular lymphoma, pediatric-type nodular follicular lymphoma
Specialty Hematology, oncology

Pediatric-type follicular lymphoma (PTFL) is a disease in which malignant B-cells (i.e. a lymphocyte subtype originating from the bone marrow) accumulate in, overcrowd, and cause the expansion of the lymphoid follicles in, and thereby enlargement of the lymph nodes in the head and neck regions [1] and, less commonly, groin and armpit regions. [2] The disease accounts for 1.5% to 2% of all the lymphomas that occur in the pediatric age group. [3]

Contents

Initially, PTFL was found only in children and adolescents and termed Pediatric follicular lymphoma. More recently, however, the disease has been found to occur also in adults. [4] [5] This lead the World health Organization (2016) to rename the disorder pediatric-type follicular lymphoma. [4] (The disease is also referred to as pediatric-type nodular follicular lymphoma. [6] [7] ) At the same time the World Health Organization also recognized PTFL as a clinical entity distinct from the follicular lymphoma disorders in which it was previously classified. This reclassification was based on fundamental differences between the two diseases. [4]

PTFL differs from follicular lymphoma in its clinical manifestations, its pathophysiology including the genomic alterations (i.e. chromosome abnormalities and gene mutations) which occur in the diseases malignant cells, and its clinical course. Relative to the last point, PTFL often presents histologically as a high-grade malignancy but unlike the small percentage of follicular lymphoma cases that similarly present as a high grade malignancy, it almost invariably takes an indolent, relapsing and remitting course without progressing to a more aggressive and incurable form. [2] Recognition of PTFL as a distinct disease separate from follicular lymphoma is critical to avoid mistaking it for a more aggressive lymphoma that requires potentially toxic chemotherapy treatments. [4] This appears to be particularly the case when PTFL occurs in children, adolescents, and perhaps very young adults. [2]

A significant percentage of cases that were once diagnosed as PTFL are now regarded as being large B-cell lymphoma with IRF4 rearrangements, a very rare disease that was provisionally defined by the World Health organization (2016) as distinctly separate from PTFL. [8] PTFL is here described based on this recently formulated and important distinction.

Presentation

PTFL occurs in male (male to female ratio ~10;1) children or adolescents (ages 1–17 years, median age ~13-14), less frequently in young adults (ages 18–30 years), and occasionally in older adults. [3] [7] In ~90% of cases, the diseases is diagnosed in an early stage (i.e. stage I or II) and localized to one or two adjacent lymph node chains. [3]

Historically, PTFL has been described as commonly presenting with swollen lymph nodes and/or tonsils in the head and neck regions, [3] less commonly as swollen lymph nodes in the axillary and/or inguinal regions, [2] and/or rarely as swollen lymph nodes in the abdomen and/or infiltrations of the malignant cells into the testes, bone marrow, and/or central nervous system. [3] However, many if not all of the latter rare cases as well as cases that exhibit tonsil involvement are now regarded by the World Health Organization (2016) as due to a provisional entity termed large B-cell lymphoma with IRF4 rearrangement. This diseases is a follicular-type large B-cell lymphoma that also afflicts children, adolescents, and young adults but is otherwise distinguished from PTFL by its lack of a strong predominance in males, its common occurrence in extra-nodal sites, its histology, its clinical course, and the genomic alterations carried by its malignant B-cells, particularly the hallmark translocation of the IRF4 (interferon regulatory factor 4) gene (also termed the MUM1 or melanoma associated antigen (mutated) 1 gene) on the short (i.e. p) arm of chromosome 6 at position 25.3 [9] near to the IGH@ immunoglobulin heavy locus on the long (i.e. q) arm of chromosome 14 at position 32.33 [10] This acquired genomic abnormality forces the overexpression of interferon regulatory factor protein. [8] Excluding cases now regarded as being large B-cell lymphomas with IRF4 rearrangement, PTFL presents almost exclusively with enlargement of lymph nodes in the head, neck, axilla, or groin. [3] [11]

Pathophysiology

PTFL is the proliferation of a clone (i.e. a group of genetically identical cells that share a common ancestry) of B-cells that act non-physiologically by invading and disrupting the structure and function of lymphoid tissues. This cell clone forms, increases in size, and spreads to other lymphoid tissues in association with its progressively increasing accumulation of numerous chromosome deletions and gene mutations, although different sets of these alterations occur in different individuals with the disease. These alterations are thought to promote the survival of the malignant cells by inhibiting their programmed cell death, blocking their maturation, increasing their ability to evade the immune system, and/or creating conditions favorable for the development of other genomic alterations that have these pro-malignancy effects. The most common chromosome deletion is the 1p36 deletion which occurs in 20-50% of PTFL cases. This alteration is a deletion in the q arm of chromosome 1 at position 36 that results in the lose of TNFAIP3, a gene that encodes tumor necrosis factor, alpha-induced protein 3. This protein functions to inhibit the activation of NF-κB, to block programmed cell death, and to regulate lymphocyte-based immune responses through its ubiquitin ligase activity. [12] Other alterations repeatedly seen in PTFL include mutations in the following genes: 1) TNFRSF14 (30-50% of cases) which encodes tumor necrosis factor receptor superfamily, member 14, a receptor that stimulates immune responses in T-cells, a set of non-B-cell lymphocytes; [13] 2) IRF8 (10-50% of cases) which encodes the interferon regulatory factor 8 protein, a protein that contributes to the maturation and function of B-cells; [14] [15] 3) MAP2K1 (10-40% of cases), which encodes mitogen-activated protein kinase kinase 1, an enzyme which activates the MAPK/ERK cell signaling pathway that regulates cell proliferation and the expression of various genes; [16] and 4) scores of other genes that are found in up to 15% of cases. [2] Recent Whole exome sequencing studies in children and adolescents with PTFL have confirmed these results, found that many of these genomic alterations result in suppressing either the MAPK/ERK or G protein-coupled receptor signaling pathways, and suggest that the suppression of these pathways contributes to the development of PFFL. [17]

Diagnosis

The diagnosis of PTFL depends on a constellation of findings related to its presentation, tissue distribution, histology, and expression of certain proteins and genomic abnormalities. The disease occurs in males (~90% of cases) that are more often children, adolescents, or young adults who have enlargement of lymph nodes located in one or two nearby sites of the head or neck or less commonly, armpit or groin regions. Histopathological examination of the involved lymph nodes reveals medium- to large-sized lymphoblasts mixed with occasional macrophages and rare centrocytes and centroblasts that together form follicular structures that partially or completely replace the nodes' normal structure with irregularly shaped and merged follicles, abnormally attenuated mantle zones, and the presence of helper T-cells that are pushed to the periphery of the follicles. Its histology is most often rated as high grade and by this criterion defines the disease as an aggressive grade III lymphoma (see follicular lymphoma grading). [2] Nonetheless, PTFL almost always behaves as a non-aggressive or minimally aggressive malignancy. Immunohistiochemical analyses of the involved tissues indicates that the malignant cells express CD20, CD10, and BCL6 but not BCL2 or interferon regulatory factor protein. Genomic analyses of these cells indicate that they have a clonal rearrangement in their IgH genes in all cases and in many cases the Ip6 deletion and gene mutations cited in the above pathophysiology section. [2] These cells lack the t(14:18)(q32:q21.3) translocation which is characteristic of malignant cells in follicular lymphoma but in a small percentage of cases still overexpress the TNFRSF14 gene product which is a consequence of this translocation. The exact cause for this overexpression is unclear. [4]

Differential diagnosis

The following lymphocyte disorders may be confused with but can be distinguished from PTFL based on the following points:

Treatment

Virtually all cases of PTFL, even if treated with minimal interventions such as surgical removal or a watch-and-wait approach, have had a relatively benign and sometimes remitting and relapsing course. Thus, past recommendations that these patients need to be evaluated by bone marrow biopsy, lumbar puncture, or other invasive and/or expensive procedures requires revaluation. The evaluation of therapeutic regimens used to treat PTFL is complicated by their purely retrospective nature and inclusion of cases which in retrospect were likely cases of large B-cell lymphoma with IRF4 rearrangement. [3] In any event, many of these cases were treated with chemotherapeutic regimens, principally, CHOP (i.e. cyclophosphamide, hydroxydaunorubicin, vincristine, prednisone) or R-CHOP (i.e. CHOP plus rituximab) [11] while others, which likely excluded large B-cell lymphoma with IRF4 rearrangement, were treated with surgical removal, localized radiation therapy, and/or watch-and-wait strategies. [2] [3] All of these treatments have yielded in pediatric patients overall survival rates of 100% and relapse rates of 0 to 6% as observed over variable observation periods of up to 5 years. Among this group, 36 pediatric patients were treated with surgical resection alone followed by observation with all patients surviving and only one having a relapse. [3] Most adults with PTFL have been treated more vigorously with regimens consisting of immunochemotherapy (e.g. R-CHOP) and/or radiation therapy. This more vigorous approach has been used because the distinction between PTFL and aggressive follicular lymphoma is not as clear in adults as it is in younger patients. [3] Thus, current recommendations for the treatment of pediatric PTFL patients is watch-and-wait following radiation therapy or complete surgical resection; in cases where surgical resection is incomplete, immunechemotherapy is added to the regimen. [2] The recommended treatment of adults with PTFL is less clear. Currently used regimens rely on immunochemotherapy but might change if the issue of discriminating PTFL from follicular lymphoma can be resolved. [2]

Related Research Articles

<span class="mw-page-title-main">Lymph node</span> Organ of the lymphatic system

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 include B and T cells. Lymph nodes are important for the proper functioning of the immune system, acting as filters for foreign particles including cancer cells, but have no detoxification function.

<span class="mw-page-title-main">Tumors of the hematopoietic and lymphoid tissues</span> Medical condition

Tumors of the hematopoietic and lymphoid tissues or tumours of the haematopoietic and lymphoid tissues are tumors that affect the blood, bone marrow, lymph, and lymphatic system. Because these tissues are all intimately connected through both the circulatory system and the immune system, a disease affecting one will often affect the others as well, making myeloproliferation and lymphoproliferation closely related and often overlapping problems. While uncommon in solid tumors, chromosomal translocations are a common cause of these diseases. This commonly leads to a different approach in diagnosis and treatment of hematological malignancies. Hematological malignancies are malignant neoplasms ("cancer"), and they are generally treated by specialists in hematology and/or oncology. In some centers "hematology/oncology" is a single subspecialty of internal medicine while in others they are considered separate divisions. Not all hematological disorders are malignant ("cancerous"); these other blood conditions may also be managed by a hematologist.

<span class="mw-page-title-main">Lymphadenopathy</span> Disease of lymph nodes

Lymphadenopathy or adenopathy is a disease of the lymph nodes, in which they are abnormal in size or consistency. Lymphadenopathy of an inflammatory type is lymphadenitis, producing swollen or enlarged lymph nodes. In clinical practice, the distinction between lymphadenopathy and lymphadenitis is rarely made and the words are usually treated as synonymous. Inflammation of the lymphatic vessels is known as lymphangitis. Infectious lymphadenitis affecting lymph nodes in the neck is often called scrofula.

<span class="mw-page-title-main">Anaplastic large-cell lymphoma</span> Medical condition

Anaplastic large cell lymphoma (ALCL) refers to a group of non-Hodgkin lymphomas in which aberrant T cells proliferate uncontrollably. Considered as a single entity, ALCL is the most common type of peripheral lymphoma and represents ~10% of all peripheral lymphomas in children. The incidence of ALCL is estimated to be 0.25 cases per 100,000 people in the United States of America. There are four distinct types of anaplastic large cell lymphomas that on microscopic examination share certain key histopathological features and tumor marker proteins. However, the four types have very different clinical presentations, gene abnormalities, prognoses, and/or treatments.

<span class="mw-page-title-main">Follicular lymphoma</span> Medical condition

Follicular lymphoma (FL) is a cancer that involves certain types of white blood cells known as lymphocytes. The cancer originates from the uncontrolled division of specific types of B-cells known as centrocytes and centroblasts. These cells normally occupy the follicles in the germinal centers of lymphoid tissues such as lymph nodes. The cancerous cells in FL typically form follicular or follicle-like structures in the tissues they invade. These structures are usually the dominant histological feature of this cancer.

Splenic marginal zone lymphoma (SMZL) is a type of cancer made up of B-cells that replace the normal architecture of the white pulp of the spleen. The neoplastic cells are both small lymphocytes and larger, transformed lymphoblasts, and they invade the mantle zone of splenic follicles and erode the marginal zone, ultimately invading the red pulp of the spleen. Frequently, the bone marrow and splenic hilar lymph nodes are involved along with the peripheral blood. The neoplastic cells circulating in the peripheral blood are termed villous lymphocytes due to their characteristic appearance.

<span class="mw-page-title-main">Diffuse large B-cell lymphoma</span> Type of blood cancer

Diffuse large B-cell lymphoma (DLBCL) is a cancer of B cells, a type of lymphocyte that is responsible for producing antibodies. It is the most common form of non-Hodgkin lymphoma among adults, with an annual incidence of 7–8 cases per 100,000 people per year in the US and UK. This cancer occurs primarily in older individuals, with a median age of diagnosis at ~70 years, although it can occur in young adults and, in rare cases, children. DLBCL can arise in virtually any part of the body and, depending on various factors, is often a very aggressive malignancy. The first sign of this illness is typically the observation of a rapidly growing mass or tissue infiltration that is sometimes associated with systemic B symptoms, e.g. fever, weight loss, and night sweats.

Angioimmunoblastic T-cell lymphoma is a mature T-cell lymphoma of blood or lymph vessel immunoblasts characterized by a polymorphous lymph node infiltrate showing a marked increase in follicular dendritic cells (FDCs) and high endothelial venules (HEVs) and systemic involvement.

Lymphoid hyperplasia is the rapid proliferation of normal lymphocytic cells that resemble lymph tissue which may occur with bacterial or viral infections. The growth is termed hyperplasia which may result in enlargement of various tissue including an organ, or cause a cutaneous lesion.

<span class="mw-page-title-main">BCL6</span> Transcription factor for converting Naive T cells to TFH

Bcl-6 is a protein that in humans is encoded by the BCL6 gene. BCL6 is a master transcription factor for regulation of T follicular helper cells proliferation. BCL6 has three evolutionary conserved structural domains. The interaction of these domains with corepressors allows for germinal center development and leads to B cell proliferation.

<span class="mw-page-title-main">IRF4</span> Protein-coding gene in the species Homo sapiens

Interferon regulatory factor 4 (IRF4) also known as MUM1 is a protein that in humans is encoded by the IRF4 gene, located at 6p25-p23. IRF4 functions as a key regulatory transcription factor in the development of human immune cells. The expression of IRF4 is essential for the differentiation of T lymphocytes and B lymphocytes as well as certain myeloid cells.

<span class="mw-page-title-main">Enteropathy-associated T-cell lymphoma</span> Complication of coeliac disease

Enteropathy-associated T-cell lymphoma (EATL), previously termed enteropathy-associated T-cell lymphoma, type I and at one time termed enteropathy-type T-cell lymphoma (ETTL), is a complication of coeliac disease in which a malignant T-cell lymphoma develops in areas of the small intestine affected by the disease's intense inflammation. While a relatively rare disease, it is the most common type of primary gastrointestinal T-cell lymphoma.

Nodal marginal zone B cell lymphoma (NMZL) is an uncommon form of marginal-zone lymphoma that can produce colonization of the follicles in the lymph node. It is a form of low grade lymphoma with similar incidence in men and women and a mean age of 61 years. It is often associated with Sjogren syndrome. It shows interfollicular infiltrate of monocytoid, centrocyte-like B cells that are 2–3× larger than small lymphocytes with partial/total effacement of lymph node architecture.

<span class="mw-page-title-main">Marginal zone B-cell lymphoma</span> Group of lymphomas

Marginal zone B-cell lymphomas, also known as marginal zone lymphomas (MZLs), are a heterogeneous group of lymphomas that derive from the malignant transformation of marginal zone B-cells. Marginal zone B cells are innate lymphoid cells that normally function by rapidly mounting IgM antibody immune responses to antigens such as those presented by infectious agents and damaged tissues. They are lymphocytes of the B-cell line that originate and mature in secondary lymphoid follicles and then move to the marginal zones of mucosa-associated lymphoid tissue, the spleen, or lymph nodes. Mucosa-associated lymphoid tissue is a diffuse system of small concentrations of lymphoid tissue found in various submucosal membrane sites of the body such as the gastrointestinal tract, mouth, nasal cavity, pharynx, thyroid gland, breast, lung, salivary glands, eye, skin and the human spleen.

<span class="mw-page-title-main">Follicular hyperplasia</span> Medical condition of lymphatic cells

Follicular hyperplasia (FH) is a type of lymphoid hyperplasia and is classified as a lymphadenopathy, which means a disease of the lymph nodes. It is caused by a stimulation of the B cell compartment and by abnormal cell growth of secondary follicles. This typically occurs in the cortex without disrupting the lymph node capsule. The follicles are pathologically polymorphous, are often contrasting and varying in size and shape. Follicular hyperplasia is distinguished from follicular lymphoma in its polyclonality and lack of bcl-2 protein expression, whereas follicular lymphoma is monoclonal, and expresses bcl-2.

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T-Cell Lymphoblastic Leukemia (T-ALL) is a type of acute lymphoblastic leukemia with aggressive malignant neoplasm of the bone marrow. Acute Lymphoblastic Leukemia (ALL) is a condition where immature white blood cells accumulate in the bone marrow, subsequently crowding out normal white blood cells and create build-up in the liver, spleen, and lymph nodes. The two most common types of ALL are B-Lymphocytes and T-Lymphocytes, where the first protects the body against viruses and bacteria through antibody production which can directly destroy target cells or trigger others to do so, whilst the latter directly destroy bacteria or cells infected with viruses. Approximately 20% of all ALL patients are categorized specifically to suffer from T-ALL and it is seen to be more prevalent in the adult population in comparison to children, with incidences shown to diminish with age. Amongst T-ALL cases in the pediatric population, a median onset of age 9 has been identified and the disease is particularly prominent amongst adolescents. The disease stems from cytogenic and molecular abnormalities, resulting in disruption of developmental pathways controlling thymocyte development, tumor suppressor development, and alterations in control of cell growth and proliferation. Distinct from adult T-Cell Leukemia where T-Cell Lymphotropic Virus Type I causes malignant maturation of T-cells, T-ALL is a precursor for lymphoid neoplasm. Its clinical presentation most commonly includes infiltration of the central nervous system (CNS), and further identifies mediastinal mass presence originating from the thymus, along with extramedullary involvement of multiple organs including the lymph node as a result of hyperleukocytosis.

References

  1. ↑ Quintanilla-Martinez L, Sander B, Chan JK, Xerri L, Ott G, Campo E, Swerdlow SH (February 2016). "Indolent lymphomas in the pediatric population: follicular lymphoma, IRF4/MUM1+ lymphoma, nodal marginal zone lymphoma and chronic lymphocytic leukemia". Virchows Archiv. 468 (2): 141–57. doi:10.1007/s00428-015-1855-z. PMID   26416032. S2CID   531366.
  2. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 Koo M, Ohgami RS (May 2017). "Pediatric-type Follicular Lymphoma and Pediatric Nodal Marginal Zone Lymphoma: Recent Clinical, Morphologic, Immunophenotypic, and Genetic Insights". Advances in Anatomic Pathology. 24 (3): 128–135. doi:10.1097/PAP.0000000000000144. PMID   28277421.
  3. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Woessmann W, Quintanilla-Martinez L (June 2019). "Rare mature B-cell lymphomas in children and adolescents". Hematological Oncology. 37 Suppl 1: 53–61. doi: 10.1002/hon.2585 . PMID   31187530.
  4. 1 2 3 4 5 Lynch RC, Gratzinger D, Advani RH (July 2017). "Clinical Impact of the 2016 Update to the WHO Lymphoma Classification". Current Treatment Options in Oncology. 18 (7): 45. doi:10.1007/s11864-017-0483-z. PMID   28670664. S2CID   4415738.
  5. ↑ Du XY, Huang R, Cao L, Wu W, Wang Z, Zhu HY, Wang L, Fan L, Xu W, Li JY (May 2019). "[Clinical observation of five pediatric-type follicular lymphoma in adult]". Zhonghua Xue Ye Xue Za Zhi = Zhonghua Xueyexue Zazhi (in Chinese). 40 (5): 393–397. doi:10.3760/cma.j.issn.0253-2727.2019.05.009. PMC   7342233 . PMID   31207704.
  6. ↑ Yamaguchi J, Kato S, Iwata E, Aoki K, Kabeya R, Natsume A, Wakabayashi T (July 2018). "Pediatric-Type Follicular Lymphoma in the Dura: A Case Report and Literature Review". World Neurosurgery. 115: 176–180. doi:10.1016/j.wneu.2018.04.053. PMID   29678710. S2CID   5029006.
  7. 1 2 Louissaint A, Schafernak KT, Geyer JT, Kovach AE, Ghandi M, Gratzinger D, Roth CG, Paxton CN, Kim S, Namgyal C, Morin R, Morgan EA, Neuberg DS, South ST, Harris MH, Hasserjian RP, Hochberg EP, Garraway LA, Harris NL, Weinstock DM (August 2016). "Pediatric-type nodal follicular lymphoma: a biologically distinct lymphoma with frequent MAPK pathway mutations". Blood. 128 (8): 1093–100. doi:10.1182/blood-2015-12-682591. PMC   5000844 . PMID   27325104.
  8. 1 2 Swerdlow SH, Campo E, Pileri SA, Harris NL, Stein H, Siebert R, Advani R, Ghielmini M, Salles GA, Zelenetz AD, Jaffe ES (May 2016). "The 2016 revision of the World Health Organization classification of lymphoid neoplasms". Blood. 127 (20): 2375–90. doi:10.1182/blood-2016-01-643569. PMC   4874220 . PMID   26980727.
  9. ↑ "IRF4 interferon regulatory factor 4 [Homo sapiens (human)] - Gene - NCBI". www.ncbi.nlm.nih.gov.
  10. ↑ "IGH immunoglobulin heavy locus [Homo sapiens (human)] - Gene - NCBI". www.ncbi.nlm.nih.gov.
  11. 1 2 3 Liu Q, Salaverria I, Pittaluga S, Jegalian AG, Xi L, Siebert R, Raffeld M, Hewitt SM, Jaffe ES (March 2013). "Follicular lymphomas in children and young adults: a comparison of the pediatric variant with usual follicular lymphoma". The American Journal of Surgical Pathology. 37 (3): 333–43. doi:10.1097/PAS.0b013e31826b9b57. PMC   3566339 . PMID   23108024.
  12. ↑ EntrezGene 7128
  13. ↑ EntrezGene 8764
  14. ↑ Shukla V, Lu R (August 2014). "IRF4 and IRF8: Governing the virtues of B Lymphocytes". Frontiers in Biology. 9 (4): 269–282. doi:10.1007/s11515-014-1318-y. PMC   4261187 . PMID   25506356.
  15. ↑ "IRF8 interferon regulatory factor 8 [Homo sapiens (human)] - Gene - NCBI". www.ncbi.nlm.nih.gov.
  16. ↑ "MAP2K1 mitogen-activated protein kinase kinase 1 [Homo sapiens (human)] - Gene - NCBI". www.ncbi.nlm.nih.gov.
  17. ↑ Lovisa F, Binatti A, Coppe A, Primerano S, Carraro E, Pillon M, Pizzi M, Guzzardo V, Buffardi S, Porta F, Farruggia P, De Santis R, Bulian P, Basso G, Lazzari E, d'Amore ES, Bortoluzzi S, Mussolin L (February 2019). "A high definition picture of key genes and pathways mutated in pediatric follicular lymphoma". Haematologica. 104 (9): e406–e409. doi:10.3324/haematol.2018.211631. PMC   6717562 . PMID   30819919.
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