In situ lymphoid neoplasia

Last updated
In situ lymphoid neoplasia
Specialty Hematology, oncology
Symptoms Asymptomatic
Complications May progress to follicular lymphoma or mantle cell lymphoma; may be associated with the development of certain other lymphoid malignancies
DurationChronic
TypesIn situ follicular lymphoma; in situ mantle cell lymphoma
TreatmentFollow-up tests for the development of follicular or mantle cell lymphoma, or other lymphoid malignancies

In situ lymphoid neoplasia (ISLN, also termed in situ lymphoma) is a precancerous condition newly classified by the World Health Organization in 2016. The Organization recognized two subtypes of ISLN: in situ follicular neoplasia (ISFN) and in situ mantle cell neoplasia (ISMCL). [1] ISFN and ISMCL are pathological accumulations of lymphocytes in the germinal centers and mantle zones, respectively, of the follicles that populate lymphoid organs such as lymph nodes. These lymphocytes are monoclonal (i.e. descendants of a single ancestral cell) B-cells that may develop into follicular (FL) and mantle cell (MCL) lymphomas, respectively. [2]

Contents

When used to characterize a neoplasm, in situ has referred to a localized, non-destructive accumulation in a tissue of cells that bear resemblances to the malignant cells of one of the cancers that can develop in this tissue. The in situ accumulations can progress to become the malignancy that their cells resemble. The term, while readily applicable to abnormal cell accumulations in solid tissues such as those of the cervix, has been difficult to apply to lymphatic tissue because many of these tissue's cells normally move through blood and lymphatic vessels to occupy other tissues. Recently, however, monoclonal B-cells with some key characteristics of the malignant B-cells in FL or MCL have been found to accumulate in one or more lymphoid tissues. These accumulations are localized, non-destructive (i.e. not effacing a tissue's normal architecture), premalignant, and therefore now regarded as in situ disorders similar to those in solid tissues. [3]

ISFN [4] and ISMCL [5] are usually indolent, asymptomatic disorders that rarely progress to malignancy. Typically, they are diagnosed based on the findings in lymphoid tissues examined for other reasons. ISLN bear similarities to monoclonal B-cell lymphocytosis (MBL). MLB consists of four subtypes: chronic lymphocytic leukemia/small lymphocyte MBL (i.e. CLL/SLL-MBL), atypical CLL/SLL-MBL, non-CLL/SLL-MBL, [3] and monoclonal B-cell lymphocytosis of the marginal zone (CBL-MZ). [6] These MBL subtypes are indolent, asymptomatic, monoclonal B-cell disorders diagnosed, generally incidentally, by finding the circulation of relatively large numbers of monoclonal B-cells that correspond in type to the malignancies to which they may progress. ISLN differs from MCL in that its B-cells are found mainly in lymphoid tissue, it involves different monoclonal B-cell types, and it usually progresses to a set of different types of lymphoid malignancies. [2] [6] [7] However, 1) MBL disorders can progress to FL or MCL, 2) small numbers of the B-cells involved in ISFN may circulate in individuals who have or will develop ISFN, [1] and 3) the B-cells in MBL may accumulate in lymphoid tissues. [7]

Presentation

ISFL and ISMCL are generally asymptomatic disorders discovered in lymphoid tissues which were examined for other reasons. Typically, a follicle(s) in a superficial lymph node(s) is the site of these disorders. However, the follicles in deep lymph nodes the abdomen or of the tonsils, intestines, spleen, parotid gland, or thyroid may harbor the disorder in ISFL whereas a follicle(s) in the small intestine, appendix, ocular adnexa, nasopharynx, oropharynx, or spleen may harboring the disorder in ISMCL. The prevalence of these disorders in unselected lymph node specimens are reported to be ~2.8% and 0.35%, respectively. Multiple tissues can be involved in some cases. Both disorders occur predominantly in middle-aged and older individuals with ISFL being twice as common in males than females. [1]

Pathophysiology

In situ follicular lymphoma

In situ follicular lymphoma has also been termed follicular lymphoma in situ; follicular lymphoma of B cells of undetermined significance; intrafollicular neoplasia/in situ follicular lymphoma; in situ localization of follicular lymphoma; incipient follicular lymphoma; and follicular lymphoma of compartmentalized follicular central cells. [8] The disorder involves an accumulation of monoclonal B-cells in the germinal centers of lymphoid tissue. These B-cells commonly bear a translocation between position 32 on the long (i.e. "q") arm of chromosome 14 and position 21 on chromosome 18's q arm. This same t(14:18)q32:q21) translocation is a genetic hallmark of FL [2] and juxtaposes the B-cell lymphoma 2 (BCL2) gene on chromosome 18 at position q21.33 with the immunoglobulin heavy chain locus (IGH@) on chromosome 14 at position q21. In consequence, BCL2 overexpresses its product, BCL2 apoptosis regulator (i.e. Bcl2). Blc2 functions to inhibit programmed cell death thereby prolonging cell survival. [9] 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. [1]

Small numbers (e.g. 1 in 100,000) of circulating blood cells bearing the t(14:18)q32:q21) translocation are found in 50-67% of otherwise healthy individuals. The prevalence of this finding increases with age, tobacco smoking, pesticide exposure, and race (50-70% in Caucasians, 10-20% in Japanese individuals). Since most individuals with this translocation in their blood cells do not develop ISFL or FL, t(14:18)(q32:q21), while prolonging cell survival, must be just one step in the development of these disorders. The translocation is proposed to occur during the early development of immature bone marrow B-cells (i.e. pre-B-cells/pro-B-cells) after which these cells circulate freely and in rare cases accumulate in the germinal centers of lymphoid follicles to form ISFL. The mechanism(s) favoring this localization and accumulation is unclear. Up to 6% of the individuals with ISFL progress to FL. [2] This progression may involve the acquisition of other genomic aberrations in the ISFL B-cells such as mutations 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 [10] and is found in up to 27% of FL cases); [1] 2) CREBBP (encodes CREB-binding protein which contributes to the activation of various genes [11] ); 3) TNFSF14 (encodes tumor necrosis factor superfamily member 14, a member of the tumor necrosis factor superfamily which may function as a co-stimulatory factor for the activation of lymphoid cells [12] [13] ); and 4) KMT2D (encodes histone-lysine N-methyltransferase 2D, a histone methyltransferase which regulates the expression of various genes [14] ). [8] ISFL may also acquire numerous copy-number variations (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. [1]

In situ mantle cell neoplasia

In situ mantle cell neoplasia has also been termed in situ involvement by MCL-like cells and in situ-like B-cells of uncertain significance. [1] The disorder involves the accumulation of monoclonal B-cells in the inner layer of the mantel zone of lymphoid follicles. In most cases of ISFL, these B-cells bear a translocation between position 13 on the q arm of chromosome 11 and position 32 on chromosome 14's q arm. This t(11:14)q13:q32) translocation, which is a hallmark found in most cases of MCL, [15] juxtaposes the CCND1 gene at position 13.3 on the q arm of chromosome 11 with the IGH@ locus on chromosome 14 at position q21. [16] In consequence, CCND1 overexpresses cyclin D1, a protein which promotes the cell cycle and thereby cellular proliferation. The overexpression of cyclin D1 is thought to be a major factor in the development of ISMCL and its progression to MCL. [1]

Extremely low numbers of circulating blood cells that bear the t(11:14)q13:q32) translocation occur in 1-8% of healthy individuals. While the role of these cells in causing ISMCL has not been clarified, it is suggested that, similar to the events in the development of ISFL, this translocation occurs in bone marrow pre-B-cells/pro-B-cells after which the cells circulate freely and in rare cases accumulate in the mantle zone of lymphoid follicles to form ISMCL and thereafter MCl. Development of ISMCL and MCL from bone marrow and circulating B-cells bearing the t(14:18)q32:q21) transformation is much less common than the development of ISFL from bone marrow and circulation ISFL cells bearing the t(11:14)q13:q32) translocation, perhaps because the overexpression of cyclin D2 is weaker than Bcl2 overexpression in driving cells to accumulate and become malignant. [2] The progression of ISMCL to MCL appears to involve the acquisition of other genetic alterations in ISMCL B-cells. Deletions and mutations of TP53 (located on the short (i.e. "p") arm of chromosome 17 at position p13.1 (i.e. at 17p13.1 and encoding a tumor suppressor protein [17] ); CDKN2A and CDKN2A [18] (both located at 9p21.3 and respectively encoding cyclin dependent kinase inhibitor 2A and cyclin dependent kinase inhibitor 2B which regulate the cell cycle); RB1 (located at 13q14.2 and encoding the tumor suppressor and cell cycle regulator, retinoblastoma 1 [19] ); and ATM (located at 11q22.3 and encoding ATM serine/threonine kinase, a kinase that regulates the activity of various tumor suppressors and cell cycle proteins [20] ). It may also involve gains in the expression of MYC and BMI1 (encoding the c-Myc and B lymphoma Mo-MLV insertion region 1 homolog proto-oncogenes). However, the roles of these gene products is uncertain because there are scores of other genetic abnormalities in MCL that could contribute to the progression of ISMCL to MCL. [1] [2] [21]

Diagnosis

ISFL

The diagnosis of ISFL requires that sensitive immunochemistry methods find that germinal centers but not other sites of involved lymph follicles contain monotonous-appearing or sometimes atypical lymphocytes that strongly express Bcl2 due to a t(13:18)(q32:q21) translocation. Usually, these cells also strongly express CD10 [2] moderately express CD20 and Bcl6, and proliferate slowly as defined by their Ki-67 levels. [1] The follicles often have a reactive, hyperplastic appearance but the follicular mantle as well as the surrounding lymphoid tissue retain an overall normal architecture. [1] ISFL is associated with overt FL that occurs concurrently in the same or other lymphoid tissues in 16-23% of cases. At diagnosis or thereafter, ISFL may also be associated with other lymphoid malignancies including splenic marginal zone lymphoma, CLL/SLL, marginal zone lymphoma, peripheral T-cell lymphoma not otherwise specified, and classical Hodgkin lymphoma.[ citation needed ]

Differential diagnosis

ISFL is distinguished form reactive hyperplastic germinal centers by the presence of lymphocytes that expression the markers cited in the previous section, particularly Bcl2. However, ISFL is associated with overt FL that occurs concurrently in the same or other lymphoid tissues in 16-23% of cases. [2] Screening studies such as CT scans and bone marrow examinations are recommended to determine the presence of splenic FL, marginal zone lymphoma, CLL/SLL, marginal zone lymphoma, peripheral T-cell lymphoma not otherwise specified, or classical Hodgkin lymphoma. [1]

ISMCL

The diagnosis of ISMCL requires that sensitive immunochemistry methods find that the marginal zone of germinal centers of involved lymph follicles contain lymphocytes that strongly express cyclin D1 due to a t(11:14)q13:q32) translocation. These germinal centers typically exhibit reactive hyperplasia. [2] The neoplastic lymphocytes usually also express CD20, SOX11, and immunoglobulin D but usually do not express two markers that are commonly expressed in MCL, CD5 and CD43. The cyclin D1-expressing lymphocytes generally populate the inner layers of the marginal zone but on occasion some of these cells may be identified in the germinal centers surrounded by these marginal zones as well as in the bone marrow. The cells do not disrupt the overall architecture of the involved follicles. At the time of diagnoses, ISMCL is occasionally found to be associated with overt MCL in the same or other tissues and at diagnosis or sometime thereafter may be associated with CLL/SLL, marginal zone lymphoma, and FL. [1]

Differential diagnosis

ISMCL is distinguished from reactive germinal center hyperplasia by the presence of mantle zone lymphocytes that express cyclin D1 as well as the other markers described above. Screening studies such as CT scans and bone marrow examinations are recommended to determine if MCL, CLL/SLL, marginal zone lymphoma, or FL is present. [1]

Treatment

The treatment of both In situ lymphoid neoplasia subtypes, when not associated with the presence of the lymphoid malignancies described above, is regular follow-ups to check for the development of these malignancies. Follow-up of 33 patients with ISFL over a period of 12 to 132 months diagnosed FL with times of progression of 15 and 29 months in two (6% of all followed) patients. Studies on the development of other types of lymphoid malignancies in ISFL are based primarily on case reports. [2] Single studies suggest that ISFL patients who present with high levels of circulating t(13:18)(q32:q21) translocation-positive lymphocytes or Bcl2-positive lymphocytes that have mutations in the EZH2 gene are at increased risk of, and/or have a shorten time before developing, FL. [1] Follow-up studies of patients with ISMCL are limited. ISMCL has been found to have been present 2–86 months prior to patients developing MCL but only 1 of 15 patients who were followed for >1 year developed the malignance. [2] It has been suggested that mutations in the ATM and CHK2 genes may be associated with an increase risk of, and/or a shorten time before developing, MCL. In situ lymphoid neoplasia patients who have or develop FL, MCL, or other lymphoid malignancy are treated for their malignancies. [5]

Related Research Articles

<span class="mw-page-title-main">Chronic lymphocytic leukemia</span> Medical condition

Chronic lymphocytic leukemia (CLL) is a type of cancer in which the bone marrow makes too many lymphocytes. Early on, there are typically no symptoms. Later, non-painful lymph node swelling, feeling tired, fever, night sweats, or weight loss for no clear reason may occur. Enlargement of the spleen and low red blood cells (anemia) may also occur. It typically worsens gradually over years.

<span class="mw-page-title-main">Tumors of the hematopoietic and lymphoid tissues</span> Tumors that affect the blood, bone marrow, lymph, and lymphatic system

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 aplasia, 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">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 (nodular swirls of various types of lymphocytes) in the germinal centers of lymphoid tissues such as lymph nodes. 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 feature of this cancer.

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

MALT lymphoma is a form of lymphoma involving the mucosa-associated lymphoid tissue (MALT), frequently of the stomach, but virtually any mucosal site can be affected. It is a cancer originating from B cells in the marginal zone of the MALT, and is also called extranodal marginal zone B cell lymphoma.

<span class="mw-page-title-main">B-cell lymphoma</span> Blood cancer that affects B-type white blood cells

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.

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.

<span class="mw-page-title-main">CXCL13</span> Mammalian protein found in Homo sapiens

Chemokineligand 13 (CXCL13), also known as B lymphocyte chemoattractant (BLC) or B cell-attracting chemokine 1 (BCA-1), is a protein ligand that in humans is encoded by the CXCL13 gene.

Richter's transformation (RT), also known as Richter's syndrome, is the conversion of chronic lymphocytic leukemia (CLL) or its variant, small lymphocytic lymphoma (SLL), into a new and more aggressively malignant disease. CLL is the circulation of malignant B lymphocytes with or without the infiltration of these cells into lymphatic or other tissues while SLL is the infiltration of these malignant B lymphocytes into lymphatic and/or other tissues with little or no circulation of these cells in the blood. CLL along with its SLL variant are grouped together in the term CLL/SLL.

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

Mantle cell lymphoma (MCL) is a type of non-Hodgkin's lymphoma, comprising about 6% of cases. It is named for the mantle zone of the lymph nodes where it develops. The term 'mantle cell lymphoma' was first adopted by Raffeld and Jaffe in 1991.

<span class="mw-page-title-main">3-dehydrosphinganine reductase</span> Protein-coding gene in the species Homo sapiens

3-dehydrosphinganine reductase also known as 3-ketodihydrosphingosine reductase (KDSR) or follicular variant translocation protein 1 (FVT1) is an enzyme that in humans is encoded by the KDSR gene.

<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">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.

Monoclonal B-cell lymphocytosis (MBL) is an asymptomatic condition in which individuals have increased blood levels of particular subtypes of monoclonal lymphocytes. This increase must persist for at least 3 months. The lymphocyte subtypes are B-cells that share certain features with the abnormal clones of lymphocytes that circulate in chronic lymphocytic leukemia/small lymphocyte lymphoma (CLL/SLL) or, less frequently, other types of B-cell malignancies. Some individuals with these circulating B-cells develop CLL/SLL or the lymphoma types indicated by their circulating monoclonal B-cells. Hence, MBL is a premalignant disorder

t(11:14) Chromosomal translocation

t(11;14) is a chromosomal translocation which essentially always involves the immunoglobulin heavy locus, also known as IGH in the q32 region of chromosome 14, as well as cyclin D1 which is located in the q13 of chromosome 11. Specifically, the translocation is at t(11;14)(q13;q32).

Gene expression profiling has revealed that diffuse large B-cell lymphoma (DLBCL) is composed of at least 3 different sub-groups, each having distinct oncogenic mechanisms that respond to therapies in different ways. Germinal Center B-Cell like (GCB) DLBCLs appear to arise from normal germinal center B cells, while Activated B-cell like (ABC) DLBCLs are thought to arise from postgerminal center B cells that are arrested during plasmacytic differentiation. The differences in gene expression between GCB DLBCL and ABC DLBCL are as vast as the differences between distinct types of leukemia, but these conditions have historically been grouped together and treated as the same disease.

<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.

Pediatric-type follicular lymphoma (PTFL) is a disease in which malignant B-cells 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 and, less commonly, groin and armpit regions. The disease accounts for 1.5% to 2% of all the lymphomas that occur in the pediatric age group.

Duodenal-type follicular lymphoma (DFL) is a form of lymphoma in which certain lymphocyte types, the B-cell-derived centrocytes and centroblasts, form lymph node follicle-like structures principally in the duodenum and other parts of the small intestine. It is an indolent disease which on rare occasions progresses to a more aggressive lymphoma that spreads beyond these originally involved sites.

Primary cutaneous diffuse large B-cell lymphoma, leg type (PCDLBCL-LT) is a cutaneous lymphoma skin disease that occurs mostly in elderly females. In this disease, B cells become malignant, accumulate in the dermis and subcutaneous tissue below the dermis to form red and violaceous skin nodules and tumors. These lesions typically occur on the lower extremities but in uncommon cases may develop on the skin at virtually any other site. In ~10% of cases, the disease presents with one or more skin lesions none of which are on the lower extremities; the disease in these cases is sometimes regarded as a variant of PCDLBL, LT termed primary cutaneous diffuse large B-cell lymphoma, other (PCDLBC-O). PCDLBCL, LT is a subtype of the diffuse large B-cell lymphomas (DLBCL) and has been thought of as a cutaneous counterpart to them. Like most variants and subtypes of the DLBCL, PCDLBCL, LT is an aggressive malignancy. It has a 5-year overall survival rate of 40–55%, although the PCDLBCL-O variant has a better prognosis than cases in which the legs are involved.

References

  1. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Oishi N, Montes-Moreno S, Feldman AL (January 2018). "In situ neoplasia in lymph node pathology". Seminars in Diagnostic Pathology. 35 (1): 76–83. doi:10.1053/j.semdp.2017.11.001. PMID   29129357.
  2. 1 2 3 4 5 6 7 8 9 10 11 Karube K, Scarfò L, Campo E, Ghia P (February 2014). "Monoclonal B cell lymphocytosis or in situ lymphoma". Seminars in Cancer Biology. 24: 3–14. doi:10.1016/j.semcancer.2013.08.003. PMID   23999128.
  3. 1 2 Choi SM, O'Malley DP (December 2018). "Diagnostically relevant updates to the 2017 WHO classification of lymphoid neoplasms". Annals of Diagnostic Pathology. 37: 67–74. doi:10.1016/j.anndiagpath.2018.09.011. PMID   30308438. S2CID   52963674.
  4. ↑ Qu Q, Xuan W, Fan GH (January 2015). "Roles of resolvins in the resolution of acute inflammation". Cell Biology International. 39 (1): 3–22. doi:10.1002/cbin.10345. PMID   25052386. S2CID   10160642.
  5. 1 2 Ye H, Desai A, Zeng D, Nomie K, Romaguera J, Ahmed M, Wang ML (December 2017). "Smoldering mantle cell lymphoma". Journal of Experimental & Clinical Cancer Research. 36 (1): 185. doi: 10.1186/s13046-017-0652-8 . PMC   5732450 . PMID   29246179.
  6. 1 2 Xochelli A, Oscier D, Stamatopoulos K (2017). "Clonal B-cell lymphocytosis of marginal zone origin". Best Practice & Research. Clinical Haematology. 30 (1–2): 77–83. doi:10.1016/j.beha.2016.08.028. PMID   28288720.
  7. 1 2 Strati P, Shanafelt TD (July 2015). "Monoclonal B-cell lymphocytosis and early-stage chronic lymphocytic leukemia: diagnosis, natural history, and risk stratification". Blood. 126 (4): 454–62. doi:10.1182/blood-2015-02-585059. PMC   4624440 . PMID   26065657.
  8. 1 2 Carbone A, Gloghini A (March 2014). "Emerging issues after the recognition of in situ follicular lymphoma". Leukemia & Lymphoma. 55 (3): 482–90. doi:10.3109/10428194.2013.807926. PMID   23713483. S2CID   39451928.
  9. ↑ "BCL2 BCL2 apoptosis regulator [Homo sapiens (human)] - Gene - NCBI".
  10. ↑ "EZH2 enhancer of zeste 2 polycomb repressive complex 2 subunit [Homo sapiens (human)] - Gene - NCBI".
  11. ↑ "CREBBP CREB binding protein [Homo sapiens (human)] - Gene - NCBI".
  12. ↑ "TNFSF14 TNF superfamily member 14 [Homo sapiens (human)] - Gene - NCBI".
  13. ↑ Xerri L, Dirnhofer S, Quintanilla-Martinez L, Sander B, Chan JK, Campo E, Swerdlow SH, Ott G (February 2016). "The heterogeneity of follicular lymphomas: from early development to transformation". Virchows Archiv. 468 (2): 127–39. doi:10.1007/s00428-015-1864-y. PMID   26481245. S2CID   2978889.
  14. ↑ "KMT2D lysine methyltransferase 2D [Homo sapiens (human)] - Gene - NCBI".
  15. ↑ Vose JM (August 2017). "Mantle cell lymphoma: 2017 update on diagnosis, risk-stratification, and clinical management". American Journal of Hematology. 92 (8): 806–813. doi: 10.1002/ajh.24797 . PMID   28699667.
  16. ↑ "CCND1 cyclin D1 [Homo sapiens (human)] - Gene - NCBI".
  17. ↑ "TP53 tumor protein p53 [Homo sapiens (human)] - Gene - NCBI".
  18. ↑ "CDKN2B cyclin dependent kinase inhibitor 2B [Homo sapiens (human)] - Gene - NCBI".
  19. ↑ "RB1 RB transcriptional corepressor 1 [Homo sapiens (human)] - Gene - NCBI".
  20. ↑ "ATM ATM serine/Threonine kinase [Homo sapiens (human)] - Gene - NCBI".
  21. ↑ Beà S, Amador V (June 2017). "Role of SOX11 and Genetic Events Cooperating with Cyclin D1 in Mantle Cell Lymphoma". Current Oncology Reports. 19 (6): 43. doi:10.1007/s11912-017-0598-1. PMID   28466437. S2CID   4481846.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.