In situ lymphoid neoplasia
In situ lymphoid neoplasia is a precancerous condition newly classified by the World Health Organization in 2016. The Organization recognized two subtypes of ISLN: in situ follicular neoplasia and in situ mantle cell neoplasia. 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 B-cells that may develop into follicular and mantle cell lymphomas, respectively.
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, premalignant, and therefore now regarded as in situ disorders similar to those in solid tissues.
ISFN and ISMCL 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. MLB consists of four subtypes: chronic lymphocytic leukemia/small lymphocyte MBL, atypical CLL/SLL-MBL, non-CLL/SLL-MBL, and monoclonal B-cell lymphocytosis of the marginal zone 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, and 3)''' the B-cells in MBL may accumulate in lymphoid tissues.
Presentation
ISFL and ISMCL are generally asymptomatic disorders discovered in lymphoid tissues which were examined for other reasons. Typically, a follicle in a superficial lymph node 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 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.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. 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 arm of chromosome 14 and position 21 on chromosome 18's q arm. This same t translocation is a genetic hallmark of FL and juxtaposes the B-cell lymphoma 2 gene on chromosome 18 at position q21.33 with the immunoglobulin heavy chain locus on chromosome 14 at position q21. In consequence, BCL2 overexpresses its product, BCL2 apoptosis regulator. Blc2 functions to inhibit programmed cell death 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 of circulating blood cells bearing the t translocation are found in 50-67% of otherwise healthy individuals. The prevalence of this finding increases with age, tobacco smoking, pesticide exposure, and race. Since most individuals with this translocation in their blood cells do not develop ISFL or FL, t, 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 after which these cells circulate freely and in rare cases accumulate in the germinal centers of lymphoid follicles to form ISFL. The mechanism EZH2 CREBBP TNFSF14 KMT2D. ISFL may also acquire numerous copy-number variations 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.
''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. 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 translocation, which is a hallmark found in most cases of MCL, 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. 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.Extremely low numbers of circulating blood cells that bear the t 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 transformation is much less common than the development of ISFL from bone marrow and circulation ISFL cells bearing the t translocation, perhaps because the overexpression of cyclin D2 is weaker than Bcl2 overexpression in driving cells to accumulate and become malignant. The progression of ISMCL to MCL appears to involve the acquisition of other genetic alterations in ISMCL B-cells. Deletions and mutations of TP53 arm of chromosome 17 at position p13.1 ; CDKN2Aand CDKN2A ; RB1 ; and ATM. It may also involve gains in the expression of MYC and BMI1. 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.
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 translocation. Usually, these cells also strongly express CD10 moderately express CD20 and Bcl6, and proliferate slowly as defined by their Ki-67 levels. The follicles often have a reactive, hyperplastic appearance but the follicular mantle as well as the surrounding lymphoid tissue retain an overall normal architecture. 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.