T-cell/histiocyte-rich large B-cell lymphoma
Other namesTHRLBCL
SpecialtyHematology, Oncology,
Differential diagnosisVariant form of nodular lymphocyte predominant Hodgkin lymphoma

T-cell/histiocyte-rich large B-cell lymphoma (THRLBCL) is a malignancy of B cells. B-cells are lymphocytes that normally function in the humoral immunity component of the adaptive immune system by secreting antibodies that, for example, bind to and neutralize invasive pathogens. Among the various forms of B-cell lymphomas, THRLBCL is a rarely occurring subtype of the diffuse large B-cell lymphomas (DLBCL). DLBCL are a large group of lymphomas that account for ~25% of all non-Hodgkin lymphomas worldwide.[1] THRLBCL is distinguished from the other DLBCL subtypes by the predominance of non-malignant T-cell lymphocytes and histiocytes over malignant B-cells in its tumors and tissue infiltrates.[2]

THRLBCL commonly afflicts middle-aged individuals but has been diagnosed in rare pediatric cases.[1] The disease usually presents with lymphadenopathy, i.e. bulky enlargements of lymph nodes in the neck, arm pit, or groin. However, most cases are at an advanced stage at diagnoses: further examinations frequently reveal that the disease has spread to multiple internal organs and tissues. The course of the disease is usually characterized as being poorly responsive to treatment: the disease's survival rates in past studies have been only ~46%.[3] However, recent studies suggest that novel treatments can improve these survival rates.

Many studies have found that THRLBCL can overlap with the variant form of nodular lymphocyte predominant Hodgkin lymphoma (NLPHL). That is, some cases of variant NLPHL, which is a relatively indolent malignancy, share with THRLBCL similar disease presentations, histologies (i.e. microscopic appearances), genetic abnormalities, and apparent etiologies.[4] Indeed, NLPHL can, in rare cases, progress into THRLBCL.[2] Comapared to THRLBCL, however, these variant NLPHL cases are less aggressive, are more responsive to treatment, and have a better prognosis.[4] Thus, THRLBCL and NLPHL may be biologically related diseases that represent opposite ends of a severity spectrum.[5]

Presentation

T-cell/histiocyte-rich large B-cell lymphoma most commonly afflicts middle-aged (i.e. 49–57 years old) individuals but has been diagnosed in persons aged 4[6] to 92 years.[2] The disease has a male predominance ranging between 1.7:1[3] to 3:1[2] in different studies. In a review of 36 reported pediatric cases, the male to female ratio was 4:1.[6] Patients typically present with enlarged lymph nodes in the neck, arm pit, and groin areas but on further examination are found to have involvement of their spleen (31% of cases), liver (52% of cases), bone marrow (27% of cases)[7] and lung/or (13%) as determined by finding enlarged spleens and/or livers on physical examination or medical imaging; abnormal results on liver function tests, and/or THRLBCL infiltrates in bone marrow biopsies.[3] Rare cases of the disease have presented with involvement of the skin (termed primary cutaneous THRLBCL), thyroid gland, thymus, gastrointestinal tract, pancreas,[8] jaw bone,[7] nasopharynx, brain, tongue, uterus, stomach, and soft tissues.[9] Many patients will also complain of having systemic B symptoms such as fever, night sweats, weight loss, and malaise.[2]

Pathogenesis

Due to its rarity, the causes of THRLBCL have not been well studied and consequently remained unclear. The malignant B-cells in the disease commonly have mutations in several genes such as:[2]

  • JUNB which codes for JunB, a protein that regulates cell growth and survival and is highly expressed in other lymphocyte malignancies;[10]
  • DUSP2 (a gene suspected of being a tumor suppressor) which codes for dual specificity protein phosphatase 2, a protein that regulates several components of the ERK/MAPK signaling pathway that controls cell proliferation;[11]
  • SGK1 which codes for serine/threonine-protein kinase, a protein that regulates several signaling pathways that control cell proliferation and survival;[12]
  • SOCS1, a known oncogene and tumor suppressor which codes for suppressor of cytokine signaling 1;[13] and
  • CREBBP, a gene that is commonly mutated in other DLBCL subtypes as well as other lymphomas and codes for the transcription coregulator, CREB-binding protein.[14]

The neoplastic cells in this disease also show gains on the short arm of chromosome 2 at position 16.1 which affect the REL protooncogene[3] which codes for c-Rel, a protein that controls the maturation of B-cells and is implicated in the development of many cancers including lymphomas;[15] as well as losses o the short armes of chromosomes 1 and 9 and 19.2 and 11.2 sites, respectively.[3] These studies allow the possibility that THRLBC, similar to the other subtypes of DLBDL as well as a wide array of other cancers[16] results at least in part from the step-wise development of gene changes such as mutations, altered expressions, amplifications (i.e. increases in the number of copies of specific genes), and chromosomal translocations that alter the expression of key genes in B-cells to result in the increasingly malignant behavior of these cells.[17] However, the underlying causes for these gene changes as well as the identity of the genes whose changes contribute to the malignant behavior of the neoplastic B-cells in THRLBC have yet to be defined.[3]

The neoplastic B-cells in THRLBCL infiltrations are dominated by high numbers of histiocytes and dendritic cells. Studies suggest that the latter cells help to create a microenvironment that is tolerant or promotes tumor growth and spread to other sites.[4]

Diagnosis

The diagnosis of THRLBCL, particularly as it pertains to differentiating it from DLBCL and other lymphomas, depends on examining involved tissues obtained by biopsy or operation for their histology, i.e. microscopic anatomy. The tissues involved in THRLBCL commonly show an effacement of their normal architecture by a diffusely growing infiltrate of non-malignant T-cell lymphocytes, histiocytes, and neoplastic (i.e. malignant) B-cells. The malignant B-cells represent <10% of the cells in these lesions[3] and bear resemblances to centroblast, immunoblasts, and/or the Reed–Sternberg cells found in Hodgkin disease, including in particular Hodgkin disease's nodular variant.[2] The non-malignant T-cells generally have a reactive morphology as indicated by their larger than normal size and irregularly shaped cell nuclei.[3] And, the histiocytes, which are not always present in these lesions, have a non-epithelial cell appearance.[3] These infiltrates often resemble these seen in inflammation.[8] The malignant B-cells in THRLBCL are definitively identified by immunophenotyping to detect B-cell marker proteins (e.g. CD19, CD20, CD22, CD79a, and/or PAX5).[4] These cells may also express other identifying marker proteins such as Bcl-6 (50–90% of cases), the product of the MYC gene, c-Myc (most cases), Bcl-2 (40% of cases), MUC1 (30% of cases), and, in a minority of cases, CD10.[2] The T cells in these lesions are predominantly cytotoxic T cells as indicated by their expression of T-cell receptor, CD8 T-cell co-receptor, and CD5 cell surface proteins. And, the histiocytes in these lesions express CD68 and CD163 cell surface proteins. Before making a diagnosis of THRLBCL in a pediatric population, congenital and acquired immunodeficiency diseases, which can cause aberrant immune responses with a histology similar to THRLBCL, must be ruled-out.[3]

Differential diagnosis

While the histological features of THRLBCL are distinctly different that those found in other DLBCL subtypes, they can closely resemble, and be mistaken for, those found in the variant form of nodular lymphocyte predominant Hodgkin lymphoma.[4] Some important histological features that favor the diagnosis of THRLBCL over NLPHL include the presence of:

  1. <10% neoplastic B-cells;
  2. CD163-expressing histiocytes (cases of THRLBCL in which histiocytes are absent appear to take a less aggressive course than cases in which these cells are present);
  3. a diffuse rather than nodular cell infiltration pattern with any nodular infiltrates present in THRLBCL containing follicular dendritic cells;
  4. PD-1-, CD4-, and CD57-expressing T-cells;
  5. cells strongly expressing the BAT3/BAG6 ubiquitin domain-containing protein;[3] and
  6. few or no small lymphocytes, variant Hodgkin i.e. popcorn and Reed-Sternberg cells.[8]

Treatment

Patients diagnosed with THRLBCL have been treated with chemotherapy regimens similar to the regimens used to treat DLBCL. These earlier used chemotherapy regimens (e.g. the CHOP regimen consisting of three chemotherapy drugs (cyclophosphamide, hydroxydoxorubicin, and oncovin) plus a glucocorticoid, either prednisone or prednisolone)[7] achieve complete response rates of 48% to 85%, 3-year overall survival rates of 50% to 64%, and 5-year overall survival rates of 46% to 58%. The addition of immunotherapy drug, rituximab, to the CHOP regimen appears to have improved these results: in one study, patients receiving the R-CHOP regimen had a three-year overall survival rate of 75%.[8] Since treatment of the variant form of nodular lymphocyte predominant Hodgkin lymphoma using different and less aggressive drug regimens achieves better results than the regimens used to treat THRLBCL, it is clinically important to distinguish the two diseases.[4]

References

  1. 1 2 Conte GA, Harmon JS, Le ML, Sun X, Schuler JW, Levitt MJ, Chinnici AA, Hossain MA (December 2019). "Hypercalcemia in T-Cell/Histiocyte-Rich Large B-Cell Lymphoma: An Unusual Presentation of a Rare Disease and Literature Review". World Journal of Oncology. 10 (6): 231–236. doi:10.14740/wjon1246. PMC 6940034. PMID 31921379.
  2. 1 2 3 4 5 6 7 8 Sukswai N, Lyapichev K, Khoury JD, Medeiros LJ (November 2019). "Diffuse large B-cell lymphoma variants: an update". Pathology. 52 (1): 53–67. doi:10.1016/j.pathol.2019.08.013. PMID 31735345. S2CID 208142227.
  3. 1 2 3 4 5 6 7 8 9 10 11 Korkolopoulou P, Vassilakopoulos T, Milionis V, Ioannou M (July 2016). "Recent Advances in Aggressive Large B-cell Lymphomas: A Comprehensive Review". Advances in Anatomic Pathology. 23 (4): 202–43. doi:10.1097/PAP.0000000000000117. PMID 27271843. S2CID 205915174.
  4. 1 2 3 4 5 6 Hartmann S, Eichenauer DA (January 2020). "Nodular lymphocyte predominant Hodgkin lymphoma: pathology, clinical course and relation to T-cell/histiocyte rich large B-cell lymphoma". Pathology. 52 (1): 142–153. doi:10.1016/j.pathol.2019.10.003. PMID 31785822. S2CID 208537001.
  5. ↑ Grimm KE, O'Malley DP (February 2019). "Aggressive B cell lymphomas in the 2017 revised WHO classification of tumors of hematopoietic and lymphoid tissues". Annals of Diagnostic Pathology. 38: 6–10. doi:10.1016/j.anndiagpath.2018.09.014. PMID 30380402. S2CID 53196244.
  6. 1 2 Wei C, Wei C, Alhalabi O, Chen L (June 2018). "T-cell/histiocyte-rich large B-cell lymphoma in a child: A case report and review of literature". World Journal of Clinical Cases. 6 (6): 121–126. doi:10.12998/wjcc.v6.i6.121. PMC 6033745. PMID 29988902.
  7. 1 2 3 Silva RNF, Mendonça EF, Batista AC, Alencar RCG, Mesquita RA, Costa NL (December 2019). "T-Cell/Histiocyte-Rich Large B-Cell Lymphoma: Report of the First Case in the Mandible". Head and Neck Pathology. 13 (4): 711–717. doi:10.1007/s12105-018-0948-9. PMC 6854205. PMID 30019325.
  8. 1 2 3 4 Zheng SM, Zhou DJ, Chen YH, Jiang R, Wang YX, Zhang Y, Xue HL, Wang HQ, Mou D, Zeng WZ (June 2017). "Pancreatic T/histiocyte-rich large B-cell lymphoma: A case report and review of literature". World Journal of Gastroenterology. 23 (24): 4467–4472. doi:10.3748/wjg.v23.i24.4467. PMC 5487512. PMID 28706431.
  9. ↑ Barut F, Kandemir NO, Gun BD, Ozdamar SO (July 2016). "T-cell/histiocyte-rich large B-cell lymphoma of stomach". The Journal of the Pakistan Medical Association. 66 (7): 905–7. PMID 27427148.
  10. ↑ Papoudou-Bai A, Hatzimichael E, Barbouti A, Kanavaros P (August 2017). "Expression patterns of the activator protein-1 (AP-1) family members in lymphoid neoplasms". Clinical and Experimental Medicine. 17 (3): 291–304. doi:10.1007/s10238-016-0436-z. PMID 27600282. S2CID 4778071.
  11. ↑ Low HB, Zhang Y (April 2016). "Regulatory Roles of MAPK Phosphatases in Cancer". Immune Network. 16 (2): 85–98. doi:10.4110/in.2016.16.2.85. PMC 4853501. PMID 27162525.
  12. ↑ Pan H, Lv W, Li Z, Han W (2019). "SGK1 protein expression is a prognostic factor of lung adenocarcinoma that regulates cell proliferation and survival". International Journal of Clinical and Experimental Pathology. 12 (2): 391–408. PMC 6945076. PMID 31933845.
  13. ↑ Beaurivage C, Champagne A, Tobelaim WS, Pomerleau V, Menendez A, Saucier C (June 2016). "SOCS1 in cancer: An oncogene and a tumor suppressor". Cytokine. 82: 87–94. doi:10.1016/j.cyto.2016.01.005. PMID 26811119.
  14. ↑ Meyer SN, Scuoppo C, Vlasevska S, Bal E, Holmes AB, Holloman M, Garcia-Ibanez L, Nataraj S, Duval R, Vantrimpont T, Basso K, Brooks N, Dalla-Favera R, Pasqualucci L (September 2019). "Unique and Shared Epigenetic Programs of the CREBBP and EP300 Acetyltransferases in Germinal Center B Cells Reveal Targetable Dependencies in Lymphoma". Immunity. 51 (3): 535–547.e9. doi:10.1016/j.immuni.2019.08.006. PMC 7362711. PMID 31519498.
  15. ↑ Kober-Hasslacher M, Schmidt-Supprian M (July 2019). "The Unsolved Puzzle of c-Rel in B Cell Lymphoma". Cancers. 11 (7): 941. doi:10.3390/cancers11070941. PMC 6678315. PMID 31277480.
  16. ↑ Liu Y, Barta SK (May 2019). "Diffuse large B-cell lymphoma: 2019 update on diagnosis, risk stratification, and treatment". American Journal of Hematology. 94 (5): 604–616. doi:10.1002/ajh.25460. PMID 30859597.
  17. ↑ Schuhmacher B, Bein J, Rausch T, Benes V, Tousseyn T, Vornanen M, Ponzoni M, Thurner L, Gascoyne R, Steidl C, Küppers R, Hansmann ML, Hartmann S (February 2019). "JUNB, DUSP2, SGK1, SOCS1 and CREBBP are frequently mutated in T-cell/histiocyte-rich large B-cell lymphoma". Haematologica. 104 (2): 330–337. doi:10.3324/haematol.2018.203224. PMC 6355500. PMID 30213827.
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