Germ line mutations and acquired conditions predisposing to development of NK/T-cell lymphomas and leukemias
| Predisposing feature . | Lymphomas . | Comments . |
|---|---|---|
| Germ line mutations | ||
| Ataxia-telangiectasia | T-lymphoblastic leukemia/lymphoma in children T-cell prolymphocytic leukemia (T-PLL) in young adults | Autosomal recessive disease with biallelic loss-of-function ATM mutations. Monoallelic mutations predispose to T-PLL in older individuals. |
| Nijmegen breakage syndrome | T-lymphoblastic leukemia/lymphoma | Autosomal recessive disease with biallelic NBS mutations. |
| HAVCR2 mutations9 | Subcutaneous panniculitis-like T-cell lymphoma (SPTCL) | 25%-60% of patients with SPTCL harbor germ line HAVCR2 mutations and more often present at a younger age with hemophagocytic lymphohistiocytosis. |
| TET2 mutations10,11 | Mature T-cell lymphoma reported in some cases (follicular helper T-cell lymphoma, ALK− anaplastic large cell lymphoma [ALCL]) in childhood or adulthood | Usually biallelic homozygous or heterozygous germ line mutations cause hypermethylation of peripheral blood DNA, childhood immunodeficiency with autoimmune lymphoproliferative syndrome (ALPS)-like features, and secondary development of various lymphomas. |
| Acquired conditions | ||
| HTLV-1 infection | Adult T-cell leukemia/lymphoma | Often by transmission of HTLV-1 through breastfeeding. |
| Chronic active EBV disease | Extranodal NK/T-cell lymphoma, nasal type, or aggressive NK-cell leukemia | Risk of progression to lymphoma or leukemia in patients with the systemic type of chronic active EBV disease not treated with allogeneic bone marrow transplantation. |
| Breast implant12,13 | Breast implant–associated ALCL (BIA-ALCL) | Textured breast implants are a risk factor for the development of BIA-ALCL, and the risk is increased in women with genetic predisposition to breast cancer (BRCA1 or TP53 germ line mutations). |
| Celiac disease | Refractory celiac disease, type II (RCD-II) and enteropathy-associated T-cell lymphoma (EATL) | RCD II/EATL is a rare complication of celiac disease, an immune-mediated enteropathy occurring in genetically susceptible individuals carrying HLA-DQ2 or HLA-DQ8. 1% of celiac disease patients will develop RCD-II. The 5-y risk of progression to EATL for individuals with RCD-II is 30%-50%. |
| Immune suppression | Hepatosplenic T-cell lymphoma (HSTL) | Many patients with HSTL have preexisting iatrogenic immune deregulation to manage solid organ transplantation, inflammatory bowel disease, or rheumatoid arthritis, and often received anti-TNFalpha or other immunomodulator agents. Given the rarity of HSTL, the risk is not quantifiable. |
| Chronic lymphocytic leukemia (CLL)14 | Cutaneous T-cell lymphoma and systemic lymphoma (peripheral T-cell lymphoma, NOS, ALCLs, follicular helper T-cell lymphoma) | The increased risk for developing cutaneous or systemic PTCLs in patients with CLL has been linked to the accumulation of oligo- or monoclonal T-cell populations with abnormal phenotypes. |
| Clonal hematopoiesis (CH)15,16 | Follicular helper T-cell lymphoma (TFHL) | Most patients with TFHL have underlying clonally linked CH often with mutations in TET2 and DNMT3A. Data suggest that a subset of peripheral T-cell lymphoma, NOS are also related to CH. |
| Lymphocytic variant eosinophilic syndrome (LHES)17 | Peripheral T-cell lymphoma, NOS, follicular helper T-cell lymphoma | LHES is a form of chronic indolent T-cell LPD encompassing a clonal and phenotypically aberrant (usually sCD3− CD4+) T-cell population in blood. A subset of the patients (up to 25%) may progress to lymphoma. |
| T-cell clones of uncertain significance (T-CUS)18 | T-cell large granular lymphocytic leukemia (T-LGLL) | Premalignant condition characterized by the presence of small clonal cell expansions in individuals without symptoms or signs of T-LGLL. |
| Predisposing feature . | Lymphomas . | Comments . |
|---|---|---|
| Germ line mutations | ||
| Ataxia-telangiectasia | T-lymphoblastic leukemia/lymphoma in children T-cell prolymphocytic leukemia (T-PLL) in young adults | Autosomal recessive disease with biallelic loss-of-function ATM mutations. Monoallelic mutations predispose to T-PLL in older individuals. |
| Nijmegen breakage syndrome | T-lymphoblastic leukemia/lymphoma | Autosomal recessive disease with biallelic NBS mutations. |
| HAVCR2 mutations9 | Subcutaneous panniculitis-like T-cell lymphoma (SPTCL) | 25%-60% of patients with SPTCL harbor germ line HAVCR2 mutations and more often present at a younger age with hemophagocytic lymphohistiocytosis. |
| TET2 mutations10,11 | Mature T-cell lymphoma reported in some cases (follicular helper T-cell lymphoma, ALK− anaplastic large cell lymphoma [ALCL]) in childhood or adulthood | Usually biallelic homozygous or heterozygous germ line mutations cause hypermethylation of peripheral blood DNA, childhood immunodeficiency with autoimmune lymphoproliferative syndrome (ALPS)-like features, and secondary development of various lymphomas. |
| Acquired conditions | ||
| HTLV-1 infection | Adult T-cell leukemia/lymphoma | Often by transmission of HTLV-1 through breastfeeding. |
| Chronic active EBV disease | Extranodal NK/T-cell lymphoma, nasal type, or aggressive NK-cell leukemia | Risk of progression to lymphoma or leukemia in patients with the systemic type of chronic active EBV disease not treated with allogeneic bone marrow transplantation. |
| Breast implant12,13 | Breast implant–associated ALCL (BIA-ALCL) | Textured breast implants are a risk factor for the development of BIA-ALCL, and the risk is increased in women with genetic predisposition to breast cancer (BRCA1 or TP53 germ line mutations). |
| Celiac disease | Refractory celiac disease, type II (RCD-II) and enteropathy-associated T-cell lymphoma (EATL) | RCD II/EATL is a rare complication of celiac disease, an immune-mediated enteropathy occurring in genetically susceptible individuals carrying HLA-DQ2 or HLA-DQ8. 1% of celiac disease patients will develop RCD-II. The 5-y risk of progression to EATL for individuals with RCD-II is 30%-50%. |
| Immune suppression | Hepatosplenic T-cell lymphoma (HSTL) | Many patients with HSTL have preexisting iatrogenic immune deregulation to manage solid organ transplantation, inflammatory bowel disease, or rheumatoid arthritis, and often received anti-TNFalpha or other immunomodulator agents. Given the rarity of HSTL, the risk is not quantifiable. |
| Chronic lymphocytic leukemia (CLL)14 | Cutaneous T-cell lymphoma and systemic lymphoma (peripheral T-cell lymphoma, NOS, ALCLs, follicular helper T-cell lymphoma) | The increased risk for developing cutaneous or systemic PTCLs in patients with CLL has been linked to the accumulation of oligo- or monoclonal T-cell populations with abnormal phenotypes. |
| Clonal hematopoiesis (CH)15,16 | Follicular helper T-cell lymphoma (TFHL) | Most patients with TFHL have underlying clonally linked CH often with mutations in TET2 and DNMT3A. Data suggest that a subset of peripheral T-cell lymphoma, NOS are also related to CH. |
| Lymphocytic variant eosinophilic syndrome (LHES)17 | Peripheral T-cell lymphoma, NOS, follicular helper T-cell lymphoma | LHES is a form of chronic indolent T-cell LPD encompassing a clonal and phenotypically aberrant (usually sCD3− CD4+) T-cell population in blood. A subset of the patients (up to 25%) may progress to lymphoma. |
| T-cell clones of uncertain significance (T-CUS)18 | T-cell large granular lymphocytic leukemia (T-LGLL) | Premalignant condition characterized by the presence of small clonal cell expansions in individuals without symptoms or signs of T-LGLL. |
EBV, Epstein-Barr virus; HTLV-1, human T-lymphotropic virus 1; TNF, tumor necrosis factor.