Hematolymphoid tumors can either be benign (non-cancerous) or malignant (cancerous). There are certain tumors that are classified as atypical (uncertain or unspecified behavior) meaning that some behave in a benign manner, or some behave in a malignant manner. A majority of the tumors diagnosed via lab studies (biopsy) are benign.

Hematolymphoid tumors are tumors of the hematopoietic and lymphoid tissues, meaning these involve the blood, bone marrow, lymph, and lymphatic system in the body.

The World Health Organization (WHO) is an authoritative body that compiles, prepares, and publishes histological and molecular classification of tumors, via their Blue Books, based on research inputs from experts worldwide. These reference books chiefly aid in global cancer research, provide gold standards for tumor diagnosis, and help in treating cancer patients.

According to the WHO Classification of Hematolymphoid Tumors (2022), 5th Ed., benign and malignant hematolymphoid tumors are classified in the following manner:

Myeloid proliferations and neoplasms:

Myeloid precursor lesions

• Clonal Hematopoiesis
  • Clonal hematopoiesis: Clonal Hematopoiesis refers to the presence of a genetically distinct population of blood cells arising from a single hematopoietic stem cell mutation, which can be detected through genetic analysis. While often asymptomatic, it may increase the risk of developing hematologic malignancies and can influence disease progression and treatment response.
  • Clonal cytopenias of undetermined significance: Clonal Cytopenia of Undetermined Significance is a condition characterized by the presence of a clonal blood cell population along with cytopenias (reduced blood cell counts) without clear evidence of malignancy. It often requires careful monitoring, as it may progress to more serious disorders like myelodysplastic syndromes or acute myeloid leukemia.

Myeloproliferative neoplasms

• Myeloproliferative neoplasms
  • Chronic myeloid leukemia: Chronic Myeloid Leukemia (CML) is a type of cancer that affects the blood and bone marrow, characterized by the overproduction of myeloid cells due to the BCR-ABL1 fusion gene. It typically progresses through phases, starting with a chronic phase and potentially advancing to an accelerated or blast phase, and is commonly treated with tyrosine kinase inhibitors like imatinib.
  • Chronic neutrophilic leukemia: Chronic Neutrophilic Leukemia is a rare myeloproliferative disorder characterized by the sustained overproduction of mature neutrophils in the blood and bone marrow. It often presents with symptoms related to excessive neutrophil levels, such as infections and inflammation, and requires management strategies aimed at controlling neutrophil counts and associated complications.
  • Chronic eosinophilic leukemia: Chronic Eosinophilic Leukemia is a rare myeloproliferative disorder characterized by the overproduction of eosinophils, leading to symptoms such as fatigue, weight loss, and organ damage due to eosinophilic infiltration. It often requires targeted therapies, such as tyrosine kinase inhibitors, to manage the disease and its complications.
  • Polycythemia vera: It is a blood-related disorder caused by an excess production of red blood cells in the body. The condition is mostly observed in older adults
  • Essential thrombocythemia: It is a condition in which the body produces too many platelet cells. The condition is mostly asymptomatic during the initial stages, and is observed in older adults
  • Primary myelofibrosis: It is the acquired scarring of bone marrow that is not a consequence of another disease or condition. The condition may be noted in middle-aged and older adults
  • Juvenile myelomonocytic leukemia: Juvenile Myelomonocytic Leukemia is a rare and aggressive pediatric leukemia characterized by the proliferation of myelomonocytic cells in the bone marrow and peripheral blood. It often presents in young children with symptoms like anemia, fever, and splenomegaly, and typically requires hematopoietic stem cell transplantation for a potential cure.
  • Myeloproliferative neoplasm, NOS

Mastocytosis: It is a rare disorder that results from abnormal and excessive numbers of mast cells in the skin, and rarely, in the organs. Both children and adults may be affected by mastocytosis.

• Cutaneous mastocytosis: It is the most common form of mastocytosis affecting the skin. Infants are generally susceptible to this form of mastocytosis
• Systemic mastocytosis: It is an uncommon form of mastocytosis affecting several tissues and organs in the body, including the skin. Middle-aged and older adults are generally susceptible to this type of mastocytosis
• Mast cell sarcoma

Myelodysplastic neoplasms

• Myelodysplastic neoplasms, with defining genetic abnormalities
  • Myelodysplastic neoplasm with low blasts and 5q deletion
  • Myelodysplastic neoplasm with low blasts and SF3B1 mutation
  • Myelodysplastic neoplasm with biallelic TP53 inactivation
• Myelodysplastic neoplasms, morphologically defined
  • Myelodysplastic neoplasm with low blasts
  • Myelodysplastic neoplasm, hypoplastic
  • Myelodysplastic neoplasm with increased blasts
• Myelodysplastic neoplasms of childhood
  • Childhood myelodysplastic neoplasm with low blasts
  • Childhood myelodysplastic neoplasm with increased blasts

Myelodysplastic/myeloproliferative neoplasms

• Chronic myelomonocytic leukemia
• Myelodysplastic/myeloproliferative neoplasm with neutrophilia
• Myelodysplastic/myeloproliferative neoplasm with SF3B1 mutation and thrombocytosis
• Myelodysplastic/myeloproliferative neoplasm, NOS

Acute myeloid leukemia

• Acute myeloid leukemia with defining genetic abnormalities
  • Acute promyelocytic leukemia with PML::RARA fusion: It is characterized by the fusion of the PML and RARA genes, resulting in the production of an abnormal protein that disrupts normal hematopoietic differentiation and promotes leukemogenesis. Targeted therapies such as ATRA (all-trans retinoic acid) and arsenic trioxide have revolutionized the treatment of this subtype, leading to high remission rates and improved survival outcomes
  • Acute myeloid leukemia with RUNX1::RUNX1T1 fusion: It involves the fusion of the RUNX1 and RUNX1T1 genes, resulting in a chimeric protein that disrupts normal hematopoietic differentiation and promotes leukemic transformation. Targeted therapies and intensive chemotherapy regimens are often employed to manage this subtype of AML, aiming for remission and improved long-term outcomes
  • Acute myeloid leukemia with CBFB::MYH11 fusion: It is characterized by the fusion of the CBFB and MYH11 genes, leading to abnormal protein production and disrupted cell function, contributing to leukemia development. This subtype of AML often presents with distinct clinical features and requires tailored treatment strategies for optimal management
  • Acute myeloid leukemia with DEK::NUP214 fusion: It is characterized by the fusion of the DEK and NUP214 genes, leading to the formation of an oncogenic protein that disrupts cellular processes and contributes to leukemogenesis. Targeted therapies and stem cell transplantation may be considered in the management of this subtype to improve treatment outcomes and patient prognosis.
  • Acute myeloid leukemia with RBM15::MRTFA fusion: It involves the fusion of RBM15 and MRTFA genes, leading to aberrant gene expression and disrupted cellular functions implicated in leukemogenesis. Understanding the molecular mechanisms of this fusion can aid in the development of targeted therapies tailored to this AML subtype, potentially improving patient outcomes.
  • Acute myeloid leukemia with BCR::ABL1 fusion: It signifies the fusion of the BCR and ABL1 genes, resulting in the production of a constitutively active tyrosine kinase that drives leukemic proliferation. Targeted therapies such as tyrosine kinase inhibitors, alongside standard chemotherapy, are crucial in managing this aggressive subtype, aiming for disease control and improved survival rates
  • Acute myeloid leukemia with KMT2A rearrangement: It involves genetic alterations affecting the KMT2A gene and is associated with aggressive disease behavior and poorer treatment response. Management typically includes intensive chemotherapy regimens and stem cell transplantation, aiming to achieve remission and improve long-term outcomes in affected patients.
  • Acute myeloid leukemia with MECOM rearrangement: It involves genetic alterations affecting the MECOM gene, leading to dysregulated gene expression and aggressive leukemic transformation. Targeted therapies and intensive chemotherapy regimens are often employed in managing this subtype, aiming to achieve remission and improve overall survival outcomes in affected individuals
  • Acute myeloid leukemia with NUP98 rearrangement: It involves genetic alterations affecting the NUP98 gene, often leading to fusion with various partner genes and aberrant cellular functions implicated in leukemogenesis. Management of this subtype may include intensive chemotherapy and targeted therapies, with outcomes varying based on specific fusion partners and associated genetic abnormalities
  • Acute myeloid leukemia with NPM1 mutation: It is characterized by mutations in the NPM1 gene, often associated with a favorable prognosis and responsiveness to standard chemotherapy regimens. Detection of NPM1 mutations serves as a prognostic marker, guiding treatment decisions and predicting outcomes in patients with AML
  • Acute myeloid leukemia with CEBPA mutation: It involves genetic alterations affecting the CEBPA gene, often associated with a favorable prognosis and better response to standard chemotherapy. Detection of CEBPA mutations serves as a prognostic marker, guiding treatment strategies and predicting outcomes in patients with AML
  • Acute myeloid leukemia, myelodysplasia-related: Myelodysplasia-Related Acute Myeloid Leukemia is a subtype of AML that evolves from a prior myelodysplastic syndrome, characterized by dysplastic and ineffective blood cell production. This form of leukemia often presents with cytopenias, complex karyotypic abnormalities, and a poorer prognosis compared to de novo AML.
  • Acute myeloid leukemia with other defined genetic alterations
• Acute myeloid leukemia, defined by differentiation
  • Acute myeloid leukemia with minimal differentiation: It represents a subtype characterized by a lack of maturation markers, often associated with poor prognosis and aggressive disease behavior. Treatment typically involves intensive chemotherapy regimens aimed at inducing remission, with additional strategies such as stem cell transplantation considered for long-term disease control
  • Acute myeloid leukemia without maturation: Acute Myeloid Leukemia without Maturation is a subtype of AML where there is a significant accumulation of immature myeloid cells (blasts) in the bone marrow, with minimal to no maturation into granulocytes. This aggressive form of leukemia leads to symptoms such as severe anemia, infections, and bleeding due to the rapid proliferation of undifferentiated cells.
  • Acute myeloid leukemia with maturation: Acute Myeloid Leukemia with Maturation is a subtype of AML characterized by the presence of myeloid blasts with evidence of maturation into granulocytes. This condition involves the proliferation of immature white blood cells in the bone marrow and blood, leading to symptoms like anemia, infections, and bleeding.
  • Acute basophilic leukemia: Acute Basophilic Leukemia is a rare and aggressive subtype of AML characterized by the proliferation of basophilic precursors in the bone marrow and peripheral blood. It often presents with symptoms like severe anemia, thrombocytopenia, and elevated histamine levels, leading to systemic issues such as skin rashes and gastrointestinal problems.
  • Acute myelomonocytic leukemia: Acute Myelomonocytic Leukemia (AML-M4) is a subtype of acute myeloid leukemia characterized by the presence of both myeloid and monocytic lineage cells in the bone marrow and peripheral blood. It typically presents with symptoms such as anemia, thrombocytopenia, and increased susceptibility to infections, requiring prompt and aggressive treatment with chemotherapy.
  • Acute monocytic leukemia: Acute Monocytic Leukemia is a subtype of AML characterized by a predominance of monoblasts and promonocytes in the bone marrow and peripheral blood. This leukemia often presents with symptoms like gum infiltration, skin lesions, and a higher risk of disseminated intravascular coagulation (DIC).
  • Acute erythroid leukemia: Acute erythroid leukemia (AEL) is a rare and aggressive subtype of acute myeloid leukemia characterized by the proliferation of immature erythroid precursors in the bone marrow. Treatment typically involves intensive chemotherapy, with poor prognosis often necessitating consideration of hematopoietic stem cell transplantation for better long-term outcomes.
  • Acute megakaryoblastic leukemia: Acute Megakaryoblastic Leukemia (AMKL) is a rare subtype of acute myeloid leukemia characterized by the proliferation of immature megakaryocytes in the bone marrow and blood. Treatment often involves aggressive chemotherapy, and in some cases, hematopoietic stem cell transplantation is considered to improve patient outcomes.
• Myeloid sarcoma
  • Myeloid sarcoma: Myeloid Sarcoma is a rare extramedullary tumor composed of myeloid blasts that can occur in various tissues outside the bone marrow. It often presents with mass lesions and may be associated with or precede acute myeloid leukemia, requiring prompt diagnosis and aggressive chemotherapy.

Myeloid neoplasms, secondary

• Myeloid neoplasms and proliferations associated with antecedent or predisposing conditions
  • Myeloid neoplasm post cytotoxic therapy
  • Myeloid neoplasms associated with germline predisposition
  • Myeloid proliferations associated with Down syndrome

Myeloid/lymphoid neoplasms

• Myeloid/lymphoid neoplasms with eosinophilia and defining gene rearrangement
  • Myeloid/lymphoid neoplasm with PDGFRA rearrangement
  • Myeloid/lymphoid neoplasm with PDGFRB rearrangement
  • Myeloid/lymphoid neoplasm with FGFR1 rearrangement
  • Myeloid/lymphoid neoplasm with JAK2 rearrangement
  • Myeloid/lymphoid neoplasm with FLT3 rearrangement
  • Myeloid/lymphoid neoplasm with ETV6::ABL1 fusion
  • Myeloid/lymphoid neoplasms with other tyrosine kinase fusion genes

Acute leukemias of mixed or ambiguous lineage

• Acute leukemia of ambiguous lineage with defining genetic abnormalities
  • Mixed-phenotype acute leukemia with BCR::ABL1 fusion
  • Mixed-phenotype acute leukemia with KMT2A rearrangement
  • Acute leukemia of ambiguous lineage with other defined genetic alterations
• Acute leukemia of ambiguous lineage, immunophenotypically defined
  • Mixed-phenotype acute leukemia, B/myeloid
  • Mixed-phenotype acute leukemia, T/myeloid
  • Mixed-phenotype acute leukemia, rare types
  • Acute leukemia of ambiguous lineage, NOS
  • Acute undifferentiated leukemia

Histiocytic/Dendritic cell neoplasms:

Plasmacytoid dendritic cell neoplasms

• Plasmacytoid dendritic cell neoplasms
  • Mature plasmacytoid dendritic cell proliferation associated with myeloid neoplasm
  • Blastic plasmacytoid dendritic cell neoplasm

Langerhans cell and other dendritic cell neoplasms

• Langerhans cells neoplasms
  • Langerhans cell histiocytosis: It is a rare, complicated, and non-heritable genetic disorder that can result in tumor formation in many different body parts. The disorder typically affects very young children
  • Langerhans cell sarcoma
• Other dendritic cell neoplasms
  • Indeterminate dendritic cell tumor
  • Interdigitating dendritic cell sarcoma

Histiocyte/macrophage neoplasms

• Histiocytic neoplasms
  • Juvenile xanthogranuloma: It is a rare benign condition affecting young children. It is characterized by the formation of papules and nodules involving the skin, and rarely, the eye
  • Erdheim-Chester disease: It is a highly infrequent disorder affecting multiple body systems, due to excess production and collection of histiocytic cells in the tissues and organs. Adults in the age group of 50-70 years are affected the most
  • Rosai-Dorfman Disease: It is a rare, benign condition that causes proliferation of histiocytes, a type of white blood cells, within the lymph nodes and other organs of the body. The condition usually affects children, teens, and young adults
  • ALK-positive histiocytosis: ALK-Positive Histiocytosis is a rare disorder characterized by the proliferation of histiocytes with ALK gene rearrangements. It can affect multiple organs, including the skin, bones, and central nervous system, and typically requires targeted therapies like ALK inhibitors for treatment.
  • Histiocytic sarcoma

B-cell lymphoid proliferations and lymphomas:

Tumor like lesions with B-cell predominance

• Reactive B-cell rich lymphoid proliferations that can mimic lymphoma
• IgG4-related disease
• Unicentric Castleman disease
• Idiopathic multicentric Castleman disease
• KSHV/HHV8-associated multicentric Castleman disease

Precursor B-cell neoplasms

• B-lymphoblastic leukemias/lymphomas
  • B-lymphoblastic leukemia/lymphoma: It is a type of blood cancer originating from immature B cells, characterized by rapid proliferation and infiltration into the bone marrow and lymphoid tissues. Treatment typically involves intensive chemotherapy regimens, targeted therapies, and sometimes stem cell transplantation, aiming for complete remission and long-term disease control
  • B-lymphoblastic leukemia/lymphoma with high hyperdiploidy
  • B-lymphoblastic leukemia/lymphoma with hypodiploidy: It is characterized by fewer than 44 chromosomes, represents a high-risk subtype associated with aggressive disease progression and inferior treatment outcomes. Intensive chemotherapy regimens and targeted therapies are often utilized in an attempt to overcome the adverse prognosis associated with this chromosomal abnormality in B-ALL
  • B-lymphoblastic leukemia/lymphoma with iAMP21: It is associated with high-risk features and poorer treatment response. Tailored treatment approaches, including intensified chemotherapy and targeted therapies, are often necessary to improve outcomes in patients with this subtype of B-ALL
  • B-lymphoblastic leukemia/lymphoma with BCR::ABL1 fusion: It is a high-risk subtype characterized by the presence of the Philadelphia chromosome, leading to constitutive activation of tyrosine kinase signaling and aggressive disease progression. Targeted therapies, such as tyrosine kinase inhibitors, alongside chemotherapy, are crucial in managing this subtype, aiming for remission and long-term disease control.
  • B-lymphoblastic leukemia/lymphoma with BCR::ABL1-like features: It shares gene expression profiles resembling BCR::ABL1-positive disease, though lacking the typical fusion. These cases often benefit from targeted therapies directed at tyrosine kinase signaling pathways, aiming to improve outcomes similar to those seen in BCR::ABL1-positive B-ALL
  • B-lymphoblastic leukemia/lymphoma with KMT2A rearrangement: It is characterized by genetic alterations involving the KMT2A gene, leading to aggressive disease behavior and resistance to standard chemotherapy. Intensive treatment approaches, including high-dose chemotherapy and stem cell transplantation, are often employed to improve outcomes in patients with this high-risk subtype of B-ALL
  • B-lymphoblastic leukemia/lymphoma with ETV6::RUNX1 fusion: It involves the fusion of ETV6 and RUNX1 genes, often associated with favorable outcomes and responsiveness to standard chemotherapy. Detection of this fusion serves as a prognostic marker, guiding treatment decisions and predicting outcomes in patients with B-ALL
  • B-lymphoblastic leukemia/lymphoma with ETV6::RUNX1-like features: B-Lymphoblastic Leukemia/Lymphoma with ETV6::RUNX1-like Features is a subtype of B-ALL characterized by genetic profiles similar to those with the ETV6-RUNX1 fusion, even without the actual translocation. This subtype often occurs in children and is associated with a favorable prognosis, though it requires precise genetic analysis for accurate diagnosis and treatment planning.
  • B-lymphoblastic leukemia/lymphoma with TCF3::PBX1 fusion: It involves the fusion of TCF3 and PBX1 genes, typically associated with intermediate risk and a favorable response to chemotherapy. Identification of this fusion aids in risk stratification and treatment planning for patients with B-ALL.
  • B-lymphoblastic leukemia/lymphoma with IGH::IL3 fusion: B-Lymphoblastic Leukemia/Lymphoma with IGH::IL3 Fusion is a subtype of B-ALL characterized by a genetic fusion between the IGH (immunoglobulin heavy chain) and IL3 (interleukin 3) genes, leading to aberrant cytokine signaling and cell proliferation. This subtype often requires targeted therapies and is associated with distinct clinical features and treatment responses compared to other forms of B-ALL.
  • B-lymphoblastic leukemia/lymphoma with TCF3::HLF fusion: B-Lymphoblastic Leukemia/Lymphoma with TCF3::HLF Fusion is a rare and aggressive subtype of B-ALL characterized by the fusion of the TCF3 and HLF genes. This genetic abnormality is associated with a poor prognosis and resistance to standard treatments, often necessitating more intensive therapeutic approaches and clinical trial options.
  • B-lymphoblastic leukemia/lymphoma with other defined genetic alterations: B-Lymphoblastic Leukemia/Lymphoma with Other Defined Genetic Alterations is a subtype of acute lymphoblastic leukemia characterized by specific genetic abnormalities other than the common ones like BCR-ABL1. These genetic alterations can influence the disease's prognosis and treatment response, necessitating tailored therapeutic approaches.
  • B-lymphoblastic leukemia/lymphoma, NOS: B-Lymphoblastic Leukemia/Lymphoma, NOS (Not Otherwise Specified), is a type of acute leukemia or lymphoma derived from immature B-lymphocytes. It is characterized by rapid proliferation of blasts in the bone marrow and can manifest with symptoms like bone pain, fatigue, and easy bruising, necessitating immediate medical intervention typically involving intensive chemotherapy.

Mature B-cell neoplasms

• Pre-neoplastic and neoplastic small lymphocytic proliferations
  • Monoclonal B-cell lymphocytosis
  • Chronic lymphocytic leukemia/small lymphocytic lymphoma: Chronic Lymphocytic Leukemia (CLL) is a type of blood cancer due to abnormal lymphocytes, typically affecting elderly adults. Small Lymphocytic Lymphoma is the most common B-cell non-Hodgkin’s lymphoma typically affecting elderly adults
• Splenic B-cell lymphomas and leukemias
  • Hairy cell leukemia
  • Splenic marginal zone lymphoma: It is a rare type of non-Hodgkin’s B-cell lymphoma that involves the spleen. It is a slow-growing tumor that is mostly seen in older adults
• Splenic diffuse red pulp small B-cell lymphoma
• Splenic B-cell lymphoma/leukemia with prominent nucleoli
• Lymphoplasmacytic lymphoma
  • Lymphoplasmacytic lymphoma
• Marginal zone lymphoma
  • Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue
  • Primary cutaneous marginal zone lymphoma: It is a rare, cutaneous B-cell non-Hodgkin’s lymphoma. It is a slow-growing tumor that affects middle-aged and older adults
  • Nodal marginal zone lymphoma: It is a rare type of non-Hodgkin’s B-cell lymphoma that affects the lymph nodes. It is a slow-growing tumor that is mostly seen in older adults
  • Pediatric nodal marginal zone lymphoma
• Follicular lymphoma
  • In situ follicular B-cell neoplasm
  • Follicular lymphoma: It is one of the most common types of B-cell non-Hodgkin’s lymphoma. It is a slow-growing lymphoma that generally affects older adults
  • Pediatric-type follicular lymphoma: Pediatric-type Follicular Lymphoma is a rare, indolent subtype of follicular lymphoma that primarily affects children and adolescents. It typically presents with localized lymphadenopathy and has an excellent prognosis, often requiring less aggressive treatment compared to adult follicular lymphoma.
  • Duodenal-type follicular lymphoma
• Cutaneous follicle centre lymphoma
  • Primary cutaneous follicle centre lymphoma
• Mantle cell lymphoma
  • In situ mantle cell neoplasm
  • Mantle cell lymphoma: It is a B-cell non-Hodgkin’s lymphoma typically affecting older adult males. It is characterized by the presence of enlarged lymph nodes
  • Leukemic non-nodal mantle cell lymphoma
• Transformations of indolent B-cell lymphomas
  • Transformations of indolent B-cell lymphomas
• Large B-cell lymphomas
  • Diffuse large B-cell lymphoma, NOS: It is the most common subtype of non-Hodgkin lymphoma, characterized by rapidly growing tumors originating from mature B cells in lymphoid tissues. Treatment typically involves combination chemotherapy regimens, often supplemented with immunotherapy or targeted therapies, tailored to individual patient factors and disease characteristics for optimal outcomes.
  • T-cell/histiocyte-rich large B-cell lymphoma: It is a rare subtype of diffuse large B-cell lymphoma characterized by a sparse population of neoplastic B-cells amidst a background of reactive T-cells and histiocytes. Treatment typically involves chemotherapy regimens tailored to DLBCL, with additional considerations for immune modulation or targeted therapies based on individual patient factors and disease characteristics
  • Diffuse large B-cell lymphoma / high grade B-cell lymphoma with MYC and BCL2 rearrangements: It is a subtype of non-Hodgkin lymphoma characterized by specific genetic alterations involving the MYC and BCL2 genes
  • ALK-positive large B-cell lymphoma: ALK-Positive Large B-Cell Lymphoma is a rare subtype of diffuse large B-cell lymphoma characterized by the expression of anaplastic lymphoma kinase (ALK) due to genetic rearrangements. This lymphoma typically presents in younger patients and has distinct clinical features and a variable prognosis, often requiring targeted therapies in addition to standard chemotherapy.
  • Large B-cell lymphoma with IRF4 rearrangement: Large B-Cell Lymphoma with IRF4 Rearrangement is a subtype of lymphoma often occurring in children and young adults, characterized by the rearrangement of the IRF4 gene. It typically presents with isolated lymph node involvement and has a favorable prognosis when treated with standard lymphoma therapies.
  • High grade B-cell lymphoma with 11q aberrations: High-Grade B-Cell Lymphoma with 11q aberrations is a distinct subtype characterized by structural abnormalities in the 11q chromosome region, often associated with aggressive clinical behavior. Treatment typically involves intensive chemotherapy regimens, with ongoing research into targeted therapies to improve outcomes in this high-risk lymphoma.
  • Lymphomatoid granulomatosis: It is a rare, non-Hodgkin’s B-cell lymphoma, which may be associated with Epstein-Barr virus infection in a vast majority of cases. It is observed in middle-aged and older adults
  • EBV-positive diffuse large B-cell lymphoma: EBV-Positive Diffuse Large B-Cell Lymphoma is a subtype of diffuse large B-cell lymphoma associated with Epstein-Barr virus (EBV) infection, typically seen in immunocompromised individuals or the elderly. This lymphoma often presents with aggressive clinical features and may require a combination of chemotherapy and antiviral therapies.
  • Diffuse large B-cell lymphoma associated with chronic inflammation: Diffuse Large B-Cell Lymphoma associated with chronic inflammation arises in the context of long-standing inflammatory conditions, such as chronic infections or autoimmune diseases. This subtype of lymphoma is characterized by diffuse proliferation of large B-cells and may require treatment of both the underlying inflammation and the lymphoma itself.
  • Fibrin-associated large B-cell lymphoma
  • Fluid overload-associated large B-cell lymphoma
  • Plasmablastic lymphoma: It is a rare type of malignancy that is most commonly found in HIV-positive individuals; it may also occur in HIV-negative individuals with immunodeficiency
  • Primary large B-cell lymphoma of immune-privileged sites: Primary Large B-Cell Lymphoma of Immune-Privileged Sites occurs in areas like the central nervous system, testis, or eye, which are less accessible to the immune system. These lymphomas often require specialized diagnostic and therapeutic approaches due to their unique location and may involve high-dose chemotherapy or radiation.
  • Primary cutaneous diffuse large B-cell lymphoma, leg type: It is a cutaneous B-cell non-Hodgkin’s lymphoma, generally affecting the skin of the leg. It is a type of diffuse large B-cell lymphoma that affects older adults
  • Intravascular large B-cell lymphoma: It is a rare, B-cell non-Hodgkin’s lymphoma. The condition is usually systemic and can affect the brain. It generally affects middle-aged and older adults
  • Primary mediastinal large B-cell lymphoma: It is a rare and aggressive non-Hodgkin’s B-cell lymphoma that usually arises from the thymus gland. The condition is mostly observed in young men and women
  • Mediastinal grey zone lymphoma: Gray Zone Lymphoma is a very rare and aggressive lymphoma, which is often present as a large mass in the mediastinum. The condition is generally seen in teens and young adults
  • High-grade B-cell lymphoma, NOS
• Burkitt lymphoma
  • Burkitt lymphoma: It is a very aggressive and fast-growing form of non-Hodgkin lymphoma. The lymphoma affects the B-cells of an individual’s immune system. The condition affects children more than adults
• KSHV/HHV8-associated B-cell lymphoid proliferations and lymphomas
  • Primary effusion lymphoma: It is a rare and aggressive non-Hodgkin’s lymphoma that is generally associated with HIV infection and other immunocompromised states
  • KSHV/HHV8-positive diffuse large B-cell lymphoma: KSHV/HHV8-Positive Diffuse Large B-Cell Lymphoma is a subtype of lymphoma linked to infection by Kaposi's sarcoma-associated herpesvirus (KSHV/HHV8), typically affecting immunocompromised individuals such as those with HIV/AIDS. It presents with aggressive lymph node involvement and may require combination chemotherapy along with antiviral therapy for effective management.
  • KSHV/HHV8-positive germinotropic lymphoproliferative disorder: KSHV/HHV8-Positive Germinotropic Lymphoproliferative Disorder is a rare lymphoproliferative disorder associated with infection by Kaposi's sarcoma-associated herpesvirus (KSHV/HHV8). It predominantly affects immunocompromised individuals and is characterized by localized lymph node enlargement and histopathological features resembling germinal center reactions. Treatment often involves antiviral therapy and management of underlying immunosuppression.
• Lymphoid proliferations and lymphomas associated with immune deficiency and dysregulation
  • Hyperplasias arising in immune deficiency/dysregulation: Hyperplasias arising in immune deficiency/dysregulation refer to benign proliferations of lymphoid or other immune cells that occur due to abnormalities in the immune system, often seen in conditions like HIV/AIDS or primary immunodeficiencies. These hyperplasias can mimic malignancies but typically do not progress to cancer and may require monitoring or specific management tailored to the underlying immune disorder.
  • Polymorphic lymphoproliferative disorders arising in immune deficiency / dysregulation: Polymorphic Lymphoproliferative Disorders arising in immune deficiency/dysregulation encompass a spectrum of heterogeneous lymphoid proliferations associated with immune system abnormalities, such as those seen in post-transplant or HIV-positive patients. These disorders can vary in presentation and severity, often requiring individualized management strategies that address both the lymphoproliferative disorder and the underlying immune deficiency.
  • EBV-positive mucocutaneous ulcer: EBV-Positive Mucocutaneous Ulcer is a rare, localized lymphoproliferative disorder associated with Epstein-Barr virus infection, presenting as an isolated ulcerative lesion in mucosal or cutaneous sites. Treatment often involves conservative management, such as antiviral therapy or immunosuppression reduction, with many cases resolving spontaneously.
  • Lymphomas arising in immune deficiency / dysregulation: Lymphomas arising in immune deficiency/dysregulation are malignancies that develop due to impaired immune function, commonly seen in conditions like HIV/AIDS, post-transplant, or primary immunodeficiencies. These lymphomas often present aggressively and may require tailored treatment strategies that include both standard lymphoma therapies and management of the underlying immune deficiency.
  • Inborn error of immunity-associated lymphoid proliferations and lymphomas: Inborn Error of Immunity-Associated Lymphoid Proliferations and Lymphomas refer to a spectrum of benign and malignant lymphoid disorders arising from genetic immunodeficiencies. These conditions often present in early childhood with atypical infections, autoimmunity, and an increased risk of developing lymphomas, necessitating tailored immunological and oncological treatments.

Hodgkin lymphoma: It is a form of malignancy that develops in the body's immune system, known as the lymphatic system. Both children and adults may be affected by the condition.

• Classic Hodgkin lymphoma
• Nodular lymphocyte predominant Hodgkin lymphoma: It is an uncommon type of Hodgkin lymphoma that is a slow-growing malignancy. It is typically seen in younger individuals
• Plasma cell neoplasms and other diseases with paraproteins
• Monoclonal gammopathies
  • Cold agglutinin disease: Cold Agglutinin Disease is a rare autoimmune hemolytic anemia where cold temperatures trigger antibodies to attack and destroy red blood cells. This leads to symptoms like fatigue, jaundice, and anemia, with management focusing on avoiding cold exposure and immunosuppressive treatments.
  • IgM monoclonal gammopathy of undetermined significance
  • Non-IgM monoclonal gammopathy of undetermined significance
  • Monoclonal gammopathy of renal significance
• Diseases with monoclonal immunoglobulin deposition
  • Immunoglobulin-related (AL) amyloidosis
  • Monoclonal immunoglobulin deposition disease
• Heavy chain diseases
  • Mu heavy chain disease
  • Gamma heavy chain disease: It is an aggressively malignant condition that is characterized by an abnormal production of antibodies. The condition mainly affects older adults
  • Alpha heavy chain disease
• Plasma cell neoplasms
  • Plasmacytoma
  • Plasma cell myeloma / multiple myeloma
  • Plasma cell neoplasms with associated paraneoplastic syndrome

T-cell and NK-cell lymphoid proliferations and lymphomas:

Tumor-like lesions with T-cell predominance

• Kikuchi-Fujimoto disease
• Autoimmune lymphoproliferative syndrome
• Indolent T-lymphoblastic proliferation

Precursor T-cell neoplasms

• T-lymphoblastic leukemia / lymphoma
  • T-lymphoblastic leukemia / lymphoma, NOS
  • Early T-precursor lymphoblastic leukemia / lymphoma

Mature T-cell and NK-cell neoplasms

• Mature T-cell and NK-cell leukemias
  • T-prolymphocytic leukemia
  • T-large granular lymphocytic leukemia
  • NK-large granular lymphocytic leukemia
  • Adult T-cell leukemia/lymphoma: It is a malignant tumor of CD4 positive T-cells caused by human T-cell leukemia virus (HTLV 1). Any individual is at risk for the condition
  • Sezary syndrome: It is a rare, aggressive form of T-cell non-Hodgkin’s lymphoma that can affect the skin. It generally affects adults 50 years old and above
  • Aggressive NK-cell leukemia: It is a very rare and highly-aggressive malignancy that is mostly observed in adults. The cancer occurs in the peripheral blood, meaning that the malignant cells are present in the peripheral blood
• Primary cutaneous T-cell lymphoid proliferations and lymphomas
  • Primary cutaneous CD4-positive small or medium T-cell lymphoproliferative disorder: Primary Cutaneous, Small-Medium, CD4-Positive, T-Cell Lymphoma is a rare, primary cutaneous T-cell non-Hodgkin’s lymphoma that is usually seen in adults
  • Primary cutaneous acral CD8-positive T-cell lymphoproliferative disorder: Primary Cutaneous Acral CD8+ T-Cell Lymphoma is a rare, primary cutaneous T-cell non-Hodgkin’s lymphoma. It is a less aggressive form of T-cell lymphoma that affects middle-aged adults
  • Mycosis fungoides: It is a cutaneous T-cell non-Hodgkin’s lymphoma. Initially, it is a low-grade malignancy that can become highly-aggressive over time. The condition is noted in both children and adults
  • Primary cutaneous CD30-positive T-cell lymphoproliferative disorder: Lymphomatoid papulosis - it is an extremely rare cutaneous T-cell non-Hodgkin’s lymphoma. It is considered to be CD-30 positive T-cell lymphoproliferative disorder. It is generally noted in adults of a wide age range
  • Primary cutaneous CD30-positive T-cell lymphoproliferative disorder: Primary cutaneous anaplastic large cell lymphoma - it is a primary cutaneous T-cell non-Hodgkin’s lymphoma that is the second most common skin T-cell lymphoma after mycosis fungoides. It is generally noted in adults of a wide age range
  • Subcutaneous panniculitis-like T-cell lymphoma: It is a rare type of primary cutaneous T-cell non-Hodgkin’s lymphoma. It is characterized by the presence of multiple subcutaneous nodules all over the body. The condition can affect both children and adults
  • Primary cutaneous gamma/delta T-cell lymphoma: It is a primary cutaneous T-cell non-Hodgkin’s lymphoma, generally affecting adults. The condition is a very rare and an aggressive form of T-cell lymphoma
  • Primary cutaneous CD8-positive aggressive epidermotropic cytotoxic T-cell lymphoma: It is an aggressive primary cutaneous T-cell non-Hodgkin’s lymphoma. It is a very rare form of T-cell lymphoma that generally affects adults
  • Primary cutaneous peripheral T-cell lymphoma, NOS: It is a rare cutaneous T-cell non-Hodgkin’s lymphoma that is difficult to be diagnosed. The condition is more commonly seen in adults
• Intestinal T-cell and NK-cell lymphoid proliferations and lymphomas
  • Indolent T-cell lymphoma of the gastrointestinal tract: Indolent T-Cell Lymphoma of the Gastrointestinal Tract is a rare, slow-growing lymphoma primarily affecting the gastrointestinal tract, often presenting with symptoms like abdominal pain or weight loss. It typically has a favorable prognosis compared to more aggressive lymphomas and may be managed with localized treatment and careful monitoring.
  • Indolent NK-cell lymphoproliferative disorder of the gastrointestinal tract
  • Enteropathy-associated T-cell lymphoma: It is a rare, T-cell non-Hodgkin’s lymphoma of the gastrointestinal tract, typically seen in adults. It is an aggressive malignancy of T-cell lymphocytes arising in the intestines
  • Monomorphic epitheliotropic intestinal T-cell lymphoma
  • Intestinal T-cell lymphoma, NOS
• Hepatosplenic T-cell lymphoma
  • Hepatosplenic T-cell lymphoma: It is an extremely rare and aggressive type of ‘extranodal lymphoma’ observed in the spleen, liver, and bone marrow. The condition is more commonly seen in adolescents and young adults
• Anaplastic large cell lymphoma
  • ALK-positive anaplastic large cell lymphoma: It is an aggressive T-cell non-Hodgkin’s lymphoma that is known to affect children and young adults
  • ALK-negative anaplastic large cell lymphoma: It is an aggressive T-cell non-Hodgkin’s lymphoma that is known to affect children and young adults
  • Breast implant-associated anaplastic large cell lymphoma
• Nodal T-follicular helper (TFH) cell lymphoma
  • Nodal TFH cell lymphoma, angioimmunoblastic-type
  • Nodal TFH cell lymphoma, follicular-type
  • Nodal TFH cell lymphoma, NOS
• Other peripheral T-cell lymphomas
  • Peripheral T-cell lymphoma, NOS: It is a type of nodal or soft tissue lymphoma that typically affects middle-aged adults
• EBV-positive NK-cell and T-cell lymphomas
  • EBV-positive nodal T- and NK-cell lymphoma
  • Extranodal NK/T-cell lymphoma
• EBV-positive T-cell and NK-cell lymphoid proliferations and lymphomas of childhood
  • Severe mosquito bite allergy
  • Hydroa vacciniforme lymphoproliferative disorder
  • Systemic chronic active EBV disease
  • Systemic EBV-positive T-cell lymphoma of childhood

Stroma-derived neoplasms of lymphoid tissues:

Mesenchymal dendritic cell neoplasms

• Follicular dendritic cell neoplasms
  • Follicular dendritic cell sarcoma
  • EBV-positive inflammatory follicular dendritic cell sarcoma
  • Fibroblastic reticular cell tumor

Myofibroblastic tumors

• Myofibroblastic tumor
  • Intranodal palisaded myofibroblastoma

Spleen-specific vascular-stromal tumors

• Splenic vascular-stromal tumors
  • Littoral cell angioma: It is a rare, vascular tumor of spleen arising from the splenic red pulp sinuses. The tumor is mostly benign and observed in middle-aged and older adults
• Splenic hamartoma
• Sclerosing angiomatoid nodular transformation (SANT) of spleen

Genetic syndromes:

• Fanconi anemia
• Bloom syndrome: It is a rare congenital disorder characterized by a significantly increased risk for cancer and various other features. The presentation of symptoms may occur at birth
• Ataxia-telangiectasia syndrome: It is an uncommon, inherited disorder affecting the brain, spinal cord, and immune system. The symptoms of the disorder generally become apparent by age 5
• RASopathies

Additional hematolymphoid tumor articles (on DoveMed) that are not part of WHO Classification of Hematolymphoid Tumors:

Acute Adult T-Cell Leukemia/Lymphoma: It is a malignant tumor of CD4 positive T-cells caused by human T-cell leukemia virus (HTLV 1). Any individual is at risk for the condition. The acute subtype is an aggressive form that develops rapidly.

Age-Related Epstein-Barr Virus Associated B-Cell Lymphoproliferative Disorders: These are rare cancer types, wherein the affected individuals have EBV positive lymphocytes. These disorders are generally observed in adults.

Aggressive Systemic Mastocytosis: It is an uncommon but aggressive form of systemic mastocytosis that involves several organ systems, such as the bone marrow, liver, spleen, gastrointestinal tract, and bones. Most cases are diagnosed in adults.

Aggressive Variant of T-Cell Large Granular Lymphocyte Leukemia: It is a rare and severe form of large granular lymphocyte leukemia, a type of blood cancer. It is typically seen in young and middle-aged adults.

Angioimmunoblastic T-Cell Lymphoma: It is a rare and aggressive type of nodal or soft tissue lymphoma. The condition is generally seen in older adults and is associated with autoimmune disorders.

Blastic Natural Killer (NK) Cell Lymphoma: It is a very rare tumor arising from the plasmacytoid dendritic cells, a type of white blood cells. The condition generally affects older adults.

Castleman Disease: It is a rare disease involving the lymph nodes and related organs. It is characterized by an abnormal proliferation of lymphocytes (a type of white blood cell). Both children and adults can be affected by this condition.

Chronic Adult T-Cell Leukemia/Lymphoma: It is a malignant tumor of CD4 positive T-cells caused by human T-cell leukemia virus (HTLV 1). Any individual is at risk for the condition. The chronic subtype is a slow-growing form that may involve the lymph nodes, liver, and spleen.

Chronic Lymphoproliferative Disorder of Natural Killer Cells: It is a rare type of potentially-cancerous condition that usually remains asymptomatic. It is typically seen in middle-aged and older adults, mostly in men.

Diffuse Large B-Cell Lymphoma: It is a type of blood cancer stemming from uncontrollably dividing lymphocytes. It generally affects elderly adults.

Double Hit Lymphoma: It is a highly uncommon and aggressive B-cell non-Hodgkin lymphoma. It generally affects elderly adults.

Idiopathic CD4 Positive T-Lymphocytopenia: It is a rare disorder of the immune system. Individuals with the condition have low levels of a white blood cell type, called CD4+ T cells. The presentation of symptoms typically occurs in adulthood.

Indolent Systemic Mastocytosis: It is the most common form of systemic mastocytosis that typically involves the skin and presents few other systemic symptoms. Most cases are diagnosed in adults.

Indolent T-Cell Large Granular Lymphocyte Leukemia: It is the most common form of large granular lymphocyte leukemia, a type of blood cancer. It is typically seen in middle-aged and older adults.

Large Granular Lymphocyte Leukemia: These represent a type of lymphoproliferative disorder, in which there is uncontrolled production of lymphocytes from various reasons. The condition is generally seen in adults.

Lennert Lymphoma: It is a rare type of non-Hodgkin lymphoma that is a variant of peripheral T-cell lymphoma. It is typically seen older adults.

Leukemia and Lymphoma: These describe malignancies that develop from normal cells in one’s blood. Depending on the type, they can be more common in young or old individuals.

Lymphoblastic Lymphoma: It is an uncommon and aggressive non-Hodgkin’s lymphoma typically affecting children and teens. It is usually seen to develop from the T-cells but may also arise from the B-cells.

Lymphocyte-Depleted Classical Hodgkin Lymphoma: It is the rarest and most aggressive subtype of classical Hodgkin lymphoma that is generally seen in young adults.

Lymphocyte-Rich Classical Hodgkin Lymphoma: It is a rare subtype of classical Hodgkin lymphoma that is generally seen in middle-aged adults.

Lymphomatous Adult T-Cell Leukemia/Lymphoma: It is a malignant tumor of CD4 positive T-cells caused by human T-cell leukemia virus (HTLV 1). Any individual is at risk for the condition. The lymphomatous subtype is a type of lymphoma that predominantly involves the lymph nodes.

Mast Cell Leukemia: It is reportedly a rare form of aggressive systemic mastocytosis, predominantly involving the bone marrow. Most cases are diagnosed in adults.

Mixed Cellularity Classical Hodgkin Lymphoma: It is among the more common subtype of classical Hodgkin lymphoma that is generally seen in middle-aged and older adults.

Monomorphic CD56+ Intestinal T-Cell Lymphoma: It is a type of enteropathy-associated T-cell lymphoma, a T-cell non-Hodgkin’s lymphoma of the gastrointestinal (GI) tract. The condition is noted in adults.

Nodular-Sclerosis Classical Hodgkin Lymphoma: It is the most common subtype of classical Hodgkin lymphoma that is generally seen in teenagers and young adults.

Refractory Cytopenia with Unilineage Dysplasia: It is a type of bone marrow disorder, called myelodysplastic syndrome (MDS) that are caused by various abnormalities of the bone marrow. Elderly adults are typically affected by this condition.

Smouldering Adult T-Cell Leukemia/Lymphoma: It is a malignant tumor of CD4 positive T-cells caused by human T-cell leukemia virus (HTLV 1). Any individual is at risk for the condition. The smouldering subtype is a slowly progressing lymphoma with prominent skin involvement.

Smouldering Systemic Mastocytosis: It is an uncommon form of systemic mastocytosis that typically involves the skin and presents few other systemic symptoms. Most cases are diagnosed in adults.

Systemic Mastocytosis with Associated Clonal Hematologic Non-Mast Cell Lineage Disease: It is a form of systemic mastocytosis that involves the bone marrow and is associated simultaneously with myeloproliferative neoplasms. The condition is mostly seen in adults.

Triple Hit Lymphoma: It is a highly uncommon and aggressive B-cell non-Hodgkin lymphoma. It generally affects elderly adults.