Lymphomas PDF

Pathophysiology of Lymphomas and Leukemias Dr. Van Den Berg Lymphomas Proliferation of malignant lymphocytes in the lymph nodes Tumors (B- or T cell in origin) most commonly originate from lymph nodes Hodgkin’s lymphoma (disease) HL -~10% of all lymphomas Incidence has two peaks: one in 2nd-3rd deca...

Pathophysiology of Lymphomas and Leukemias Dr. Van Den Berg Lymphomas Proliferation of malignant lymphocytes in the lymph nodes Tumors (B- or T cell in origin) most commonly originate from lymph nodes Hodgkin’s lymphoma (disease) HL -~10% of all lymphomas Incidence has two peaks: one in 2nd-3rd decade of life and the other in 6th- 7th decade. Median age is 39 yrs NHL ~90% of all lymphomas Median age at diagnosis is 67 yrs Multiple Myeloma Median age at diagnosis is 69 yrs Lymphoma Hodgkin’s Disease New diagnoses in 2024: 8,570 new cases (4,570 in males; 3,970 in females) Deaths in 2024: 910 Non-Hodgkin’s Lymphoma New cases in 2024: 80,620 people (44,120 males; 36,350 females) Est Deaths in 2024: 20,140 Multiple Myeloma New cases in 2024: 35,780 new cases will be diagnosed (19,520 in men and 16,260 in women). Deaths in 2024: 12,540 Clinical Differences Between NHL and HL Characteristic Nodal Involvement Spread B symptoms* Extranodal Involvement Extent of Disease NHL Multiple peripheral LNs Mesenteric nodes and Waldeyer ring commonly involved Noncontiguous Uncommon Common Rarely localized HL Localized to single axial grp of nodes (i.e cervical, mediastinal, para-aortic) Mesenteric nodes and Waldeyer ring rarely involved Orderly spread by contiguity Common Rare Often localized Hodgkin’s Lymphoma Appears to be typically derived from a B cell in the germinal center that has not undergone successful immunoglobulin gene rearrangement Abnormal cells secrete and release cytokines that induce an inflammatory response causing systemic effects Clinical Manifestations: enlarged painless lymph node often in the neck, discovery of asymptomatic mediastinal lymph node is common. Cervical, axillary, inguinal and retroperitoneal LNs are commonly affected. One third of patients also have intermittent fever, without other symptoms of infection, drenching night sweats, itchy skin, and fatigue. If accompanied by weight loss, these symptoms convey poor prognosis. Spleen can also be involved Hodgkin’s Lymphoma Diagnosis and Staging Biopsy PET-CT CBC and Chemistry Classical HL - ~95% of HL Reed-Sternberg CellRepresents the malignant lymphocyte binucleated Hallmark Nodular lymphocyte predominant HL- ~5% of HL Popcorn cells – lymphocyte predominant Ann Arbor staging system and Cotswold modifications for Hodgkin's lymphoma Stage I- Involvement of one lymph-node region or lymphoid structure II- Involvement of two or more lymph-node regions on the same side of the diaphragm III- Involvement of lymph nodes on both sides of the diaphragm. IV- Involvement of extranodal sites other than one contiguous or proximal extranodal site Modifying features A- No symptoms B- Presence of fever, drenching night sweats, loss of >10% of bodyweight over 6 mo X- Bulky disease (mediastinal mass larger than a third of thoracic diameter, or any nodal mass >10 cm in diameter) E- Involvement of one contiguous or proximal extranodal site Treatment of Hodgkin’s Lymphoma Initial treatment is based on the histologic characteristics of the disease, stage at presentation, and the presence or absence of prognostic factors. Early-stage: commonly receive combined-modality therapies that include abbreviated courses of chemotherapy followed by involved-field radiation treatment. Advanced-stage: commonly receive a more prolonged course of combination chemotherapy, with radiation therapy used only in selected cases. Relapse or refractory disease: salvage chemotherapy followed by high-dose treatment and an autologous stem cell transplant is the standard of care. Outcomes of Hodgkin’s Lymphoma Depends on age of patient 75% of patients cured with combined chemotherapy and radiation therapy. Therapeutic antibodies are also used. 5-year survival rate 90-95% combination chemotherapy, XRT + chemo Early Stage Disease 82-90% More aggressive combination chemotherapy Advanced Disease Salvage Relapsed/Refractory ~26% w/i 3 mo, 46% w/i 3-12 mo, 71% >12 mo chemo therapy, followed by autologous/allogeneic bone marrow transplant Non-Hodgkin’s Lymphoma Originate from congenital or viral immune deficiency (HIV, EBV and HHV-8 etc) leading to monoclonal expansion of T or B cells Normally somatic gene rearrangements occur during cellular differentiation to produce constant and variable regions to produce immunoglobin heavy and light chains that make functional antibodies Most have karyotypic abnormalities (mostly translocation events), involving an immunoglobulin heavy chain gene locus (14q32) fused with an oncogene. This translocation event leads to deregulation and overexpression B-cell type (Cell of origin)- 80-90% and diagnosed using clinical and cytogenetics and immunoreactivity (cell marker) tests T-cell or NK cell type (cell of origin) Non-Hodgkin’s Lymphoma Risk Factors Family history Exposure to a variety of mutagenic chemicals Irradiation Infection with cancer related viruses (EBV, Human Herpes Virus 8, HIV, HTLV-1, hepatitis C) Immune suppression related to organ transplant Gastric infection with H. pylori Non-Hodgkin’s Lymphoma Lymphadenopathy of involved nodes and/or symptoms associated with enlarged LNs Low grade lymphomas : commonly present with painless peripheral adenopathy. May spontaneously regress or even transform to an aggressive type of lymphoma. With advanced disease, night sweats, extranodal involvement may occur. Extranodal involvement can include skin, GI tract, bone marrow, sinuses, genitourinary tract etc. Cytopenias may develop which reflects bone marrow involvement. Hepatomegaly, splenomegaly are also common. NHL Diagnosis LN Biopsy CT scan of head, neck, chest, abdomen, pelvis Bone marrow biopsy Several different subtypes, but diffuse large B-cell lymphoma, which is usually aggressive, and follicular lymphoma, which is usually indolent are the most common. Chromosomal Translocations of Hematologic Neoplasms Neoplasm Follicular lymphoma Mantle cell lymphoma Follicular lymphoma Diffuse large cell lymphoma Burkitt’s lymphoma Anaplastic large T-/null-cell lymphoma CML AML M3 AML T-cell ALL Chromosomal Translocation Fusion Gene Resulting Fusion Protein from Translocation Function t(14;18) t(11;14) t(14;19) t(3;14) t(8;14) t(2;5) IgH-bcl-2 IgH-bcl-1 IgH-bcl-3 IgH/K/L-bcl-6 IgH-myc NPM-ALK Inhibitor of apoptosis Cyclin Transcription repressor Transcription repressor Transcription factor Tyrosine kinase t(9;22) t(15;17) t(8;21) t(1;14) bcr-abl PML-RAR AML1 tal-1-TCR Tyrosine kinase Transcription factor Transcription factor Transcription factor Burkitt’s lymphoma: t(8;14) IgH-myc NHL Staging Stage Criteria I Involvement of single LN II Involvement of two or more LN regions III Involvement of two or more LN on both sides of the diaphragm Diffuse involvement of one or more extralymphatic organs with or without associated LN involvement IV Subclassifications E-involvement of adjacent extra-lymphatic site, S- involvement of spleen A-asymptomatic, B-Fever, night sweats, weight loss Non-Hodgkin’s Lymphoma Treatment Treatment success depends on Type of lymphoma, Stage of disease, Cell type, Age of patient, Involvement of organs, Presence of night sweats, weight loss & fever Treatment options include: Observation only for indolent lymphomas chemotherapy alone or in combination with radiation, bone marrow transplant recurrent disease Therapeutic antibody for B-cell type NHLs Radioimmune therapy Survival rates: 1 yr ~77%, 5 yr ~59%, 10 yrs ~42% Multiple Myeloma- Risk Factors Age- Most people diagnosed with MM are at least 65 years old. Gender- Males slightly more likely Race- more than twice as common in African Americans than in white Americans. Family History Obesity Other plasma cell diseases- monoclonal gammopathies of undetermined significance (MGUS) or solitary plasmacytoma MM Symptoms MM- Lytic bone lesions Leukemias Leukemias-Anticipated in 2024 All Leukemias New Cases: 62,770 Deaths: 23,670 Acute lymphocytic leukemia (ALL) – most common leukemia in children (0-19 yrs) New cases: 6,550 Deaths: 1,330 Chronic lymphocytic leukemia (CLL)- most common leukemia in adults New Cases: 20,700 21,250 Deaths: 4,440 4,320 Acute myeloid leukemia (AML) New Cases 20,800 Deaths: 11,220 Chronic myeloid leukemia (CML) New Cases: 9,280 9,110 Deaths: 1,280 1,220 AML CML ALL CLL Leukemia- Risk Factors Radiation exposure- usually prior radiation or chemotherapy cancer treatment. Certain genetic abnormalities Workers exposed to certain chemicals, such as benzene (e.g., during oil refining or rubber manufacturing). Cigarette smoking increases risk for AML in adults Accumulating evidence that parental smoking before and after childbirth may increase risk of acute leukemia in children. Leukemia Signs and Symptoms Can appear suddenly for acute subtypes fatigue, paleness, weight loss, repeated infections, fever, bleeding or bruising easily, bone or joint pain, and swelling in the lymph nodes or abdomen. Chronic leukemia typically progresses slowly with few symptoms during early stages. Diagnosis- Bone Marrow Biopsy Other tests at Diagnosis Peripheral blood smear and CBC (abnormal cells present and higher representation of abnormal cells compared to other lineages) Cytogenetics (chromosomal abnormalities) Flow cytometry (looking for cell surface markers) Lumbar puncture (+ or – for leukemia cells) Imaging as needed more mature lymphoblasts more mature myelohoblasts Predisposing factors of ALL Genetic susceptibility -Congenital syndromes: Down’s syndrome, Fanconi anemia, Ataxia telangiectasia (ATM), Bloom syndrome, Nijmegen breakage syndrome -Inherited gene variants: ARID5B, IKZF1, CEBPE, CDKN2A or CDKN2B, PIP4K2A, ETV6 -Constitutional Robertsonian translocation between chromosomes 15 and 21, rob(15;21)(q10;q10) -Single nucleotide polymorphisms: rs12402181 in miR-3117 and rs62571442 in miR-3689d2 Environmental factors Pesticide exposure, Ionizing radiation, Childhood infection ALL Prognostic Factors Favourable factor Adverse factor Age 1 year to