Lymphoma - Lecture notes 12 PDF

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Lymphoma...

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Lymphoma Learning Objectives - Define lymphoma. How are lymphomas classified? - Know differences between Hodgkin and nonHodgkin lymphoma. - Know epidemiology, clinical features and subtypes of Hodgkin lymphoma. - Know which non-Hodgkin lymphomas are common. Know epidemiology, clinical features, microscopic features and molecular mechanisms underlying the common non-Hodgkin lymphomas - Understand which micro-organisms are associated with lymphomas. Nomenclature Leukaemia - NEOPLASMS of WHITE BLOOD CELLS (of either myeloid or lymphoid lineage), which present with involvement of bone marrow, usually with large numbers of cells in PERIPHERAL BLOOD Lymphoma - NEOPLASMS of LYMPHOCYTES, which present as discrete tissue masses (e.g. arising in lymph node) - Best to think of lymphomas as “starting in lymph nodes or extranodal peripheral sites and sometimes spreading to the bone marrow” Some diseases exist as a continuum between leukaemia and lymphoma - Small lymphocytic lymphoma and chronic lymphocytic leukaemia are basically the same disease but differ based on location of neoplastic cells - Acute lymphoblastic leukaemia / lymphoma - Burkitt lymphoma, which usually presents as a tissue mass, may also have a leukaemic component Many mature B-cell non-Hodgkin lymphomas are named according to the cell population of the normal lymph node which they most resemble (follicular lymphoma, mantle cell lymphoma, marginal zone lymphoma, germinal centre-type DLBCL) Haematopoiesis in humans

Classification • WHO Classification of Tumours of Haematopoeitic and Lymphoid Tissues (4th edition, 2008) • Older classification schemes: – Rappaport – Kiel – Working Formulation – REAL

• Why classify? - To group together patients who have diseases with similar natural history and prognosis and similar responses to treatment How do you define disease entities? - Symptoms? - Signs? - Distribution? - Macroscopic morphology? - Microscopic morphology? - Immunophenotype? - Chromosomal abnormalities? - Single gene mutations? • Previous classification systems relied heavily on morphology • WHO uses a combination of everything, is best currently available system • There are still variations in survival among common lymphomas however • In future – perhaps classification systems will be obsolete, and every patient will have an individualised diagnosis and treatment based on molecular genetics • Hodgkin lymphoma • Non-Hodgkin lymphoma - Mature / peripheral B-cell lymphomas - Mature / peripheral T / NK-cell lymphomas - Precursor B and T cell neoplasms Clinical Presentation Hodgkin lymphomas - Painless lymphadenopathy NB – a minority of patients experience pain in affected nodes after consuming alcohol (very specific) - Itchy skin -Due to increased circulating eosinophils Non-Hodgkin lymphomas - Painless lymphadenopathy (low grade) - Rapidly enlarging mass (high grade) - For extranodal lymphomas, symptoms related to site  E.g. skin rash, abdominal pain, ulceration Systemic symptoms (“B symptoms”) - Fever, night sweats, weight loss • Symptoms related to hepatosplenomegaly • Symptoms related to complications of bone marrow infiltration

 Infections, anaemia, bleeding and coagulopathies Investigations • Imaging (CT, MRI, PET, Ultrasound) • Biopsy – Clinical or U/S-guided FNA – Core biopsy – Excision biopsy of lymph node Although lymphoma may be suspected on clinical and radiological grounds, microscopic examination of a tissue biopsy is the only way to make the diagnosis of lymphoma and to subclassify it.

Reed-Sternberg cells express the protein CD30 in Classical Hodgkin Lymphoma, but not in NLPHL. Antibodies against this protein can be labelled with a coloured pigment (red in this image). When incubated with a solution containing the labelled antibody, the pigment will adhere to a thin section of lymph node mounted on a glass slide. When viewed under the microscope, the CD30 protein expression by Reed Sternberg cells can then be directly visualised.

HODGKIN LYMPHOMA First described by Thomas Hodgkin at Guy’s Hospital in London in 1832 - “On some Morbid Appearances of the Absorbent Glands and Spleen” - Case series of seven patients with painless lymphadenopathy - Did not appear to be associated with local inflammation or a nearby cancerous tumour - No microscopic examination Later expanded upon by Samuel Wilks at the same institution in the 1850s – Named the condition “Hodgkin’s disease”

Characteristic features - Arises in a single node or chain of nodes (esp. cervical) and spreads to anatomically contiguous nodes - Contains rare neoplastic distinctive giant cells (“Reed Sternberg cells”), in a background of abundant reactive inflammatory cells - One of the most common cancers in young adults (average age at diagnosis is 32)

Classification - Nodular lymphocyte predominant Hodgkin lymphoma - Classical Hodgkin lymphoma Nodular sclerosis Hodgkin lymphoma Mixed cellularity Hodgkin lymphoma Lymphocyte-rich Hodgkin lymphoma Lymphocyte-depleted Hodgkin lymphoma - Distinction between Classical HL and Nodular LP HL is based partly on immunophenotype  Classical: CD15+ CD30+ CD45- CD20 NLPHL: CD15- CD30- CD45+ CD20+

Nodular LP Hodgkin Lymphoma 5% of all Hodgkin lymphoma “Popcorn cells” / “L&H cells” rather than RS cells Background of small B-lymphocytes Clinical - No bimodal age incidence pattern - Tendency to be restricted to cervical nodes - Very good prognosis

Classical Hodgkin Lymphoma Lymphocyte Rich (5%) - Scattered RS cells in lymphocyte rich background Nodular Sclerosis (66%) - Fibrous bands and cellular nodules - “Lacunar cell” variant of RS cell Mixed Cellularity (25%) - Abundant RS cells - Background of lymphocytes, eosinophils, plasma cells, neutrophils Lymphocyte Depleted ( F • Bimodal age incidence pattern overall – NS tends to be young adults – MC true bimodal pattern – LR older patients – LD older patients, HIV-infected individuals

Ann Arbor Staging System I – Involvement of a single 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 node regions or structures on both sides of diaphragm IV – Involvement of extranodal sites Suffices: A, B, E etc Hodgkin Lymphoma Prognosis - Generally better than non-Hodgkin lymphomas Depends greatly on stage (more so than histological subtype) - 90-100% of Stage IA and IIA curable - Even in stage IVA and IVB, 5-yr survival up to 6070% Non-Hodgkin Lymphomas - Very diverse group of disorders - Unimodal age distribution, with increasnig incidence with age - Many arise in extranodal sites (although the majority are nodal) Divided clinically into Low grade - Indolent, slow-growing, but resistant to therapy and rarely curable - Often present with painless generalised lymphadenopathy High grade - Aggressive, rapidly progressive, but sensitive to treatment and potentially curable - Often present with solitary rapidly enlarging mass

Non-Hodgkin lymphomas: Mature B-cell neoplasms Follicular lymphoma - One of most common NHLs - Usually presents in middle age - Presents with painless, generalised lymphadenopathy - Neoplastic cells closely resemble normal germinal centre B-cells - Incurable, but usually behaves as a low grade lymphoma with median survival 7-9 years - May transform to a high grade lymphoma (usually DLBCL)

- t(14;18)(q32;q21) translocation most frequent - bcl2 gene transposed to site of immunoglobulin light chain, with overexpression of protein product, which is an antagonist of apoptosis - Antiapoptotic activity of excess bcl2 leads to slow accumulation of neoplastic cells

Fluorescent in-situ hybridisation (FISH) RED probe hybridises to bcl2 locus at 14q32 GREEN probe hybridises to immunoglobulin heavy chain locus at 18q21 - In normal cells, these are visualised as distinct red and green signals (two copies of each in diploid cells)

- In follicular lymphoma cells, the translocation results in merging of red and green to give a combined YELLOW signal. Diffuse large B-cell lymphoma Heterogenous group of tumours, unified by - Large cell size (4x-5x size of small lymphocyte) - Diffuse growth pattern  Unlike nodular growth pattern of follicular lymphoma - Express B-cell markers (CD20, CD79a) Can be divided by gene expression profiling into two groups - Germinal centre type - Activated B-cell type Using immunohistochemistry for CD10, BCL6 and MUM1 we can divide them into similar groups without recourse to genetic tests (Hans algorithm)

Presentation - Usually present with a rapidly enlarging, often symptomatic mass at a single nodal or extranodal site - Common extranodal sites of origin include tonsil, GI tract, skin, brain, bone etc - Secondary involvement of liver or spleen is common - Bone marrow involvement may be a late feature

MALT lymphoma - Lymphoma of mucosa-associated lymphoid tissue - Properly classified as extranodal marginal zone lymphoma  (nodal and splenic types of marginal zone lymphoma also occur) - Arise at mucosal sites, often in association with chronic inflammation or infection – Gastric – Helicobacter pylori (NB!!!) – Conjunctival – Chlamydia psittaci – Cutaneous – Borrelia burgdorferi – Salivary gland – Sjogren’s syndrome - Gastric MALToma may be indolent, and can resolve when the infectious stimulus is removed (triple Rx)

Burkitt Lymphoma - Clinical syndrome of children in sub-Saharan Africa, aged 4-7, male:female ratio 2:1, with tumours of jaws and facial bones (“endemic Burkitt lymphoma”) - Sporadic Burkitt lymphoma occurs worldwide in children and young adults and only rarely involves jaw – ileocaecal tumours, breasts, kidneys, ovaries - Burkitt lymphoma is usually (but not always) an EXTRANODAL lymphoma

Outlook - If untreated – rapidly fatal - If treated (e.g. R-CHOP) – 60-80% achieve remission, 50% long-term cure

Specific subtypes Primary effusion lymphoma - Arises within body cavities, often in HIV infection - Associated with HHV8 EBV+ DLBCL of the elderly - EBV expression in DLBCL increases with age - Aggressive disease Primary cutaneous DLBCL, leg-type - Usually non-germinal centre type

Three types of BL – African (endemic) – Sporadic (nonendemic) – HIV-associated - 100% of African and ~20% of other types have latent EBV infection - All are associated with translocations of c-MYC gene on chromosome 8 - Usually translocation with IgH locus on chr. 14 - Very aggressive but usually responds well to short-course, high-dose chemotherapy  frequently curable (esp. in children)

- Cases without ALK rearrangements usually in older adults – bad prognosis, similar to PTCL NOS

Non-Hodgkin lymphomas: Mature T/NK-cell neoplasms

Mature T-cell / NK-cell neoplasms - Account for ~15% of non-Hodgkin lymphomas - Selected types: – Mycosis fungoides / Sezary syndrome – Anaplastic large cell lymphoma – Extranodal NK/T-cell lymphoma – Peripheral T-cell lymphoma, NOS Mycosis fungoides / Sezary syndrome - Neoplasm of CD4+ helper T-cells with a marked prediliction for the skin Mycosis fungoides - Develop from flat (patches) to tumourous masses over a prolonged period Sezary syndrome - Generalized exfoliative erythroderma - Does not produce tumourous masses - Associated with a leukaemia of “Sezary cells” in the peripheral blood • Indolent tumours, median survival 8-9 years • May transform to a high grade T-cell lymphoma as a terminal event

Extranodal NK/T-cell lymphoma Old names: lethal midline granuloma, midline malignant reticulosis - Rare in Europe / USA, relatively common in Asia - Destructive mass, usually involving nasopharynx - Microscopic features Cells surround and invade small blood vessels, causing ischaemic necrosis EBV-positive Often express NK-cell markers by immunohistochemistry - Aggressive and poorly responsive to therapy Different clinical forms of NK/T-cell lymphomas. (A) Nasal lymphoma showing an initial ulcer (left) that ultimately perforated into the oral cavity, creating a communication between the oral cavity and the nasal cavity. In the past, such a lesion was referred to as “lethal midline granuloma.” (B) Lymphoma initially localized to the calf, presenting as nonhealing ulcers. PET/CT showed occult nasal involvement. This case could be erroneously classified as “nonnasal” lymphoma. (C) Aggressive NK-cell leukemia showing neoplastic cells that were large granular lymphocyte in morphology in the peripheral blood and in the bone marrow (arrow)

Peripheral T-cell lymphoma, NOS

Anaplastic large cell lymphoma - Closely associated with rearrangements of ALK gene (2p23) - Rearrangements lead to ALK fusion gene products, behaving as constitutively active tyrosine kinases - Cases with ALK rearrangements usually in children or young adults – very good prognosis

• T-cell lymphomas which cannot be fitted into any of the specific diagnostic categories • A “wastebasket” diagnosis • One of the most frequent mature T-cell lymphomas (~25% of total) • Most patients present with generalised lymphadenopathy, +/- eosinophilia, pruritus, fever, weight loss • Much worse prognosis than comparably aggressive high grade mature B-cell lymphomas (e.g. DLBCL). Rarely curable.

Non-Hodgkin lymphomas: Precursor B- and T-cell neoplasms

Acute lymphoblastic leukaemia / lymphoma - Neoplasms composed of immature precursor B or T lymphocytes: “lymphoblasts” - 85% are pre-B ALL … usually manifest as childhood acute leukaemias - Pre-T ALL tends to present in adolescent males as lymphomas - Significant overlap in presentation between B and T, and individual patient may have both a tissue mass and large numbers of circulating neoplastic cells - Distinction between pre-B and pre-T lymphoblasts requires immunophenotyping, as they are morphologically indistinguishable

Acute lymphoblastic leukaemia / lymphoma Most cases < 15 years of age - For pre-B, peak at age 4 (maximal numbers of normal BM B-lymphoblasts) - For pre-T, peak in adolescence (maximal size of thymus) M>F 90% have numerical or structural chromosomal alterations, some of which predict prognosis – Hyperploidy (>50 chromosomes) – t(12;21) – t(9;22) – the Philadelphia chromosome seen in CML – t(4;11) These recurrent genetic abnormalities are used to subclassify ALL Clinical features - Abrupt stormy onset - Symptoms related to depression of normal bone marrow (anaemia, infections, bleeding) - Bone pain and tenderness - Generalised lymphadenopathy, splenomegaly and hepatomegaly - CNS manifestations Prognosis - Generally good with treatment. 90% of children achieve CR, 70% can be considered cured. - Poor prognostic indicators: Age < 2, presentation in adolescence or adulthood, PB blast counts > 100,000, presence of certain recurrent genetic abnormalities (esp. Ph chromosome)

Summary • Hodgkin lymphoma – Nodular lymphocyte predominant HL – Classical HL • Nodular sclerosing CHL • Mixed cellularity CHL • Lymphocyte predominant CHL • Lymphocyte depleted CHL • Non-Hodgkin lymphoma – Mature / peripheral B-cell lymphomas • Follicular lymphoma • DLBCL – Germinal centre type – Non-germinal centre type • MALT lymphoma • Burkitt lymphoma • (CLL / SLL – Haematology CPCs) • (Multiple myeloma – Haematology lectures) – Mature / peripheral T / NK-cell lymphomas • Mycosis fungoides / Sezary syndrome • Anaplastic large cell lymphoma • Extranodal NK/T cell lymphoma

• PTCL, NOS – Precursor B and T cell neoplasms • Acute lymphoblastic leukaemia / lymphoma – Pre-B – Pre-T...