lymphoma review

·         Malignant neoplasm characterized by proliferation of lymphoreticular cells:

o   Lymphocytes

o   Histiocytes

o   Precursors and derivatives

o   Pathogenesis:

§  Chronic hyperplasia/dysregulation

§  Genetic “mistakes” affecting multiple oncogenes and/or TSG

§  Maturation arrest in single clone of cells

·  Overgrowth neoplastic clone with characteristic morphologic features and growth potential

· Inhibition of normal clones

o   Etiology:

§  Hereditary

§  Immunodeficiency (inherited / acquired / iatrogenic – immunosuppressive agents)

§  Autoimmine disorders

§  Chromosome/genetic abnormalities

§  Microorganisms: EBV, HHV8, H. pylori

o   Oncogeness/TSG

§  Modifications / inappropriate activation

·  Oncogenes: proteins regulating cell proliferation, apoptosis, maturation

o   Myc (8;14):  burkitt (cell proliferation)

o   cyclinD1 (11;14): mantle cell (cell proliferation)

o   BCL-2 (14;18): follicular lymphoma (anti-apoptotic)

o   BCL-6 (chromosome 3) - maturation

·         **NHL (18.9/100,000/yr) > plasma cell disorders (6/100,000/yr)> HL (2.8/100000/yr) > histiocytic neoplasm (rare)

	NHL	HL
Age	Childhood -- elderly	Bimodal incidence in classic types (15-35, >45)
Sex	Male predominance (most)	Male predominance (except NS)
Symptoms	Insidious onset Painless LAD +/- fever, night sweats, weight loss	Painless LAD +/- fever, night sweat, weight loss
sites	Lymphoreticular (LN, spleen, thymus) Extranodal: (BM, GI, liver, skin, pharynx, orbit, CNS, lung, thyroid, breast, ect)	LN (cervical/mediastinal), spleen, liver, BM
patterns	Nodular: vaguely to distinctly nodular aggregates of neoplastic cells Several B cell subtypes exhibit pattern  - ex: follicular Diffuse: diffuse growth neoplastic cells seen in B/T types	Younger: localized w. minimal symptoms Older: disseminated, B symptoms

NHL B cell Tcell ·         Small lymphocytic ·         Mantle cell ·         Follicular ·         Marginal zone / MALT ·         Diffuse large B ·         Burkitt ·         Peripheral T cell  (many subtypes) ·         Anaplastic large cell  ·         Mycosis fungoides/sezary syndrome
Follicular lymphoma		·         2nd most common NHL (esp in the West) ·         >40 ·         Neoplasm of follicular center B cells ·         14;18 with BCL2 abnormality (~90%) ·         Nodules of small cleaved --> large B cells ·         Disseminated at presentation o   Slowly progressive Grade1 Grade 2 Grade 3 Mostly small cleaved cells Small cleaved and a few large B Mostly large B ·         Grades 1,2: median survival 8-10 yrs (may progress to higher grade)
Diffuse large B lymphoma		·         Most common NHL worldwide ·         Occurs at any age ·         Diffuse proliferation of large B lymphocytes with open (vesicular) chromatin, o   Nucleoli o    variable amount of cytoplasm o    numerous mitoses ·         Many morphologic / genetic variants ·         Occurs in LN or extranodally ·         Usually localized at presentation o   Aggressive if untreated (~50% cure rate)
Marginal zone, MALT lymphoma		·         Low grade lymphoma ·         Specialized type of small B lymphocyte ·         Extranodal sites result from chronic hyperplasia of B cells (induced by autoimmune or infectious o   Autoimmune: thyroid o   Infectious: H.pylori : stomach – will respond to AB ·         >40 ·         Indolent clinical course – often remains in extranodal site for years
Burkitt lymphoma		·         Occurs mostly in children / HIV infected patients ·         Endemic in Africa – but occurs worldwide ·         MYC – 8;14 ·         EBV: seen in most endemic cases ·         Usually extranodal – jaw (endemic), abdominal (sporadic) -- may see                 leukemic phase ·         Diffuse proliferation of uniform intermediate size B lymphocytes with fine chromatin, small nucleoli, extremely numerous mitoses ·         Starry sky: histiocytes ·         Very aggressive if not treated: highly curable – except in HIV ·         Note: in malaria belt:  Burkitt, large B –cell type, primary effusion type lymphomas
Mycosis fungoides, sezary sndrome		·         >40 ·         Primary skin involvement: plaques, tumors with MF, erytroderma with SS o   Peripheral blood (SS) o   Late LN/spleen involvement ·         Epidermal and high dermal infiltrate of small T lymphocytes with cerebriform nuclei ·         Neoplasm of CD4+ ·         MF: slowly progressive; SS aggressive
HL: ·         Reed-Sternberg cells and variants surrounded by benign reactive cells ·         Classics types associated with EBV (95% HL) o   Nodular sclerosing (70%) o   Mixed cellularity (20%) o   Lymphocyte rich (5%) o   Lymphocyte depleted (<1%) ·         Nodular lymphocyte predominant HL (5%) Stage 1 Stage 2 Stage 3 Stage 4 Single node group or extranodal site Multiple node groups or nodes + extranodal sites (same side diaphragm) Node groups on both sides of diaphragm with possible localized extranodal site or spleen Disseminated nodal and extranodal Modifiers: A.      No “ b” symptoms B.      Fever, night  sweats, weight loss
Nodular sclerosing	·         70% classic ·         Partially nodular growth pattern with fibrous bands separating nodules ·         RS = rare ·         +/- necrosis
Mixed cellularity	·         Diffuse or vaguely nodular growth ·         No band forming sclerosis
Lymphocyte rich	·         Typically had nodular growth (maybe diffuse) ·         RS present  with rare eosinophils/ PMN in background
Lymphocyte depleted	·         Hypocellular ·         Fibrosis, necrosis ·         Large number RS – bizarre variants
Plasma cell disorder
Plasmcytoma: plasma cell myeloma = multiple myeloma	·         Solitary (plasmacytoma) or multiple (plasma cell myeloma) collections of relatively mature plasma cells ·         Usually within bone ·         Produce single “species” of Ig ·         90% >50 ·         Present with monoclonal gammopathy +/- anemia, bone pain, lytic bone lesions ·         Clinical course: indolent (smoldering)--- aggressive ·         Complications o   Excess plasma cells: hypercalcemia (RANKL -- activate osteoclasts), bone fractures, marrow insufficiency  o   Excess monoclonal Ig: renal insufficiency, amyloidosis o   Decreased normal Ig: infections ·         Lab features: o   Peripheral blood:monoclonal gammopathy, anemia, +/0 hypercalcemia o   Urine: free light chain (bence jones) proteinuria (805) o   Bonemarrow: increased plasma cells (>10%) usually in clusters, vary in maturity
Waldenstrom macroglobulinemia --  lymphoplasmacytic lymphoma	Syndrome associated with lymphoplasmacytic lymphoma characterized by infiltration of small lymphocytes and “plasmacytoid” lymphocytes in BM, LN, spleen, liver ·         Lymphocytes (MM: plasma) ·         Neoplastic cells secrete single species of IgM (MM: any Ig can be produced) ·         Serum hyperviscocity (macro – pentamer structure IgM) (rare in MM) ·         25% bence jones (80% MM)
Heavy chain diseases	Rare neoplasms in which a single clone  of plasma cells or lymphocytes produces and  secretes immunoglobulin heave chains only • Structurally abnormal heavy chain molecules are  produced that cannot bind with light chains, resulting  in secretion of heavy chains only
Primary amylodiosis	Neoplastic condition in which a single  clone of plasma cells secretes excess monoclonal  intact immunoglobulin or free light chain (rarely free heavy chain) that is deposited as amyloid in many  tissues and organs, often causing organ failure • In some cases, this is a manifestation of myeloma,  but most patients have only minimal bone marrow  plasmacytosis and no other findings of myeloma.
Monoclonal gammopathy of undetermined significance (MGUS)	·         Monoclonal Ig in serum  - no demonstrable evidence of plasma cell neoplasm ·         Prevelance increases with age o   >50: 3% o   >70 5% o   >80 12% ·         Monoclonal Ig usually <3 g/dl (no or minimal Bence-Jones proteinuria) ·         Up to 25% of MGUS patients develop plasma cell neoplasm (1%/yr)
Histiocytic neoplams
Langerhan cell histiocytosis	·         Neoplasm of specialized dendritic cell ·         Varies from unifocal (older children – adults) to multifocal in one organ system (young kids) to widely disseminated (infants) ·         Benign à highly aggressive
Histiocytic sarcoma	·         Neoplasm of mature histiocytes/macrophages ·         Occurs at any age ·         Highly malignant