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Neoplasms: Lymphoid (Plasma cell disorders: oversecretion of a unique,…

- - - - Most common lymphoid neoplasm in African Americans, second most common lymphoid neoplasm in Caucasians. Median age of diagnosis = 70 yrs. Male to female ratio 1:1.
    - - Clinical consequences
        
        Amyloidosis
        
        Ig (most often lambda light chains) settle out in unique beta-pleated sheets to form acellular tissue deposits that interfere with organ function.
        
        Cryoglobulinemia
        
        Precipitation of large Ig moieties at low temperatures can be a problem in the extremities (Raynaud's disease).
        
        Renal failure
        
        Cast nephropathy due to excess light chain aggregates in distal nephron leading to obstruction, toxicity of light chains for proximal tubular epithelial cells, hypercalcemia leading to hypovolemia, light chains settling as amyloid deposits. [note: casts are physically composed of cells - RBC/WBC - and are a sign of inflammation].
        
        Hematologic/vascular problems
        
        Bleeding phenomena due to interference of Ig with platelet function and clotting cascade proteins. Serum hyperviscosity also results from paraproteinemia and produces sluggish bloodflow and subsequent vascular complications.
        
        Immunodeficiency
        
        Decreased normal Ig production results in predisposition to recurrent bacterial infections. A leading cause of death for MM patients.
      - In MM the most common paraproteins are IgG (50%) and IgA (25%), both of which have greater kappa than lambda light chains. An M spike consists of increased monoclonal Ig >3 gm/dL serum and >6 gm/dL urine. This spike is detected through electrophoresis and immunofixation.
    - - Increased plasma cells (clusters and sheets), replacement of marrow elements, destruction and resorption of bone. Loss of normal marrow cells like erythroid/myeloid precursors and megakaryocytes leads to anemia.
        
        Flame cells - morphologic variants due to the pink border of IgA expressing cells.
        
        Mott cells - globules of intracytoplasmic monoclonal Ig.
        
        More aggressive myeloma show marked cytologic "atypia" with large bizarre nuclei, prominent nucleoli, and pronounced mitotic activity.
    - - Malignant cells destroy normal marrow microenvironment. Trabecular destruction and osteoclast activation leads to hypercalcemia and marrow replacement leads to anemia. Renal failure also contribution to anemia via underproduction of RBCs due to insufficient EPO.
      - Multifocal, causes bone pain, osteolytic lesions, and pathologic fractures. Lytic bone lesions are found at most prominent at sites of active hematopoiesis in the axial skeleton (ribs, skull, vertebrae). Pathologic fracture of vertebrae can be an emergency due to potential spinal cord compression.
    - - Variable course (one year to many years). Ultimately poor response to current therapies. Autotransplantation following an initial round of highly toxic therapy has been shown to prolong survival in MM, but is not curative. Current cytogenetics: deletions of 13q (more aggressive), translocations 14q32 (common).
- - - - Diffuse large B cell lymphoma (DLBCL)
        
        Epi:
        
        Aggressive lymphomas represent ~50% of the NHLs diagnosed in Western countries with the most common subtype being DLBCL which accounts for ~31% of all NHLs, affecting both children and the elderly. Associated with being immunocompromised (EBV+).
        
        Morphology:
        
        Gross pathology: homogenous fish-flesh replacement of involved tissue. Hemorrhage, necrosis, fibrosis. DLBCLs are locally destructive lesions. The discohesive nature of the proliferating cells that make up these masses lead to a soft bland "fish-flesh" appearance.
        
        Microscopic: diffuse architectural effacement, large cells, mitotically active, invasive, necrotic. Mature B cell: CD19+, CD20+, surface and/or cytoplasmic Ig+. Proliferation rate usually high - 40-90% of cells Ki67+.
        
        Immunoblastic: large, single centrally located nucleolus, abundant cytoplasm (can be plasmacytoid in appearance). Lymphoblastic lymphomas have cells that vaguely resemble large transformed lymphocytes seen in the interfollicular areas in reactive lymph nodes. These mostly arise as EBV+ primary CNS lymphomas.
        
        Centroblastic: (like centroblasts from follicular lymphoma) medium-saved to large cells, oval vesicular nuclei, multiple membrane bound nucleoli, scant cytoplasm. Centroblastic tumors are composed of cells that resemble the transformed cell seen in a germinal center. These lesions are far more common than immunoblastic lymphomas, which are seen mostly in states of immunosuppression.
        
        Clinical features:
        
        Presentation
        
        Rapidly enlarging symptomatic mass at a single nodal or extranodal (40%, typically GI tract) site (unlike indolent lymphomas). Can arise from (1) progression/transformation of an indolent lymphoma or (2) de novo. Primary presentation with BM or PBL involvement is rare.
        
        Biology:
        
        Immunosuppression: a subset of DLBCLs are more commonly EBV positive due to lack of immune surveillance resulting in proliferation of EBV infected B cells. These EBV+ B cells then acquire genetic accidents that lead to neoplastic transformation, typically to an aggressive lesion.
        
        Prognosis & Treatment:
        
        Aggressive, but many respond to chemotherapy. Difficult to predict behavior (40% resistant to therapy). No distinct immunophenotypic profile.
        
        International Prognostic Index (IPI): age > 60, elevated serum LDH (measure of cell death and thus tumor burden), poor performance status (how fit the patient is), extensive disease (both sides of diaphragm - Ann Arbor clinical stage III or IV), involvement of multiple extranodal sites.
        
        Gene expression profile analysis (based on putative stages of B cell development): GCB phenotype has significantly better survival than ABC phenotype.
    - - Burkitt's lymphoma: CD10+, BCL6+, BCL2-, Ki67 100%. Recapitulation of GC out of control.
        
        Clinical features:
        
        This is an emergency! Rapid doubling time, high tumor burden, bulky disease, tumor lysis syndrome, potentially curable and as such treatment should begin ASAP. Doubling rate makes Burkitt's lymphoma responsive to DNA damaging agents.
        
        Biology:
        
        Biological underpinnings for all three variants of Burkitt lymphoma. Translocation of the oncogene cMYC into the heavy or light Ig chain regulatory machinery results in overexpression.
        
        Morphology:
        
        Monotonous infiltrate of medium-sized cells, very high proliferative and apoptotic rates, "starry sky" pattern (numerous tingible body macrophages), round nuclei with multiple central nucleoli, cytoplasm deeply basophilic with lipid vacuoles.
        
        Prognosis & Treatment: if intervention is swift with intensive chemotherapy Burkitt's can be cured. However, timing is critical.
        
        Epi: three variants, all forms aggressive extranodal lymphoma and/or leukemia with propensity for CNS involvement.
        
        Immunodeficiency associated BL:
        
        LN and BM involvement more frequent.
        
        Primarily seen in association with HIV infection. Often the initial manifestation of AIDS. Associated with EBV in 25-40% of cases.
        
        Sporadic BL:
        
        Abdominal (ileocecal) masses more common, less common: ovaries, kidneys, breasts. LN involvement rare (more common in adults).
        
        Seen throughout the world (children and young adults). Low incidence (1-2%) of NHL in West. Makes up 30-50% of childhood lymphoma, rare in adults. Adult median age - young (30), M:F ratio 2-3:1. Associated with EBV in < 30% of cases.
        
        Endemic BL:
        
        Facial bones 50% (jaws, orbit), less common: ileocecum, ovaries, kidneys, breast.
        
        Most common childhood malignancy in equatorial Africa (malaria belt). Incidence peaks at 4-7 years, M:F ratio 2:1. Associated with EBV in all cases.
    - - Indolent
        
        Marginal: CD5-, CD10-. There is no distinct immunophenotypic marker for these lymphomas.
        
        Biology:
        
        For MALT, recurrent translocations include t(11;18), which help to explain their inhibition of apoptosis/promotion of cell growth through dysregulation of the NF-kB pathway. Mechanistically antigen driven (infections/autoimmune) and spread from one mucosal site to the next.
        
        Epi:
        
        Three separate diseases that are all morphologically and immunophenotypically similar. Different sites of origin: extranodal, nodal, splenic. Different clinical presentations. Uncommon (<5%). Focus on extranodal marginal zone lymphoma of mucosa associated lymphoid tissue (MALT).
        
        Morphology:
        
        Abnormal GCs associated with expansions of the margin and effacement of the underlying architecture. B cells from these neoplasms tend to demonstrate three appearances: small mature lymphocytes, monocytoid B cells forming the 'margins' (often disrupt keratin positive epithelial cells), and plasma cells (sometimes so numerous that the tumor has appearance of a pure plasma cell lesion, or "plasmocytoma." Predominance of CD20+ B cells with rare CD3+ T cells. CD21 highlights abnormal follicular dendritic meshworks encroached upon by the marginal zone cells.
        
        Prognosis & Treatment:
        
        Low grade lymphoma, indolent. Can transform to diffuse large B cell lymphoma (DLBCL). Treatment to interrupt stimulus and stop tumor development: early intervention with antibiotics, not radiation/chemotherapy.
        
        Clinical features:
        
        Specifically MALT: unique presentation associated with chronic inflammation. Some known site specific infectious agents include H. pylori in the stomach, C. jejuni in the small bowel, Borrelia burgdorferi in skin, Chlamydia psittaci in the orbit, infection/autoimmunity in lung/parotid/thyroid. In spleen (not MALT, but SMZL) Hep C could be a player.
        
        CLL/SLL: CD5+, CD10-, Bcl6-, Bcl2+ (not germinal center origin). Better prognosis - deletion 13q*, worse prognosis - trisomy 12, deletion 11q, deletion 17p (p53).
        
        Biology: Naive form versus post-GC form
        
        Group 2: hypermutated IgV segments - has traversed the germinal center (post-GC), Zap70 negative, indolent.
        
        Group 1: Unmutated IgV segements - have not traversed the GC, naive B cell, Zap70 positive, aggressive.
        
        Epi:
        
        A spectrum: circulating cells (leukemia) <--> solid mass (lymphoma). CLL: most common adult leukemia, SLL: uncommon NHL when lacking peripheral blood component (4%). Presents in 6th decade, male to female ration 2:1.
        
        Morphology
        
        Diffuse effacement of architecture, proliferation centers "pseudofollicles", prolymphocytes, paraimmunoblasts. These centers are not to be confused with germinal centers, the true site of B cell proliferation in the lymph node. Peripheral blood smear: lymphocytosis (small, mature lymphocytes), smudge cells (CLL cells are unusually fragile and easily disrupted during slide prep), and in AIHA microspherocytes, nucleated RBCs, increased retics. Marrow biopsy shows interstitial pattern of infiltration - can be diffuse or in nodular aggregates.
        
        Prognosis & Treatment
        
        Extremely variable: median survival of 4-6 years. Some cases are indolent, others progress rapidly. CLL/SLL can transform to prolymphocytic leukemia (15-30%), Richter's transformation to diffuse large B cell lymphoma (10%). With transformation survival is less than 1 year.
        
        Clinical features:
        
        Usually asymptomatic (or non-specific complaints), generalized lymphadenopathy, BM involvement in virtually all cases, spleen and liver involvement very common (hepatosplenomegaly 50%), peripheral blood involvement very common, immune dysregulation (AIHA and thrombocytopenia). Note that the dysregulated immunity is caused by residual non-neoplastic lymphocytes, not malignant B cells.
        
        Follicular: Germinal center B-cells CD5-, CD10+, Bcl6+, Bcl2+, light chain restricted. Low Ki67 (reduced proliferation rate). Cytogenetic hallmark is t(14;18).
        
        Morphology:
        
        Nodular appearance (lots of germinal centers) due to recapitulation of functions of cells of origin (germinal center B cells), centrocytes and centroblasts present but polarization absent. Follicles are crowded and have no discernible tingible body macrophages or mantle zone. More nodular = more indolent; more diffuse = more aggressive. Unusual bone marrow pattern of growth that is virtually diagnostic -- "paratrabecular" growth along the bone.
        
        Prognosis & Treatment:
        
        Median survival of 8 years with waxing waning course. Often transformation (30-50%) into diffuse large B cell lymphoma for which median survival is less than 1 year. Indolent lesions are largely incurable (less responsive to conventional therapy). Current therapies: observation, symptomatic relief, anti-CD20 (Rituxan), multi-agent regimens (CHOP).
        
        Clinical features:
        
        Generalized lymphadenopathy, bone marrow involvement common (85%). Painless splenomegaly with fine diffuse nodularity (upper left quadrant fullness and early satiety). Occasional involvement of peripheral blood (10%) and uncommonly extranodal involvement (GI tract, CNS testis).
        
        Epi:
        
        Most common NHL (45%), presents in middle age, male to female ratio 1:1, uncommon in Asia