– lymphoid neoplasms that present with widespread involvement of the bone marrow, usually accompanied by the presence of large #’s of tumor cells in the peripheral blood
Lymphoma
– proliferations arising as discretetissue masses
Plasma cell neoplasms
– tumors composed of terminally differentiated B cells. Such tumors most commonly arise in the bone marrow, only rarely involving lymph nodes or producing a leukemic peripheral blood picture.
The clinical presentation of the various lymphoid neoplasms is dictated by the anatomic distribution of disease.
2/3
of NHL’s present with nontender nodal enlargement (often >2 cm) that may be localized or generalized
1/3
arise at extranodal site (e.g., skin, stomach, brain).
Plasma cell neoplasms
involving skeleton cause local bony destruction Þ present with pain owing to pathologic fractures
Classifications
1982 = Working Formulation for Clinical Usage
– divided NHL into 3 prognostic groups Þ low, intermediate, high grade
classification was based on morphologic criteria
Þ pattern of tumor growth within lymph nodes (nodular or diffuse), size of the tumor cells (small, large, or mixed small and large).
1994 = Revised European-American Classification of Lymphoid Neoplasms (REAL)
– describes neoplasms that are believed to constitute distinct clinicopathologic entities based on clinical features, morphology, immunophenotype, and genotype. Includes the lymphocytic leukemias, NHLs, and plasma cell neoplasms.
Classification
(REAL classification listed hear, followed by working formulation equilvalent in italics and parentheses; C = most common tumors in children, A= most common tumors in adult)
I. Precursor B-Cell Neoplasms (neoplasms of immature B cells)
Precursor B lymphoblastic leukemia/lymphoma (C) (Leukemias: not included; lymphomas: high-grade, lymphoblastic)
II. Precursor T-Cell Neoplasms (neoplasms of mature B cells)
Precursor T lymphoblastic leukemia/lymphoma (C) (Leukemias: not included; lymphomas: high-grade, lymphoblastic)
III. Peripheral B-Cell Neoplasms (neoplasms of immature T cells)
Chronic lymphocytic leukemia/small lymphocytic lymphoma (A) (Low-grade, small lymphocytic)
Lymphoplasmacytic lymphoma (Low-grade, small lymphocytic plasmacytoid)
Mantle cell lymphoma (Intermediate-grade, diffuse small cleaved cell)
Follicular lymphoma (cytologic grade I, II, and III) (A) (Low-grade, Low-grade, Intermediate grade, respectively)
Marginal zone lymphoma (Low-grade, small lymphocytic)
Hairy cell leukemia (Not included in working formulation)
Plasmacytoma/plasma cell myeloma (multiple myeloma) (A) (Not included in working formulation)
Diffuse large B-cell lymphoma (A) (Intermediate-grade, diffuse large cell or high-grade, large cell)
Burkitt lymphoma (C) (High-grade, small noncleaved cell)
IV. Peripheral T-Cell and Natural Killer Cell Neoplasms (neoplasms of mature T cells and NK cells)
T-cell chronic lymphocytic leukemia (Low-grade, small lymphocytic)
Large granular lymphocytic leukemia (Low-grade, small lymphocytic)
Mycosis fungoides and Sezary syndrome (Low-grade, mycosis fungoides)
Peripheral T-cell lymphoma, unspecified (Most often intermediate-grade, diffuse mixed small and large cell)
Angioimmunoblastic T-cell lymphoma (Most often intermediate-grade, diffuse mixed small and large cell)
Angiocentric lymphoma (NK/T-cell lymphoma) (Most often intermediate-grade, diffuse mixed small and large cell)
Intestinal T-cell leukemia/lymphoma (Most often high-grade, large cell immunoblastic)
Adult T-cell leukemia/lymphoma (Most often intermediate-grade, diffuse mixed small and large cell)
Anaplastic large cell lymphoma (Most often high-grade, large cell immunoblastic)
Important Principles
Histologic examination of lymph nodes or other involved tissues is required for diagnosis.
Although all lymphoid neoplasms have traditionally been considered to be malignant, a wide range of behavior from seemingly benign to rapidly fatal is observed.
The vast majority of lymphoid neoplasms (80 to 85%) are of B-cell origin, with most of the remainder being T-cell tumors; only rarely are tumors of NK or histiocytic origin observed. Tumors of T and B cells may represent cells arrested at any stage along their differentiation pathways.
As tumors of the immune system, lymphoid neoplasms tend to disrupt normal regulatory mechanisms, leading to frequent immune abnormalities. Both a loss if vigilance (as evidenced by susceptibility to infection) and a breakdown of tolerance (manifested by autoimmunity) may be seen.
All lymphoid neoplasms are derived from a single transformed cell and are therefore monoclonal. In most lymphoid neoplasms, antigen receptor gene rearrangement precedes transformation; as a result, the daughter cells derived from the malignant progenitor share the same antigen receptor gene configuration and sequence and synthesize identical antigen receptor proteins (either Ig or T-cell receptors).
Neoplastic B and T cells tend to home to and grow in areas where their normal counterparts reside resulting in characteristic patterns of tissue involvement in certain lymphoid neoplasms.
Given that normal B and T lymphoid cells recirculate through the lymphatics and peripheral blood to distant lymphoid tissues, it is not surprising that neoplastic lymphoctyes show a similar wanderlust.
The spread of NHL is less predictable than HD, hence most patients are assumed to have systemic disease at the time of diagnosis.
Etiology of NHL = unknown; viral infection (EBV); immunodeficiency disorder; chemical exposure (agent orange).
Phenotype Categorization
B cells:
CD19+, CD20+
CD5+ B cell Þ
virginal or "immature" B cell
CD10+ B cell Þ
follicle center B cell
T cells:
CD3+
CD30+ T cell Þ
"activated" T cell
CD4+ T cell Þ
"helper" T cell
Any cell with TdT cannot be a lymphocytic cell since it is expressed too early in the lineage – most likely leukemic
: relatively condensed chromatin (delicate and finely stippled); absent or inconspicuous nucleoli; presence of scant, agranular cytoplasm; starry sky pattern produced by interspersed benign macrophages; lack peroxidase-positive granules; often contain cytoplasmic aggregates of PAS-positive material.
: Diverse chromosomal translocations, many involving Ig loci. t(12;21) involving TEL1 and AML1 genes most common rearrangement.
Salient Clinical Features
: 85% of ALL. Predominantly children with symptoms relating to pancytopenia due to marrow involvement. Whites:non-whites = 2:1; boys>girls.
Clinical Features
: Accumulation of blast cells in the bone marrow that suppress normal hematopoiesis by physical crowding and other poorly understood mechanisms Þ anemia, neutropenia, thrombocytopenia. Abrupt stormy onset. Symptoms related to depression of normal marrow function (fatigue, fever, bleeding). Bone pain and tenderness (due to marrow expansion). Generalized lymphadenopathy, splenomegaly, and hepatomegaly (caused by neoplastic infiltration). CNS manifestations (HA, vomiting, nerve palsies resulting from meningeal spread).
: Pre-T cells (lymphoblasts) expressing CD1 and TdT; variable expression of other pan T-cell markers (CD2, CD3, CD4, CD5, and CD8).
Genotype
: Diverse chromosomal translocations, many involving T-cell receptor loci. Rearrangements of the TAL1 gene are most common.
Salient Clinical Features
: 15% of ALL. Adolescent males; present as lymphomas often with thymic involvement (mediastinal masses); variable splenic, hepatic, bone marrow involvement. Whites:non-whites = 2:1; boys>girls.
Clinical Features
: see above.
(3) Small lymphocytic lymphoma (SLL)/chronic lymphocytic leukemia (CLL)
– basically two versions of the same malignancy
Morphology
: Lymph node architecture is diffusely effaced by a predominant population of small lymphocytes containing round to slightly irregular nuclei with condensed chromatin and scant cytoplasm. Mixed with variable number of larger cells called prolymphocytes which gather together focally to form loose aggregates called proliferation centers (contain
Ý #s of mitotically active cells). In CLL, smudge cells are seen in blood smear.
Immunophenotype
: CD5+peripheral B-cell tumor; CD23+, CD10-. Express the pan B-cell markers CD19 and CD20. Expresses low levels of surface IgM.
Genotype
: Trisomy 12, deletions of 11q23, abnormalities of 13q, t(14;19) (rare)
Salient Clinical Features
: Older patients (male predominance) with bone marrow, lymph node, spleen, and liver disease. Most present with leukemic picture, often asymptomatic (symptoms = fatigue, weight loss, anorexia). CLL is the most common leukemia of adults in the Western world. CLL and SLL disrupt normal immune function through uncertain mechanisms. Autoimmune hemolysis and thrombocytopenia in a minority. Tendency for CLL and SLL to transform to more aggressive lymphoid neoplasms in the form of prolymphocytic transformation or transformation to diffuse large B-cell lymphoma (Richter syndrome).
(4) Follicular lymphoma
Morphology
: nodular and diffuse growth pattern in involved lymph nodes. Two principal cell types observed: (1) centrocytes (small cleaved cells with scant cytoplasm) and (2) centroblasts (larger cells with open nuclear chromatin, several nucleoli, and modest amounts of cytoplasm).
Immunophenotype
: CD10+peripheral B-cell tumor (closely resemble normal germinal/follicular center B cells); CD19+, CD20+, CD5-. Expresses high levels of surface Ig (usually IgG)
Genotype
: t(14;18) involving the BCL2 gene; results in overexpression of BCL2 protein Þ neoplastic follicles lack apoptotic cells
Salient Clinical Features
: Older patients with generalized painless lymphadenopathy and marrow (paratrabecular lymphoid aggregates) involvement. Most common form of NHL in the US. Affects men and women equally. Incurable with a waxing and waning course. Histologic transformation occurs in 30 to 50% of follicular lymphomas (most commonly to diffuse large B-cell lymphoma).
(5) Diffuse large B-cell lymphoma
Morphology
: large cell size (4-5x a small lymphocyte) and a diffuse pattern of growth.
Immunophenotype
: Peripheral B-cell phenotype, variable CD5 and CD10. CD19+, CD20+, TdT-. Usually express surface Ig.
Genotype
: Diverse chromosomal aberrations. 30% contain t(14;18) and are of follicular center cell origin; 20-30% have rearrangements of the BCL6 gene on chromosome 3 (encodes a zinc-finger transcription factor normally expressed in germinal centers for controlling B-cell differentiation).
Salient Clinical Features
: All ages, most common in adults. Often a rapidly growing mass at a single nodal or extranodal site. 30% extranodal. Constitute 60 to 70% of aggressive lymphoid neoplasms. Male predominance.
(6) Burkitt lymphoma
Morphology
: involved tissues are effaced by a diffuse infiltrate of intermediate-sized lymphoid cells containing round nuclei with coarse chromatin, several nucleoli and a moderate amount of basophilic cytoplasm. High mitotic index is typical, as is apoptotic tumor cell death Þ numerous tissue macrophages with ingested nuclear debris. These benign macrophages are often surrounded by a clear space creating a characteristic starry sky pattern.
Immunophenotype
: Peripheral B cells (mature) expressing CD10, CD19, CD20 and surface IgM.
Genotype
: Translocations involving c-myc and Ig loci; usually t(8;14), but also t(2;8) or t(8;22). African (endemic) cases latently infected with EBV.
Salient Clinical Features
: Adolescents or young adults with jaw or extranodalabdominal masses. Uncommonly presents similar to leukemia (B-cell ALL).
(7) Multiple myeloma/solitary plasmacytoma
Morphology
: multiple tumorous masses (multiple myeloma) of neoplastic plasma cells scattered throughout the skeletal system (appear as sharply punched out defects on X-ray) or a solitary neoplastic mass (solitary plasmacytoma) of plasma cells found in bone or some soft tissue site. Normal appearing plasma cells or a number of cytologic variants may predominate including plasmablasts, bizarre multinucleated cells, flame cells, Mott cells, and cells with a variety of inclusions (fibrils, crystalline rods, Russell bodies, Dutcher bodies).
Immunophenotype
: Terminally differentiated B-cell tumor; expresses CD38. Expansion of a single clone (dyscrasias) of Ig-secreting plasma cells and a resultant Ý in serum levels of a single homogeneous Ig or its fragments.
Genotype
: t(4;14) (approximately 25% of cases), leading to Ý expression of FGFR3
Salient Clinical Features
: Myeloma: older patients with lytic bone lesions, pathologic fractures, hypercalcemia, renalfailure, recurrent infections and primary amyloidosis. Plasmacytoma: isolated plasma cell masses in bone or soft tissue (e.g., oropharnyx). Behaves as a malignant disease. Production of excess light or heavy chains along with complete Ig. Free light chains (Bence Jones proteins) rapidly excreted in the urine. Proliferation and survival of myeloma cells seem to be dependent on several cytokines, most notably IL-6 (also mediates bone destruction).
Less Common Lymphoid Neoplasms
(1) Lymphoplasmacytic lymphoma
Morphology
: diffuse, sparse-to-heavy infiltrate in the bone marrow of lymphocytes, plasma cells, and intermediate plasmacytoid lymphocytes (plymphocytes). PAS+ inclusions containing Ig may be seen in the cytoplasm (Russellbodies) or nucleus (Dutcher bodies).
Immunophenotype
: Peripheral B-cell tumor; CD5-, CD10-, CD23-. Expresses surface Ig (usually IgM) and cytoplasmic Ig in plasma cell component.
Genotype
: t(9;14) in 50% of cases, apparently producing aberrant expression of PAX5, a transcription factor that is essential for normal B-cell differentiation.
Salient Clinical Features
: Older patients with marrow, lymph node, spleen, and liver disease. Often associated with a hyperviscosity syndrome (Waldenstrom macroglobulinemia). 10% have autoimmune hemolysis (due to cold agglutinins). Symptoms = weakness, fatigue, and weight loss.
(2) Mantle cell lymphoma
Morphology
: tumor cells closely resemble the normal mantle zone cells that surround follicular centers. The proliferation consists of a homogeneous population of small lymphocytes with round to irregular to occasionally deeply clefted (cleaved) nuclear contours. Nuclear chromatin is condensed, nucleoli are inconspicuous, and cytoplasm is scant. Multifocal mucosal involvement of the small bowel and colon produces lymphomatoid polyposis.
: t(11;14) involving the BCL1 gene; results in overexpression of BCL1 protein (i.e., cyclin D1 Þ tumorigenesis by causing loss of cell cycle control)
Salient Clinical Features
: Older male patients with lymphadenopathy and marrow involvement. May arise at extranodal sites or present as splenomegaly.
(3) Marginal zone lymphoma (MALToma)
Immunophenotype
: Peripheral B-cell tumor; CD5-, CD10-, CD23-. Expresses surface Ig and may have cytoplasmic Ig in plasma cell component.
Genotype
: Trisomy 18, t(11;18)
Salient Clinical Features
: Frequently arises at extranodal sites in adult patients with chronic inflammatory diseases. Tends to remain localized for long periods of time. Composed of cells at various stages of B lymphoid differentiation often including terminally differentiated plasma cells. Referred to as MALToma (mucosa-associated lymphoid tissues) because these tumors were initially recognized at mucosal sites.
(4) Hairy cell leukemia
Morphology
: these leukemic cells have fine hairlike projections that are best recognized under the phase-contrast microscope.
Immunophenotype
: Peripheral B-cell tumor coexpressing CD11c, CD25, and surface Ig. Express the pan B-cell markers CD19 and CD20.
Genotype
: No specific chromosomal rearrangements
Salient Clinical Features
: Older males with pancytopenia and splenomegaly. Bone marrow is always involved.
(5) Peripheral T-cell lymphoma, unspecified
Morphology
: diffusely efface the architecture of involved lymph nodes. Composed of a pleomorphic mixture of small, intermediate, and large-sized malignant T cells.
Immunophenotype
: Mature T-cell tumor; positive for pan T-cell markers and usually CD4 or CD8. TdT-, CD1-, CD2+, CD5+, surface CD3+
Genotype
: Diverse chromosomal translocations. Clonal T-cell receptor rearrangements.
Salient Clinical Features
: Usually adult patients with generalized lymphadenopathy, sometimes accompanied by pruritus