Chapter 12- WBC: Peripheral B-cell Neoplasms Flashcards
What is leukemia?
Leukemia is used for neoplasms that present with widespread
involvement of the bone marrowand(usually, but not always) the peripheral blood
What is Lymphoma?
Lymphoma is used for proliferations that arise as discrete tissue masses.
Many entities called “lymphoma” occasionally have leukemic presentations, and evolution to “leukemia” is not unusual during the progression of incurable
“lymphomas.”
Conversely, tumors identical to “leukemias” sometimes arise as soft-tissue
masses unaccompanied by bone marrow disease. Hence, when applied to particular
neoplasms, the terms leukemia and lymphoma merely reflect the usual tissue distribution of
each disease at presentation.
Within the large group of lymphomas, what is segregated from all other forms?
Hodgkin lymphoma,
which constitute the non-Hodgkin lymphomas (NHLs).
Hodgkin lymphoma has
distinctive pathologic features and is treated in a unique fashion.
The other important group of
lymphoid tumors is the plasma cell neoplasms.
These most often arise in the bone marrow and
only infrequently involve lymph nodes or the peripheral blood. Taken together, the diverse
lymphoid neoplasms constitute a complex, clinically important group of cancers, with about
100,000 new cases being diagnosed each year in the United States
The clinical presentation of the various lymphoid neoplasms is most often determined by what?
anatomic distribution of disease.
Two thirds of NHLs and virtually all Hodgkin lymphomas
present as what?
enlarged nontender lymph nodes (often >2 cm).
The remaining one third of NHLs
present with symptoms related to the involvement of what?
involvement of extranodal sites (e.g., skin, stomach, or
brain).
What is the reason lymphocytic leukemias most often come to attention?
The lymphocytic leukemias most often come to attention because of signs and
symptoms related to the suppression of normal hematopoiesis by tumor cells in the bone
marrow
What is the most common plasma cell neoplasm?
- *multiple myeloma**, causes bony
- *destruction of the skeleton** and often presents with pain due to pathologic fractures.
However, it
should also be kept in mind that certain lymphoid tumors cause symptoms through the
secretion of circulating factors.
Specific examples include the plasma cell tumors, in which much of the pathophysiology is related to the secretion of whole antibodies or Ig fragments; and
Hodgkin lymphoma, which is often associated with fever related to the release of inflammatory
cytokines.
The current World Health Organization (WHO)
classification scheme ( Table 13-4 ) uses morphologic, immunophenotypic, genotypic, and
clinical fea tures to sort the lymphoid neoplasms into five broad categories, [11] which are
separated according to the cell of origin:
- Precursor B-cell neoplasms (neoplasms of immature B cells)
- Peripheral B-cell neoplasms (neoplasms of mature B cells)
- Precursor T-cell neoplasms (neoplasms of immature T cells)
- Peripheral T-cell and NK-cell neoplasms (neoplasms of mature T cells and NK cells)
- Hodgkin lymphoma (neoplasms of Reed-Sternberg cells and variants)
TABLE 13-4 – The WHO Classification of the Lymphoid Neoplasms
I. PRECURSOR B-CELL NEOPLASMS
B-cell acute lymphoblastic leukemia/lymphoma (B-ALL)
TABLE 13-4 – The WHO Classification of the Lymphoid Neoplasms
II. PERIPHERAL B-CELL NEOPLASMS
- Chronic lymphocytic leukemia/small lymphocytic lymphoma
- B-cell prolymphocytic leukemia
- Lymphoplasmacytic lymphoma
- Splenic and nodal marginal zone lymphomas
- Extranodal marginal zone lymphoma
- Mantle cell lymphoma
- Follicular lymphoma
- Marginal zone lymphoma
- Hairy cell leukemia
- Plasmacytoma/plasma cell myeloma
- Diffuse large B-cell lymphoma
- Burkitt lymphoma
TABLE 13-4 – The WHO Classification of the Lymphoid Neoplasms
III. PRECURSOR T-CELL NEOPLASMS
TABLE 13-4 – The WHO Classification of the Lymphoid Neoplasms
IV. PERIPHERAL T-CELL AND NK-CELL NEOPLASMS
- T-cell prolymphocytic leukemia
- Large granular lymphocytic leukemia
- Mycosis fungoides/Sézary syndrome
- Peripheral T-cell lymphoma, unspecified
- Anaplastic large-cell lymphoma
- Angioimmunoblastic T-cell lymphoma
- Enteropathy-associated T-cell lymphoma
- Panniculitis-like T-cell lymphoma
- Hepatosplenic γδ T-cell lymphoma
- Adult T-cell leukemia/lymphoma
- Extranodal NK/T-cell lymphoma
- NK-cell leukemia
TABLE 13-4 – The WHO Classification of the Lymphoid Neoplasms
V. HODGKIN LYMPHOMA
Classical subtypes
- Nodular sclerosis
- Mixed cellularity
- Lymphocyte-rich
- Lymphocyte depletion
Lymphocyte
predominance
important principles
relevant to the lymphoid neoplasms should be emphasized.
- Lymphoid neoplasia can be suspected from the clinical features, but histologic examination of lymph nodes or other involved tissues is required for diagnosis.
- In most lymphoid neoplasms, antigen receptor gene rearrangement precedes transformation;
- The vast majority (85% to 90%) of lymphoid neoplasms are of B-cell origin, with most of
the remainder being T-cell tumors; only rarely are tumors of NK cell origin encountered. - Lymphoid neoplasms are often associated with immune abnormalities
- Neoplastic B and T cells tend to recapitulate the behavior of their normal counterparts. Like normal lymphocytes, neoplastic B and T cells home to certain tissue sites, leading to characteristic patterns of involvement
- Hodgkin lymphoma spreads in an orderly fashion
Why do analyses of antigen receptor genes and their protein products can be used to distinguish reactive (polyclonal) and malignant (monoclonal)
lymphoid proliferations.
In most lymphoid neoplasms, antigen receptor gene rearrangement precedes transformation; hence, all of the daughter cells derived from the malignant progenitor share the same antigen receptor gene configuration and sequence, and synthesize
identical antigen receptor proteins (either Igs or T-cell receptors).
In contrast, normal
immune responses comprise polyclonal populations of lymphocytes that express many
different antigen receptors.
In addition, each antigen receptor gene rearrangement
produces a unique DNA sequence that constitutes a highly specific clonal marker, which
can be used to detect small numbers of residual malignant lymphoid cells after
therapy.
What is the vast majority (85% to 90%) of lymphoid neoplasms ?
B-cell origin, with most of
the remainder being T-cell tumors; only rarely are tumors of NK cell origin encountered.
Most lymphoid neoplasms resemble some recognizable stage of B- or Tcell
differentiation ( Fig. 13-5 ), a feature that is used in their classification.
Markers
recognized by antibodies that are helpful in the characterization of lymphomas and
leukemias are listed in Table 13-5
Lymphoid neoplasms are often associated with immune abnormalities .
T or F
True
Lymphoid neoplasms are often associated with immune abnormalities .
Both a loss of
protective immunity (susceptibility to infection) and a breakdown of tolerance (autoimmunity) can be seen, sometimes in the same patient. In a further ironic twist,
individuals with inherited or acquired immunodeficiency are themselves at high risk of
developing certain lymphoid neoplasms, particularly those caused by oncogenic viruses
(e.g., EBV).
Neoplastic B and T cells tend to recapitulate the behavior of their normal counterparts
T or F
What is a notable exception to the rule of Neoplastic B and T cells tend to recapitulate the behavior of their normal counterparts?
Hodgkin lymphomas, which are
sometimes restricted to one group of lymph nodes, and marginal zone B-cell
lymphomas, which are often restricted to sites of chronic inflammation.
In what fashion does the Hodgkin lymphoma spreads?
Hodgkin lymphoma spreads in an orderly fashion .
In contrast, most forms of NHL spread
widely early in their course in a less predictable fashion.
Hence, while lymphoma staging
provides generally useful prognostic information, it is of most utility in guiding therapy in
Hodgkin lymphoma.
FIGURE 13-5 Origin of lymphoid neoplasms. Stages of B- and T-cell differentiation from
which specific lymphoid tumors emerge are shown. CLP, common lymphoid precursor; BLB,
pre-B lymphoblast; DN, CD4/CD8 double-negative pro-T cell; DP, CD4/CD8 double-positive
pre-T cell; GC, germinal-center B cell; MC, mantle B cell; MZ, marginal zone B cell; NBC,
naive B cell; PTC, peripheral T cell.
TABLE 13-6 – Summary of Major Types of Lymphoid Leukemias and Non-Hodgkin
Lymphomas
NEOPLASMS OF IMMATURE B AND T CELLS
- B-cell acute lymphoblastic leukemia/lymphoma
- T-cell acute lymphoblastic leukemia/lymphoma
TABLE 13-6 – Summary of Major Types of Lymphoid Leukemias and Non-Hodgkin
Lymphomas
NEOPLASMS OF MATURE B CELLS
- Burkitt lymphoma
- Diffuse large B-cell lymphoma
- Extranodal marginal zone lymphoma
- Follicular lymphoma
- Hairy cell leukemia
- Mantle cell lymphoma
- Multiple myeloma/solitary plasmacytoma
- Small lymphocytic lymphoma/chronic lymphocytic
leukemia
TABLE 13-6 – Summary of Major Types of Lymphoid Leukemias and Non-Hodgkin
Lymphomas
NEOPLASMS OF MATURE T CELLS OR NK CELLS
- Adult T-cell leukemia/lymphoma
- Peripheral T-cell lymphoma, unspecified
- Anaplastic largecell lymphoma
- Extranodal NK/Tcell lymphoma
- Mycosis fungoides/Sézary syndrome
TABLE 13-6 – Summary of Major Types of Lymphoid Leukemias and Non-Hodgkin
Lymphomas
NEOPLASMS OF IMMATURE B AND T CELLS
B-cell acute lymphoblastic leukemia/lymphoma
- Diagnosis
- Cell of Origin
- Genotype
- Salient Clinical Features
- Bone marrow precursor B cell
- Diverse chromosomal translocations; t(12;21) involving CBFα and ETV6 present in 25%
- Predominantly children; symptoms relating to marrow replacement and pancytopenia; aggressive
TABLE 13-6 – Summary of Major Types of Lymphoid Leukemias and Non-Hodgkin
Lymphomas
NEOPLASMS OF IMMATURE B AND T CELLS
T-cell acute lymphoblastic
leukemia/lymphoma
- Diagnosis
- Cell of Origin
- Genotype
- Salient Clinical Features
- Precursor T cell (often of thymic origin)
- Diverse chromosomal translocations, NOTCH1 mutations (50% to 70%)
- Predominantly adolescent males; thymic masses and variable bone marrow involvement; aggressive
TAM 2x ( T-cell adolescent males)
TABLE 13-6 – Summary of Major Types of Lymphoid Leukemias and Non-Hodgkin
Lymphomas
NEOPLASMS OF MATURE B CELLS
Burkitt lymphoma
Diagnosis
Cell of Origin
Genotype
Salient Clinical Features
- Germinalcenter B cell
- Translocations involving c-MYC and lg loci, usually t(8;14); subset EBVassociated
- Adolescents or young adults with extranodal masses; uncommonly presents as “leukemia”; aggressive
TABLE 13-6 – Summary of Major Types of Lymphoid Leukemias and Non-Hodgkin
Lymphomas
NEOPLASMS OF MATURE B CELLS
Diffuse large B-cell
lymphoma
- Diagnosis
- Cell of Origin
- Genotype
- Salient Clinical Features
- Germinalcenter or post–germinalcenter B cell
- Diverse chromosomal rearrangements, most often of BCL6 (30%), BCL2 (10%), or c-MYC (5%)
- All ages, but most common in adults; often appears as a rapidly growing mass; 30% extranodal; aggressive
TABLE 13-6 – Summary of Major Types of Lymphoid Leukemias and Non-Hodgkin
Lymphomas
NEOPLASMS OF MATURE B CELLS
Extranodal
marginal zone
lymphoma
Diagnosis
Cell of Origin
Genotype
Salient Clinical Features
- Memory B cell
- t(11;18), t(1;14), and t(14;18) creating MALT1- IAP2, BCL10-IgH, and MALT1-IgH fusion genes, respectively
- Arises at extranodal sites in adults with chronic inflammatory diseases; may remain localized; indolent
TABLE 13-6 – Summary of Major Types of Lymphoid Leukemias and Non-Hodgkin
Lymphomas
NEOPLASMS OF MATURE B CELLS
Follicular
lymphoma
Diagnosis
Cell of Origin
Genotype
Salient Clinical Features
- Germinalcenter B cell
- t(14;18) creating BCL2-IgH fusion gene
- Older adults with generalized lymphadenopathy and marrow involvement; indolent
TABLE 13-6 – Summary of Major Types of Lymphoid Leukemias and Non-Hodgkin
Lymphomas
NEOPLASMS OF MATURE B CELLS
Hairy cell leukemia
Diagnosis
Cell of Origin
Genotype
Salient Clinical Features
- Memory B cell
- No specific chromosomal abnormality
- Older males with pancytopenia and splenomegaly; indolent
TABLE 13-6 – Summary of Major Types of Lymphoid Leukemias and Non-Hodgkin
Lymphomas
NEOPLASMS OF MATURE B CELLS
Mantle cell
lymphoma
Diagnosis
Cell of Origin
Genotype
Salient Clinical Features
- Naive B cell
- t(11;14) creating CyclinD1-IgH fusion gene
- Older males with disseminated disease; moderately aggressive
TABLE 13-6 – Summary of Major Types of Lymphoid Leukemias and Non-Hodgkin
Lymphomas
NEOPLASMS OF MATURE B CELLS
Multiple
myeloma/solitary
plasmacytoma
Diagnosis
Cell of Origin
Genotype
Salient Clinical Features
- Post –germinalcenter bone marrow homing plasma cell
- Diverse rearrangements involving IgH; 13q deletions
- Myeloma: older adults with lytic bone lesions, pathologic fractures, hypercalcemia, and renal failure; moderately aggressive Plasmacytoma: isolated plasma cell masses
TABLE 13-6 – Summary of Major Types of Lymphoid Leukemias and Non-Hodgkin
Lymphomas
NEOPLASMS OF MATURE B CELLS
Small lymphocytic
lymphoma/chronic
lymphocytic
leukemia
Diagnosis
Cell of Origin
Genotype
Salient Clinical Features
- Naive B cell or memory B cell
- Trisomy 12, deletions of 11q, 13q, and 17p
- Older adults with bone marrow, lymph node, spleen, and liverdisease; autoimmune hemolysisand thrombocytopenia in a minority; indolent
TABLE 13-6 – Summary of Major Types of Lymphoid Leukemias and Non-Hodgkin
Lymphomas
NEOPLASMS OF MATURE T CELLS OR NK CELLS
Adult T-cell
leukemia/lymphoma
Diagnosis
Cell of Origin
Genotype
Salient Clinical Features
- Helper T cell
- HTLV-1 provirus present in tumor cells
- Adults with cutaneous lesions, marrow involvement, and hypercalcemia; occurs mainly in Japan, West Africa, and the Caribbean; aggressive
TABLE 13-6 – Summary of Major Types of Lymphoid Leukemias and Non-Hodgkin
Lymphomas
NEOPLASMS OF MATURE T CELLS OR NK CELLS
Peripheral T-cell
lymphoma,
unspecified
Diagnosis
Cell of Origin
Genotype
Salient Clinical Features
- Helper or cytotoxic T cell
- No specific chromosomal abnormality
- Mainly older adults; usually presents with lymphadenopathy; aggressive
TABLE 13-6 – Summary of Major Types of Lymphoid Leukemias and Non-Hodgkin
Lymphomas
NEOPLASMS OF MATURE T CELLS OR NK CELLS
Anaplastic largecell
lymphoma
Diagnosis
Cell of Origin
Genotype
Salient Clinical Features
- Cytotoxic T cell
- Rearrangements of ALK Children and young adults, usually with lymph node and soft-tissue disease; aggressive
TABLE 13-6 – Summary of Major Types of Lymphoid Leukemias and Non-Hodgkin
Lymphomas
NEOPLASMS OF MATURE T CELLS OR NK CELLS
Extranodal NK/Tcell
lymphoma
Diagnosis
Cell of Origin
Genotype
Salient Clinical Features
- NK-cell (common) or cytotoxic T cell (rare)
- EBV-associated; no specific chromosomal abnormality
- Adults with destructive extranodal masses, most commonly sinonasal; aggressive
TABLE 13-6 – Summary of Major Types of Lymphoid Leukemias and Non-Hodgkin
Lymphomas
NEOPLASMS OF MATURE T CELLS OR NK CELLS
Mycosis
fungoides/Sézary
syndrome
Diagnosis
Cell of Origin
Genotype
Salient Clinical Features
- Helper T cell
- No specific chromosomalabnormality
- Adult patients with cutaneous patches, plaques, nodules, or generalized erythema; indolent
FIGURE 13-6 A, Acute lymphoblastic leukemia/lymphoma. Lymphoblasts with condensed
nuclear chromatin, small nucleoli, and scant agranular cytoplasm. B and C represent the
phenotype of the ALL shown in
A, analyzed by flow cytometry.
B, Note that the
lymphoblasts represented by the red dots express terminal deoxynucleotidyl-transferase
(TdT) and the B-cell marker CD22.
C, The same cells are positive for two other markers,
CD10 and CD19, commonly expressed on pre-B lymphoblasts. Thus, this is a B-ALL.
FIGURE 13-15 Burkitt lymphoma. A, At low power, numerous pale tingible body
macrophages are evident, producing a “starry sky” appearance. B, At high power, tumor
cells have multiple small nucleoli and high mitotic index. The lack of significant variation in
nuclear shape and size lends a monotonous appearance.
What is Immunophenotypee?
Immunostaining for terminal deoxynucleotidyl-transferase (TdT), a specialized DNA polymerase
that is expressed only in pre-B and pre-T lymphoblasts, is positive in more than 95% of cases (
Fig. 13-6B ). B- and T-ALLs are distinguished with stains for B- and T-cell–specific markers
B-ALLs are arrested at various stages of ____________
pre-B cell development._________-
The lymphoblasts usually
express what markers_________ ?
pan B-cell marker CD19 and the transcription factor PAX5, as well as CD10.
What is the pan B- cell marker?
pan B-cell marker CD19 and the transcription factor
In very
immature B-ALLs, CD10 is positive
True or False
FALSE
Its negative
Alternatively, more mature “late pre-B” ALLs express what markers?
CD10, CD19, CD20, and cytoplasmic IgM heavy chain (μ chain).
Similarly, T-ALLs are arrested at various stages of____________
pre-T cell development.
In most cases the
T cells are positive for what markers?
CD1, CD2, CD5, and CD7.
The more immature tumors are usually
negative for surface________ whereas “late” pre-T cell tumors are positive for
these markers.
CD3, CD4, and CD8,
Approximately 90% of ALLs have numerical or structural chromosomal changes . What is the most common?
hyperploidy (>50 chromosomes), but hypoploidy and a variety of balanced chromosomal
translocations are also seen.
These alterations frequently correlate with immunophenotype and
sometimes prognosis.
For example, hyperdiploidy and hypodiploidy are seen only in B-ALL.
In
addition, B- and T-ALL are associated with completely different sets of translocations, indicating
that they are pathogenetically distinct. RNA profiling using “gene chips” has also shown that
certain chromosomal translocations correlate with unique patterns of gene expression.
FIGURE 13-7 Small lymphocytic lymphoma/chronic lymphocytic leukemia (lymph node). A,
Low-power view shows diffuse efface-ment of nodal architecture. B, At high power the
majority of the tumor cells are small round lymphocytes. A “prolymphocyte,” a larger cell
with a centrally placed nucleolus, is also present in this field (arrow).
FIGURE 13-8 Chronic lymphocytic leukemia. This peripheral blood smear is flooded with
small lymphocytes with condensed chromatin and scant cytoplasm.
A characteristic finding
is the presence of disrupted tumor cells (smudge cells). A coexistent autoimmune hemolytic anemia ( Chapter 14 ) explains the presence of spherocytes (hyperchromatic, round erythrocytes).
A nucleated erythroid cell is present in the lower left-hand corner of the field. In this setting, circulating nucleated red cells could stem from premature release of progenitors in the face of severe anemia, marrow infiltration by tumor
(leukoerythroblastosis), or both.
FIGURE 13-10 Follicular lymphoma (lymph node).
- A, Nodular aggregates of lymphoma cells are present throughout lymph node.
- B, At high magnification, small lymphoid cells with condensed chromatin and irregular or cleaved nuclear outlines (centrocytes) are mixed with a population of larger cells with nucleoli (centroblasts)
FIGURE 13-11 Follicular lymphoma (spleen).
Prominent nodules represent white pulp
follicles expanded by follicular lymphoma cells. Other indolent B-cell lymphomas (small
lymphocytic lymphoma, mantle cell lymphoma, marginal zone lymphoma) can produce an
identical pattern of involvement.
FIGURE 13-12 BCL2 expression in reactive and neoplastic follicles. BCL2 protein was
detected by using an immunohistochemical technique that produces a brown stain.
In reactive follicles (A), BCL2 is present in mantle zone cells but not follicular-center B cells, whereas follicular lymphoma cells (B) show strong BCL2 staining.
FIGURE 13-13 Diffuse large B-cell lymphoma. Tumor cells have large nuclei, open
chromatin, and prominent nucleoli
FIGURE 13-14 Diffuse large B-cell lymphoma involving the spleen. The isolated large mass is typical. In contrast, indolent B-cell lymphomas usually produce multifocal expansion of white pulp (see Fig. 13-11 ).
