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.
Many of the chromosomal aberrations seen in ALL dysregulate the expression and function of
transcription factors that are required for normal B- and T-cell development.
T or F
True
Up to 70% of TALLs
have gain-of-function mutations in __________ a gene that is essential for T-cell
development. [14]
NOTCH1,
On the other hand, a high fraction of B-ALLs have loss-of-function mutations
in genes that are required for B-cell development, such as ______, [15]
PAX5, E2A, and EBF
On the other hand, a high fraction of B-ALLs have loss-of-function mutations
in genes that
balanced t(12;21) involving the genes , two genes that are needed in very early hematopoietic precursors. All of these varied mutations seem to disturb the differentiation oflymphoid precursors and promote maturation arrest. As we will see, similar themes are relevant
in the genesis of AML.
TEL and AML1_______
In keeping with the multistep origin of cancer ( Chapter 7 ), single mutations are not sufficient to
produce ALL
T or F
True
This conclusion stems in part from studies of identical twins with concordant BALL.
[16] In these rare cases, the ALLs in both twins share a common chromosomal aberration
and are derived from a single clone transmitted from one twin to the other by transfusion in
utero. Despite the presence of the leukemogenic aberration at birth, ALL most often makes its
clinical appearance in such patients between 4 and 12 years of age. This lengthy prodrome is
most consistent with the existence of a “pre-leukemic” clone that must acquire additional
mutations before ALL can develop. The identity of these complementary mutations is
incomplete, but aberrations that increase growth and survival, such as activating mutations in
tyrosine kinases, are commonly present.
It should be emphasized that although ALL and AML are genetically and immunophenotypically
distinct, they are clinically very similar.
T or F
True
In both, the accumulation of neoplastic “blasts” in the
bone marrow suppresses normal hematopoiesis by physical crowding, competition for growth
factors, and other poorly understood mechanisms.
The common features and those more
characteristic of ALL are the following:
- Abrupt stormy onset within days to a few weeks of the first symptoms
- • Symptoms related to depression of marrow function , including fatigue due to anemia; fever, reflecting infections secondary to neutropenia; and bleeding due to thrombocytopenia
- • Mass effects caused by neoplastic infiltration (which are more common in ALL),
- including bone pain resulting from marrow expansion and infiltration of the subperiosteum; generalized lymphadenopathy, splenomegaly, and hepatomegaly; testicular enlargement; and in T-ALL, complications related to compression of large vessels and airways in the mediastinum
- • Central nervous system manifestations such as headache, vomiting, and nerve palsies resulting from meningeal spread, all of which are also more common in ALL
Pediatric ALL is one of the great success stories of oncology.
T or F
True
With aggressive chemotherapy
about 95% of children with ALL obtain a complete remission, and 75% to 85% are cured.
Despite these achievements, however, ALL remains the leading cause of cancer deaths in
children, and only 35% to 40% of adults are cured
Several factors have been consistently
associated with a worse prognosis of ALL :
- (1) age under 2, largely because of the strong association of infantile ALL with translocations involving the MLL gene;
- (2) presentation in adolescence or
- adulthood;
- (3) peripheral blood blast counts greater than 100,000, which probably reflects a high tumor burden; and
- (4) the presence of particular cytogenetic aberrations such as the t(9;22) (the Philadelphia chromosome). [17] The t(9;22) is present in only 3% of childhood ALL, but up to 25% of adult cases, which partially explains the poor outcome in adults.
What are the Favorable
prognostic markers of ALL include:
- (1) an age of 2 to 10 years,
- (2) a low white cell count,
- (3) hyperploidy,
- (4) trisomy of chromosomes 4, 7, and 10, and
- (5) the presence of a t(12;21). [17]
Notably, the molecular detection of residual disease after therapy is predictive of a worse outcome in both B- and T-ALL and is being used to guide new clinical trials. [12]
Although most chromosomal aberrations in ALL alter the function of transcription factors, the
t(9;22) instead creates a fusion gene that encodes a constitutively active BCR-ABL tyrosine
kinase (described in more detail under chronic myeloid leukemia).
T or F
True
What is the difference on the BCR-ABL between ALL and CLL?
In B-ALL, the BCR-ABL
protein is usually 190 kDa in size and has stronger tyrosine kinase activity than the form of
BCR-ABL that is found in chronic myeloid leukemia, in which a BCR-ABL protein of 210 kDa in
size is usually seen. Treatment of t(9;22)-positive ALLs with BCR-ABL kinase inhibitors leads to clinical responses, but patients relapse quickly because of acquired mutations in BCR-ABL that
render the tumor cells drug-resistant. [18] BCR-ABL-positive B-ALL generates mutations at a
high rate, a phenomenon referred to as genomic instability that contributes to the clinical
progression and therapeutic resistance of many aggressive malignant tumors.
What is the difference between Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL)?
These two disorders differ only in the degree of peripheral blood lymphocytosis.
Most affected
patients have sufficient lymphocytosis to fulfill the diagnostic requirement for CLL (absolute
lymphocyte count >4000 per mm3 ).
What is CLL?
CLL is the most common leukemia of adults in the Western world.
There are about 15,000 new cases of CLL each year in the United States.
The median age at diagnosis is 60 years, and there is a 2 : 1 male predominance.
In contrast, SLL
constitutes only 4% of NHLs. CLL/SLL is much less common in Japan and other Asian countries
than in the West.
What is the median age for CLL?
The median age at diagnosis is 60 years, and there is a 2 : 1 male predominance.
Wha is the pathognomonic for CLL/SLL?
Lymph nodes are diffusely effaced by an infiltrate of predominantly small lymphocytes 6 to 12 μm in diameter with round to slightly irregular nuclei, condensed
chromatin, and scant cytoplasm ( Fig. 13-7 ).
Admixed are variable numbers of larger
activated lymphocytes that often gather in loose aggregates referred to as proliferation
centers, which contain mitotically active cells.
When present, proliferation centers are
pathognomonic for CLL/SLL.
What is the microscopic appearance of CLL/ SLL?
The blood contains large numbers of small round
lymphocytes with scant cytoplasm ( Fig. 13-8 ).
Some of these cells are usually disrupted in
the process of making smears, producing so-called smudge cells.
The bone marrow is
almost always involved by interstitial infiltrates or aggregates of tumor cells.
Infiltrates are also
virtually always seen in the splenic white and red pulp and the hepatic portal tracts ( Fig. 13-9
).
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 13-9 Small lymphocytic lymphoma/chronic lymphocytic leukemia involving the
liver. Low-power view of a typical periportal lymphocytic infiltrate
What is the phenotype of CLL and SLL?
CLL/SLL has a distinctive immunophenotype.
The tumor cells express the pan-B cell markers
CD19 and CD20, as well asCD23 and CD5, the latter a marker that is found on a small subset
of normal B cells. Low-level expression of surface Ig (usually IgM or IgM and IgD) is also typical@
What is the molecular pathology of CLL/ SLL?
Unlike most other lymphoid malignancies, chromosomal translocations are rare in CLL/SLL.
The most common findings are deletions of 13q14.3, 11q, and 17p, and trisomy 12q.
Molecular
characterization of the region deleted on chromosome 13 has implicated two microRNAs, miR-
15a and miR-16-1, as possible tumor suppressor genes. [19] DNA sequencing has revealed
that the Ig genes of some CLL/SLL are somatically hypermutated, whereas others are not,
suggesting that the cell of origin may be either a postgerminal center memory B cell or a naive
B cell. For unclear reasons, tumors with unmutated Ig segments (those putatively of naive B-cell
origin) pursue a more aggressive couUnlike most other lymphoid malignancies, chromosomal translocations are rare in CLL/SLL. The
most common findings are deletions of 13q14.3, 11q, and 17p, and trisomy 12q. Molecular
characterization of the region deleted on chromosome 13 has implicated two microRNAs, miR-
15a and miR-16-1, as possible tumor suppressor genes. [19] DNA sequencing has revealed
that the Ig genes of some CLL/SLL are somatically hypermutated, whereas others are not,
suggesting that the cell of origin may be either a postgerminal center memory B cell or a naive
B cell. For unclear reasons, tumors with unmutated Ig segments (those putatively of naive B-cell
origin) pursue a more aggressive course.rse.
What are the clinical features of patients with CLL at diagnosis?
Patients are often asymptomatic at diagnosis
What are the clinical features of patients of CLL when they are symptomatic?
When symptoms appear, they are nonspecific
and include easy fatigability, weight loss, and anorexia.
- *Generalized lymphadenopathy** and
- *hepatosplenomegal**y are present in 50% to 60% of symptomatic patients.
The leukocyte count
is highly variable; leukopenia can be seen in individuals with SLL and marrow involvement, while
counts in excess of 200,000 per mm3 are sometimes seen in CLL patients with heavy tumor
burdens.
At the other end of the spectrum are asymptomatic patients that have in their peripheral blood monoclonal CD5+ B cells in numbers that are too few to merit the diagnosis of CLL.
These abnormal B cells often have some of the same chromosomal aberrations that are
seen in CLL, such as 13q deletions and trisomy 12, yet only about 1% of such patients progress to symptomatic CLL per year, presumably due to acquisition of additional genetic
lesions that have yet to be identified.
A small monoclonal Ig “spike” is present in the blood of some patients
CLL/SLL disrupts normal immune function through uncertain mechanisms.
What are the common contributors to this?
CLL/SLL disrupts normal immune function through uncertain mechanisms.
Hypogammaglobulinemia is common and contributes to an increased susceptibility to infections, particularly those caused by bacteria.
Conversely, 10% to 15% of patients develop hemolytic
anemia or thrombocytopenia due to autoantibodies made by non-neoplastic B cells.
Why does 10% to 15 % of CLL/SLL develop hemolytic
anemia or thrombocytopenia?
due to autoantibodies made by non-neoplastic B cells.
What is the course and prognosis of CLL/SLL?
The course and prognosis are extremely variable and depend primarily on the clinical stage.
Overall median survival is 4 to 6 years, but over 10 years in individuals with minimal tumor
burdens at diagnosis.
What are the Other variables that correlate with a worse outcome of CLL/SLL?
- (1) the presence of deletions of 11q and 17p,
- (2) a lack of somatic hypermutation, and
- (3) the expression of ZAP-70, a protein that augments signals produced by the Ig receptor. [19]
How are patients of CLL/SLL treated?
Patients are generally treated with “gentle” chemotherapy to control symptoms.
Immunotherapy with antibodies against proteins found on the surface of CLL/SLL cells, such as CD20 and CD52, is finding increasing use. [22]
Bone marrow transplantation is being offered to the relatively young
What is an additional factor in patient’s survival of CLL/SLL?
tendency of CLL/SLL to transform to more
aggressive tumors.
Most commonly this takes the form of a prolymphocytic transform-ation
(15% to 30% of patients) or a transformation to diffuse large B-cell lymphoma, so-called Richter
syndrome (∼5% to 10% of patients).
Prolymphocytic transformation is marked by worsening
cytopenias, increasing splenomegaly, and the appearance of increased numbers of
“prolymphocytes” (large cells with a single prominent, centrally placed nucleolus) in the
peripheral blood.
What is a Richter
syndrome ?
An additional factor in patient survival is the tendency of CLL/SLL to transform to more
aggressive tumors.
Most commonly this takes the form of a prolymphocytic transform-ation
(15% to 30% of patients)or atransformation to diffuse large B-cell lymphoma, so-called Richter
syndrome (∼5% to 10% of patients).
How to identify Prolymphocytic transformation in patients with CLL/SLL?
Prolymphocytic transformation is marked by worsening cytopenias, increasing splenomegaly, and the appearance of increased numbers of
“prolymphocytes” (large cells with a single prominent, centrally placed nucleolus)in the
peripheral blood.
Transformation to diffuse large B-cell lymphoma is often heralded by the
development of a rapidly enlarging mass within a lymph node or the spleen. These
transformations probably stem from the acquisition of additional, still unknown mutations that
increase growth.
Both prolymphocytic and large-cell transformation are ominous events, with
most patients surviving less than 1 year. [23]
What is the most common form of indolent NHL in the US?
- *Follicular lymphoma** , affecting
- *15,000 to 20,000 individuals per year.**
What age does Follicular Lymphoma presents?
It usually presents in middle age and afflicts males and
females equally.
It is less common in Europe and rare in Asian populations.
Where does The tumor of Follicular lymphoma likely
arises ?
germinal center B cells and is strongly associated with chromosomal translocations
involving BCL2
Follicular lymphoma is strongly associated with chromosomal translocations involving what?
BCL2
What is the microscopic apperance of Follicular lymphoma?
In most cases, at low magnification, a predominantly nodular or nodular and
diffuse growth pattern is observed in involved lymph nodes
What are the Two principal
cell types are present in varying proportions of Follicular lymphoma?
- (1) small cells with irregular or
- cleaved nuclear contours and scant cytoplasm, referred to as centrocytes (small cleaved cells); and (2) larger cells with open nuclear chromatin, several nucleoli, and modest amounts of cytoplasm, referred to as centroblasts ( Fig. 13-10B ).
What are centrocytes?
small cells with irregular or
cleaved nuclear contours and scant cytoplasm, referred to as centrocytes (small
cleaved cells)
What are centroblasts?
larger cells with open nuclear chromatin, several nucleoli, and modest amounts of cytoplasm, referred to as centroblasts
In most
follicular lymphomas, what cells are majority?
small cleaved cells
Peripheral blood involvement in Follicular lymphoma is
sufficient to produce lymphocytosis (usually under 20,000 cells per mm3 ) is seen in about
10% of cases.
T or F
True
What is the appearance of the Bone marrow of Follicular Lymphoma?
Bone marrow involvement occurs in 85% of cases and characteristically takes the form of paratrabecular lymphoid aggregates.
The splenic white pulp ( Fig. 13-11 ) and
hepatic portal triads are also frequently involved.
What are involved in Follicular Lymphoma?
- Peripheral blood
- Bone marrow
- splenic white pulp
- hepatic portal triads
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.
What is the immunophenotype of Follicular lymphoma?
The neoplastic cells closely resemble normal germinal center B cells, expressing CD19, CD20,
CD10, surface Ig, and BCL6.
Unlike CLL/SLL and mantle cell lymphoma, CD5 is not expressed.
BCL2 is expressed in more than 90% of cases, in distinction to normal follicular center B cells,
which are BCL2-negative ( Fig. 13-12 ).
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.
What is the hallmark of follicular lymphoma?
The hallmark of follicular lymphoma is a (14;18) translocation that juxtaposes the IgH locus on
chromosome 14and theBCL2 locus on chromosome 18.
The t(14;18) is seen in up to 90% of follicular lymphomas, and **leads to overexpression of BCL2 (see Fig. 13-12 )**.
BCL2 antagonizes apoptosis ( Chapter 7 ) and promotes the survival of follicular lymphoma cells.
Notably, while
normal germinal centers contain numerous B cells undergoing apoptosis, follicular lymphoma is
characteristically devoid of apoptotic cells.
Particularly early in the disease, follicular lymphoma cells growing in lymph nodes are found
within a network of reactive follicular dendritic cells admixed with macrophages and T cells.
Expression profiling studies have shown that differences in the genes expressed by these
reactive cells are predictive of outcome, implying that the response of follicular lymphoma cells
to therapy is somehow influenced by the surrounding microenvironment.
Wha is the clinical presentation of Follicular lymphoma?
Follicular lymphoma tends to present with painless, generalized lymphadenopathy.
Involvement of extranodal sites, such as the gastrointestinal tract, central nervous system, or testis, is relatively uncommon.
Although incurable, it usually follows an indolent waxing and waning course.
Survival (median, 7–9 years) is not improved by aggressive therapy; hence, the usual approach is to palliate patients with low-dose chemotherapy or immunotherapy (such as anti-
CD20 antibody) when they become symptomatic
Follicular lymphoma in 30% to 50% of follicular lymphomas , most commonly to
diffuse large B-cell lymphoma.
T or F
True
Less commonly, tumors resembling Burkitt lymphoma emerge that are associated with chromosomal translocations involving c-MYC. Like normal germinal
center B cells, follicular lymphomas have ongoing somatic hypermutation, which may promote
transformation by causing point mutations or chromosomal aberrations. The median survival is
less than 1 year after transformation
What is the most common form of NHL?
Diffuse large B-cell lymphoma (DLBCL)
What gender is predominated by Diffuse Large B-Cell Lymphoma?
slight male predominance
What is the median age for Diffuse large B-cell lymphoma (DLBCL) is the most common form of NHL?
The
median patient age is about 60 years, but DLBCL also occurs in young adults and children.
What are the common features of DBCL?
The common features are a relatively large cell size (usually four to
five times the diameter of a small lymphocyte)and adiffuse pattern of growth
” Kaya diffuse un name nya dba”
What is the morphology of DCBL?
- The common features are a relatively large cell size (usually four to five times the diameter of a small lymphocyte) and a diffuse pattern of growth ( Fig. 13-13 ).
- In other respects, substantial morphologic variation is seen.
- Most commonly, the tumor cells have a round or oval nucleus that appears vesicular due to margination of chromatin to the nuclear membrane, but large multilobated or cleaved nuclei are prominent in some cases.
- Nucleoli may be two to three in number and
- *located adjacent to the nuclear** membrane, or single and centrally placed.
- The cytoplasm is usually moderately abundant and may be pale or basophilic.
- More anaplastic tumors may even contain multinucleated cells with large inclusion-like nucleoli that resemble Reed-Sternberg cells (the malignant cell of Hodgkin
- lymphoma).
FIGURE 13-13 Diffuse large B-cell lymphoma. Tumor cells have large nuclei, open
chromatin, and prominent nucleoli
What is the Immunophenotype of DCBL?
These mature B-cell tumors express CD19 and CD20 and show variable expression of germinal
center B-cell markerssuch asCD10 and BCL6.
Most have surface Ig.
What is the molecular pathogenesis of DBCL?
DLBCL
is heterogeneous.
- One frequent pathogenic event is dysregulation of BCL6, a DNAbinding zinc-finger transcriptional repressor that is required for the formation of normal germinal centers
- About 30% of DLBCLs contain various translocations that have in common a breakpoint in BCL6 at chromosome 3q27
- Acquired mutations in BCL6 promoter sequences thatabrogate BCL6 autoregulation (an important negative-regulatory mechanism) are seen even more frequently.
- It is hypothesized that both types of lesions are inadvertent byproducts of somatic hypermutation that result in overexpression of BCL6, which has several important consequences.
- BCL6 represses the expression of factors that promote germinal center B-cell differentiation and growth arrest, and thereby holds cells in a relatively undifferentiated, proliferative state. [28,] [29]
- BCL6 can also silence the expression of p53, the “guardian of the genome” ( Chapter 7 ). [30] This “anti-p53” activity may serve to prevent the activation of DNA repair mechanisms in germinal center B cells undergoing somatic hypermutation and class switch recombination.
- Each of these activities is believed to contribute to the development of DLBCL.
- Mutations similar to those found in BCL6 are also seen in multiple other oncogenes,
- including c-MYC, [10] suggesting that somatic hypermutation in DLBCL cells is “mistargeted” to a wide variety of loci.
Another 10% to 20% of tumors of DBCL are associated with what?
the t(14;18) , which (as discussed under
follicular lymphoma) leads to the overexpression of the anti-apoptotic protein BCL2.
Tumors with BCL2 rearrangements almost always lack BCL6 rearrangements, suggesting that these
rearrangements define two distinct molecular classes of DLBCL.
Some tumors with BCL2 rearrangements may arise from unrecognized underlying follicular lymphomas, which (as discussed already) frequently transform to DLBCL.
Special Subtypes Associated with Oncogenic Herpesviruses
Several other subtypes of DLBCL are sufficiently distinctive to merit brief discussion.
- Immunodeficiency-associated large B-cell lymphoma
- Primary effusion lymphoma
Where does Immunodeficiency-associated large B-cell lymphoma occurs?
occurs in the setting of severe Tcell immunodeficiency (e.g., advanced HIV infection and allogeneic bone marrow
transplantation).
The neoplastic B cells are usually infected with EBV, which plays a critical pathogenic role.
Restoration of T-cell immunity may lead to regression of these proliferations.
What is the presentation of Primary effusion lymphoma?
presents as a malignant pleural or ascitic effusion, mostly in patients with advanced HIV infection or the elderly.
What is the microscopic appearance of tumor cells of Primary effusion lymphoma?
The tumor cells are often anaplastic
in appearanceandtypically fail to express surface B-orT-cell markers, buthave clonal
IgH gene rearrangements.
In all cases the tumor cells are infected with KSHV/HHV-8 ,
which appears to have a causal role.
What is the clinical feature of DCBL?
- typically presents as a rapidly enlarging mass at a nodal or extranodal site.
- It can arise virtually anywhere in the body. Waldeyer ring, the oropharyngeal lymphoid tissue that includes the tonsils and adenoids, is involved commonly.
- Primary or secondary involvement of the liver and spleen may take the form of large destructive masses ( Fig. 13-14 ).
- Extranodal sites include the gastrointestinal tract, skin, bone, brain, and other tissues.
- Bone marrow involvement is relatively uncommon and usually occurs late in the course.
- Rarely, a leukemic picture emerges.
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 ).
What is the treatment of DCBLs?
DLBCLs are aggressive tumors that are rapidly fatal without treatment.
- With intensive combination chemotherapy, 60% to 80% of patients achieve a complete remission, and 40% to 50% are cured.
- Immunotherapy with anti-CD20 antibody seems to improve both the initial response and the overall outcome, particularly in the elderly. Individuals with limited disease fare better than those with widespread disease or bulky tumor masses.
- Expression profiling has identified distinct molecular subtypes with differing clinical outcomes and led to new targeted therapeutic approaches directed at components of the NF-κB and B cell receptor signaling pathways.
What are the categories of Burkitt lymphomz
- (1) African (endemic) Burkitt lymphoma,
- (2) sporadic (nonendemic) Burkitt lymphoma, and
- (3) a subset of aggressive lymphomas occurring in individuals infected with HIV.
Burkitt lymphomas occurring in each of these settings are histologically identical but
differ in some clinical, genotypic, and virologic characteristics.
What is the morphology of Burkitt Lymphoma?
Involved tissues are effaced by a diffuse infiltrate of intermediate-sized lymphoid cells 10 to 25 μm in diameter with round or oval nuclei, coarse chromatin, several nucleoli, and a moderate amount of cytoplasm ( Fig. 13-15 ).
The tumor exhibits a high
mitotic indexandcontains numerous apoptotic cells, the nuclear remnants of which
are phagocytosed by interspersed benign macrophages.
These phagocytes have abundant
clear cytoplasm,creating a characteristic“starry sky” pattern.
When the bone marrow is
involved, aspirates reveal tumor cells with slightly clumped nuclear chromatin, two to five distinct nucleoli, and royal blue cytoplasm containing clear cytoplasmic vacuoles
What is the immunotype of Burkitt lymphoma?
These are tumors of mature B cells that express surface IgM, CD19, CD20, CD10, and BCL6, a
phenotype consistent with a germinal center B-cell origin.
These are tumors of mature B cells that express surface IgM, CD19, CD20, CD10, and BCL6, a
phenotype consistent with a germinal center B-cell origin. Unlike other tumors of germinal
center origin, Burkitt lymphoma almost always fails to express the anti-apoptotic protein BCL2.
What is uniqe to Burkitt lymphoma unlike other tumors of germinal center origin?
. Unlike other tumors of germinal
center origin, Burkitt lymphoma almost always fails to express the anti-apoptotic protein BCL2.
What is the molecular pathogenesis of Burkitt lymphoma?
All forms of Burkitt lymphoma are associated with translocations of the c-MYC gene on
chromosome 8.
The translocation partner is usually the IgH locus [t(8;14)] but may also be the
Ig κ [t(2;8)] or γ [t(8;22)] light-chain loci.
Discuss the molecular pathogenesis of Burkitt lymphoma.
The **breakpoints in the IgH locus in sporadic** Burkitt lymphoma are **usually found in the class switch regions**, whereas the **breakpoints in endemic Burkitt lymphoma tend to lie within more 5′ V(D)J sequences**.
The basis for this subtle molecular
distinction is not known, but both types of translocations can be induced in germinal center B
cells by AID, [8,] [9] which you will recall is a specialized DNA-modifying enzyme that is required
for both Ig class switching and somatic hypermutation.
The net effect of these translocations is
similar; the c-MYC coding sequence is repositioned adjacent to strong Ig promoter and
enhancer elements, which drive increased c-MYC expression. In addition, the translocated c-
MYC alleleoften harbors point mutations that further increase its activity. [31]
Burkitt lymphomas also commonly have mutations that inactivate p53, an event that increases the
frequency of c-MYC translocations in germinal center B cells. [9]
Hence, it is possible that preexistent
defects in p53set the stage for the acquisition of c-MYC translocations.
Essentially all endemic tumors are latently infected with what , which is also present in about
25% of HIV-associated tumors and 15% to 20% of sporadic cases.
EBV
The configuration of the EBV
DNA is identical in all tumor cells within individual cases, indicating that infection precedes
transformation.
Although this places EBV at the “scene of the crime,” its precise role in the genesis of Burkitt lymphoma remains poorly understood.
Why is DCBL difficult to distinguish from Burkiit Lymphoma?
About 5% of DLBCLs have c-MYC translocations, and in such instances DLBCL may be difficult
to distinguish from Burkitt lymphoma by conventional diagnostic tests.
This distinction can be
important, since DLBCL and Burkitt lymphomaare oftentreated with different chemotherapeutic
regimens. Gene expression profiling may provide a more accurate assay for differentiating
between these two tumors in difficult cases. [32]
What is the clinical feature of Burkitt Lymphoma?
Both endemic and sporadic Burkitt lymphomas are found mainly in children or young adults;
overall, it accounts for about 30% of childhood NHLs in the United States.
Most tumors manifest
at extranodal sites.
WHat is the presentation of Endemic Burkitt lymphoma?
often presents as a mass involving the mandible and shows an unusual predilection for involvement of abdominal viscera, particularly the kidneys, ovaries, and adrenal glands.
What is the presentation , sporadic Burkitt lymphoma
In contrast to Endemic Burkitt lymphoma, sporadic Burkitt lymphoma most often
appears as a mass involving the ileocecumandperitoneum.
Involvement of the bone marrow
and peripheral blood is uncommon, especially in endemic cases.
Burkitt lymphoma is very
aggressive but responds well to intensive chemotherapy.
Most children and young adults can
be cured.The outcome is more guarded in older adults.
