Chapter 12- WBC: Peripheral B-cell Neoplasms Flashcards

Question

TABLE 13-6 -- Summary of Major Types of Lymphoid Leukemias and Non-Hodgkin Lymphomas NEOPLASMS OF IMMATURE B AND T CELLS

Answer 1

* B-cell acute lymphoblastic leukemia/lymphoma * T-cell acute lymphoblastic leukemia/lymphoma

Answer 2

* 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

Answer 3

* Adult T-cell leukemia/lymphoma * Peripheral T-cell lymphoma, unspecified * Anaplastic largecell lymphoma * Extranodal NK/Tcell lymphoma * Mycosis fungoides/Sézary syndrome

Answer 4

* 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

Answer 5

* **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)**

Answer 6

* 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

Answer 7

* 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

Answer 8

* 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

Answer 9

* Germinalcenter B cell * t(14;18) creating BCL2-IgH fusion gene * Older adults with generalized lymphadenopathy and marrow involvement; indolent

Answer 10

* Memory B cell * No specific chromosomal abnormality * Older males with pancytopenia and splenomegaly; indolent

Answer 11

* Naive B cell * t(11;14) creating CyclinD1-IgH fusion gene * Older males with disseminated disease; moderately aggressive

Answer 12

* 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

Answer 13

* 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

Answer 14

* 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

Answer 15

* Helper or cytotoxic T cell * No specific chromosomal abnormality * Mainly older adults; usually presents with lymphadenopathy; aggressive

Answer 16

* Cytotoxic T cell * Rearrangements of ALK Children and young adults, usually with lymph node and soft-tissue disease; aggressive

Answer 17

* NK-cell (common) or cytotoxic T cell (rare) * EBV-associated; no specific chromosomal abnormality * Adults with destructive extranodal masses, most commonly sinonasal; aggressive

Answer 18

* Helper T cell * No specific chromosomalabnormality * Adult patients with cutaneous patches, plaques, nodules, or generalized erythema; indolent

Answer 19

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.

Answer 20

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.

Answer 21

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

Answer 22

pre-B cell development.\_\_\_\_\_\_\_\_\_-

Answer 23

**pan B-cell marker CD19** and the transcription factor **PAX5, as well as CD10.**

Answer 24

pan B-cell marker **CD19** and the transcription factor

Answer 25

FALSE Its negative

Answer 26

CD10, CD19, CD20, and cytoplasmic IgM heavy chain (μ chain).

Answer 27

pre-T cell development.

Answer 28

CD1, CD2, CD5, and CD7.

Answer 29

CD3, CD4, and CD8,

Answer 30

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.

Answer 31

PAX5, E2A, and EBF

Answer 32

TEL and AML1\_\_\_\_\_\_\_

Answer 33

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.

Answer 34

* **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

Answer 35

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

Answer 36

* (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.

Answer 37

* (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]

Answer 38

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.

Answer 39

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 ).

Answer 40

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.

Answer 41

The median age at diagnosis is **60 years,** and there is a **2 : 1 male predominance.**

Answer 42

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.**

Answer 43

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 ).

Answer 44

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).

Answer 45

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.

Answer 46

FIGURE 13-9 Small lymphocytic lymphoma/chronic lymphocytic leukemia involving the liver. Low-power view of a typical periportal lymphocytic infiltrate

Answer 47

CLL/SLL has a distinctive immunophenotype. The **tumor cells express the pan-B cell markers CD19 and CD20**, as well as**CD23 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@

Answer 48

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.

Answer 49

Patients are often **asymptomatic at diagnosis**

Answer 50

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 yea**r, 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**

Answer 51

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.

Answer 52

Conversely, 10% to 15% of patients develop hemolytic anemia or thrombocytopenia due to autoantibodies made by non-neoplastic B cells.

Answer 53

due t**o autoantibodies made by non-neoplastic B cells.**

Answer 54

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**.

Answer 55

* (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]

Answer 56

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

Answer 57

**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.

Answer 58

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 a**transformation to diffuse large B-cell lymphoma**, so-called Richter syndrome (∼5% to 10% of patients).

Answer 59

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]

Answer 60

* *Follicular lymphoma** , affecting * *15,000 to 20,000 individuals per year.**

Answer 61

It usually presents in **middle age and afflicts males and females equally.** **I**t is less common in Europe and rare in Asian populations.

Answer 62

**germinal center B cells** and is strongly associated with **chromosomal translocations involving BCL2**

Answer 63

In most cases, at **low magnification**, a **predominantly nodular or nodular and diffuse growth pattern is observed in involved lymph nodes**

Answer 64

* (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 ).

Answer 65

**small cells with irregular or** **cleaved nuclear contours** and **scant cytoplasm,** referred to as **centrocytes (small cleaved cells)**

Answer 66

**larger cells with open nuclear chromatin**, **several nucleoli,** and **modest amounts of cytoplasm**, referred to as centroblasts

Answer 67

**small cleaved cells**

Answer 68

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.

Answer 69

* Peripheral blood * Bone marrow * splenic white pulp * hepatic portal triads

Answer 70

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)

Answer 71

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.

Answer 72

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 ).

Answer 73

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.**

Answer 74

The hallmark of follicular lymphoma is a **(14;18) translocation** that **juxtaposes the IgH locus on chromosome 14**and the**BCL2 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.

Answer 75

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) i**s 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

Answer 76

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

Answer 77

Diffuse large B-cell lymphoma (DLBCL)

Answer 78

slight male predominance

Answer 79

The median patient age is about **60 years,** **but DLBCL also occurs in young adults and children.**

Answer 80

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** **" Kaya diffuse un name nya dba"**

Answer 81

* 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 cell**s with **large inclusion-like nucleoli** that **resemble Reed-Sternberg cells (the malignant cell of Hodgkin** * **lymphoma).**

Answer 82

FIGURE 13-13 Diffuse large B-cell lymphoma. Tumor cells have large nuclei, open chromatin, and prominent nucleoli

Answer 83

These mature B-cell tumors express **CD19 and CD20** and show **variable expression of germinal center B-cell markers**such as**CD10 and BCL6**. Most have surface Ig.

Answer 84

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.

Answer 85

**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.

Answer 86

* Immunodeficiency-associated large B-cell lymphoma * Primary effusion lymphoma

Answer 87

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.

Answer 88

presents as a **malignant pleural or ascitic effusion**, mostly in **patients with advanced HIV infection** or the **elderly.**

Answer 89

The tumor cells are often **anaplastic in appearance**and**typically fail to express surface B-**or**T-cell markers**, but**have clonal IgH gene rearrangements**. In all cases the tumor cells are **infected with KSHV/HHV-8** , which appears to have a causal role.

Answer 90

* 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.

Answer 91

``` 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 ). ```

Answer 92

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.

Answer 93

* (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.**

Answer 94

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 index**and**contains 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

Answer 95

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.

Answer 96

. Unlike other tumors of germinal center origin, Burkitt lymphoma **almost always fails to express the anti-apoptotic protein BCL2.**

Answer 97

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.**

Answer 98

``` 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 allele**often harbors point mutations that further increase its activity. [31] Burkitt lymphomas a**lso commonly have mutations that inactivate p53**, an event that i**ncreases the frequency of c-MYC translocations** in germinal center B cells. [9] Hence, **it is possible that preexistent defects in p53*****set the stage for the acquisition of c-MYC translocations.***

Answer 99

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.

Answer 100

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 lymphoma**are often**treated with different chemotherapeutic** regimens. Gene expression profiling may provide a more accurate assay for differentiating between these two tumors in difficult cases. [32]

Answer 101

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.

Answer 102

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.**

Answer 103

In contrast to Endemic Burkitt lymphoma, sporadic Burkitt lymphoma **most often appears as a mass involving the ileocecum**and**peritoneum**. 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.