Lymphadepathy

Question 1

How do lymphocytes bind to lymph nodes

Answer 1

Following their initial development from precursors in the central (also called primary) lymphoid organs- the bone marrow for B cells and the thymus for T cells - lymphocytes circulate through the blood and, under the influence of specific cytokines and chemokines, home to lymph nodes, spleen, tonsils, adenoids, and Peer patches, which constitute the peripheral (secondary) lymphoid tissues.

Question 2

What is follicular hyperplasia

Answer 2

Follicular hyperplasia is caused by stimuli that activate humoral immune responses. It is defined by the presence of large oblong germinal centers (secondary follicles), which are surrounded by a collar of small resting naive B cells (the mantle zone) (Fig. 13.3).
Germinal centers are polarized, consisting of two distinct regions:
(1) a dark zone with proliferating blast-like B cells (centroblasts) and (2) a light zone composed of B cells with irregular or cleaved nuclear contours (centrocytes). Interspersed among the germinal center B cells is an inconspicuous network of antigen-presenting follicular dendritic cells and macrophages (often referred to as tingible-body macrophages) containing the nuclear debris of B cells, which undergo apoptosis if they fail to produce an antibody with a high affinity for antigen.

Question 3

What are some causes of follicular hyperplasia

Answer 3

Causes of follicular hyperplasia include rheumatoid arthritis, toxoplasmosis, and early HIV infection. This form of hyperplasia is morphologically similar to follicular lymphoma (discussed later).
Features favoring a reactive (nonneoplastic) hyperplasia include
(1) preservation of the lymph node architecture, including the interfollicular T-cell zones and the sinusoids, (2) marked variation in the shape and size of the follicles, and (3) the presence of frequent mitotic figures, phagocytic macrophages, and recognizable light and dark zones, all of which tend to be absent from neoplastic follicles.

Question 4

What is paracortical hyperplasia

Answer 4

Paracortical hyperplasia is caused by stimuli that trigger T-cell-mediated immune responses, such as acute viral infections (e.g., infectious mononucleosis). The T-cell regions typically contain immunoblasts, activated T cells three to four times the size of resting lymphocytes that have round nuclei, open chromatin, several prominent nucleoli, and moderate amounts of pale cytoplasm.

The expanded T-cell zones encroach on and, in particularly exuberant reactions, may efface the B-cell follicles. In such cases, immunoblasts are so numerous that special studies may be needed to exclude a lymphoid neoplasm. In addition, there is often hypertrophy of sinusoidal and vascular endothelial cells, sometimes accompanied by infiltrating macrophages and eosinophils.

Question 5

What is sinus histiocytosis

Answer 5

Sinus histiocytosis (also called reticular hyperplasia) is marked by an increase in the number and size of the endothelial cells that line lymphatic sinusoids and increased numbers of intrasinu-soidal macrophages, which expand and distort the sinusoids. This form of hyperplasia may be particularly prominent in lymph nodes draining cancers such as carcinoma of the breast.

Question 6

Mention some common areas where chronic lymphadenitis is found

Answer 6

Chronic lymphadenitis is particularly common in inguinal and axillary nodes, which drain relatively large areas of the body and are frequently stimulated by immune reactions to trivial injuries and infections of the extremities.

Question 7

What is Hodgkin’s lymphoma

Answer 7

Hodgkin lymphoma encompasses a group of lymphoid neoplasms that differ from NHL in several respects (Table
13.7). While NHLs frequently occur at extranodal sites and spread in an unpredictable fashion, Hodgkin lymphoma arises in a single node or chain of nodes and spreads first to anatomically contiguous lymphoid tissues. Morphologi-cally, the distinctive feature of Hodgkin lymphoma is the presence of neoplastic giant cells called Reed-Sternberg cells. These cells release factors that induce the accumulation of reactive lymphocytes, macrophages, and granulocytes, which typically make up greater than 90% of the tumor cellularity. Molecular studies have shown that the neoplastic Reed-Sternberg cells are derived from germinal center or post-germinal center B cells.
Hodgkin lymphoma accounts for 0.7% of all new cancers in the United States; there are about 8000 cases each year.
The average age at diagnosis is 32 years. It is one of the most common cancers of young adults and adolescents, but also occurs in the aged. It was the first human cancer to be successfully treated with radiation therapy and chemotherapy and is curable in most cases.

Question 8

The WHO classification recognizes five subtypes of Hodgkin lymphoma
What are they

Answer 8

1. Nodular sclerosis
2. Mixed cellularity
3. Lymphocyte-rich
4. Lymphocyte depletion
5. Nodular lymphocyte predominance

Question 9

In the first four subtypes -nodular sclerosis, mixed cellularity, lymphocyte-rich, and lymphocyte depletion - the Reed-Sternberg cells have a similar distinctive immunophe-notype. These subtypes are often lumped together as classic forms of Hodgkin lymphoma. In the remaining subtype, lymphocyte predominance, the Reed-Sternberg cells have a B-cell immunophenotype that differs from that of the classic types
True or false

Answer 9

True

Question 10

What is the pathogenesis of Hodgkin’s lymphoma

Answer 10

The origin of the neoplastic Reed-Sternberg cells of classic Hodgkin lymphoma was solved through elegant molecular studies of single isolated Reed-Sternberg cells. These revealed clonal IGH gene rearrangements and the telltale signs of somatic hypermutation, establishing that Reed-Sternberg cells originate from a germinal center or post-germinal center B cell. Despite their B-cell origin, the Reed-Sternberg cells of classic Hodgkin lymphoma fail to express most B-cell-specific genes, including the Ig genes. The cause of this wholesale reprogramming of gene expression has yet to be explained and presumably results from widespread epi-genetic changes of uncertain etiology.
Activation of the transcription factor NF-kB is a common event in classic Hodgkin lymphoma and turns on genes that are believed to promote the growth and survival of Reed-Sternberg cells. This can occur by several mechanisms:
• EBV+ tumor cells express latent membrane protein-1
(LMP-1), a protein encoded by the EBV genome that transmits signals that up-regulate NF-B.
• Activation of NF-KB mav occur in EBV- tumors as a result of acquired loss-of-function mutations in IkB or TNF-a-induced protein 3, both of which are negative regulators of NF-kB.
It is hypothesized that activation of NF-KB rescues
“crippled” germinal center B cells that cannot express g from apoptosis, setting the stage for the acquisition of other unknown mutations that collaborate to produce Reed-Sternberg cells. Little is known about the basis for the morphology of Reed-Sternberg cells and variants, but it is intriguing that EBV-infected B cells resembling Reed-Sternberg cells may be found in the lymph nodes of individuals with infectious mononucleosis, strongly suggesting that EBV-encoded proteins play a part in the remarkable metamorphosis of B cells into Reed-Sternberg cells.
Reed-Sternberg cells are aneuploid and possess diverse clonal chromosomal aberrations. Copy number gains in the REL proto-oncogene on chromosome 2p are particularly common and may also contribute to increases in NF-KB activity. Also frequent are copy number gains in genes encoding PD-L1 and PD-L2, located together on chromosome 9p, which you will recall are immune checkpoint proteins that inhibit antitumor T-cell responses (Chapter 7).
The florid accumulation of reactive cells in tissues involved by classic Hodgkin lymphoma occurs in response to a wide variety of cytokines (e.g., IL-5, IL-10, and M-CSF), chemokines (e.g., eotaxin), and other factors that are secreted by Reed-Sternberg cells. Once attracted, the reactive cells produce factors that support the growth and survival of the tumor cells and further modify the reactive cell response.
For example, eosinophils and T cells express ligands that activate the CD30 and CD40 receptors found on Reed-Sternberg cells, producing signals that up-regulate NF-B.
Although Reed-Sternberg cells induce a host response, it is ineffective because of factors produced by the Reed-Sternberg cells. Most notably among these factors are PD-L1 and PD-L2, which antagonize cytotoxic T-cell responses.

Question 11

What are Reed-Sternberg cells

Answer 11

the diagnosis. Diagnostic Reed-Sternberg cells are large cells (45 Mm in diameter) with multiple nuclei or a single nucleus with multiple nuclear lobes, each with a large inclusion-like nucleolus about the size of a small lymphocyte (5 to 7 um in diameter) abundant. Several Reed-Sternberg cell variants are also recognized.

Question 12

What are some variants of Reed-Sternberg cells

Answer 12

Mononuclear variants
Lacunar cells
Lymphohistiocytic variants (L&H cells)

Question 13

Describe the mononuclear variant

Answer 13

Mononuclear variants contain a single nucleus with a large inclusion-like nucleolus

Question 14

Describe the lacunar cell variant

Answer 14

Lacunar cells (seen in the nodular sclerosis subtype) have more delicate, folded, or multilobate nuclei and abundant pale cytoplasm that is often disrupted during the cutting of sections, leaving the nucleus sitting in an empty space (a lacuna)

Question 15

What is the name of the death a Reed-Sternberg cells undergoes in a classical Hodgkin

Answer 15

In classic forms of Hodgkin lymphoma, Reed-Sternberg cells undergo a peculiar form of cell death in which the cells shrink and become pyknotic, a process described as “mummification.”

Question 16

Describe the lymphohistiocytic variants

Answer 16

Lymphohistiocytic variants (L&H cells) with polypoid nuclei, inconspicuous nucleoli, and moderately abundant cytoplasm are characteristic of the lymphocyte predominance subtype

Question 17

Describe the nodular sclerosis type of Hodgkin’s

Answer 17

Nodular Sclerosis Type. This is the most common form of Hodgkin lymphoma, constituting 65% to 70% of cases. It is characterized by the presence of lacunar variant Reed-Sternberg cells and the deposition of collagen in bands that divide involved lymph nodes into circumscribed nodules (Fig. 13.25). The fibrosis may be scant or abundant. The Reed-Sternberg cells are found in a polymorphous background ofT cells, eosinophils, plasma cells, and macrophages. Diagnostic Reed-Sternberg cells are often uncom-mon. The Reed-Sternberg cells in this and other classic Hodgkin lymphoma subtypes have a characteristic immunophenotype; they are positive for PAX5 (a B-cell transcription factor), CD 15, and CD30 and negative for other B-cell markers, T-cell markers, and CD45 (leukocyte common antigen).As in other forms of Hodgkin lymphoma, involvement of the spleen, liver, bone marrow, and other organs and tissues may appear in due course in the form of irregular tumor nodules resembling those seen in lymph nodes.
This subtype is uncommonly associated with EBV.
The nodular sclerosis type occurs with equal frequency in males and females. It has a propensity to involve the lower cervical, supraclavicular, and mediastinal lymph nodes of adolescents or young adults. The prognosis is excellent.

Question 18

Describe the mixed-cellularity type of Hodgkin’s

Answer 18

Mixed-Cellularity Type. This form of Hodgkin lymphoma constitutes about 20% to 25% of cases. Involved lymph nodes are diffusely effaced by a heterogeneous cellular infiltrate, which includes T cells, eosinophils, plasma cells, and benign macrophages admixed with Reed-Sternberg cells (Fig. 13.26). Diagnostic Reed-Sternberg cells and mononuclear variants are usually plentiful. The Reed-Sternberg cells are infected with EBV in about 70% of cases. The immunophenotype is identical to that observed in the nodular sclerosis type.
Mixed-cellularity Hodgkin lymphoma is more common in males.
Compared with the lymphocyte predominance and nodular sclerosis subtypes, it is more likely to be associated with older age, systemic symptoms such as night sweats and weight loss, and advanced tumor stage. Nonetheless, the overall prognosis is very good.

Question 19

Describe the lymphocyte-rich type of Hodgkin’s

Answer 19

Lymphocyte-Rich Type. This is an uncommon form of classic Hodgkin lymphoma in which reactive lymphocytes make up the vast majority of the cellular infiltrate. In most cases, involved lymph nodes are diffusely effaced, but vague nodularity due to the presence of residual B-cell follicles is sometimes seen.
This entity is distinguished from the lymphocyte predominance type by the presence of frequent mononuclear variants and diagnostic Reed-Sternberg cells with a “classic” immunophenotypic profile. It is associated with EBV in about 40% of cases and has a very good to excellent prognosis.

Question 20

Describe the lymphocyte-depleted type of Hodgkin’s

Answer 20

Lymphocyte Depletion Type. This is the least common form of Hodgkin lymphoma, amounting to less than 5% of cases. It is characterized by a paucity of lymphocytes and a relative abundance of Reed-Sternberg cells or their pleomorphic variants. The immunophenotype of the Reed-Sternberg cells is identical to that seen in other classic types of Hodgkin lymphoma. Immunophe-notyping is essential, since most tumors suspected of being lymphocyte depletion Hodgkin lymphomas actually prove to be large-cell NHLs. The Reed-Sternberg cells are infected with EBV in over 90% of cases.
Lymphocyte depletion Hodgkin lymphoma occurs predominantly in older adults, in HIV-positive individuals of any age, and in individuals living in lower-income countries. Advanced stage and systemic symptoms are frequent, and the overall outcome is less favorable than in the other subtypes.

Question 21

Describe the nodular lymphocyte predominance type

Answer 21

Nodular Lymphocyte Predominance Type. This uncommon “nonclas-sic” variant of Hodgkin lymphoma accounts for about 5% of cases.
Involved nodes are effaced by nodules of small lymphocytes admixed with variable numbers of macrophages (Fig. 13.27).
“Classic” Reed-Sternberg cells are usually difficult to find. Instead, this tumor contains so-called L&H variants with multilobed nuclei resembling popcorn kernels (popcorn cell). Eosinophils and plasma cells are usually scant or absent.
In contrast to the Reed-Sternberg cells found in classic forms of Hodgkin lymphoma, L&H variants express B-cell markers typical of germinal center B cells, such as CD20 and BCL6, and are usually negative for CD 15 and CD30. The nodular pattern of growth is due to the presence of expanded B-cell follicles populated by L&H variants, numerous reactive B cells, and follicular dendritic cells. The IGH genes of the L&H variants show evidence of ongoing somatic hypermutation, further marking these cells as transformed germinal center B cells. In 3% to 5% of cases, this type transforms into a tumor resembling diffuse large B-cell lymphoma. EBV is rarely associated with this subtype.
A majority of patients are males, usually younger than 35 years of age, presenting with cervical or axillary lymphadenopathy.
Mediastinal and bone marrow involvement is rare. In some series, this form of Hodgkin lymphoma is more likely to recur than the classic subtypes, but the prognosis is excellent.

Question 22

What are some clinical features of Hodgkin’s lymphoma

Answer 22

Hodgkin lymphoma most commonly presents as painless lymphadenopathy. Patients with the nodular sclerosis or lymphocyte predominance types tend to have stage I or II disease and are usually free of systemic manifestations.
Patients with disseminated disease (stages Ill and IV) or the mixed-cellularity or lymphocyte depletion subtypes are more likely to have constitutional symptoms such as fever, night sweats, and weight loss. Cutaneous immune unre-sponsiveness (also called anergy) resulting from depressed cell-mediated immunity is seen in most cases of classic Hodgkin lymphoma and is attributable to the expression of factors such as IL-10 by Reed-Sternberg cells that suppress Th1 immune responses. This is but one of many examples of cross-talk between Reed-Sternberg cells, various stromal cells, and immune cells (Fig. 13.28).
The spread of Hodgkin lymphoma is remarkably ste-reotypic: nodal disease first, then splenic disease, hepatic disease, and finally involvement of the marrow and other tissues. Staging involves physical examination; radiologic imaging of the abdomen, pelvis, and chest; and biopsy of the bone marrow (Table 13.9). With current treatment protocols, tumor stage rather than histologic type is the most important prognostic variable. The cure rate of patients with stages I and IIA is close to 90%. Even with advanced disease (stages IVA and IVB), disease-free survival at 5 years is 60% to 70%.
Low-stage localized Hodgkin lymphoma can be cured with involved field radiotherapy, and indeed cure of such patients was one of the early success stories in oncology.
However, it was subsequently recognized that long-term survivors treated with radiotherapy had a much higher incidence of certain other malignancies, including lung cancer, melanoma, and breast cancer. Patients treated with early chemotherapy regimens containing alkylating agents also had a high incidence of secondary tumors, particularly AML. These sobering results spurred the development of current treatment regimens, which minimize the use of radiotherapy and employ less genotoxic chemotherapeutic agents; as a result, the incidence of secondary tumors appears to have been reduced markedly, without any loss of therapeutic efficacy.
For patients with classic Hodgkin lymphoma who fail conventional therapy, immune checkpoint inhibitors that block PD-1, the receptor for PD-L1 and PD-L2, have proven to be highly effective. These agents prevent the CD8+ cvtotoxic T-cell “exhaustion” that is caused by PD-L1 and PD-L2 expressed on Reed-Sternberg cells (see Fig. 13.28) and lead to sustained responses in almost 90% of cases. indeed, classic Hodgkin lymphoma appears to be the human cancer that is most responsive to immune checkpoint inhibitor therapy.

Question 23

Neoplasms that present with widespread involvement of the bone marrow and (usually, but not always) the peripheral blood are called leukemias. Proliferations of white cells, typically lymphocytes, that usually present as discrete tissue masses are called lymphomas.
True or false

Answer 23

True

Question 24

What are the five broad lymphoid neoplasm categorizations

Answer 24

1. Precursor B-cell neoplasms (neoplasms of immature
   B cells)
2. Peripheral B-cell neoplasms (neoplasms of mature B cells)
3. Precursor T-cell neoplasms (neoplasms of immature T cells)
4. Peripheral T-cell and NK-cell neoplasms (neoplasms of mature T cells and NK cells)
5. Hodgkin lymphomas (neoplasms of Reed-Sternberg cells and variants)

Question 25

What are some principles of lymphoid neoplasms

Answer 25

Lymphoid neoplasia can be suspected based on clinical features, but histologic examination of lymph nodes or other involved tissues is required for diagnosis. Analysis of lineage-specific protein (marker) expression and genetic alterations is an important complement to the morphologic studies.
Markers recognized by antibodies that are helpful in the characterization of lymphomas and leukemias are listed in Table 13.5.
• Antigen receptor gene rearrangement generally precedes transformation of lymphoid cells; hence all 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 are comprised of polyclonal populations of lymphocytes that express many different antigen receptors. Thus, analyses of antigen receptor genes and their protein products can be used to distinguish reactive (polyclonal) and malignant (monoclonal) lymphoid proliferations. 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.
• Most lymphoid neoplasms resemble some recognizable stage of B- or T-cell differentiation (Fig. 13.5), a feature that is used in their classification. The vast majority (85% to 90%) of lymphoid neoplasms are of B-cell origin, with most of the remainder being T-cell tumors; tumors of NK-cell origin are rare.
• Lymphoid neoplasms are often associated with immune abnormalities. Both a loss of protective immunity (sus-ceptibility to infection) and a breakdown of tolerance (autoimmunity) may 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. Like normal lymphocytes, neoplastic B and T cells express adhesion molecules and chemokine receptors that govern their homing to certain tissue sites, leading to characteristic patterns of involve-ment. For example, follicular lymphomas home to germinal centers in lymph nodes, whereas cutaneous I-cell lymphomas home to the skin. Variable numbers of neoplastic B and T lymphoid cells also recirculate through the lymphatics and peripheral blood to distant sites; as a result, most lymphoid tumors are widely disseminated at the time of diagnosis. Notable exceptions to this rule include 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.

Hodgkin lymphoma spreads in an orderly stepwise fashion, whereas most forms of NHL disseminate widely and somewhat unpredictably early in their course. Hence, while lymphoma staging provides useful prognostic information, it is of most utility in guiding therapy in Hodgkin lymphoma.

Question 26

What is follicular lymphoma

Answer 26

Follicular lymphoma is the most common form of indolent
NHL in the United States, trailing only diffuse large B-cell lymphoma (discussed later) in frequency among lymphomas.

Question 27

What is the pathogenesis of follicular lymphoma

Answer 27

Follicular lymphoma is strongly associated with chromosomal translocations involving BCL2. Its hallmark 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 (Chapters 2 and 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. Deep sequencing of follicular lymphoma genomes have identified mutations in the KMT2D gene in about 90% of cases as well. KMT2D encodes a histone methyltransferase, suggesting that epigenetic abnormalities such as changes in the patterns of histone marks have an important role in this neoplasm.
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 stromal cells are predictive of outcome, implying that the response of follicular lymphoma cells to therapy is influenced by the surrounding microenvironment.

Question 28

What are the clinical features of follicular lymphoma

Answer 28

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 to 9 years) is not improved by aggressive therapy; hence the usual approach is to palliate patients with low-dose chemotherapy or immunotherapy (e.g., anti-CD20 antibody) when they become symptomatic. Like CLL, it also is responsive to inhibitors of B-cell receptor signaling (e.g., BTK inhibitors) and inhibitors of BCL2.
Histologic transformation occurs in 30% to 50% of follicular lymphomas, most commonly to DILBCL. These transformation events are frequently associated with aberrations that increase the expression of MYC, which you will recall drives Warburg metabolism and rapid cell growth.
Follicular lymphomas show evidence of ongoing somatic hypermutation, which may promote transformation by causing point mutations or chromosomal aberrations. The median survival is less than 1 year after transformation.

Question 29

What is the most common form of non-Hodgkin’s lymphoma

Answer 29

Diffuse large B cell lymphoma

Question 30

What is the pathogenesis of diffuse large b-cell neoplasia

Answer 30

Genetic, gene expression profiling, and immunohistochemical studies indicate that DLBCL is molecularly heterogeneous.
One frequent pathogenic event is dysregulation of BCL6, a DNA-binding 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 327. Acquired mutations in BCL6 promoter sequences that abrogate BCL6 autoregulation (an important negative-regulatory mecha-nism) are seen even more frequently. It is hypothesized that both types of lesions are inadvertent by-products of somatic hypermutation that result in overexpression of BCL6, which has several important consequences. BCL6 represses the expression of factors that normally serve to promote germinal center B-cell differentiation, growth arrest, and apoptosis, and each of these effects is believed to contribute to the development of DLBCL. Mutations similar to those found in BCL6 are also seen in multiple other oncogenes, including MYC, suggesting that somatic hypermutation in DLBCL cells is’
“mistargeted” to a wide variety of loci.
Another 10% to 20% of tumors are associated with the t(14;18) (discussed earlier under Follicular Lymphoma), which leads to the overexpression of the antiapoptotic protein BCL2. Tumors with BCL2 rearrangements usually 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 frequently transform to DLBCL. Roughly 5% of DLBCLs are associated with translocations involving MYC; these tumors may have a distinctive biology (discussed later under Burkitt lymphoma).
Finally, sequencing of DLBCL genomes has identified frequent mutations in genes encoding histone acetyltransferases such as p300 and CREBP, proteins that regulate gene expression by modifying histones and altering chromatin Structure.

Question 31

Describe a diffuse large B cell

Answer 31

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). Other morphologic features show substantial variation. 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 irregular 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 contain multinucleated cells with large inclusion-like nucleoli that resemble Reed-Sternberg cells (the malignant cell of Hodgkin lymphoma).

Question 32

What is the immunephenotype of a diffuse large B cell lymphoma

Answer 32

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. High-level expression of both MYC and BCL2 proteins is seen in some cases and may predict more aggressive behavior.

Question 33

What are some clinical features of diffuse large b-cell lymphoma

Answer 33

DLBCL typically presents as a rapidly enlarging mass at a nodal or extranodal site. It can arise virtuall anvwhere 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.

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.
DLBCLs are aggressive tumors that are rapidly fatal without treatment. With intensive combination chemo-therapy, 60% to 80% of patients achieve a complete remission, and 40% to 50% are cured. Adjuvant therapy with anti-CD20 antibody improves both the initial response and the overall outcome. Individuals with limited disease fare better than those with widespread disease or bulky tumor masses.
Expression profiling has identified several distinct molecular subtypes, including one resembling germinal center B cells and a second resembling activated post-germinal center B cells, each with differing clinical outcomes. DLBCLs with MYC translocations have a worse prognosis than those without and may be better treated with chemotherapy regimens that are now standard for Burkitt lymphoma. CAR cells directed against the B-cell antigen CD19 are now available for the treatment of patients with relapsed refractory DLBCL.

Question 34

What is Burkitt’s lymphoma

Answer 34

Within the category of Burkitt lymphoma fall (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 these three settings are histologically identical but have distinct clinical, genotypic, and virologic characteristics.

Question 35

What is the pathogenesis of Burkitt’s lymphoma

Answer 35

All forms of Burkitt lymphoma are associated with translocations of the MYC gene on chromosome 8 that lead to increased MYC protein levels. MYC is a master transcriptional regulator that increases the expression of genes that are required for aerobic glycolysis, the so-called Warburg effect (Chapter 7). When nutrients such as glucose and glutamine are available, Warburg metabolism allows cells to biosynthesize all the building blocks - nucleotides, lipids, proteins - that are needed for growth and cell division. In line with the importance of MYC in regulating proliferation, Burkitt lymphoma is among the fastest-growing human tumors. The MYC translocation partner is usually the IGH locus [t(8;14) 1, but may also be the Ig k [t(2;8)] or ½ [t(8;22)] light chain loci. 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, a specialized DNA-modifying enzyme required for both Ig class switching and somatic hypermuta-tion (see earlier). The net effect of these translocations is similar; the MYC coding sequence is repositioned adjacent to strong Ig enhancer elements, which drive increased MYC expression. In addition, the translocated MYC allele often harbors point mutations that stabilize MYC protein and further increase its activity.
Sequencing of the genomes of Burkitt lymphoma cells has revealed that most tumors have mutations that increase the activity of the transcription factor TCF3 (also known as E2A), an important regulator of gene expression in germinal center B cells. It is believed that TCF3 drives the expression of a set of genes, including cyclin D, that collaborate with MYC to enable the very rapid growth that characterizes Burkitt lymphoma.
Essentially all endemic Burkitt lymphomas are latently infected with EBV, which also is present in about 25% of HIV-associated tumors and 15% to 20% of sporadic cases.
The configuration of the EBV DNA is identical in all tumor cells within individual cases, indicating that infection precedes transformation. Although this places EB at the
“scene of the crime,” its precise role in the genesis of Burkitt lymphoma remains speculative.

Question 36

What is the morphology of Burkitt lymphoma cells

Answer 36

The tumor exhibits a high mitotic index and contains numerous apoptotic cells, the nuclear remnants of which are phagocytosed by interspersed benign

Question 37

What is the immunophenotype of Burkitt lymphoma

Answer 37

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 most other tumors of germinal center origin, Burkitt lymphoma almost always fails to express the antiapoptotic protein BCL2.

Question 38

What are the clinical features of Burkitt lymphoma

Answer 38

Both endemic and sporadic Burkitt lymphomas are found mainly in children or young adults; overall, Burkitt lymphoma accounts for about 30% of childhood NHLs in the United States. Most tumors manifest at extranodal sites.
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. In contrast, 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.

Question 39

What is the pathogenesis of mantle cell lymphoma

Answer 39

Virtually all mantle cell lymphomas have an (11;14) translocation involving the IGH locus on chromosome 14 and the cyclin D1 locus on chromosome 11 that leads to overexpres-sion of cyclin D1. The resulting up-regulation of cyclin D1 promotes G.- to S-phase progression during the cell cycle

Question 40

What is cell morphology in mantle cell lymphoma

Answer 40

At diagnosis the majority of patients have generalized lymph-adenopathy, and 20% to 40% have peripheral blood involvement.
Frequent sites of extranodal involvement include the bone marrow, spleen, liver, and gut. Occasionally, mucosal involvement of the small bowel or colon produces polyp-like lesions (lymphomatoid polyposis; of all forms of NHL, mantle cell lymphoma is most likely to spread in this fashion.
Nodal tumor cells may surround reactive germinal centers to produce a nodular appearance at low power or diffusely efface the node. Typically, the proliferation consists of a homogeneous population of small lymphocytes with irregular to occasionally deeply clefted (cleaved) nuclear contours (Fig. 13.16). Large cells resembling centroblasts and proliferation centers are absent, distinguishing mantle cell lymphoma from follicular lymphoma and CLL/SLL, respectively. In most cases the nuclear chromatin is condensed, nucleoli are inconspicuous, and the cytoplasm is scant. Occasionally, tumors composed of intermediate-sized cells with more open chromatin and a brisk mitotic rate are observed; immunophenotyping is necessary to distinguish these “blastoid” variants from ALL.

Question 41

What is the immunophenotype of mantle cell lymphoma

Answer 41

Mantle cell lymphomas express high levels of cyclin D1, CD19, and CD20 and moderately high levels of surface Ig (usually IgM and IgD with k or I light chain). This tumor is usually CD5+ and CD23-, which help to distinguish it from CLL/SLL. The IGH genes lack somatic hypermutation, supporting an origin from a naive B cell.

Question 42

What are some clinical features of mantle cell lymphomas

Answer 42

I’he most common presentation is painless lymphadenopathy.
Symptoms related to involvement of the spleen (present in approximately 50% of cases) and gut also are common. Mantle cell lymphoma is moderately aggressive and incurable; the median survival is 8 to 10 years. The blastoid variant, a “proliferative” expression profiling signature, and TP53 mutations are associated with shorter survivals.

Question 43

What is a marginal zone lymphoma

Answer 43

The category of marginal zone lymphomas encompasses a heterogeneous group of B-cell tumors that arise within lymph nodes, spleen, or extranodal tissues. The extranodal tumors were initially recognized at mucosal sites and are often referred to as mucosa-associated Ivmphoid tumors (or MALTomas). In most cases, the tumor cells show evidence of somatic hypermutation and are considered to be of memory B-cell origin.
Although all marginal zone lymphomas share certain features, those occurring at extranodal sites deserve special attention because of their unusual pathogenesis and three exceptional characteristics.
• They often arise within tissues involved by chronic inflammatory disorders of autoimmune or infectious etiology; examples include the salivary gland in Sjögren disease, the thyroid gland in Hashimoto thyroiditis, and the stomach in Helicobacter gastritis.
• They remain localized for prolonged periods, spreading systemically only late in their course.
• They may regress if the inciting agent (e.g., H. pylori) is eradicated.
These characteristics suggest that extranodal marginal zone lymphomas arising in chronically inflamed tissues lie on a continuum between reactive lymphoid hyperplasia and full-blown lymphoma.

Question 44

How does a marginal zone lymphoma start

Answer 44

The disease begins as a polyclonal immune reaction. With the acquisition of unknown initiating mutations, a B-cell clone emerges that still depends on antigen-stimulated T-helper cells for signals that drive growth and survival. At this stage, withdrawal of the responsible antigen causes tumor involution. A clinically relevant example is found in gastric MALToma, in which antibiotic therapy directed against H. pylori often leads to tumor regression (Chapter 17). With time, however, tumors may acquire additional mutations that render their growth and survival antigen-independent, such as (11;18), (14;18), or (1;14) chromosomal translocations, which are relatively specific for extranodal marginal zone lymphomas. All of these translocations up-regulate the expression and function of BCL10 or MALT1, protein components of a signaling complex that activates NF-kB and promotes the growth and survival of B cells. With further clonal evolution, spread to distant sites and transformation to DLBCL may occur.
This theme of polyclonal-to-monoclonal transition during lymphomagenesis is also applicable to the pathogenesis of EBV-induced lymphoma and is discussed