Lymphoid Neoplasms V2 PDF

Module 04: Basic Pathologies 2 Hematology Lymphoid Neoplasms Rose Lou Marie C. Agbay, M.D., FPSP | 10/08/24 | Asynchr...

Module 04: Basic Pathologies 2 Hematology Lymphoid Neoplasms Rose Lou Marie C. Agbay, M.D., FPSP | 10/08/24 | Asynchronous TABLE OF CONTENTS Originate from the bone marrow However, it may also involve the spleen and lymph nodes I. Introduction 1 F. Lympho- 11 → Red blood cell disorders A. Normal 1 plasmacytic In some cases, result from the formation of auto-antibodies Morphology of Lymphoma which indicates a primary disorder of lymphocytes Lymph Nodes V. Mature T-Cell and 11 Exhibits how it is not possible to distinguish diseases II. Lymphadenitis 1 NK-Cell Neoplasms involving the myeloid and the lymphoid tissues A. Acute Nonspecific 1 A. Peripheral T-Cell 11 Lymphadenitis Lymphoma, NOS A. NORMAL MORPHOLOGY OF LYMPH NODES B. Chronic B. Anaplastic Large 11 Parts of the lymph node: Nonspecific 2 Cell Lymphoma, → Cortex Lymphadenitis ALK-Positive Outer layer III. Neoplastic C. Mycosis 11 Can have primary or secondary follicles Proliferations of 3 Fungoides/Sézary ○ Composed mostly of B-lymphocytes White Cells Syndrome ○ Secondary follicles have a central germinal center A. Etiologic & VI. Hodgkin 12 surrounded by a layer of mantle zone Pathogenic Factors 3 Lymphoma Interfollicular cells B. Precursor B-Cell A. Hodgkin vs 12 ○ Composed mostly of T-lymphocytes and T-Cell 4 Non-Hodgkin → Medulla Neoplasms Lymphoma Inner layer C. Mature B-Cell B. Classic Hodgkin 12 Neoplasms 5 Lymphoma IV. Plasma Cell C. Nodular 13 Neoplasms and Lymphocyte Related Disorders 9 Predominant A. Plasma Cell Hodgkin Neoplasms 9 Lymphoma B. Multiple Myeloma VII. ANN Arbor 13 C. Solitary Myeloma 9 Classification (Plasmacytoma) 10 Summary & Key 14 D. Smoldering Points Myeloma 10 Review Questions 14 E. Monoclonal Rationale 15 Gammopathy 10 Figure 2. Morphology of a lymph node. (A) Lymph node; (B) B-lymphocytes (green) I. INTRODUCTION and T-lymphocytes (red) on a follicle; (C) Secondary follicle with central germinal center Components of the hematopoietic system are divided into: → Myeloid Tissues II. LYMPHADENITIS Bone marrow and cells derived from it: A. ACUTE NONSPECIFIC LYMPHADENITIS ○ Red cells Lymph nodes ○ Platelets → Enlarged (swollen) and painful ○ Granulocytes → Extensive abscess ○ Monocytes Nodes become fluctuant → Lymphoid Tissues Overlying skin is red Thymus → At times, suppurative infections penetrate through the Lymph nodes capsule of the node and produce track to the skin Spleen Produces draining sinuses → Healing of lesions is associated with scarring Gross → Nodes are swollen, gray-red, and engorged Acute nonspecific lymphadenitis can occur in different regions: → Cervical region Due to microbial drainage or microbial products from infections of teeth or tonsils → Axillary or inguinal regions Most often caused by infections in the extremities → Mesenteric lymph nodes Acute appendicitis Figure 1. Components of the hematopoietic system Other self-limited infections which induce symptoms This division above is artificial with respect to the normal mimicking acute appendicitis physiology of the hematopoietic cells and the diseases affecting ○ Inflammatory conditions involving the GI tract them → Acute generalized lymphadenitis or lymphadenopathy → Even if the bone marrow contains relatively few Systemic viral infections lymphocytes, it is the source of all lymphoid progenitors, ○ Particularly in children plasma cells, and memory lymphocytes Bacteremia → Neoplastic disorders of myeloid progenitor cells (e.g. leukemia) YL6 04.12b TG16: Trans Police [Tan] | CG7: Trans Police [Lengwa] | Version 2 1 of 16  Figure 5. Follicular hyperplasia in higher magnification Figure 5. Follicular hyperplasia in higher magnification Figure 3. Acute Nonspecific Lymphadenitis Left image: low-power view showing a reactive follicle surrounding the mantle zone Figure 3. Acute specific lymphadenitis → Dark staining mantle zone is more prominent adjacent to Left image: Scanner view the germinal-center light zone, in the left half of the follicle, → Pale areas of necrosis composed mostly of centrocytes Right image: Higher magnification → The other half of the follicle is a dark zone composed → Numerous inflammatory cells (black arrow) mostly of centroblasts Mostly neutrophils Right image (higher magnification): Tingible body → Adjacent area of necrosis (white arrow) macrophages → Numerous macrophages with phagocytosed apoptotic cells B. CHRONIC NONSPECIFIC LYMPHADENITIS Lymph nodes Paracortical Hyperplasia → Nontender Caused by stimuli that trigger T-cell mediated immune Nodal enlargement occurs slowly over time responses Acute inflammation with associated tissue damage is absent → Such as acute viral infections Common in inguinal and axillary lymph nodes E.g., Infectious mononucleosis → Drain relatively large areas of the body T-cell regions typically contain immunoblasts → Frequently stimulated by immune reactions due to injuries There is often active hypertrophy of sinusoidal and vascular and infections of the extremities endothelial cells → Sometimes accompanied by infiltrating macrophages and → FEATURES FAVORING REACTIVE (NON-NEOPLASTIC) HYPERPLASIA eosinophils Microscopic features which favor chronic non-specific lymphadenitis including the following: → Preservation of the lymph node architecture Including the interfollicular T-cell zones and the sinusoids → Marked variation in shape and size of the follicles → Presence of frequent mitotic figures, phagocytic macrophages, and recognizable light and dark zones All of which tend to be absent from neoplastic follicles → MORPHOLOGICAL EXAMPLES Follicular Hyperplasia Caused by stimuli that activate humoral immune responses Figure 6. Paracortical hyperplasia Presence of large oblong germinal centers (secondary follicles) which are surrounded by a collar of small resting naive B-cells Figure 6. Paracortical hyperplasia (mantle zone) Left image: Paracortex is expanded → Composed mostly of T-lymphocytes Right image: Higher magnification → Activated T-cells or immunoblasts have round nuclei, prominent nucleoli, and moderate cytoplasm Sinus Histiocytosis Also called Reticular Hyperplasia Marked by an increase in the number and size of cells that line the lymphatic sinusoids → Lining lymphatic endothelial cells are markedly hypertrophied → Intrasinusoidal macrophages are greatly increased in numbers → Results in the expansion and distortion of the sinusoids Prominent in lymph node draining cancers (e.g. Breast carcinoma) Figure 4. Follicular hyperplasia in low magnification Figure 4. Follicular hyperplasia in low magnification Increased number of follicles Follicles are of different sizes but still well-circumscribed by a layer of mantle zone YL6 04.12b Lymphoid Neoplasms 2 of 16  Lymphoid neoplasms include a diverse group of tumors of B-cell, T-cell, and NK-cell origin Myeloid neoplasms arise from early hematopoietic progenitors and is divided in three categories: → Acute myeloid leukemias Immature progenitor cells accumulate in the bone marrow → Myelodysplastic syndrome Associated with ineffective hematopoiesis and resulted peripheral blood cytopenias → Chronic Myeloproliferative neoplasms Increased production of one or more terminally Figure 7. Sinus histiocytosis or reticular hyperplasia differentiated myeloid elements usually leads to elevated peripheral blood counts Figure 7. Sinus histiocytosis or reticular hyperplasia Histiocytes Sinus exhibits hyperplasia → Uncommon proliferative lesions of the macrophages and → Cells present in the sinus represent an admixture of dendritic cells histiocytes and sinus lining cells → Langerhans cell Sinuses are expanded Special type of immature dendritic cell → Contains numerous macrophages or histiocytes Gives rise to a spectrum of neoplastic disorders CLINICAL CORRELATES ○ Known as the Langerhans cell histiocytosis CHRONIC NONSPECIFIC LYMPHADENITIS Chronic immune reactions can promote the appearance of organized collection of immune cells in non-lymphoid tissues also known as tertiary lymphoid organs Chronic Gastritis Classic example is chronic gastritis caused by Helicobacter pylori → Aggregates of mucosal lymphocytes are seen which stimulate the appearance of Peyer’s patches Rheumatoid Arthritis B-cell follicles often appear in the inflamed synovium Lymphotoxin → A cytokine required for the formation of normal Peyer’s patches. → Probably involved in the establishment of these extra-nodal Figure 8. Neoplastic proliferations of white cells inflammation induced collection of lymphoid cells. A. ETIOLOGIC & PATHOGENETIC FACTORS Hemophagocytic Lymphohistiocytosis (HLH) As in other cancers, the development of white blood cell Also known as macrophage activation syndrome. neoplasms involves: A reactive condition marked by cytopenias and signs and → Genetic alterations symptoms of systemic inflammation related to the macrophage → Infections activation. → Sometimes, a background of chronic inflammation Common features of all forms of HLH: The World Health Organization (WHO) classified lymphoid → Systemic activation of macrophages neoplasms into: → CD8+ cytotoxic T-cells → Hodgkin lymphoma Activated macrophages phagocytose blood cell progenitors in → Non-Hodgkin lymphoma the marrow and formed elements in the peripheral tissues. Large group composed of: Mediators released from macrophages and lymphocytes ○ Precursor B-cell neoplasms suppress hematopoiesis and produce symptoms of systemic ○ Peripheral B-cell neoplasms inflammation. ○ Precursor T-cell neoplasms Most common trigger for HLH infection is Epstein-Barr virus ○ Peripheral T-cell and NK-cell neoplasms (EBV). Most patients present with acute febrile illness associated with Take Note! splenomegaly and hepatomegaly. Refer to Table A in Master Tables for the WHO Classification of Laboratory studies typically reveal: Lymphoid Neoplasms → Anemia → Thrombocytopenia → Very high levels of plasma ferritin and soluble interleukin-2 (IL-2) receptor Both indicative of severe inflammation → Elevated liver function tests and triglyceride levels Both related to hepatitis → Coagulation studies may show evidence of disseminated intravascular coagulation If untreated, this patient can progress rapidly to multiorgan failure, shock, and death III. NEOPLASTIC PROLIFERATIONS OF WHITE CELLS Malignancies are clinically the most important disorders of Figure 9. Etiologic & pathogenetic factors in white blood cell neoplasia white cells YL6 04.12b Lymphoid Neoplasms 3 of 16  B. PRECURSOR B-CELL AND T-CELL NEOPLASMS Table 2. Immunophenotype of Acute Lymphoblastic Leukemia/Lymphoma B-ALL T-ALL ACUTE LYMPHOBLASTIC LEUKEMIA/LYMPHOMA (ALL) (+) CD19 Neoplasms composed of lymphoblasts (+) CD1, CD2, CD5 and Lymphoblasts (+) PAX5 CD7 → Immature B (pre-B) or T (pre-T) cells (+) CD10 Most common cancer of children (-) CD3 → Approximately 2,500 new cases are diagnosed each year in Very immature (-) CD10 (-) CD4 the United States (-) CD8 → Occurring in individuals under 15 years of age (+) CD10 → Almost three times as common in Whites as in Blacks (+) CD19 (+) CD3 More mature “late Hispanics: highest incidence of any ethnic group pre-B/T” (+) CD20 (+) CD4 → Slightly more frequent in boys than in girls (+) Cytoplasmic IgM (+) CD8 → heavy chain (μ chain) Table 1. B-ALL vs. T-ALL B-ALL T-ALL TdT About 85% of all ALLs Less common Molecular Pathogenesis Thymic “lymphomas” in adolescent Approximately 90% of ALLs have numerical or structural Childhood acute “leukemias” males chromosomal changes Peaks in incidence at about the age of 3 Peaks in incidence at adolescence Many of the chromosomal aberrations seen in ALL dysregulate the expression and function of transcription factors that are Number of normal bone marrow pre-B cells (the cell of origin) is greatest very Age when the thymus reaches its required for normal B- and T-cell development maximal size → Up to 70% of T-ALLs have gain of function mutations in early in life NOTCH1 Occur less frequently in adults of all ages → A high fraction of B-ALLs have loss of function mutations— Table 1. Immunophenotype of Acute Lymphoblastic PAX5, E2A, and EBF or a balanced t(12;21) involving the Leukemia/Lymphoma genes TEL and AML1 Single mutations are not sufficient to produce ALL Doc emphasized these information in the lecture: → 85% are B-ALLs which typically manifests as childhood Clinical Features acute leukemias Abrupt stormy onset within days to a few weeks of the first → The less common T-ALL tend to present in adolescent symptoms males as thymic lymphomas Symptoms related to depression of marrow function, including → Both occur less frequently in adults of all ages fatigue due to the following: → Anemia → Fever reflecting infections secondary to neutropenia → Bleeding due to thrombocytopenia Mass effects caused by neoplastic infiltration including the following: → Bone pain resulting from marrow expansion and infiltration of the subperiostium → Generalized lymphadenopathy, Splenomegaly, and Hepatomegaly → Testicular enlargement → In T-ALL: complications related to compression of large vessels and airways in the mediastinum Central nervous system manifestations are also more common in ALL, and includes the following: → Headache → Vomiting → Nerve palsies resulting from meningeal spread Prognosis With aggressive chemotherapy, about 95% of children with ALL obtain a complete remission Figure 10. (Top) Shows Acute Lymphoblastic Leukemia / Lymphoma 75% to 85% are cured (ALL). (Bottom) represent phenotype of the ALL shown in ALL analyzed by flow Factors associated with a worse prognosis: cytometry → Age younger than 2 years Figure 10. ALL and Flow Cytometry → Presentation in adolescence or adulthood Lymphoblasts (top) have: → Peripheral blood blast counts greater than 100,000 → Condensed nuclear chromatin → Presence of particular cytogenetic aberrations such as the → Small nucleoli t(9;22) (the Philadelphia chromosome) → Scant agranular cytoplasm Favorable prognostic markers: Flow cytometry (bottom) can show the phenotype of ALL → Age of 2 to 10 years → ALL (right) is represented by the red dots → Low white cell count The lymphoblasts are expressing TdT and a B-cell → Hyperdiploidy marker CD22 as well as CD10 and CD19. → Trisomy of chromosomes 4, 7, and 10 → Presence of a t(12;21) Immunophenotype B cell markers and T cell markers are required to diagnose Take Note! B-ALL and T-ALL, respectively Notes from Robbins & Cotran Pathologic Basis of Disease However, the most important important marker to diagnose 10th Edition, Chapter 13 (Kumar et al., 2021) lymphoblastic leukemia/lymphoma is Terminal → On Molecular Pathogenesis (unknown source for the deoxynucleotidyl transferase (TdT) genes cited in Dr. Agbay’s Lecture) YL6 04.12b Lymphoid Neoplasms 4 of 16  “Most T-ALLs have mutations in NOTCH1, a gene that is essential for T-cell development, while a high fraction of B-ALLs have mutations affecting genes such as PAX5, TCF3, ETV6, and RUNX1, all of which are required for the proper differentiation of early hematopoietic precursors. By disturbing the expression and function of "master" regulatory factors, these mutations promote maturation arrest and increased self-renewal, a stem cell-like phenotype.” (p. 594) → On Prognosis: Dr. Agbay’s lecture slide notes “hyperploidy” She mentions “hyperdiploidy” which is consistent with the book (p. 597) C. MATURE B-CELL NEOPLASMS CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) / SMALL LYMPHOCYTIC LEUKEMIA (SLL) CLL and SLL differ only in the degree of peripheral blood lymphocytosis Figure 12. CLL In Bone Marrow CLL → Most common leukemia of adults in the Western world Figure 12. CLL in Bone Marrow → About 15,000 new cases of CLL each year (US) The bone marrow is hypercellular and is completely filled with → Median age at diagnosis is 60 years numerous neoplastic lymphoid cells. → 2:1 (Male: Female) male predominance → Diagnostic requirement: Absolute lymphocyte count > 5,000 per mm³ SLL → 4% of Non-Hodgkin Lymphomas Figure 13. SLL/CLL (Lymph Node) Figure 13. SLL/CLL (Lymph Node) SLL involving a lymph node will show diffuse effacement of nodal architecture. Figure 11. CLL with Smudge Cells (green arrow) Figure 11. CLL with Smudge Cells In CLL, the peripheral blood smear will show numerous small lymphocytes with condensed chromatin and scant cytoplasm → Characteristic finding is the presence of disrupted tumor cells also known as smudge cells. → A coexistent autoimmune hemolytic anemia explains the presence of spherocytes (hyperchromatic, round erythrocytes). → A nucleated erythroid cell is present in the lower left-hand corner of the field. → 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 14. Higher Magnification of SLL/CLL (Lymph Node) Figure 14. Higher Magnification of SLL/CLL (Lymph Node) Higher magnification will show that the majority of the tumor cells are small round lymphocytes A prolymphocyte, a larger cell with a centrally placed nucleolus, is also presented in this field (arrow) Immunophenotype The distinctive immunophenotype of CLL/SLL is the expression of the pan-B cell markers → CD19 and CD20 → CD23 and CD5 Low-level expression of surface Ig (usually IgM, or IgM and IgD) is also typical YL6 04.12b Lymphoid Neoplasms 5 of 16  Molecular Pathogenesis Most common anomalies are the following: → Deletions of 13q14.3, 11q, 17p, and trisomy 12q → The growth of CLL/SLL cells is largely confined to proliferation centers where tumor cells receive critical cues from the microenvironment → Stromal cells in the proliferation centers express a variety of factors that stimulate the activity of transcription factors: Nuclear factor kappa B (NF-KB): promotes survival MYC: promotes cell growth Clinical Features Patients are often asymptomatic at diagnosis When symptoms appear, they are: → Nonspecific: Figure 16. FL in lymph nodes gross specimen (left) and Easy fatigability microscopic view (right) Weight loss Anorexia Figure 16. Follicular Lymphoma samples → Generalized lymphadenopathy and hepatosplenomegaly In most cases, a nodular or nodular and diffuse pattern is (50% to 60% of symptomatic patients) observed in involved lymph nodes both grossly and → Total leukocyte count is highly variable: microscopically Leukopenia can be seen in individuals with SLL and marrow involvement Counts in excess of 200,000 cells/µL are sometimes seen in CLL patients with heavy tumor burdens → Hypogammaglobulinemia is common and contributes to an increased susceptibility to infection, particularly those caused by bacteria → Autoimmune hemolytic anemia and thrombocytopenia due to antibodies (10% to 15% of patients) Overall median survival is 4 to 6 years → Over 10 years in individuals with minimal tumor burden at diagnosis Variables that correlate with a worse outcome: → Presence of deletions of 11q and 17p Figure 17A. Follicular lymphoma (lymph node) → Lack of somatic hypermutation → Expression of ZAP-70 → Presence of NOTCH1 mutations Figure 15. Factors that impact patient survival with CLL/SLL Figure 15. Factors that impact patient survival Figure 17B. Higher magnification of FL (lymph node) with centrocytes Tendency of CLL/SLL to transform to a more aggressive tumor (yellow circle) and centroblasts (green circle) → Most commonly takes the form of prolymphocytic Figure 17. FL under the microscope transformation or diffuse large B-cell lymphoma also A: Nodular aggregates of lymphoma cells are present known as Richter syndrome (in ~5% to 10% of patients) throughout the lymph node FOLLICULAR LYMPHOMA (FL) B: At higher magnification, centrocytes are mixed with Likely arises from germinal center B cells centroblasts Strongly associated with chromosomal translocations involving → Centrocytes BCL2 Small lymphoid cells with condensed chromatin and Most common form of indolent Non-Hodgkin Lymphoma (in the irregular or cleaved nuclear outlines US) → Centroblasts → Less common in Europe Large lymphoid cells with nucleoli → Rare in Asian populations Immunophenotype 15,000 to 20,000 individuals per year Neoplastic cells closely resemble normal germinal center B cells → Usually presents in middle age expressing: CD19, CD20, CD10, surface Ig, and BCL6 → Afflicts males and females equally BCL2 is expressed in more than 90% of cases in distinction to normal follicular center B cells which are BCL2 negative YL6 04.12b Lymphoid Neoplasms 6 of 16  High level expression of MYC and BCL2 in some cases → May predict more aggressive behavior Dysregulation of BLC6 Frequent pathogenic event BCL6 represses the expression of factors that may normally serve to promote germinal center B cell differentiation, growth arrest and apoptosis Another 10-20% of tumors are associated with the translocation 14;18 which leads to the overexpression of the anti-apoptotic protein BCL2 Rearrangements of the BCL2 gene, located on 3q27 Acquired mutations in BCL6 promoter sequence Figure 18. BCL2 expression in reactive follicles (A) and neoplastic follicles (B) Figure 18. Follicular lymphoma in Immunohistochemical Studies BCL2 can be detected by using an immunohistochemical technique that produces a brown stain A: In reactive follicles, BCL2 is present in the mantle zone Figure 20. Dysregulation of B6 cells but not in the follicular-center B cells Treatment B: In follicular lymphoma, there is a strong BCL2 staining in the germinal center B cells Aggressive tumors - rapidly fatal without treatment Intensive combination chemotherapy Molecular Pathogenesis → 60% to 80% of patients achieve complete remission Strongly associated with chromosomal translocations → 40% to 50% are cured involving BCL2 BURKITT LYMPHOMA Hallmark: (14;18) translocation → Fuses the BCL2 gene on chromosome 18q21 to the IGH Categories: locus on chromosome 14 → overexpression of BCL2 → → African (endemic) Burkitt Lymphoma antagonizes apoptosis → promotes survival of follicular Latently infected with EBV lymphoma cells → Sporadic (nonendemic) Burkitt Lymphoma → Seen in 90% of FLs → A subset of aggressive lymphomas occurring in individuals infected with HIV Clinical Features Burkitt lymphoma occurring in these three settings are Presents with generalized painless lymphadenopathy histologically identical but have distinct clinical, genotypic, and Bone marrow almost always contains lymphoma at the time of neurological characteristics diagnosis → Involvement of visceral sites is uncommon Although typically incurable, it usually follows an indolent waxing and waning course Median survival: 7 to 9 years Histologic transformation occurs in 30% to 50% of FLs, most commonly to diffuse large B-cell lymphoma DIFFUSE LARGE B-CELL LYMPHOMA Figure 21. Burkitt lymphoma Most common form of Non-Hodgkin Lymphoma Figure 21. Burkitt Lymphoma About 25,000 new cases each year (US) Slight male predominance Involved tissues are Median patient age: 60 years old → Faced by a diffuse infiltrate of intermediate size lymphoid → DLBCL also occurs in young adults and children cells Typically presents as a rapidly enlarging mass at a nodal or At low magnification extranodal site and can arise anywhere in the body → Numerous pale, tingible body macrophages are evident → Primary or secondary involvement of the liver and spleen producing a starry sky appearance may take the form of large masses (Fig. 19 left) At higher magnification → Microscopically, the tumor cells have large nuclei, open → Tumor cells have multiple small nucleoli and high chromatin, and prominent nucleoli (Fig. 19 right) mitotic index The lack of significant variation in nuclear shape and size lends to a monotonous appearance Immunophenotype Tumors of mature B cells express IgM, CD19, CD20, CD10 and BCL6 → A phenotype consistent with a germinal B cell origin Unlike most other tumors of germinal center B cell origin: almost Figure 19. DLBCL gross specimen (left) and microscopic view (right) always fails to express the anti-apoptotic protein BCL2 Immunophenotype Molecular Pathogenesis B cell markers (CD20, CD19) All forms of Burkitt lymphomas are associated with Variable expression of germinal center B cell markers CD10 translocations of the c-MYC gene on chromosome 8 that and BCL6 (variable) leads to increased MYC protein levels YL6 04.12b Lymphoid Neoplasms 7 of 16 Table 3. Molecular pathogenesis of Burkitt lymphoma At high power (B) Translocations of the c-MYC gene on chromosome 8 → Homogenous populations of small lymphoid cells with somewhat irregular nucleus outlines, condensed most translocations fuse MYC with variant translocations involving the κ chromatin, and scant cytoplasm the IgH gene on chromosome 14 or γ light chain loci on chromosomes 2 and 22, respectively → Large cells resembling the prolymphocytes (seen in chronic lymphocytic leukemia) and centroblasts (seen in dysregulation and overexpression of the MYC protein follicular lymphoma) are absent Immunophenotype Demographic and Categories Express high levels of cyclin D1 Both Endemic and Sporadic Burkitt lymphomas are found mainly Express CD19, CD20 in children or young adults Moderately high levels of surface Ig → 30% of childhood NHLs (US) → Usually IgM and IgD with kappa or γ light chain Most tumors manifest at extranodal sites CD5+ and CD23- Very aggressive but responds well to intensive chemotherapy → Help to distinguish it from chronic/small lymphocytic → Most children but young adults can be cured leukemia (CLL/SLL) Table 4. Categories of Burkitt lymphoma Molecular Pathogenesis Endemic Burkitt lymphoma Sporadic Burkitt lymphoma Cyclin D1 overexpression Mass involving the mandible Mass involving the ileocecal and → Due to (11;14) translocation involving: peritoneum IGH locus on chromosome 14 Unusual predilection for involvement Cyclin D1 locus on chromosome 11 of abdominal viscera (kidneys, Promotes G1- to S-phase progression during cell cycle ovaries, and adrenal glands) Detected in about 70% of cases Take Note! Clinical Features The following (Mantle Cell Lymphoma, Marginal Zone B-Cell Painless lymphadenopathy Lymphoma, and Hairy Cell Leukemia) were discussed in the → Most common presentation asynchronous lecture under Plasma neoplasms. However, Symptoms involving spleen (around 50% of cases) and gut they are classified under peripheral B-cell neoplasms in → Also common Robbins & Cotran, which is why it was moved here. Moderately aggressive and incurable Median survival is 8 to 10 years MANTLE CELL LYMPHOMA Blastoid variant (i.e. a proliferative expression profiling Tumor cells closely resemble the normal mantle zone B cells signature) and TP53 mutations that surround germinal centers → Associated with shorter survivals Uncommon lymphoid neoplasm MARGINAL ZONE B-CELL LYMPHOMA Presents in the 5th-6th decades of life Male predominance Heterogenous group of B-cell tumors that arise within lymph US: 2.5% of NHL nodes, spleen or extranodal tissues Europe: 7-9%% of NHL Extranodal tumors were initially recognized at mucosal sites → Often referred to as mucosa-associated lymphoid tumors (MALT or “maltomas”) Special Characteristics Often arise within tissues involved by chronic inflammatory disorders of autoimmune or infectious etiology → Salivary gland in Sjögren disease → Thyroid gland in Hashimoto thyroiditis → Stomach in Helicobacter gastritis They remain localized from prolonged periods → Spreading systemically only in their late course May regress if inciting agent (e.g., Helicobacter pylori) is eradicated Figure 22. Mantle Cell Lymphoma [Robbins and Cotran, 2021] Figure 22. Mantle Cell Lymphoma At low power (A) Figure 23. Lymph node involvement by marginal zone B-cell lymphoma → Neoplastic lymphoid cells surround a small, atrophic germinal center Figure 23. Marginal Zone B-cell Lymphoma → Produces a mantle zone pattern of growth Shows expanded marginal zones YL6 04.12b Lymphoid Neoplasms 8 of 16  → Contains neoplastic lymphoid cells There are numerous residual germinal centers ACTIVE RECALL HAIRY CELL LEUKEMIA 1. In Burkitt Lymphoma this almost always fails to express? A. IgM Rare but distinctive B-cell neoplasm Constitutes 2% of all leukemias B. CD19 Predominantly a disease of middle-aged (median age of 55) C. BCL2 white males D. BCL6 Male-to-female ratio of 5:1 2. T/F: Mantle Cell Lymphoma often arise within tissues Indolent course involved by chronic inflammatory disorders of Exceptionally sensitive to chemotherapeutic regimens autoimmune or infectious etiology → Produce long-lasting remissions 3. What is the most common form of Non-Hodgkin Tumors often relapse after 5 or more years Lymphoma? → But generally respond well when treated with chemotherapy BRAF inhibitors appear to produce excellent responses in Answer Key: 1C, 2F, 3Diffuse Large B-Cell Lymphoma tumors that have failed conventional chemotherapy IV. PLASMA CELL NEOPLASMS AND RELATED DISORDERS Overall prognosis is excellent Multiple Myeloma Solitary Myeloma Smoldering Myeloma Monoclonal Gammopathy of Uncertain Significance (MGUS) Lymphoplasmacytic Lymphoma A. PLASMA CELL NEOPLASMS B-cell proliferations → Neoplastic plasma cells that secrete a monoclonal Ig or Ig fragments Serve as tumor markers which often have pathological consequences Excess light or heavy chains along with complete Igs → M component Monoclonal Ig identified in the blood Molecular weights of 160,000 or higher Restricted to plasma and extracellular fluid ○ Excluded from the urine in the absence of glomerular Figure 24. Hairy cell leukemia peripheral blood smear damage Figure 24. Hairy Cell Leukemia → Bence-Jones protein Leukemic cells have fine, hair-like projections Free light chains are small enough to be excreted in the → A (upper left): Best recognized under phase-contrast urine microscopy Accounts for about 15% of the deaths caused by lymphoid B (upper right) On routine peripheral blood smears, hairy cells neoplasms have round, oblong, or folded nuclei and moderate amounts of B. MULTIPLE MYELOMA pale blue, agranular cytoplasm with thread-like extensions Clonal proliferation of neoplastic plasma cells in the bone marrow Immunophenotype → A plasma cell neoplasm commonly associated with: Express the pan-B-cell markers CD19 and CD20, surface Ig Lytic bone lesions (usually IgG) Hypercalcemia Relatively distinctive markers: CD11c, CD25, CD103 and Renal failure annexin A1 Acquired immune abnormalities Incidence is higher in men and people of African descent Molecular Pathogenesis Peak age of incidence: 65-70 years old Associated in more than 90% of cases with activating point → Strictly a disease of older adults mutations in the serine/threonine kinase BRAF MOLECULAR PATHOGENESIS → Which lies immediately downstream of RAS in the MAPK signaling cascade Genetically heterogeneous Associated with frequent rearrangements involving IGH locus on Clinical Features chromosome 14q32 and various proto-oncogenes Results from infiltration of the bone marrow, liver, and spleen Proliferation and survival of myeloma cells are dependent on → Splenomegaly several cytokines, most notably IL-6 Massive → IL-6 Most common Important growth factor for plasma cells Sometimes the only abnormal physical finding Produced by the tumor cells themselves and resident → Hepatomegaly marrow stromal cells Less common (rare) → High serum levels of IL-6 Not as marked Seen in patients with active disease → Lymphadenopathy Associated with poor prognosis Rare Major pathological feature: bone destruction → Pancytopenia → Mediated by factors produced by neoplastic plasma cells: Results from marrow involvement and sequestration of Myeloma-derived MIP1α cells in the enlarged spleen ○ Chemokines that augments osteoclast formation → Infections ○ Upregulates the expression of the receptor activator of Found in about 1/3 of cases NF-kB ligand (RANKL) by bone marrow stromal cells Atypical mycobacterial infections, possibly related to ○ Net effect: marked increase in bone resorption frequent unexplained monocytopenia ○ Leads to hypercalcemia and pathologic fractures YL6 04.12b Lymphoid Neoplasms 9 of 16  Modulators of the Wnt pathway SERUM PROTEIN ELECTROPHORESIS ○ Potent inhibitors of osteoblast function ○ Net effect: marked increase in bone resorption ○ Leads to hypercalcemia and pathologic fractures RADIOGRAPHIC PRESENTATION The bone lesions appear radiographically as punched-out defects → Usually about 1-4 cm in diameter → Figure 27. Serum protein electrophoresis [Robbins and Cotran, 2021] Used to screen for M protein Polyclonal IgG → Normal serum: appears a broad band → Patient serum: a single sharp protein band Cross-linked by antisera specific for IgG heavy chain and Figure 25. Multiple myeloma of the skull (radiograph, lateral view) kappa light chain indicating the presence of IgG kappa M HISTOLOGIC PRESENTATION protein Normal bone marrow cells are largely replaced by plasma cells PROGNOSIS This include forms with multiple prominent nuclei and Variable cytoplasmic droplets containing immunoglobulin Median survival: 4-7 years Good outcome: translocations involving cyclin D1 Aggressive course: deletions of 13q, deletions of 17p, and the t(4;14) C. SOLITARY MYELOMA (PLASMACYTOMA) 3-5% present as a solitary lesion of bone or soft tissue Bone lesions occur in the same locations as multiple myeloma Extra osseous lesions occur in the lungs, oronasopharynx, or nasal sinuses Modest elevations of M proteins in the blood or urine may be found in some patients Solitary osseous plasmacytoma almost inevitably progress to multiple myeloma Figure 26. Multiple myeloma (bone marrow aspirate) → Can take 10-20 years or longer CLINICAL FEATURES Extraosseous plasmacytomas involving the upper respiratory tract are frequently cured by local resection Stems from → The effects of plasma cell growth in tissues, particularly the D. SMOLDERING MYELOMA bones Middle ground between multiple myeloma and monoclonal → The production of excessive Igs, which often have abnormal gammopathy of uncertain significance (MGUS) physicochemical properties Plasma cells make up 10-30% of the marrow cellularity → The suppression of normal humoral immunity Serum M protein level is >3 g/dL, but patients are asymptomatic >3 g/dL Igs in the blood About 75% of patients progress to multiple myeloma over a >6 g/dL light chains (Bence-Jones proteins) in the urine 15-year period Table 7. Multiple Myeloma E. MONOCLONAL GAMMOPATHY OF UNCERTAIN Pathology Outcome SIGNIFICANCE (MGUS) Pathologic fractures and chronic Most common plasma cell disorder Bone Resorption pain → Occurring in 3% of persons >50 years of age Neurologic manifestations, such → Occurring in 5% of individuals over 70 years of age as confusion, weakness, lethargy, Patients are asymptomatic Hypercalcemia constipation, and polyuria Renal Dysfunction Serum M protein level is