12. Lymphoid Pathology.pdf

LYMPHOID PATHOLOGY Dr Mbayah Etabale Lecturer and Anatomical Pathologist Outline ◦ Development and Organisation of Lymphoid Cells ◦ Congenital Anomalies ◦ Lymphadenopathy ◦ Lymphoid Neoplasms ◦ Hodgkin Lymphoma ◦ Non-Hodgkin Lymphoma ◦ Multiple Myeloma...

LYMPHOID PATHOLOGY Dr Mbayah Etabale Lecturer and Anatomical Pathologist Outline ◦ Development and Organisation of Lymphoid Cells ◦ Congenital Anomalies ◦ Lymphadenopathy ◦ Lymphoid Neoplasms ◦ Hodgkin Lymphoma ◦ Non-Hodgkin Lymphoma ◦ Multiple Myeloma Lymphoid Pathology 2 Objectives ◦ Describe the development and organisation of lymphoid cells ◦ Write short notes on congenital anomalies affecting lymphoid tissue ◦ Discuss lymphadenopathy ◦ State the 2 main classes of lymphoma bases on clinical and morphological features ◦ Discuss mature B-cell lymphomas ◦ Discuss splenomegaly ◦ Write brief notes on diseases of the thymus Lymphoid Pathology 3  DEVELOPMENT AND ORGANISATION OF LYMPHOID CELLS Lymphoid Pathology 4 Lymphoid Pathology 5 Development of Lymphoid Cells BM, Foetal BM, Foetal BM, Liver Liver Thymus Common Myeloid Pro-B Cell Pre-B Cell Naïve B Cell Progenitor Pluripotential HSC Common Lø Pro-T Cell Pre-T Cell Naïve T Cell Progenitor NK-Cell NK-Cell Precursor Lymphoid Pathology 6 Lymphoid Organs ◦ Organised tissues containing large numbers of lymphocytes in a framework of non-lymphoid cells ◦ Primary (central) lymphoid organs ◦ Generation and maturation of lymphocytes ◦ Bone marrow ◦ Origin of B and T lymphocytes ◦ Site of maturation for B lymphocytes ◦ Thymus ◦ Site of maturation of T lymphocytes ◦ Important for central tolerance ◦ Secondary (peripheral) lymphoid organs ◦ Specialised to trap antigens ◦ Sites of initiation of adaptive immune responses ◦ Maintenance of lymphocytes ◦ Include lymph nodes, spleen, mucosa-associated lymphoid tissue (MALT) Source: Immunobiology – The Immune System in Health and Disease, 5e Lymphoid Pathology 7 Thymus ◦ Anatomy ◦ Function ◦ Located in the superior mediastinum, anterior to the ◦ Site for development and maturation of T great vessels and posterior to the sternum lymphocytes (T cells) ◦ Two lobes ± thin isthmus ◦ T cell precursors from the bone marrow migrate to ◦ Each lobe consists of a cortex and a medulla: the thymus where they undergo maturation and selection processes ◦ Cortex: Contains densely packed lymphocytes (thymocytes) and epithelial cells ◦ Maturation ◦ Medulla: Contains fewer lymphocytes and numerous ◦ Differentiation into various T cell subsets (e.g., CD4+ epithelial reticular cells (Hassall's corpuscles) helper T cells, CD8+ cytotoxic T cells) under the influence of thymic epithelial cells and cytokines ◦ Development ◦ Selection ◦ Originates from the third pharyngeal pouch (week 6) ◦ Positive selection: T cells that recognize self-major ◦ Descends into the anterior mediastinum (week 7) histocompatibility complex (MHC) molecules with low affinity undergo positive selection, ensuring recognition ◦ Continues to develop postnatally until puberty of self-antigens presented by MHC molecules ◦ Involutes with age, decreasing in size and activity ◦ Negative selection: T cells that recognize self-antigens after puberty, but continues to play a role in T cell with high affinity undergo negative selection, leading homeostasis throughout life to the elimination of potentially auto-reactive T cells Lymphoid Pathology 8 Lymphoid Pathology 9 Thymus Source: Wheater’s Functional Histology – A Text and Colour Atlas, 6e Source: Textbook of Histology, 4e Lymphoid Pathology 10 Lymph Node ◦ A secondary lymphoid organ, where B and T cells proliferate in response to exogenous antigen ◦ Organised to detect and inactivate foreign antigens present in lymph fluid that drains the major organs in contact with the environment ◦ Soft ovoid structures, 2 cm max ◦ Composed of: 1. Capsule 2. Cortex 3. Paracortex 4. Medulla 5. Sinus Lymphoid Pathology 11 Lymph Node Source: Textbook of Histology, 4e Source: Wheater’s Functional Histology – A Text and Colour Atlas, 6e Lymphoid Pathology 12 Lymph Node – Capsule ◦ Penetrated by afferent vessels which drain into the subcapsular sinus Source: Wheater’s Functional Histology – A Text and Colour Atlas, 6e Source: Textbook of Histology, 4e Lymphoid Pathology 13  Lymph Node - Cortex ◦ 10 follicles ◦ Aggregates of small naïve B cells Naïve B Cell Centroblast ◦ 20 follicles ◦ Arise from 10 follicles that develop GC due to antigenic stimulation ◦ GC B ◦ Centroblasts and centrocytes; Centrocyte Immunoblast ◦ T-helper cells; ◦ T regs; ◦ Tingible-body Mø ◦ Follicular dendritic cells Memory B Cell & Plasma Cell Source: Wheater’s Functional Histology – A Text and Colour Atlas, 6e Lymphoid Pathology 14  Lymph Node – Paracortex ◦ Mature T cells ◦ B immunoblasts ◦ Interdigitating dendritic cells ◦ Histiocytes ◦ Expand during cell mediated immune responses Source: Wheater’s Functional Histology – A Text and Colour Atlas, 6e Source: Textbook of Histology, 4e Lymphoid Pathology 15  Lymph Node – Medulla ◦ Medullary cords, sinuses and blood vessels Source: Wheater’s Functional Histology – A Text and Colour Atlas, 6e Source: Textbook of Histology, 4e Lymphoid Pathology 16 Spleen ◦ Anatomy ◦ Function ◦ White pulp: Composed of lymphoid tissue ◦ Adaptive immune responses, including the (periarteriolar lymphoid sheaths and lymphoid production of antibodies and activation of T cells follicles) involved in immune function ◦ Filtering blood, removing old or damaged ◦ Red pulp: Comprised of sinusoidal capillaries and erythrocytes, removing foreign particles, and splenic cords, involved in blood filtration and recycling iron and other components removal of old or damaged blood cells ◦ Haematopoiesis during fetal development and in ◦ Blood supply: Mainly from the splenic artery, a certain pathological conditions branch of the celiac trunk. Blood drains into the ◦ Reservoir for blood, releasing stored cells in times of splenic vein, which joins the superior mesenteric vein need (e.g., haemorrhage) to form the portal vein. ◦ Development ◦ The spleen arises ~ week 5 from mesoderm: mesenchyme of the dorsal mesogastrium ◦ Subsequent infiltration by haematopoietic cells. ◦ Haematopoiesis in ~ week 9 ◦ Fully developed by the fifth month Lymphoid Pathology 17 Spleen Source: Wheater’s Functional Histology – A Text and Colour Atlas, 6e Source: Textbook of Histology, 4e Lymphoid Pathology 18 Mucosa-Associated Lymphoid Tissue (MALT) ◦ Component of the lymphoid tissue found in ◦ First line of defense against pathogens that enter mucosal linings throughout the body the body through mucosal surfaces: ◦ Composed of diffuse lymphoid tissue, organized ◦ MALT captures and processes antigens present in the mucosal environment, facilitating immune lymphoid follicles, and associated lymphoid surveillance aggregates ◦ Production of secretory IgA antibodies ◦ Contains various immune cells, including lymphocytes (T and B cells), macrophages, ◦ MALT helps maintain immune tolerance to dendritic cells, and plasma cells harmless antigens encountered at mucosal surfaces, preventing inappropriate immune ◦ Examples: reactions and autoimmune responses ◦ Bronchus-associated lymphoid tissue (BALT) ◦ Generation and maintenance of immunological ◦ Gut-associated lymphoid tissue (GALT), including memory, allowing for rapid and effective immune Peyer's patches in the small intestine and lymphoid responses upon re-exposure to previously follicles in the appendix encountered antigens ◦ Genitourinary-associated lymphoid tissue (GUALT) ◦ Conjunctiva-associated lymphoid tissue (CALT) Lymphoid Pathology 19 MALT Source: Junqueira’s Basic Histology – A Text and Atlas, 14e Lymphoid Pathology 20  CONGENITAL ANOMALIES Lymphoid Pathology 21 Congenital Anomalies ◦ Primary Antibody Deficiency ◦ X-Linked Agammaglobulinaemia (Bruton’s Disease) ◦ Common Variable Immunodeficiency ◦ IgA Deficiency ◦ Di George Syndrome ◦ Severe Combined Immunodeficiency (SCID) Lymphoid Pathology 22 X-Linked Agammaglobulinaemia (Bruton’s Disease) ◦ Rare disorder caused by deficient B cells and ◦ Diagnosis deficient antibody production ◦ Reduced B cells ◦ Mutation in Bruton Tyrosine Kinase (BTK) gene ◦ Low immunoglobulin levels located on the X chromosome ◦ Genetic testing to confirm the presence of BTK ◦ BTK is crucial for the development and gene mutation maturation of B cells ◦ Treatment ◦ X-linked recessive inheritance pattern ◦ Lifelong immunoglobulin replacement therapy ◦ Carrier mothers pass the mutation to affected to provide passive immunity male children ◦ Antibiotic therapy to manage and prevent infections ◦ Clinical Presentation ◦ Onset usually occurs in the first or second year of◦ Complications life ◦ Chronic lung disease ◦ Recurrent bacterial infections, especially ◦ Autoimmune disorders respiratory and gastrointestinal ◦ Absence or extremely low levels of immunoglobulins, particularly IgG, IgA, and IgM Lymphoid Pathology 23 Common Variable Immunodeficiency CVID) ◦ Rare ◦ Diagnosis ◦ Defects in B cell differentiation and function ◦ Low immunoglobulin levels: (IgG, IgA, and IgM) ◦ Exclusion other causes of ◦ Unknown cause hypogammaglobulinemia or immunodeficiency ◦ Sporadic or familial ◦ Treatment ◦ Affects both males and females ◦ Immunoglobulin replacement therapy is the mainstay of treatment ◦ Clinical Features ◦ Antibiotic therapy for managing and preventing ◦ Adolescence and early adulthood infections ◦ Recurrent bacterial infections, particularly in ◦ Immunosuppressive therapy for autoimmune respiratory and gastrointestinal tracts complications ◦ Increased susceptibility to viral and fungal ◦ Complications infections ◦ Chronic lung disease and bronchiectasis ◦ Autoimmune manifestations, such as arthritis or autoimmune cytopenias ◦ Increased risk of autoimmune disorders e.g., thyroiditis ◦ Granulomatous inflammation in various organs ◦ Malignancies, particularly lymphomas Lymphoid Pathology 24 IgA Deficiency ◦ Deficiency or absence of immunoglobulin ◦ Management A (IgA) ◦ Treatment is mainly supportive and focused on managing infections as they arise ◦ Clinical features: ◦ Antibiotic therapy is used to treat bacterial ◦ Asymptomatic: many patients and may infections, and antiviral or antifungal remain undiagnosed medications may be necessary for other ◦ Recurrent respiratory and gastrointestinal infections infections ◦ Allergic conditions ◦ Complications ◦ Autoimmune diseases ◦ Autoimmune disorders, particularly celiac disease ◦ Diagnosis ◦ Allergic conditions, such as asthma and ◦ Persistently low serum IgA levels allergic rhinitis ◦ May be seen as part of common variable immunodeficiency (CVID) Lymphoid Pathology 25 Severe Combined Immunodeficiency (SCID) ◦ Group of diseases characterized by severe ◦ Chronic diarrhoea deficiencies in both T and B lymphocytes ◦ Persistent skin rashes ◦ Caused by genetic mutations genes in: ◦ Diagnosis ◦ T cell receptor signaling ◦ Low lymphocyte count ◦ Cytokine receptors ◦ Treatment ◦ Enzymes essential for lymphocyte ◦ Haematopoietic stem cell transplantation development (HSCT) is the primary curative treatment for ◦ Onset and Presentation SCID ◦ Infancy ◦ Antimicrobial prophylaxis and isolation measures ◦ Recurrent and severe infections, especially from opportunistic pathogens ◦ Failure to thrive Lymphoid Pathology 26  LYMPH NODE PATHOLOGY Lymphoid Pathology 27 Lymphadenopathy ◦ Clinical term referring to enlargement of a lymph node ◦ Two main subtypes ◦ Reactive (Benign) Lymphadenopathy ◦ Commonest type of lymphadenopathy ◦ Underlying inflammatory cause ◦ Acute inflammatory lymphadenitis and chronic lymphadenitis ◦ Malignant Lymphadenopathy ◦ Due to a neoplastic process ◦ Commonest cause is a metastasis Lymphoid Pathology 28 Acute Lymphadenitis ◦ Most often due to a bacterial infection in the area drained by the lymph node ◦ In systemic bacterial sepsis or viraemia, it is generalised ◦ Neutrophil infiltration and even abscess formation may be seen in the lymph node ◦ Due to sudden onset and stretching of the capsule, acute lymphadenitis is tender Arrow – Acute Inflammatory Infiltrate; Arrow Head – Foamy Macrophages Lymphoid Pathology 29 Chronic Lymphadenitis ◦ 3 distinctive patterns: ◦ Follicular hyperplasia ◦ Parafollicular hyperplasia ◦ Sinus hyperplasia Lymphoid Pathology 30 Follicular Hyperplasia ◦ Inflammations/infections that activate the humoral systems ◦ Many big follicles with active GC ◦ GC contains ◦ Centroblasts, centrocytes ◦ Follicular dendritic Mø ◦ Tingible-body macrophages ◦ Due to longstanding contact with stimulating microbes/antigens ◦ Results in the production and clonal expansion of antibody-secreting plasma cells ◦ Toxoplasmosis, HIV-AIDS, RA, syphilis Lymphoid Pathology 31 Paracortical Hyperplasia ◦ Reactive changes within the T-cell regions of the lymph node ◦ Naïve parafollicular T cells transform into large proliferating immunoblasts ◦ Encountered in conditions activating specific cell mediated response: ◦ Viral infections (such as EBV) ◦ Certain vaccinations (e.g., smallpox) ◦ Immune reactions to certain drugs Lymphoid Pathology 32 Sinus Hyperplasia ◦ Characterized by distention and prominence of the lymphatic sinusoids: ◦ Marked hypertrophy of lining endothelial cells ◦ Infiltration by macrophages (histiocytes) ◦ Seen in nodes draining tissues from which endogenous particulate matter such as lipid is released ◦ Lymph nodes draining cancers ◦ Whipple’s disease ◦ Haemolysis Lymphoid Pathology 33  Source: Wheater’s Pathology – A Text, Atlas and Review of Histopathology, 6e Lymphoid Pathology 34  Granulomatous Lymphadenitis ◦ Lymph node structure partly or completely effaced by granulomas ◦ Necrotising granulomas seen in mycobacterial lymphadenitis ◦ Typical vs atypical mycobacteria ◦ Well-made granulomas without caseation: ◦ Sarcoidosis ◦ Crohn’s disease ◦ Hodgkin disease ◦ Granulomas with pus in their centres: ◦ Cat scratch disease ◦ Brucellosis ◦ Plague ◦ Yersiniosis ◦ X-lined chronic granulomatous disease Lymphoid Pathology 35  Malignant Lymphadenopathy ◦ Less common than reactive lymphadenopathy ◦ Secondary vs Primary ◦ Secondary ◦ Commoner ◦ Important staging and prognosticating feature ◦ Enter into subcapsular sinus ◦ May enlarge and replace entire node ◦ Tumour usually looks like the primary tumour ◦ Examples ◦ Carcinoma ◦ Melanoma ◦ Primary ◦ Lymphoma Source: Wheater’s Pathology – A Text, ◦ Langerhan cell histiocytosis Atlas and Review of Histopathology, 6e Lymphoid Pathology 36 Lymphoma ◦ Malignant tumour of lymphoid tissue ◦ 2 broad categories based on differences in clinical behaviour and tumour morphology ◦ Hodgkin Lymphoma ◦ Characterised by the presence of Reed-Sternberg (RS) cells ◦ Non-Hodgkin Lymphoma ◦ Derived from B or T cells ◦ Presents with involvement of a group of lymph nodes and may then spread to involve multiple nodal groups, as well as other haematolymphoid organs such as bone marrow and spleen ◦ Non-Hodgkin lymphoma may arise in other organs or tissues such as skin, gut, thyroid, brain, salivary gland, lung and testis Lymphoid Pathology 37 Lymphoid Pathology 38 Hodgkin Lymphoma ◦ 30% of all lymphomas ◦ Arise from a single node or a chain of nodes ◦ Commonest presentation involves cervical lymph nodes; axial nodes may be involved too ◦ Spreads to anatomically contiguous nodes (Ann Arbor Staging) ◦ Extranodal involvement is uncommon ◦ Nodal disease > splenic disease > hepatic disease > BM involvement > extranodal disease ◦ Bimodal age distribution with majority in young adults, mean age 32 year ◦ Peak 1(larger) – Ages 15 to 35 ◦ Peak 2 – Ages > 55 ◦ Diagnostic cell is the Reed-Sternberg cell constituting 1 – 5% of tumour mass in the appropriate non-neoplastic inflammatory background ◦ Curable Lymphoid Pathology 39 Reed-Sternberg Cell ◦ Large and binucleate or mononucleated bi-lobed cell ◦ Large, eosinophilic, owl-eyed nucleoli are generally surrounded by a clear halo ◦ The nucleus is enclosed within an abundant cytoplasm Source: Rosai and Ackerman’s Surgical Pathologist, 11e Lymphoid Pathology 40  Hodgkin Lymphoma - Pathogenesis GC B-Cell / Post GC B-Cell ◦ RS cells produce cytokines attracting reactive cells EBV Infection 1. IL-5 Expression of LMP-1 2. IL-6 Upregulation of NF-κβ 3. IL-13 4. TNF Evasion of Apoptosis 5. GM-CSF Further Acquired Mutations Source: Robbin’s Basic Pathology, 10e H/RS Cells Lymphoid Pathology 41 Clinical Features Distinguishing HL form NHL HL NHL ◦ Localised to a single axial group of ◦ Involvement of multiple peripheral nodes nodes ◦ Contiguous spread ◦ Non-contiguous spread ◦ Rarely involves mesenteric nodes and ◦ Usually involves mesenteric nodes and Waldeyer’s ring Waldeyer’s ring ◦ Rare extranodal involvement ◦ Common extranodal involvement Lymphoid Pathology 42  Hodgkin Lymphoma Source: Diagnostic Lymph Node Pathology Source: Wheater’s Pathology – A Text, Atlas and Review of Histopathology, 6e Lymphoid Pathology 43  Staging (Ann Arbor Classification) Stage Distribution of Disease I Involvement of one LN, one LN region or one lymphoid structure e.g. spleen, thymus, Waldeyer’s ring II Involvement of 2 or more LN regions/structures on the same side of the diaphragm III Involvement of 2 or more LN regions/structures on opposite sides of the diaphragm IV Involvement of extranodal sites such a liver and bone marrow A – No systemic symptoms B – Fever and/or night sweats and/or ≥10% weight loss Lymphoid Pathology 44 Presentation, Course & Prognosis Presentation, Course Prognosis, Rx ◦ LNPathy ◦ Good prognosticators ◦ Firm ◦ Early stage ◦ Mobile ◦ Young age ◦ Non-tender ◦ Absence of B symptoms ◦ Tender on ingestion of alcohol ◦ Rx ◦ B symptoms ◦ Early presentation – radioRx ◦ Spread to contiguous lymphoid ◦ Later stages – multidrug ChemoRx structures ◦ Some nodes remain stable for long ◦ Complications of Rx periods ◦ 20 malignancies: MDS, AML, lung Ca ◦ Some nodes regress spontaneously Lymphoid Pathology 45 Non-Hodgkin Lymphoma 1. Painless LNpathy 2. Localised to one nodal group or may be widely disseminated, with generalised LNpathy and involvement of other organs 3. Biopsy establishes the diagnosis and allows classification 4. Definitive classification involves: i. Assessment of cell morphology ii. Immunophenotype iii. Molecular/cytogenetic features 5. A number of NHL show characteristic chromosomal abnormalities which are useful in Dx and, in assessing prognosis 6. Most tumours are derived from a clonal proliferation of B or T cells and may be broadly divided into low- grade and high-grade types 7. B-cell lymphomas >>>> T-cell lymphomas 8. B-cell lymphomas may arise at extranodal sites e.g., MALT-lymphomas, and these behave differently from nodal lymphomas 9. T-cell lymphomas most frequently occur in skin and present as a disease termed mycosis fungoides Lymphoid Pathology 46 NHL Classification SLL/CLL Low Grade B Follicular Extranodal Marginal Zone Mantle Cell Cell High Grade DLBCL Burkitt Mycosis Fungoides T Cell Anaplastic Large Cell Lymphoid Pathology 47 Source: Robbin’s Basic Pathology, 10e Lymphoid Pathology 48 NHL Classification SLL/CLL Low Grade B Follicular Extranodal Marginal Zone Mantle Cell Cell High Grade DLBCL Burkitt Mycosis Fungoides T Cell Anaplastic Large Cell Lymphoid Pathology 49 Small Lymphocytic Lymphoma - SLL ◦ Malignant clonal expansion of well-differentiated lymphoid cells ◦ Disease spectrum from predominantly leukaemic to a lymphoma ◦ FBC: Lymphocytosis > 5 000/μL → CLL ◦ FBC: Lymphocytosis < 5 000/ μL → SLL ◦ Postulated normal counterpart – Naïve B Cell ◦ Tumour cells suppress B-cell function and interfere with immune regulation: ◦ ↓γglobulinaemia ◦ Anti-RBC autoantibodies ◦ Anti-platelet autoantibodies ◦ Spread is by involving lymph nodes, spleen, liver and bone marrow ◦ Fragile neoplastic cells – smudge cells in PBFs ◦ Over time, it may transform to high-grade DLBCL (Richter syndrome) ◦ Rare but aggressive Lymphoid Pathology 50 Small Lymphocytic Lymphoma - SLL Lymphoid Pathology 51 SLL - Morphology Source: Robbins Basic Pathology, 10e Lymphoid Pathology 52 SLL: Clinical Features ◦ M:F = 2:1 SLL ◦ Often asymptomatic ◦ Other haematological features ◦ Disease of the older age group (median ◦ Increased susceptibility to infections (↓γglobulinaemia) age is 60 years) ◦ Autoimmune haemolytic anaemia ◦ Initial nonspecific symptoms: ◦ Autoimmune thrombocytopenia ◦ Easy fatiguability ◦ Incurable ◦ Weight loss ◦ Anorexia ◦ Disease progresses very slowly ◦ Generalised LNpathy and ◦ Median survival: 4 – 6 years hepatosplenomegaly (50 – 60%) ◦ BM involvement in CLL and many cases of Lymphoid Pathology 53 NHL Classification SLL/CLL Low Grade B Follicular Extranodal Marginal Zone Mantle Cell Cell High Grade DLBCL Burkitt Mycosis Fungoides T Cell Anaplastic Large Cell Lymphoid Pathology 54 Follicular Lymphoma ◦ Commonest form of NHL (approx. 40%) ◦ M:F = 1:1 ◦ Disease of middle-aged and older ◦ Composed of follicular centre B cells that partially or completely form follicles ◦ Presents with painless LNPathy; frequently generalised ◦ Bone marrow involvement in 85% of cases ◦ Frequently involves splenic white pulp and hepatic portal triads Lymphoid Pathology 55 Follicular Lymphoma - FL Lymphoid Pathology 56  Follicular Lymphoma - Morphology Source: Robbins Basic Pathology, 10e Source: Rosai and Ackerman’s Surgical Pathologist, 11e Lymphoid Pathology 57 Follicular Lymphoma Pathogenesis Clinical course ◦ Chromosomal abnormality: t(14; 18) ◦ Incurable ◦ Ch 14 – promoter site for immunoglobulin ◦ Median survival of 7 to 9 years expression ◦ Ch 18 – bcl2 gene (anti-apoptotic gene) ◦ Transformation to DLBCL in 30 – 50% of ◦ This gene is normally turned off in the GC cases ◦ Consequent increased survival of the ◦ Aggressive therapy does not improve neoplastic cells survival ◦ Approach is to palliate patients with low dose chemo-Rx or radio-Rx when they become symptomatic Lymphoid Pathology 58 NHL Classification SLL/CLL Low Grade B Follicular Extranodal Marginal Zone Mantle Cell Cell High Grade DLBCL Burkitt Mycosis Fungoides T Cell Anaplastic Large Cell Lymphoid Pathology 59  Marginal Zone Lymphoma ◦ A group of low-grade B-cell neoplasms composed of small post-germinal centre lymphocytes 1. Nodal Marginal Zone Lymphoma H. Pylori DLBCL infection 2. Extranodal Marginal Zone Lymphoma ◦ Aka MALT lymphoma; MALToma ◦ Commoner ◦ Chronic immune stimulation: ◦ H. pylori gastritis→ gastric MALToma ◦ Sjörgen’s disease → salivary MALToma Reactive Distant polyclonal ◦ Hashimoto’s disease → thyroid MALToma spread immune stimulation ◦ 50s ◦ F>M ◦ Indolent ◦ Tend to remain localised for long periods ◦ May even regress in some circumstances ◦ Curable Monoclonal MALToma B-Cell 3. Splenic Marginal Zone Lymphoma neoplasm Lymphoid Pathology 60 Marginal Zone Lymphoma - MZL Lymphoid Pathology 61 Marginal Zone Lymphoma Source: Wheater’s Pathology, A Text, Atlas and Review of Hisptopathology, 6e Lymphoid Pathology 62 NHL Classification SLL/CLL Low Grade B Follicular Extranodal Marginal Zone Mantle Cell Cell High Grade DLBCL Burkitt Mycosis Fungoides T Cell Anaplastic Large Cell Lymphoid Pathology 63 Mantle Cell Lymphoma ◦ Uncommon ◦ Normal cell counterpart is the naïve B cell in the mantle zone of the lymphoid follicle ◦ Characteristic genetic lesion is t(11;14) ◦ Fusion of cyclin D1 gene (Ch 11) to IgH promoter locus (Ch 14) ◦ Increased cyclin D1 expression leading to increased G1-S cycling ◦ May occur at extranodal sites ◦ Clinically more aggressive than other low grade B cell tumours Lymphoid Pathology 64 Mantle Cell Lymphoma - MCL Lymphoid Pathology 65 NHL Classification SLL/CLL Low Grade B Follicular Extranodal Marginal Zone Mantle Cell Cell High Grade DLBCL Burkitt Mycosis Fungoides T Cell Anaplastic Large Cell Lymphoid Pathology 66 Burkitt Lymphoma ◦ Neoplasm of germinal centre B-cells ◦ Malaria infection may interfere with T-cell response to EBV ◦ Tumour of relatively mature B-cells ◦ Preferentially affects children ◦ Fastest growing solid human tumour ◦ Presents as a mass: ◦ Mandible, Abdomen (Kidneys, Ovaries, ◦ Associated with translocations involving c- Adrenals), Orbit, Breast myc gene ◦ Curable with chemotherapy ◦ t(8;14) 2. Sporadic (non-endemic) Burkitt lymphoma ◦ Ch 8 – c-myc gene (oncogene) ◦ Global distribution ◦ Ch 14 – promoter region for immunoglobulin ◦ Preferentially affects children and adolescents heavy genes ◦ Presents as an abdominal mass: Ileocaecum, ◦ 3 clinical syndromes differing in clinical, Peritoneum genotypic and aetiologic factors: ◦ Responds well to chemotherapy ◦ Worse prognosis than Endemic Burkitt lymphoma 1. African (endemic) Burkitt lymphoma ◦ Equatorial strip of Africa 3. HIV-associated Burkitt lymphoma ◦ Common in malaria-endemic areas ◦ ~ 95% associated with EBV infection Lymphoid Pathology 67 Burkitt Lymphoma - BL Lymphoid Pathology 68 Burkitt Lymphoma - Morphology ◦ Gross ◦ Mass lesion: ◦ Mandible ◦ Abdominal ◦ Micro ◦ Diffuse infiltration of lymph nodes by intermediate-sized lymphoid cells ◦ Big round to oval blue nuclei ◦ Deep blue cytoplasm laden with lipid droplets ◦ Mitotic figures (high proliferative index) ◦ Numerous apoptotic cells. These are engulfed by resident Mø imparting a “starry-sky” appearance ◦ Extranodal involvement is common Lymphoid Pathology 69 Lymphoid Pathology Burkitt Lymphoma - Morphology Source: Wheater’s Pathology, A Text, Atlas and Review of Hisptopathology, 6e 70 NHL Classification SLL/CLL Low Grade B Follicular Extranodal Marginal Zone Mantle Cell Cell High Grade DLBCL Burkitt Mycosis Fungoides T Cell Anaplastic Large Cell Lymphoid Pathology 71  Diffuse Large B Cell Lymphoma ◦ Group of NHL with the following features: ◦ Rapidly enlarging, symptomatic mass(es) ◦ B cell phenotype ◦ Nodal or extranodal site ◦ Relatively large size of lymphoma cells ◦ GI, Skin, Bone, Brain, Waldeyer’s ring, Liver, Spleen ◦ 3 – 4× the size of resting Lø ◦ Considerable morphological variation from cell to cell ◦ BM involvement occurs late in disease ◦ Diffuse growth pattern resulting in effacement of ◦ Dx typically happens before this lymph node architecture ◦ Leukaemic picture is rare ◦ An aggressive clinical course ◦ Localised disease has a better prognosis than ◦ 40 - 50% of adult lymphomas widespread or bulky tumours ◦ Any age ◦ Rx ◦ Two forms ◦ Combination chemoRx ◦ DLBCL arising de novo ◦ Complete remission in 60 – 80% ◦ 40 – 50% cured ◦ DLBCL arising from high grade transformation of other lymphomas (SLL, FL) ◦ Untreated, rapidly fatal Lymphoid Pathology 72 DLBCL Source: Wheater’s Pathology, A Text, Atlas and Review of Hisptopathology, 6e Lymphoid Pathology 73 Multiple Myeloma & Related Tumours ◦ Lymphoid neoplasms of terminally-differentiated B-cells ◦ Expansion of a single clone of Ab-secreting plasma cells ◦ Consequent resultant increase in serum of a single homogenous Ab or its fragments ◦ Monoclonal Ab or its fragments = M protein ◦ May also appear in urine, in case of GBM damage, with heavy proteinuria ◦ Often, these proliferations/dyscrasias show malignant behaviour ◦ Entities ◦ Multiple myeloma ◦ Solitary myeloma/plasmacytoma ◦ Waldenström macroglobulinaemia Lymphoid Pathology 74 Plasma Cell Neoplasms Lymphoid Pathology 75 MM: Clinico-Pathological Features ◦ Incidence higher in men and older adults ◦ ↑Ca+2aemia ◦ Peak age 50 – 60 years ◦ Confusion ◦ Weakness ◦ Characterised by multiple tumorous ◦ Lethargy masses which involve the skeletal system ◦ Constipation ◦ Frequently located in the vertebral column, ◦ Polyuria ribs, skull, clavicle and scapula ◦ Renal disease ◦ Micro: ◦ Recurrent infections ◦ In the BM, diffuse infiltration of plasma cells (> ◦ NCNC anaemia 30%) with prominent Golgi apparatus and ◦ Leucopenia eccentric nuclei ◦ Thrombocytopenia ◦ C/F: ◦ Solitary myeloma/solitary plasmacytoma is ◦ Bone pain an infrequent variant ◦ Pathological # Lymphoid Pathology 76  MM: Dx ◦ Radiographic and Laboratory findings ◦ Radiographic ◦ Sharply-punched out defects in bone ◦ Rounded, soap-bubble appearance ◦ Generalised osteoporosis ◦ Laboratory ◦ Electrophoretic analysis ◦ 99% have ↑ serum IgG (Ig A) ◦ Urine light chains (Bence Jones proteins) Pitfall – 1% of myelomas are non- secretory! ◦ Trephine Biopsy ◦ Increased interstitial plasma cells ◦ May entirely replace normal marrow elements Source: Wheater’s Pathology, A Text, Atlas Lymphoid Pathology and Review of Hisptopathology, 6e 77 MM Bence Jones Proteins Complications ◦ Normal plasma cells are characterised ◦ Bone pain (osteoclastic activity) by tightly-balanced production and ◦ Micro# and pathological # coupling of heavy and light chains ◦ Anaemia ◦ This balance is lost in neoplastic cells ◦ How? 4 marks ◦ Consequent production of excessive light chains, heavy chains and Abs ◦ Infections ◦ Light chains small enough to be rapidly ◦ Urinary stones excreted in urine [Bence Jones Proteins ◦ Amyloidosis (BJP)] ◦ Hyperviscosity syndromes ◦ Low plasma levels or completely cleared ◦ Renal failure Lymphoid Pathology 78  SPLENIC PATHOLOGY Lymphoid Pathology 79 Splenic Pathology ◦ Congenital Spleen Disorders: ◦ Neoplastic Conditions: ◦ Asplenia ◦ Benign: haemangioma, lymphangioma ◦ Polysplenia ◦ Malignant ◦ Congenital cysts ◦ Splenic lymphomas: Non-Hodgkin lymphomas ◦ Vascular malformations ◦ Splenic involvement in haematologic malignancies ◦ Metastasis ◦ Inflammatory and Infectious Conditions: ◦ Splenomegaly ◦ Traumatic Injuries: ◦ Splenic abscess ◦ Splenic rupture ◦ Infectious mononucleosis ◦ Splenic haematoma ◦ Hematologic Disorders: ◦ Autoimmune Disorders: ◦ Splenic infarction ◦ Autoimmune hemolytic anemia ◦ Hemolytic anemias ◦ Autoimmune thrombocytopenia ◦ Sickle cell disease Lymphoid Pathology 80 Splenomegaly ◦ Response of the spleen to a wide variety spherocytosis, thalassemia major, of diseases autoimmune haemolytic anemia ◦ Amyloidosis ◦ Massive splenomegaly (weight > 1000 g) ◦ Niemann-Pick disease ◦ Myeloproliferative neoplasms (CML, primary myelofibrosis) ◦ Infections e.g., infective endocarditis, tuberculosis, typhoid ◦ Indolent leukemias (CLL and hairy cell leukemia) ◦ Sarcoidosis ◦ Lymphomas ◦ Metastatic carcinoma or sarcoma ◦ Infectious diseases (e.g., malaria) ◦ Mild splenomegaly (weight < 500 g) ◦ Gaucher disease ◦ Acute splenic congestion ◦ Moderate splenomegaly (weight 500 – ◦ Infections: infectious mononucleosis, 1000 g) septicemia, intraabdominal infections ◦ Chronic congestive splenomegaly (portal ◦ Autoimmune disease e.g., systemic lupus hypertension or splenic vein obstruction erythematosus ◦ Acute leukemias ◦ Complication: Hypersplenism ◦ Extravascular haemolysis: hereditary Lymphoid Pathology 81 Thymic Pathology ◦ Congenital Anomalies ◦ Thymic aplasia / hypoplasia ◦ Thymic cyst – remnant of thymopharyngeal duct ◦ Thymic Hyperplasia ◦ Neoplastic Disorders ◦ Thymoma ◦ Thymic carcinoma ◦ Thymic lymphoma ◦ Thymic neuroendocrine tumours Lymphoid Pathology 82 Thymic Hyperplasia ◦ Non-neoplastic increase in thymic tissue ◦ Immune mediated: myasthenia gravis, systemic lupus erythematosus, rheumatoid arthritis, mass Graves’ disease, etc. ◦ Associated with the presence of lymphoid ◦ Diagnosis follicles, or germinal centers, within the ◦ Histopathology medulla ◦ Management ◦ Causes ◦ Monitoring ◦ Physiological: ◦ Symptomatic management e.g., ◦ Childhood, adolescence acetylcholinesterase inhibitors ◦ Compensatory hyperplasia: in response to lymphopenia (viral infections, chemotherapy, ◦ Immunomodulatory therapy e.g., steroids irradiation) ◦ Surgical resection ◦ Pathological ◦ Chronic infections: HIV, sarcoidosis, EBV, etc. Lymphoid Pathology 83 Thymoma ◦ Rare neoplasm arising from the epithelial ◦ Dyspnoea cells of the thymus gland ◦ Superior vena cava syndrome ◦ ~ 20% of all mediastinal tumours ◦ Paraneoplastic syndromes: myasthenia gravis, pure red cell aplasia, hypogammaglobulinemia, ◦ Ages 40 to 60 years multi-organ autoimmunity ◦ Slight female predilection ◦ Diagnosis ◦ Associated with autoimmune diseases, ◦ Histopathology particularly myasthenia gravis in ~ 30% of ◦ Management patients ◦ Symptomatic management e.g., ◦ Classification acetylcholinesterase inhibitors ◦ Benign thymoma ◦ Immunomodulatory therapy e.g., steroids ◦ Malignant thymoma / thymic carcinoma ◦ Surgical resection ◦ Clinical features ◦ Chemotherapy ◦ Chest pain ◦ Radiotherapy ◦ Cough Lymphoid Pathology 84 References ◦ Immunobiology – The Immune System in Health and Disease, 5e ◦ Textbook of Histology, 4e ◦ Wheater’s Functional Histology – A Text and Colour Atlas, 6e ◦ Junqueira’s Basic Histology – A Text and Atlas, 14e ◦ Wheater’s Pathology – A Text, Atlas and Review of Histopathology, 6e ◦ Robbins Basic Pathology, 10e ◦ Rosai and Ackerman’s Surgical Pathologist, 11e ◦ Diagnostic Lymph Node Pathology ◦ pathologyoutlines.com Lymphoid Pathology 85