Comprehensive Study Guide to Hodgkin And Non-Hodgkin Lymphomas

Introduction to Lymphomas

• Definition: Lymphoma refers to a heterogeneous group of biologically and clinically distinct neoplasms that originate from cells within the lymphoid tissue.
• Historical Classification: Historically divided into two distinct categories: Hodgkin’s Lymphoma (HL) and Non-Hodgkin Lymphoma (NHL).
• Cellular Lineage Statistics:     * $\text{85\%}$ of lymphomas originate from mature B cells.     * $\text{10\%}$ to $\text{15\%}$ are derived from the T-cell lineage.

Anatomy and Histology of the Lymphoid System

• Primary (Central) Lymphoid Tissues: These are sites where lymphoid precursor cells mature to be capable of performing functions in response to antigens. Includes:     * Bone Marrow.     * Thymus.
• Secondary (Peripheral) Lymphoid Tissues: These are where antigen-specific reactions occur. Includes:     * Lymph Nodes.     * Spleen.     * Mucosa Associated Lymphoid Tissue (MALT).
• Lymph Node Histology:     * Structure: Divided into a capsule, cortex, paracortex, medulla, and sinuses.     * Sinuses: Located at subcapsular, cortical, and medullary sites. They contain numerous macrophages aimed at filtering lymph fluid, identifying/processing antigens, and presenting them to lymphocytes.     * Cortex: Contains B-cell follicles.     * Paracortex: Contains T-cell zones and High Endothelial Venules (HEVs).     * Medulla: Consists of medullary cords and sinuses.
• B-Cell Compartments: Peripheral lymphoid organs feature three major B-cell compartments characterized by differentiation markers, specifically $\text{CD27}$ and $\text{IgD}$.

Hodgkin Lymphoma (HL)

• Historical Context: Named after Sir Thomas Hodgkin (first described in $\text{1832}$). Dorothy Reed and Carl Sternberg identified the malignant cells (Reed-Sternberg cells).
• Pathological Spread: Arises in a single lymph node or chain and typically spreads in a stepwise fashion to anatomically contiguous nodes.
• General Characteristics:     * Uncommon hematological malignancy arising from mature B cells.     * Accounts for $\text{10\%}$ of all lymphomas.     * Annual incidence: approximately $\text{3}$ cases per $\text{100,000}$ persons.     * Bimodal age distribution curve ($\text{20s}$ and $>60$ years).
• Risk Factors:     * Epstein-Barr Virus (EBV) infection.     * HIV infection.     * First-degree relatives (five-fold increase in risk).     * Gender/Race: Men > women; Whites > Blacks > Asians.     * Immunosuppression and autoimmune disorders.     * Higher socio-economic status in young adults.
• Clinical Presentation:     * Peripheral Lymphadenopathy: Painless, firm, discrete, and freely movable nodes. Cervical and supraclavicular ($\text{60-80\%}$) are most common, followed by axillary. Inguinal and femoral are less common.     * B Symptoms: Fever ($\text{25-50\%}$), drenching night sweats, and weight loss (greater than $\text{10\%}$ of body weight).     * Non-specific Symptoms: Pruritus, fatigue, and pain in lymph nodes after drinking alcohol.     * Extranodal Manifestations:         * Liver: Hepatomegaly, hepatosplenomegaly, jaundice, and ascites.         * Mediastinal: Retrosternal chest pain, cough, shortness of breath, pleural and pericardial effusion.

Reed-Sternberg (RS) Cells and Variants

• The RS Cell: The "sine qua non" of Hodgkin’s lymphoma. Derived from B lymphocytes.
• Morphology: Enormous bilobed or multilobate nucleus with exceptionally prominent nucleoli and abundant, slightly eosinophilic cytoplasm.
• "Owl-Eye" Appearance: Characteristic cells with two mirror-image nuclei, each containing a large acidophilic nucleolus surrounded by a clear zone.
• Variants:     * Lacunar Cells: Characteristic of the Nodular Sclerosis subtype.     * Popcorn Cells (Lymphohistiocytic variant): Characteristic of Nodular Lymphocyte Predominance HL; features a delicate, puffy, multilobed nucleus.

Subtypes of Hodgkin Lymphoma

• Classic Hodgkin’s Lymphoma (cHL):     * Nodular Sclerosis: Most common subtype; frequent in adolescents/young adults. Centralized in mediastinum and supraclavicular sites. Features collagen bands and lacunar RS cells.     * Mixed Cellularity: Comprises $\text{15-30\%}$ of cases. Common in abdominal nodes and spleen. Infiltrate includes eosinophils, lymphocytes, and histiocytes.     * Lymphocyte Rich: Characterized by a background of many reactive lymphocytes.     * Lymphocyte Depleted: Rarest form; carries a poorer prognosis with few lymphocytes and many RS cells.
• Nodular Lymphocyte Predominant HL (NLPHL):     * Comprises $\text{5\%}$ of HL cases; more common in males.     * Isolated cervical or axillary lymphadenopathy.     * Indolent course with better prognosis.     * Immunophenotype: Expresses B-cell antigens ($\text{CD19}$ and $\text{CD20}$).

Staging and Investigations for HL

• Investigations:     * Biopsy: Excisional lymph node biopsy is the diagnostic gold standard. Fine Needle Aspiration (FNA) is usually insufficient.     * Blood Tests: CBC (low Hb/platelets, WBC variant), ESR (elevated), LFT, Serum Ferritin, Serum Copper.     * Imaging: CXR (mediastinal mass), CT scan (determining extent/sites), PET scan (utility in initial evaluation and post-treatment assessment).     * Immunohistochemistry: cHL is usually $\text{CD30+}$ and $\text{CD15+}$.
• Ann Arbor Staging System:     * Stage I: One lymph node region or single extralymphatic site ($I_E$).     * Stage II: Two or more regions on the same side of the diaphragm.     * Stage III: Regions on both sides of the diaphragm; may include spleen ($III_S$).     * Stage IV: Diffuse extralymphatic disease (liver, bone marrow, lung, skin).
• Treatment:     * Early Stage (Favorable): ABVD x $\text{4-6}$ cycles or ABVD x $\text{2}$ cycles + Radiotherapy (XR).     * Early Stage (Unfavorable): ABVD x $\text{4}$ cycles + Localized XRT or ABVD x $\text{6}$ cycles.     * Advanced Stage: ABVD, Stanford V, or Escalated BEACOPP.

Non-Hodgkin Lymphoma (NHL)

• Definition: Neoplastic transformations of mature B, T, and NK cells.
• Comparison to HL: Poorer prognosis generally; cure rates are less than $\text{50\%}$ compared to $\text{80\%}$ for HL. Spreads non-contiguously.
• Classification (WHO 5th Edition, 2022): Based on cell of origin and stage of differentiation. Categories include Precursor B-cell, Peripheral B-cell, Precursor T-cell, and Peripheral T-cell.
• Clinical Behavior Groups:     * Low-Grade (Indolent): Painless, slowly progressive lymphadenopathy. Nodes may "wax and wane" (spontaneous regression). B symptoms and extranodal disease are rare.     * High-Grade (Aggressive): Rapidly enlarging masses. Extranodal involvement ($>\text{1/3}$ of patients) in GI tract, skin, bone marrow, CNS, etc.
• Etiology (Conditions Associated):     * Inherited: Klinefelter's, Bloom syndrome, Ataxia telangiectasia.     * Autoimmune: Sjögren’s syndrome, Rheumatoid Arthritis, SLE, Hashimoto's thyroiditis.     * Infections: EBV, HTLV-1, HHV-8, HCV, H. pylori, Borrelia, Campylobacter jejuni.     * Chemicals/Drugs: Phenytoin, Dioxin, Pesticides, Chemotherapy.

Common NHL Entities

• Diffuse Large B-Cell Lymphoma (DLBCL):     * Most common histologic subtype ($\text{20-50\%}$ of cases). Mean age: $\text{64}$.     * Rapidly enlarging masses, highly invasive, fatal if untreated.     * Cell of origin: Germinal center (GC) or post-GC activated B cells.     * Associated with rearranged or mutated $\text{BCL6}$ gene or $t(14; 18)$ translocation.
• Follicular Lymphoma:     * Second most common lymphoma ($\text{20\%}$ of NHLs).     * Recapitulates normal germinal center B cells (centrocytes and centroblasts).     * Association: $t(14; 18)$ translocation results in $\text{BCL2}$ overexpression (apoptosis suppressor).
• Marginal Zone Lymphomas (MZL):     * Nodal MZL: Restricted to nodes ($<\text{1\%}$ of lymphomas).     * Splenic MZL: Expansion of splenic marginal zones; replacement of white pulp follicles. Associated with HCV.     * Extranodal MZL (MALT): Common site: Stomach. Associated with H. pylori, Sjögren’s, and autoimmune thyroiditis. Features lymphoepithelial lesions.
• Mantle Cell Lymphoma (MCL):     * Malignancy of naive B cells in the mantle zone. Often presents at an advanced stage.     * Association: $t(11; 14)$ translocation causing overexpression of Cyclin D1 (cell cycle regulator).
• Burkitt’s Lymphoma:     * Highly aggressive, endemic (Africa) vs. sporadic forms.     * Mnemonic S.T.A.R.R.: Sporadic/Endemic, Translocation $t(8; 14)$, Aggressive, "Starry Sky" appearance (macrophages eating lipid), Related to EBV.     * Genetic Lesion: $MYC$ gene on chromosome $8$.

CD Markers and Translocations Reference

• CD Markers Table:     * B-cells: $\text{CD19, CD20, CD21, CD22}$.     * T-cells: $\text{CD2, CD3, CD4, CD5, CD7, CD8}$.     * Reed-Sternberg Cells: $\text{CD15, CD30}$.     * Hairy Cell Leukemia: $\text{CD11c, CD25, CD103, CD123}$.     * CLL/SLL: $\text{CD23}$ positive and $\text{CD5}$ positive.     * Mantle Cell: $\text{CD23}$ negative and $\text{CD5}$ positive.     * Early Pre-B (Immature): $\text{CD10}$.
• Chromosomal Translocations:     * Follicular: $t(14; 18)$ (\text{IGH/BCL2})     * Mantle Cell: $t(11; 14)$ (\text{CCND1/IGH})     * DLBCL: $t(3; 4)$ (\text{BCL6})     * Burkitt: $t(8; 14)$ (\text{MYC/IGH})     * Anaplastic (ALCL): $t(2; 5)$ (\text{NPM1/ALK})     * MALT: $t(11; 18)$ (\text{BIRC3/MALT1})

Prognosis: International Prognostic Index (IPI)

• Criteria (One point for each):     1. Age $\ge 60$ years.     2. Elevated Serum Lactate Dehydrogenase (LDH).     3. Performance Status $\ge 2$ (ECOG) or $\le 70$ (Karnofsky).     4. Ann Arbor Stage III or IV.     5. More than $1$ extranodal site.
• Risk Categories for DLBCL:     * Low: $0-1$ factor ($\text{73\%}$ 5-year survival).     * Low-Intermediate: $2$ factors.     * High-Intermediate: $3$ factors.     * High: $4-5$ factors ($\text{26\%}$ 5-year survival).
• R-CHOP Adjusted IPI: Very good ($0$ factors); Good ($1-2$ factors); Poor ($3-5$ factors).