---

PATHOLOGY NOTES - MUHS 2nd MBBS

Based on Robbins & Kumar Basic Pathology + Harshmohan

---

1. HODGKIN'S LYMPHOMA (HL)

Classification - Five Subtypes (WHO)

---

MIXED CELLULARITY HL - Two Important Features (★★ Exam Favorite)

1. Abundant classic Reed-Sternberg cells - Binucleate/multinucleate RS cells are plentiful in a heterogeneous inflammatory background of lymphocytes, eosinophils, plasma cells, and macrophages
2. Strong EBV association - EBV is demonstrable in RS cells in up to 70% of cases (highest of all HL subtypes); the integration site is identical in all RS cells, confirming EBV infection precedes clonal transformation

• Most common subtype in patients >50 years, with male predominance
• More likely to be disseminated and associated with systemic "B symptoms" compared to nodular sclerosis
• EBV likely contributes to transformation via oncogenic LMP1 protein

---

REED-STERNBERG (RS) CELL - Description

Classic RS Cell (Diagnostic / "Owl-Eye" Cell)

• Size: Large, 15-45 µm in diameter
• Nucleus: Enormous multilobate nucleus (typically binucleate or bilobed)
• Nucleolus: Exceptionally prominent, large, inclusion-like, acidophilic nucleolus surrounded by a clear halo - classically two nucleoli in mirror-image lobes giving the "owl-eye" appearance
• Cytoplasm: Abundant, slightly eosinophilic
• Immunophenotype: CD15(+), CD30(+), CD45(-), B-cell and T-cell markers (-)
• Origin: Derived from germinal center B cells (proven by identical Ig gene rearrangements in single microdissected RS cells)

---

RS Cell Variants (★★ Must Know for Exam)

---

GROSS AND MICROSCOPIC FEATURES (Pg. 348 reference = Harshmohan equivalent)

Gross Features

• Affected lymph nodes are enlarged, rubbery, matted, and discrete
• In Nodular Sclerosis type: the lymph node is firm due to fibrous bands and may show a white-glistening cut surface
• Involved nodes may coalesce into large masses, particularly in the mediastinum
• Spleen, liver, bone marrow involvement shows irregular nodules of RS cells mixed with reactive cells

Microscopic Features

• Lacunar cells in cellular nodules
• Collagen bands divide tissue into circumscribed nodules
• Background: lymphocytes, eosinophils, plasma cells

---

• Classic RS cells plentiful
• Heterogeneous infiltrate: lymphocytes, eosinophils, plasma cells, macrophages
• No collagen bands

---

• "Popcorn cells" within large nodules of small B cells + macrophages
• Eosinophils scanty/absent; classic RS cells rare

---

Pathogenesis (Quick Points)

• RS cells derive from germinal center B cells (proven by identical Ig gene rearrangements)
• EBV encodes LMP1 (a functional mimic of CD40) - most important in mixed cellularity
• RS cells secrete: IL-5 (eosinophil recruitment), TGF-β (fibrosis), IL-13 (autocrine growth)
• RS cells overexpress PD-L1 and PD-L2 → suppress host T-cell response (explains response to anti-PD-1 therapy)

---

Clinical Features and Staging

• Painless lymphadenopathy (most common presentation)
• B symptoms: fever, night sweats, >10% weight loss
• Pruritus
• Spreads in a stepwise/contiguous fashion (unlike NHL)
• Rarely involves mesenteric nodes or Waldeyer's ring

---

2. SPLENOMEGALY - Classification and Associated Diseases

Definition

Classification with Associated Diseases (Table 10.12, Robbins)

I. INFECTIONS

• Nonspecific splenitis (blood-borne infections, especially infective endocarditis)
• Infectious mononucleosis (EBV) - risk of splenic rupture
• Tuberculosis
• Typhoid fever
• Brucellosis
• Cytomegalovirus (CMV)
• Syphilis
• Malaria (massive splenomegaly/"Tropical splenomegaly")
• Histoplasmosis
• Toxoplasmosis
• Trypanosomiasis
• Schistosomiasis
• Leishmaniasis (kala-azar - massive splenomegaly)
• Echinococcosis

II. CONGESTIVE STATES (related to Portal Hypertension)

• Cirrhosis of the liver (most common cause of massive congestive splenomegaly)
• Portal vein thrombosis
• Splenic vein thrombosis
• Cardiac failure (congestive heart failure)

III. LYMPHOHEMATOGENOUS DISORDERS

• Hodgkin lymphoma
• Non-Hodgkin lymphomas and lymphocytic leukemias
• Myeloproliferative neoplasms (CML, polycythemia vera, primary myelofibrosis - massive splenomegaly)
• Hemolytic anemias (hereditary spherocytosis, thalassemia, sickle cell)

IV. IMMUNOLOGIC / INFLAMMATORY CONDITIONS

• Rheumatoid arthritis (Felty's syndrome: RA + splenomegaly + neutropenia)
• Systemic Lupus Erythematosus (SLE)

V. STORAGE / CONGENITAL (Lipid Storage Diseases)

• Gaucher disease (most common - massive splenomegaly)
• Niemann-Pick disease
• Mucopolysaccharidoses

VI. MISCELLANEOUS

• Amyloidosis
• Primary neoplasms and cysts (hemangioma - most common benign tumor)
• Secondary (metastatic) neoplasms

---

Quick Memory Aid for Splenomegaly Causes:

"I CAN LIST"
I - Infections (malaria, TB, EBV)
C - Congestive (portal HTN, cirrhosis)
A - Autoimmune (SLE, RA)
N - Neoplasms (lymphomas, leukemias)
L - Lipid storage (Gaucher, NPC)
I - Inflammatory
S - Storage disorders
T - Thalassemia/hemolytic anemias

---

3. NON-HODGKIN'S LYMPHOMA (NHL) - Detailed

Definition

---

Classification - By Cell of Origin + Grade

WHO Classification Principles:

1. Based on cell of origin (B cell vs T cell vs NK cell)
2. Stage of differentiation (precursor vs mature/peripheral)
3. Growth pattern (follicular vs diffuse)
4. Grade (indolent/low grade vs aggressive/high grade)

---

B-CELL NHLs (most common - ~85% of all NHL)

1. Small Lymphocytic Lymphoma / Chronic Lymphocytic Leukemia (SLL/CLL)

• Most common adult leukemia (CLL)
• Cell type: Mature CD5+ B cells
• Histology: Diffuse effacement of lymph node architecture with proliferation centers (pseudofollicles containing larger prolymphocytes) - pathognomonic
• High BCL2 expression (antiapoptotic)
• Indolent course; immune abnormalities (autoimmune hemolytic anemia, hypogammaglobulinemia)
• ~10% transform to aggressive DLBCL (Richter transformation)
• Key exam: CD5(+), CD23(+), CD20(dim+)

2. Follicular Lymphoma

• Most common indolent lymphoma (~20% of all NHL in adults)
• Cell type: Germinal center B cells
• Key genetic lesion: t(14;18) - juxtaposes BCL2 gene with IgH locus → BCL2 overexpression → blocked apoptosis
• Histology: Back-to-back follicles recapitulating germinal center B-cell growth; follicles are uniform, closely packed, lack polarization; mantle zones thin/absent
• Indolent but incurable with standard therapy
• 30-40% transform to aggressive DLBCL
• Key exam: CD10(+), BCL2(+), BCL6(+)

3. Mantle Cell Lymphoma

• Cell type: Mature CD5+ B cells (like CLL but different)
• Key genetic lesion: t(11;14) → Cyclin D1 overexpression (diagnostic marker)
• Moderately aggressive; poor prognosis
• Involves mantle zone of lymphoid follicles
• Key exam: CD5(+), CD23(-), Cyclin D1(+)

4. Extranodal Marginal Zone Lymphoma (MALT lymphoma)

• Arises at extranodal sites with chronic inflammation: stomach (H. pylori), salivary glands (Sjögren's), thyroid (Hashimoto's), lung
• Mature B cells; expresses CD20 and surface IgM
• Forms lymphoepithelial lesions (tumor cells infiltrate epithelium)
• Eradication of H. pylori causes regression of gastric MALT lymphoma (important exam point)
• Localized, indolent; often cured by excision + radiotherapy

5. Diffuse Large B-Cell Lymphoma (DLBCL)

• Most common type of lymphoma in adults (~35% of adult NHL)
• Aggressive; heterogeneous group
• Key genetic lesions:
  • BCL6 rearrangements (3q27) - ~1/3 of cases
  • t(14;18) with BCL2 - ~30% (may be "transformed" follicular lymphoma)
  • MYC translocations
• Histology: Large cells (3-4x resting lymphocyte), round/oval nuclei, dispersed chromatin, distinct nucleoli, pale cytoplasm; diffuse growth pattern; architectural effacement
• Immunophenotype: CD20(+), CD45(+)
• ~50% cured with aggressive chemotherapy (R-CHOP)
• "Double-hit" lymphoma (BCL2 + MYC rearrangements) = very aggressive

6. Burkitt Lymphoma

• Very aggressive B-cell tumor
• Mostly extranodal (jaw in endemic African form; abdominal in sporadic form)
• Key genetic lesion: t(8;14) - MYC translocation (also t(2;8) or t(8;22)) → MYC overexpression
• EBV strongly associated with endemic (African) form; less so in sporadic
• Histology: "Starry-sky" pattern - sheets of medium-sized uniform blastic cells with numerous mitotic figures + scattered pale macrophages (tangible-body macrophages) giving a starry-sky appearance
• Immunophenotype: CD20(+), CD10(+), BCL6(+), BCL2(-), Ki-67 ~100%
• Potentially curable with intensive chemotherapy

7. Hairy Cell Leukemia (HCL)

• Rare indolent B-cell tumor
• Cells have characteristic "hairy" cytoplasmic extensions
• Massive splenomegaly + cytopenias (characteristic clinical triad)
• BRAF mutation (V600E) - diagnostic; excellent response to BRAF inhibitors and cladribine
• Tartrate-resistant acid phosphatase (TRAP) positive

---

T-CELL NHLs (~15% of all NHL)

8. Mycosis Fungoides (MF) / Sézary Syndrome (SS)

• Tumor of CD4+ skin-homing T cells
• MF: Indolent, localized skin involvement; responds well to topical therapy
  • Histology: Pautrier microabscesses (clusters of atypical T cells in epidermis)
• SS: Leukemic variant with diffuse erythroderma and circulating tumor cells; aggressive
• Key exam: CD4(+), CD7(-) (aberrant T-cell phenotype)

9. Adult T-Cell Leukemia/Lymphoma (ATLL)

• Caused by HTLV-1 retrovirus (only human cancer caused by a retrovirus - ★exam)
• CD4(+) T cells expressing high levels of CD25 (IL-2 receptor α chain)
• Clinical: Skin lesions, lymphadenopathy, hepatosplenomegaly, hypercalcemia (osteoclast activating factors)
• Peripheral blood: cells with markedly irregular nuclear contours ("flower cells")
• Aggressive; median survival ~8 months

10. Peripheral T-Cell Lymphoma (PTCL, NOS)

• Heterogeneous group (~10% adult NHL)
• Lack defining features; "not otherwise specified"
• Aggressive; respond poorly to therapy
• Produce cytokines causing systemic symptoms even at low tumor burden

---

KEY DIFFERENCES: HL vs NHL (★★ Must Know)

---

QUICK EXAM SUMMARY TABLE: NHL subtypes

---

Easy Diagrams to Draw in Exam

1. Reed-Sternberg Cell (draw this for any HL question)

     ___________
    /           \
   | O[nucleolus]|  <-- Nucleus 1 with large eosinophilic nucleolus
   |   (halo)    |      surrounded by clear halo
    \___________/
         |
         |  "Owl-eye"
    _____|_____
   /           \
  | O[nucleolus]|  <-- Mirror-image Nucleus 2
  |   (halo)    |
   \___________/
   
Abundant eosinophilic cytoplasm all around
Background: lymphocytes + eosinophils + plasma cells

2. Nodular Sclerosis HL (draw for microscopy question)

|===Collagen band===|===Collagen band===|===Collagen band===|
|                   |                   |                   |
|  [Lacunar cell]   |  [Lacunar cell]   |  [Lacunar cell]   |
|  lymphocytes      |  lymphocytes      |  lymphocytes      |
|  eosinophils      |  eosinophils      |  eosinophils      |
|      Nodule 1     |      Nodule 2     |      Nodule 3     |
|___________________|___________________|___________________|

3. Burkitt "Starry-Sky" Pattern (draw for NHL question)

●●●●●●●●●●●●●●●●●●●●   (dark tumor cells = the "night sky")
●●● ☆ ●●●●●●● ☆ ●●●   (pale macrophages = "stars")
●●●●●●●● ☆ ●●●●●●●●
●● ☆ ●●●●●●●●● ☆ ●●
●●●●●●●●●●●●●●●●●●●●

---

Pathogenesis Summary - B-cell NHL oncogene table

---