University Exam Answers - Hematology Questions

SHORT ANSWER TYPE QUESTIONS (3 Marks each)

Q1. 22-year-old man - Enlarged rubbery lymph nodes, weight loss, night sweats, FNAC shows "owl eye" cells

Part 1) Most likely diagnosis (1 mark)

The "owl-eye" appearance of cells in FNAC is the hallmark of Reed-Sternberg (RS) cells, which are the diagnostic cells of Hodgkin lymphoma. These are very large cells (15-45 µm in diameter) with an enormous multilobate nucleus, exceptionally prominent nucleoli, and abundant cytoplasm. Characteristic are two mirror-image nuclei or nuclear lobes, each containing a large, inclusion-like acidophilic nucleolus surrounded by a clear zone - giving the "owl-eye" appearance. - Robbins & Kumar Basic Pathology

Part 2) Classification of Hodgkin Lymphoma (2 marks)

1. Nodular Sclerosis (most common; adolescents/young adults; collagen bands; lacunar cells)
2. Mixed Cellularity (classic RS cells plentiful; male predominance; >50 years)
3. Lymphocyte-Rich (rare; good prognosis)
4. Lymphocyte-Depleted (rare; worst prognosis; elderly/HIV)

RS cells in classic subtypes express CD15 and CD30 and are negative for CD45. - Robbins & Kumar Basic Pathology

Q2. Young adult - Fever, sore throat, generalized lymphadenopathy, peripheral smear shows atypical lymphocytes

Part 1) Most likely diagnosis (1 mark)

Infectious mononucleosis is an acute self-limited disease of adolescents and young adults characterized by: (1) fever, sore throat, and generalized lymphadenopathy, and (2) a lymphocytosis of activated CD8+ T cells (seen as atypical lymphocytes on peripheral smear). - Robbins & Kumar Basic Pathology

Part 2) Name the virus that causes it (1 mark)

EBV binds to CD21 on B cells via its envelope glycoprotein, explaining B-cell tropism. Note: CMV can cause a similar syndrome but is distinguished by serology. - Robbins & Kumar Basic Pathology

Part 3) Laboratory test other than peripheral smear (1 mark)

• Detects heterophile antibodies (IgM) against sheep/horse red blood cells produced in EBV infection
• Specific EBV serology: Anti-VCA (Viral Capsid Antigen) IgM - confirms acute infection
• Other options to mention: Anti-EA (Early Antigen), EBNA antibodies, EBV PCR, Throat swab culture

Q3. Elderly patient - Generalized lymphadenopathy, absolute lymphocytosis with smudge cells

Part 1) Most likely diagnosis (1 mark)

• Elderly patient
• Absolute lymphocytosis (mature-looking small lymphocytes)
• Smudge cells (basket cells) on peripheral smear - fragile CLL lymphocytes that rupture during smear preparation - PATHOGNOMONIC of CLL
• Generalized lymphadenopathy

Part 2) Richter's Transformation (2 marks)

• Most commonly transforms into Diffuse Large B-Cell Lymphoma (DLBCL) (~95% of cases)
• WHO also recognizes transformation into Hodgkin Lymphoma (HL) as a variant
• Prevalence: ~0.5% per year for DLBCL transformation; 0.05% per year for HL transformation
• Clinically heralded by: sudden onset of fever, night sweats, weight loss (B symptoms), rapidly enlarging lymph nodes, elevated LDH
• Risk factors: Bulky lymphadenopathy, NOTCH1 mutations, del(17p13.1)
• Prognosis: Poor - clonally related transformations have significantly worse outcomes than clonally unrelated cases
• Diagnosis: PET scan - SUV >5 suspicious; ≥10 highly suspicious for Richter's transformation; biopsy confirms

"One of the most devastating complications of CLL is Richter's transformation...The prevalence estimated at 0.5% per year for DLBCL." - Harrison's Principles of Internal Medicine 22E (2025)

EXAM WRITING TIPS

• Robbins & Kumar Basic Pathology - Reed-Sternberg cells, Hodgkin classification, EBV/Infectious Mononucleosis
• Harrison's Principles of Internal Medicine 22E (2025) - Richter's transformation in CLL

Remaining Questions - University Exam Answers

SHORT ANSWER QUESTIONS (1 mark each)

Q1. Describe the inheritance pattern of Hemophilia A and explain why it preferentially affects males (1 mark)

• The gene for Factor VIII (deficient in Hemophilia A) is located on the X chromosome
• Males are hemizygous (XY) - they have only ONE X chromosome, so a single defective copy of the gene causes disease
• Females are heterozygous carriers (X^H X^h) - they have TWO X chromosomes; the normal allele on the second X compensates, so they are usually unaffected carriers
• A female would need TWO defective copies (X^h X^h) to manifest the disease - this is extremely rare

Carrier Mother (X^H X^h)  ×  Normal Father (X^H Y)
Daughters: X^H X^H (normal), X^H X^h (carrier)
Sons:      X^H Y (normal),   X^h Y (affected)

• 50% of sons are affected; 50% of daughters are carriers

Q2. Platelet count of 20,000/cumm in a young woman - What is this condition called? List 4 causes

1. ITP (Immune Thrombocytopenic Purpura) - autoantibodies (IgG) against platelet GPIIb/IIIa
2. SLE (Systemic Lupus Erythematosus)
3. Aplastic anemia (decreased production)
4. Drug-induced thrombocytopenia (e.g., heparin, quinine, sulfonamides)

Q3. Why is splenectomy beneficial in cases of Chronic ITP? (1 mark)

• In ITP, autoantibodies (IgG) coat platelets via GPIIb/IIIa antigens
• The spleen is the primary site where these antibody-coated platelets are recognized and destroyed by splenic macrophages (reticuloendothelial system)
• Removing the spleen eliminates this destruction

• The spleen contains the B-lymphocytes that produce anti-platelet IgG antibodies
• Splenectomy reduces the antibody burden, allowing platelet survival to improve

SHORT ESSAY TYPE QUESTIONS (5 Marks each)

Essay Q1. Tabulate differences between Chronic Myeloid Leukemia (CML) and Chronic Lymphocytic Leukemia (CLL) (5 marks)

Essay Q2. Tabulate differences between Hodgkin and Non-Hodgkin Lymphoma (including clinical features, histology, immunophenotype) (5 marks)

Essay Q3. Describe differences between Myeloblasts and Lymphoblasts (with labelled diagrams) (5 marks)

Differences Table:

Diagram to draw:

MYELOBLAST                    LYMPHOBLAST
   _____                          ___
  /     \                        /   \
 | [NUC] |  ← Large nucleus     |[NUC]|  ← Smaller, clumped
  \  2-5 /    with prominent     \ 1-2/    chromatin, 1-2
   nucleoli                      nucleoli  nucleoli
  /~~~~~\                       /~~~~~\
 |  MPO+ |                     |  TdT+ |
 |granules|                    |       |  ← Scanty cytoplasm
  \_____/                       \_____/
 Auer rods                     No Auer rods
 present!                      

Essay Q4. Laboratory findings in Chronic Myeloid Leukemia - CML (with peripheral smear and bone marrow diagrams) (5 marks)

Clinical features briefly:

• Middle-aged patient, insidious onset
• Massive splenomegaly (most striking feature)
• Weight loss, fatigue, night sweats, abdominal fullness

Laboratory Findings:

• WBC: Markedly elevated, often >1,00,000/cumm (can reach 5,00,000/cumm)
• Hb: Decreased (normocytic normochromic anemia)
• Platelets: Initially normal or elevated; decreased in blast crisis

• Full myeloid spectrum - all stages from myeloblasts to mature neutrophils (promyelocytes, myelocytes, metamyelocytes, bands, segmented neutrophils)
• Basophilia (characteristic - absolute basophil count elevated)
• Eosinophilia
• Myeloblasts <10% in chronic phase
• Thrombocytosis (increased platelets) may be seen early

• Hypercellular (100% cellularity - "packed marrow")
• Granulocytic hyperplasia - all myeloid stages
• Increased megakaryocytes (dwarf megakaryocytes)
• Fat spaces absent
• Myeloblasts <10% in chronic phase; 10-19% = accelerated phase; ≥20% = blast crisis

• Markedly DECREASED / Low (differentiates CML from leukemoid reaction, where LAP is high)

• Philadelphia chromosome - t(9;22)(q34;q11) in 95% of patients
• Creates BCR-ABL fusion gene → constitutively active tyrosine kinase → uncontrolled proliferation

• Elevated uric acid (from cell turnover)
• Elevated LDH, vitamin B12 levels
• Elevated serum muramidase (lysozyme)

Peripheral Smear Diagram:

CML Peripheral Smear - showing "myeloid spectrum":
[Myeloblast][Promyelocyte][Myelocyte][Metamyelocyte][Band][Neutrophil]
+ Basophils (characteristic!) + Eosinophils

Phases of CML (mention in exam for extra marks):

QUICK REVISION SUMMARY TABLE

Multiple Myeloma - Peripheral Blood & Bone Marrow Findings

INTRODUCTION (write briefly)

• C - hyperCalcemia
• R - Renal insufficiency
• A - Anemia
• B - Bone lesions (punched-out lytic lesions on X-ray)

A. PERIPHERAL BLOOD FINDINGS

1. Red Blood Cells (RBCs)

• Normochromic, normocytic anemia - most consistent finding
• Rouleaux formation (most characteristic!) - RBCs stack like coins due to markedly elevated serum globulins (M-protein) coating RBC surfaces
• Normoblasts (nucleated RBCs) may appear in peripheral blood
• Markedly elevated ESR - directly due to rouleaux formation and raised globulins

2. White Blood Cells (WBCs)

• WBC count is slightly decreased, normal, or slightly increased
• Occasional myeloid left shift (up to myeloblast level) may be noted

3. Platelets

• Platelet count is usually normal in early disease
• May decrease in advanced disease due to marrow replacement

4. Plasma Cells in Peripheral Blood

• In most cases, few or no plasma cells are seen in blood
• If plasma cells >20% of leucocytes OR >2 × 10⁹/L → termed Plasma Cell Leukemia (a rare, severe variant with poor prognosis)

B. BONE MARROW FINDINGS

1. Cellularity

• Bone marrow is hypercellular, with normal fat spaces replaced

2. Plasma Cell Infiltration (KEY FINDING)

• Presence of clonal plasma cells ranging from <1% to >90%
• Diagnosis of myeloma requires ≥10% clonal plasma cells in marrow (in symptomatic myeloma, no lower limit if other CRAB features are present)

3. Morphology of Myeloma Cells

4. Special Myeloma Cell Variants (high-yield for exams)

Bone marrow aspirate in myeloma: large plasma cells with prominent nucleoli and abundant cytoplasm (×1000) - Henry's Clinical Diagnosis and Management by Laboratory Methods

5. Immunophenotype of Myeloma Cells

• CD38 + (strongly positive - key marker)
• CD138 + (syndecan-1 - most specific marker for plasma cells)
• CD19 - (lost, unlike normal plasma cells)
• CD20 -
• CD56 + (abnormally acquired - helps distinguish from reactive plasmacytosis)
• Monoclonal κ or λ light chain restriction (proves clonality)

C. OTHER LABORATORY FINDINGS (to complete the picture)

Serum Studies

Urine Studies

• Bence Jones Protein - free monoclonal light chains (κ or λ) detected in urine
• Positive in ~25% of cases (light chain only myeloma)
• Method: heat test - precipitates at 40-60°C, redissolves at 100°C
• Causes myeloma kidney (cast nephropathy) → renal failure

Radiology

• Punched-out (lytic) bone lesions - skull X-ray is classic ("pepper pot skull")
• Pathological fractures
• Diffuse osteoporosis

D. DIAGNOSTIC CRITERIA SUMMARY

EXAM DIAGRAM TO DRAW

PERIPHERAL BLOOD SMEAR - Multiple Myeloma:

[RBC][RBC][RBC][RBC][RBC]  ← Rouleaux formation
[RBC][RBC][RBC][RBC][RBC]    (coin-stack arrangement)

Also shows: Normochromic, normocytic RBCs
            ↑ ESR (markedly)
            Occasional plasma cell (Plasma Cell Leukemia if >20%)

BONE MARROW ASPIRATE - Multiple Myeloma:

  [PC] [PC] [PC]      PC = Plasma cell with:
  [PC] [PC] [PC]       - Eccentric nucleus
  [PC] [PC] [PC]       - Prominent nucleoli
                        - Abundant blue cytoplasm
  Special variants:     - Perinuclear hof (clear zone)
  [Flame cell] → fiery red cytoplasm (IgA)
  [Mott/Morula cell] → Russell bodies (grape-like inclusions)

Multiple Myeloma - Peripheral Blood Findings

1. Hemoglobin / Red Blood Cells

• Normochromic, normocytic anemia - present in majority of patients
• Hb is decreased (most common presenting lab finding)
• Normoblasts (nucleated RBCs) may appear

2. White Blood Cells

• WBC count is slightly decreased, normal, or slightly increased
• Occasional mild left shift (up to myeloblast level) may be seen
• Leukopenia develops in advanced disease (marrow replacement)

3. Platelets

• Normal in early disease
• Thrombocytopenia in advanced disease due to marrow infiltration by plasma cells

4. ESR

• Markedly elevated - one of the most striking findings
• Due to raised serum globulins (M-protein) causing rouleaux and increased plasma viscosity

5. Serum Calcium

• Elevated (hypercalcemia) - due to osteoclast activation and bone destruction

6. Serum Proteins / Globulins

• Total serum protein - elevated
• Serum globulin - markedly increased (M-protein/paraprotein)
• Albumin - decreased (poor prognostic marker)
• M-spike on serum protein electrophoresis (SPEP) - IgG >50%, IgA ~20%

7. Renal Function Tests

• Serum creatinine and urea - elevated (renal insufficiency)
• Caused by myeloma kidney (cast nephropathy from Bence Jones proteins)

8. Uric Acid

• Elevated (due to increased cell turnover)

9. LDH

• Elevated (marker of disease burden and activity)

10. β2-Microglobulin

• Elevated - most important prognostic marker in myeloma
• Used in the ISS (International Staging System) for staging

11. Serum Viscosity

• Increased - due to high M-protein levels
• Can cause hyperviscosity syndrome (headache, visual disturbances, bleeding)

12. Plasma Cells in Blood

• Normally absent
• If plasma cells >20% of WBCs or >2 × 10⁹/L → Plasma Cell Leukemia (severe variant)

Quick Summary Table

"There is usually normochromic, normocytic anemia. Serum globulin is usually increased, often strikingly so - responsible for elevated ESR. The monoclonal protein is IgG in over 50% of cases, IgA in about 20%." - Henry's Clinical Diagnosis and Management by Laboratory Methods