Wbc disorders and lymphoid neoplasms chapter pathology mbbs important and answers

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WBC Disorders and Lymphoid Neoplasms - Pathology MBBS Important Questions & Answers

Based on Robbins & Kumar Basic Pathology and Robbins, Cotran & Kumar Pathologic Basis of Disease

PART 1: NONNEOPLASTIC WBC DISORDERS

Q1. What is neutropenia/agranulocytosis? Give causes and consequences.

Neutropenia = reduction in circulating neutrophils (absolute neutrophil count <1800/µL). Severe neutropenia (<500/µL) is called agranulocytosis.

Causes:

Decreased production: drug toxicity (alkylating agents, antimetabolites, chloramphenicol, phenylbutazone), aplastic anemia, vitamin B12/folate deficiency, infiltrative marrow disease
Increased destruction: immune-mediated (antibodies against neutrophils), hypersplenism
Ineffective granulopoiesis: seen in myelodysplastic syndromes

Consequences: Severe bacterial and fungal infections; life-threatening at ANC <500. Patients develop ulcerative necrotic lesions of oral mucosa, skin, and GI tract.

Q2. What is reactive leukocytosis? Give causes.

Reactive leukocytosis = increased WBC count as a physiologic response to stress, infection, or inflammation.

Type	Condition
Neutrophilia	Bacterial infections, tissue necrosis, burns, stress
Lymphocytosis	Viral infections (EBV, CMV, hepatitis), pertussis
Monocytosis	Chronic infections (TB, brucella), SLE, IBD
Eosinophilia	Allergies, parasitic infections, Addison disease
Basophilia	Rare; hypothyroidism, myeloproliferative neoplasms

Left shift = increased immature neutrophils (bands, metamyelocytes) in severe bacterial infection. Leukemoid reaction = WBC >50,000/µL mimicking leukemia (benign cause).

- Robbins & Kumar Basic Pathology (Robbins Pathology), p. 362

Q3. Describe Infectious Mononucleosis (IM).

Cause: Epstein-Barr virus (EBV) - infects B lymphocytes via the CD21 receptor.

Pathogenesis:

EBV infects oropharyngeal epithelium and B cells
Infected B cells undergo polyclonal activation and spread via lymphatics
Reactive CD8+ cytotoxic T cells (Downey/atypical lymphocytes) destroy infected B cells
Eventually EBV establishes latent infection in memory B cells

Clinical features:

Fever, sore throat, lymphadenopathy (especially posterior cervical)
Splenomegaly (present in >50%, risk of rupture)
Mild hepatomegaly + hepatitis

Peripheral blood: Marked lymphocytosis (>60%) with large atypical "Downey cells" (activated CD8+ T cells with abundant cytoplasm)

Diagnosis:

Monospot test (heterophil antibody test): positive in >90%
Anti-VCA (viral capsid antigen) IgM: most sensitive
Lymphocytosis + atypical lymphocytes

Complications: Splenic rupture, aplastic anemia, EBV-associated lymphoma (in immunocompromised), Guillain-Barré syndrome

PART 2: CLASSIFICATION OF LYMPHOID NEOPLASMS

Q4. Give the WHO classification of lymphoid neoplasms.

The WHO classification uses morphologic, immunophenotypic, genotypic, and clinical features.

Five broad categories:

Category	Examples
I. Precursor B-cell neoplasms	B-cell ALL (B-ALL)
II. Peripheral B-cell neoplasms	CLL/SLL, Follicular lymphoma, DLBCL, Burkitt lymphoma, Mantle cell lymphoma, Marginal zone lymphoma, Plasma cell neoplasms
III. Precursor T-cell neoplasms	T-cell ALL (T-ALL)
IV. Peripheral T/NK-cell neoplasms	Mycosis fungoides, Sézary syndrome, ATLL, Anaplastic large cell lymphoma
V. Hodgkin lymphoma	Nodular sclerosis, Mixed cellularity, Lymphocyte-rich, Lymphocyte-depleted, Nodular lymphocyte predominant

Key principle: Leukemia = widespread bone marrow + blood involvement. Lymphoma = discrete tissue masses. These terms reflect clinical presentation, not fundamental differences in biology.

- Robbins, Cotran & Kumar Pathologic Basis of Disease, p. 554-555

PART 3: ACUTE LEUKEMIAS

Q5. Compare ALL and AML. ★ (Very Important)

Feature	ALL (Lymphoblastic)	AML (Myeloblastic)
Age	Children (peak 2-5 yrs)	Adults (>60 yrs)
Cell type	Lymphoblasts	Myeloblasts
Auer rods	Absent	Present (pathognomonic)
TdT (terminal deoxytransferase)	Positive	Negative
Myeloperoxidase (MPO)	Negative	Positive
CD markers	CD10, CD19, CD20 (B-ALL); CD2, CD3, CD7 (T-ALL)	CD13, CD33, CD117, CD34
Cytogenetics	t(12;21) RUNX1-ETV6 (good prognosis B-ALL); t(9;22) Philadelphia (poor)	t(8;21), t(15;17) APL
Response to Rx	Better (80-90% complete remission in children)	Worse overall
CSF involvement	More common	Less common

t(15;17) in AML-M3 (APL): Creates PML-RARα fusion; treated with all-trans retinoic acid (ATRA) - landmark targeted therapy.

Clinical features of acute leukemia (both):

Marrow failure → anemia (fatigue, pallor), thrombocytopenia (bleeding, petechiae), neutropenia (recurrent infections)
Organ infiltration → lymphadenopathy, hepatosplenomegaly
ALL specifically: testicular enlargement, CNS infiltration (headache, vomiting)
AML specifically: gum hypertrophy (monocytic variant), Auer rods on smear, chloroma (granulocytic sarcoma)

- Robbins & Kumar Basic Pathology (Robbins Pathology), p. 365-368

PART 4: CHRONIC LYMPHOID LEUKEMIAS AND NHL

Q6. Describe CLL/SLL. ★★

Chronic Lymphocytic Leukemia (CLL) / Small Lymphocytic Lymphoma (SLL) are the same disease; CLL = leukemic phase, SLL = lymphomatous phase.

Epidemiology: Most common adult leukemia in the West; older adults; M > F.

Cell of origin: Mature naïve B cell

Pathology:

Peripheral blood: small, round lymphocytes with scant cytoplasm and "soccer ball" nuclei
Characteristic "smudge cells" (fragile CLL cells lysed on making smear)
Bone marrow and lymph nodes: diffuse effacement by small lymphocytes
Admixed proliferation centers (paraimmunoblasts) = pathognomonic of CLL/SLL

Immunophenotype: CD5+, CD19+, CD20+(dim), CD23+; weak surface immunoglobulin

Genetics: Deletion 13q14 (most common, best prognosis), trisomy 12, deletion 17p (worst prognosis); IGHV mutation status important

Clinical:

Often asymptomatic, found on routine CBC
Hypogammaglobulinemia → recurrent bacterial infections
Autoimmune hemolytic anemia (warm antibody type)
Lymphadenopathy, splenomegaly
Richter transformation = conversion to aggressive DLBCL (bad prognosis)

Q7. Describe Follicular Lymphoma. ★

Most common indolent lymphoma in adults (>35% of adult NHLs in the West)

Genetics: t(14;18) - BCL2::IGH fusion gene → BCL2 protein overexpression → blocks apoptosis of germinal center B cells → accumulation

Pathology:

Lymph nodes: effaced by back-to-back follicles (nodular pattern) lacking mantle zones
Mixture of centrocytes (small cleaved cells) and centroblasts (large cells)
Lack of tingible body macrophages (cf. reactive follicles)

Immunophenotype: CD10+, CD20+, BCL2+ (key!), BCL6+; CD5-, CD23-

Clinical:

Older adults with generalized painless lymphadenopathy
Bone marrow involvement common
Indolent but incurable with current therapy
May transform to DLBCL ("high-grade transformation") - associated with MYC rearrangement

Q8. Describe Diffuse Large B-Cell Lymphoma (DLBCL). ★★

Most common NHL worldwide (~30-40% of all lymphomas)

Cell of origin: Germinal center B cell (GCB subtype) or activated B cell (ABC subtype)

Morphology:

Sheets of large lymphoid cells with vesicular nuclei, prominent nucleoli, moderate cytoplasm
"Starry sky" not typical (cf. Burkitt)

Genetics: BCL6 rearrangements most common; BCL2 rearrangement in subset; "double hit" = MYC + BCL2 rearrangements = very aggressive

Important subtypes:

Primary mediastinal large B-cell lymphoma (young women, thymus, PD-L1 overexpression)
Primary effusion lymphoma (HHV-8+, HIV patients)
Immunodeficiency-associated (EBV+)
Intravascular DLBCL (CNS vessels, diagnosed on skin biopsy)

Clinical: Rapidly enlarging nodal or extranodal mass; aggressive but potentially curable with R-CHOP (rituximab + chemotherapy); 60-70% cure rate.

Q9. Describe Burkitt Lymphoma. ★★ (Classic MBBS Question)

Epidemiology:

Endemic (African) form: Children; jaw/facial bones; EBV-associated (>95%)
Sporadic form: Ileo-cecal region/abdomen; EBV in 20-30%
Immunodeficiency-associated: HIV patients

Pathogenesis: Translocation of MYC oncogene (chromosome 8q24) to immunoglobulin loci:

t(8;14) - IGH (most common, 80%)
t(2;8) - IGκ
t(8;22) - IGλ

MYC overexpression → uncontrolled cell proliferation

Morphology:

Monomorphic medium-sized lymphoid cells with multiple small nucleoli
"Starry sky" pattern: tingible body macrophages (stars) amidst sheets of blue tumor cells (sky) - due to high apoptotic activity
Extremely high mitotic rate (Ki-67 ~100%)

Immunophenotype: CD10+, CD20+, BCL6+; BCL2- (key negative marker); TdT-

Clinical: Rapidly growing mass (doubling time ~24 hours); excellent response to high-dose chemotherapy if treated promptly; tumor lysis syndrome is a major complication of treatment.

- Robbins & Kumar Basic Pathology, p. 376; Robbins Cotran, p. 565-567

Q10. Describe Mantle Cell Lymphoma.

Cell of origin: Naive (pre-germinal center) B cell from mantle zone

Key genetics: t(11;14) - cyclin D1::IGH fusion → Cyclin D1 overexpression → G1/S transition dysregulation

Immunophenotype: CD5+, CD19+, CD20+, Cyclin D1+ (key!), CD23- (cf. CLL: CD23+)

Clinical: Older males; disseminated disease at presentation; moderately aggressive (median survival 3-4 years); considered incurable with conventional therapy.

PART 5: HODGKIN LYMPHOMA

Q11. Classify Hodgkin Lymphoma and describe Reed-Sternberg cell. ★★★ (Most Important)

Hodgkin Lymphoma (HL) is unique among lymphomas because the neoplastic cells (Reed-Sternberg cells) constitute <1% of the tumor mass, with the remainder being reactive inflammatory cells.

Reed-Sternberg (RS) Cell - Pathognomonic

Large cells (15-45 µm) with bilobed or multilobed nucleus
"Owl eye" nucleoli - large eosinophilic nucleoli with clear halo, resembling owl eyes
Abundant pale cytoplasm
Origin: Crippled germinal center B cell (has non-functional immunoglobulin gene mutations)
Immunophenotype: CD15+, CD30+, PAX5+(weak), EBV LMP1+ in some; CD20-, CD45-

Variants of RS cells:

Lacunar cells - pale, multilobed nucleus in lacunar space (retraction artifact) - seen in Nodular Sclerosis
Lymphocytic and histiocytic (L&H) / "Popcorn" cells - polylobated nucleus - Nodular Lymphocyte Predominant HL; CD20+, CD30-

WHO Classification of HL:

Subtype	Frequency	Morphology	Prognosis
Nodular Sclerosis	65-70% (most common)	Collagen bands dividing node into nodules; lacunar RS cells	Good
Mixed Cellularity	20-25%	Classic RS cells, eosinophils, plasma cells, macrophages	Intermediate
Lymphocyte-Rich	5%	Abundant lymphocytes, rare RS cells	Best
Lymphocyte-Depleted	<5% (rarest)	Diffuse fibrosis; many RS cells, few lymphocytes; HIV-associated	Worst
Nodular Lymphocyte Predominant	5%	Popcorn/L&H cells; CD20+; indolent	Excellent

Clinical features:

Bimodal age distribution: Young adults (15-34) and >55 years
Reed-Sternberg law: Contiguous spread from one lymph node group to adjacent nodes (orderly spread, unlike NHL)
Painless cervical or mediastinal lymphadenopathy (most common)
"B" symptoms: Fever, night sweats, weight loss (>10% in 6 months) - indicate worse prognosis
Pel-Ebstein fever = cyclic fever (classic but rare)
Mediastinal involvement → superior vena cava syndrome (especially NS type)
Alcohol-induced pain in affected lymph nodes (pathognomonic but uncommon)

Staging (Ann Arbor):

Stage I: Single lymph node region
Stage II: ≥2 regions same side of diaphragm
Stage III: Both sides of diaphragm
Stage IV: Diffuse extranodal involvement

Treatment: ABVD chemotherapy ± radiation; cure rate ~80-90% overall.

- Robbins & Kumar Basic Pathology (Robbins Pathology), p. 377-380; Robbins Cotran, p. 570-578

PART 6: PLASMA CELL NEOPLASMS

Q12. Describe Multiple Myeloma. ★★

Definition: Malignant proliferation of plasma cells in bone marrow secreting a single class of immunoglobulin (monoclonal/M protein).

M protein (paraprotein): Usually IgG (60%) or IgA (20%); light chains excreted in urine = Bence Jones proteins

Pathogenesis:

Plasma cells produce IL-6 (growth factor), RANKL (osteoclast activation) → bone destruction
M protein → hyperviscosity syndrome, amyloidosis
Suppression of normal immunoglobulin production → hypogammaglobulinemia

Clinical features (CRAB criteria):

C - hyperCalcemia (osteoclast activation)
R - Renal failure (Bence Jones proteinuria, hypercalcemia, amyloidosis)
A - Anemia (marrow replacement)
B - Bone lesions ("punched out" lytic lesions on X-ray, pathological fractures)

Additional features:

Rouleaux formation on peripheral smear
Elevated ESR (very high - >100 mm/hr common)
Bence Jones proteinuria (positive heat test)
"Mott cells" and "flame cells" (plasma cells with accumulated Ig)
Increased infections (bacterial)

Investigations:

Serum/urine protein electrophoresis → M spike
Bone marrow biopsy → >10% plasma cells (>60% = definitive myeloma)
Skeletal survey X-ray ("pepper pot skull", lytic lesions)

Diagnosis (IMWG criteria): ≥10% clonal marrow plasma cells + one CRAB criterion OR ≥60% clonal plasma cells.

Q13. What is Lymphoplasmacytic Lymphoma / Waldenström Macroglobulinemia?

Neoplasm of B cells differentiating toward plasma cells that secrete IgM (macroglobulin)
Associated with MYD88 L265P mutation (very specific, >90%)
Hyperviscosity syndrome (visual changes, neurological symptoms, bleeding due to high IgM)
No bone lesions (cf. multiple myeloma)
Biopsy: lymph nodes and bone marrow with lymphoplasmacytic infiltrate + Dutcher bodies (intranuclear Ig inclusions)

PART 7: MYELOPROLIFERATIVE NEOPLASMS

Q14. Classify myeloproliferative neoplasms. Describe CML. ★★

Myeloproliferative neoplasms (MPNs): Clonal neoplasms of multipotent hematopoietic progenitor cells with effective terminal differentiation → increase in mature cells.

MPN	Predominant Cell	Key Mutation	Key Feature
CML	Granulocytes	t(9;22) BCR-ABL (Philadelphia chromosome)	Leukocytosis, splenomegaly
Polycythemia Vera (PV)	Red cells (all lines)	JAK2 V617F (~95%)	Thrombosis, ruddy cyanosis
Essential Thrombocythemia	Platelets	JAK2 V617F (50%), CALR (30%)	Thrombosis/bleeding
Primary Myelofibrosis	Fibroblasts secondary	JAK2 V617F (~50%), CALR (30%)	Massive splenomegaly, leukoerythroblastic smear

Chronic Myeloid Leukemia (CML):

Philadelphia chromosome: t(9;22) → BCR-ABL fusion protein (constitutively active tyrosine kinase)
Peripheral blood: striking leukocytosis (>100,000/µL), basophilia, eosinophilia, thrombocytosis
Splenomegaly (often massive)
Bone marrow: hypercellular with granulocytic hyperplasia
3 phases: Chronic phase → Accelerated phase → Blast crisis (AML or ALL phenotype)
Treatment: Imatinib (Gleevec) - first BCR-ABL tyrosine kinase inhibitor; revolutionized treatment; excellent prognosis in chronic phase

LAP score (Leukocyte Alkaline Phosphatase):

CML: Low/absent LAP score
Leukemoid reaction: High LAP score
This distinguishes CML from leukemoid reaction

PART 8: MYELODYSPLASTIC SYNDROMES

Q15. What are myelodysplastic syndromes (MDS)?

Clonal hematopoietic stem cell disorders characterized by dysplastic maturation of blood cells
Ineffective hematopoiesis → cytopenias despite hypercellular marrow
Ring sideroblasts (iron-laden mitochondria around erythroid nucleus)
Dysgranulopoiesis (hypogranular, hyposegmented neutrophils - Pelger-Huet cells)
Risk of progression to AML ("pre-leukemia")
Most common in elderly; may be de novo or therapy-related (after alkylating agents)
Common mutations: SF3B1, TET2, DNMT3A, TP53

PART 9: HISTIOCYTIC NEOPLASMS

Q16. Describe Langerhans Cell Histiocytosis (LCH).

Neoplasm of Langerhans cells (specialized dendritic APCs of skin/mucosa)
BRAF V600E mutation in ~50% of cases
Pathology: Large cells with folded/grooved "coffee bean" nuclei; Birbeck granules (racket/rod-shaped pentalaminar organelles) on electron microscopy; immunostain: CD1a+, S100+, langerin+

Clinical spectrum:

Letterer-Siwe disease (multisystem, infants, worst prognosis): skin rash, hepatosplenomegaly, lymphadenopathy, bone marrow failure
Hand-Schüller-Christian disease (chronic multifocal): classic triad of diabetes insipidus + exophthalmos + lytic skull lesions
Eosinophilic granuloma (single bone/organ, adults, best prognosis): painless lytic bone lesion

QUICK SUMMARY TABLE - High-Yield Facts for MBBS Exams

Entity	Key Marker	Key Gene	Buzzword
ALL	TdT+, CD10+	RUNX1-ETV6 t(12;21); BCR-ABL t(9;22)	Children, TdT
AML-M3 (APL)	MPO+, Auer rods	t(15;17) PML-RARα	ATRA treatment
CML	Low LAP	t(9;22) BCR-ABL	Philadelphia chromosome
CLL/SLL	CD5+, CD23+	del 13q	Smudge cells
Follicular lymphoma	BCL2+, CD10+	t(14;18) BCL2	Indolent, BCL2
Mantle cell	Cyclin D1+, CD5+	t(11;14)	CD23- (cf CLL)
Burkitt lymphoma	TdT-, BCL2-, Ki67~100%	t(8;14) MYC	Starry sky, jaw
DLBCL	CD20+	BCL6, BCL2, MYC	Most common NHL
Hodgkin lymphoma	CD15+, CD30+	EBV association	Reed-Sternberg "owl eye"
Multiple myeloma	CD138+	t(4;14), del17p	CRAB, Bence Jones
Hairy cell leukemia	CD103+, CD11c+	BRAF V600E	Tartrate-resistant ACP (TRAP+)
LCH	CD1a+, S100+	BRAF V600E	Birbeck granules
Mycosis fungoides	CD4+ T cell	-	Sézary cell, cerebriform nucleus
ATLL	CD4+ T cell	HTLV-1	Endemic Japan/Caribbean
Waldenström	IgM paraprotein	MYD88 L265P	Hyperviscosity

HIGH-YIELD ONE-LINERS FOR MCQs

Reed-Sternberg cell = pathognomonic of Hodgkin lymphoma; CD15+, CD30+, "owl eye" nucleoli
Most common subtype of HL = Nodular Sclerosis (65-70%)
Best prognosis HL = Nodular Lymphocyte Predominant (indolent) or Lymphocyte-Rich classic
Worst prognosis HL = Lymphocyte-Depleted
Starry sky pattern = Burkitt lymphoma (also reactive follicular hyperplasia, but in context = Burkitt)
Auer rods = AML (not seen in ALL or lymphomas)
TdT positive = ALL (precursor B or T cell, NOT mature lymphoid tumors)
Philadelphia chromosome = CML (also poor-prognosis ALL)
t(14;18) = Follicular lymphoma (BCL2 overexpression)
t(8;14) = Burkitt lymphoma (MYC)
t(11;14) = Mantle cell lymphoma (Cyclin D1)
t(15;17) = AML-M3 (APL) - treated with ATRA
Smudge cells = CLL
Bence Jones protein = Multiple myeloma (free light chains in urine)
Birbeck granules = Langerhans cell histiocytosis
TRAP stain positive = Hairy cell leukemia
JAK2 V617F = Polycythemia vera, essential thrombocythemia, primary myelofibrosis
HTLV-1 = Adult T-cell leukemia/lymphoma

Sources: Robbins & Kumar Basic Pathology (Robbins Pathology), 10th edition; Robbins, Cotran & Kumar Pathologic Basis of Disease, 10th edition - Chapters on WBC Disorders and Lymphoid Neoplasms

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