9

Key Points
  Hematopoiesis starts between 3-4th wk of Intrauterine life in yolk sac
 Leukopenia is abnormally low WBC (TLC <4000/uL) while Leukocytosis is
increase in the count of WBCs (>11,000/uL)
 eukemia refers to hematological neoplasms with involvement of bone marrow &
  L
peripheral blood Lymphoma refers to discrete tissue massesQ usually involving
Lymph node, Spleen and Liver
  ALL is the most common cancer of children.
  The most common leukemia of adults in the Western world is CLL.
  The most common site for extranodal lymphoma is stomach
  Follicular lymphoma is the most common form of indolent (low grade) NHL in
the West.
  DLBCL, is the most common form of NHL in India
  Burkitts lymphoma shows “starry sky” pattern
  Diagnostic Hallmark of Hodgkins lymphoma are Reed-Sternberg cells
  Cut off for blast counts in AML is <20% if AML is associated with cytogenetic
abnormalities like t(15;17), t(8;21), inv(16)
  BCR-­ABL geneQ (210 kDa in size) is hallmark of CML

Key Recent Updates

  CSF3R mutation is seen in CNL
  Provisional response to TKI is added in accelerated phase of CML

WHITE BLOOD CELLS AND

ITS DISORDERS
 HEMATOPOIESIS
Formation of blood components during embryonic stage and throughout adult life
ƒƒ Definitive hematopoiesis:
234
{{ Forms multipotent hematopoietic cells (HSCs) at 4th week of intrauterine life around Aorta, gonads and mesonephros

ƒƒ Sites at different ages:

Age group Site of Hematopoiesis

Complete Review of Pathology

EmbryoQ Till the 3rd wk in Yolk sac;Q Upto 3rd month in LiverQ
Fetus 4th month onwards: Bone marrowQ
Birth Bone marrowQ
Child Bone marrow: throughout the skeletonQ
Adult Bone marrow: Flat bone (Vertebra, ribs, sternum, pelvis)Q & proximal epiphysis of humerus & femur

Properties of Hematopoietic Stem Cells

ƒƒ PluripotencyQ - Ability of a single HSC to generate all mature blood cells
ƒƒ Capacity for self-renewalQ
ƒƒ Not seen usually in peripheral bloodQ
ƒƒ Under conditions of stress, e.g. severe anemia or acute inflammation, HSCs are mobilized from bone marrow and appear in the
peripheral blood.Q

Morphology of Bone Marrow

Normal Myeloid: Erythroid ratio = 3-4:1Q
Normal ratio of marrow cells: fat cells=1:1Q
Normal Cellularity (%) = 100 – AgeQ
•• Decreases with age
•• At 10 yrs = 100-10 = 90% cellularity
•• At 30 yrs = 100-30 = 70% cellularity
Light Microscopy
•• Thin-walled sinusoidsQ lined by single layer of endothelial cells
•• Clusters of hematopoietic & fat cells within the interstitium
•• Megakaryocytes lie next to sinusoidsQ where they release
platelets
•• Red cell precursors (Erythroblasts) surround macrophages
(so-called nurse cells)Q

High Yield Facts

•• Agranulocytosis: Clinically significant reduction in neutro-
phils making one susceptible to bacterial & fungal infections.Q
•• Drugs are the most common cause of agranulocytosisQ
•• Serious infection increases when ANC < 500/mm3

DISORDERS OF WHITE BLOOD CELLS

ƒƒ Quantitative defects
Leucopenia
{{

Leucocytosis
{{

ƒƒ Qualitative defects

Leukopenia
A-Lymphocyte B-Monocyte C-Neutrophil ƒƒ Definition:
D-Eosinophil E-Basophil An abnormally low white cell count (leukopenia; TLC
T {{

<4000/mL)Q
H
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Lymphopenia yy Anti-inflammatory- IbuprofenQ
ƒƒ Definition yy Antithyroid- Carbimazole, Propylthiouracil
{{ Reduction in number of lymphocytes in blood yy Anticonvulsants- Valproate, Phenytoin
ƒƒ Etiology: B. Inadequate or ineffective granulopoiesis:Q 235
{{ Congenital immunodeficiency diseases, e.g. SCIDQ yy Aplastic anemiaQ
{{ Human immunodeficiency virus (HIV) infectionQ yy Infiltrative marrow disorders (e.g., tumors, granuloma-
{{ GlucocorticoidsQ or cytotoxic drugs tous disease)

Chapter 9   White Blood Cells and its Disorders

{{ Autoimmune disorders yy Infections: Viral- Parvo B19Q, HIV, EBV
{{ Malnutrition yy Ineffective hematopoiesis: Megaloblastic anemiasQ &
{{ Acute viral infectionsQ Myelodysplastic syndromes
yy Kostmann syndromeQ: Autosomal recessive congenital
Neutropenia neutropenia
ƒƒ Definition yy Cyclic Neutropenia
{{ Reduction in the number of neutrophils (<1500/mL) in C. Accelerated destruction or sequestration of neutro-
the bloodQ phils
ƒƒ Etiology yy Immunological injury to neutrophils, e.g. SLEQ
A. Drug Induced Neutropenia yy SplenomegalyQ
yy Anti-bacterials – Chloramphenicol,Q Cotrimoxazole, yy Increased peripheral utilization: bacterial, fungal, or
Ciprofloxacin, Nitrofurantoin rickettsial infections

Leukocytosis
Increase in the number of WBCs (>11,000/mL)Q

Causes of LeukocytosisQ
Type of Leukocytosis
Neutrophilia (>75%)
Eosinophilia (>400/mL)
Basophillia (>1%)
Monocytosis
Lymphocytosis
Causes
•• Infection (bacterial)Q & Inflammation including MIQ
•• Acute stress states (burns, post-surgery)
•• Myeloproliferative disorders: CML, Polycythemia vera
•• Others: steroidQ therapy, Renal failureQ
•• Allergies: AsthmaQ, hay feverQ, urticaria
•• Skin diseases: Eczema, dermatitis herpetiformisQ
•• Parasitic: Ascariasis, HookwormQ, Filariasis, Trichinosis
•• Others: Tropical eosinophiliaQ, Hypereosinophilic syndrome, Hodgkin’s disease
CMLQ, PCV, Ulcerative colitisQ, MastocytosisQ, Myxedema
•• Infections: TBQ, Kala azar, malaria, Syphilis
•• Malignancies: AML-M4/5Q, CMML, Hodgkin’s
•• Inflammatory diseases: Ulcerative colitisQ, Crohn’s, SLE, Sarcoidosis
•• Bacterial: TB, brucellosis, Syphilis, pertussis, DiphtheriaQ
•• Viral infections: Infectious mononucleosisQ, Mumps, Malignancies: CLLQ, NHL, Hairy Cell LeukemiaQ

Qualitative defects in WBCs

Anomaly Inheritance Characteristic Other features
May Hegglin anomaly AD Basophilic inclusions in WBCs Giant platelets & thrombocytopenia
Alder-Reilly anomaly AR Lilac inclusions in Neutrophils Stains with Toluidine Blue
Pegler Huet anomaly AD Hypo-segmented Neutrophils Distinct from Pseudo Pegler-Huet anomaly
Döhle bodies Patches of dilated endoplasmic reticulum that T
appear as sky-blue cytoplasmic “puddles.”
H
Toxic granules Which are coarser and darker than the normal
neutrophilic granules, represent abnormal E
azurophilic (primary) granules. O
R
Y
 High Yield Facts
•• Infection of B lymphocytes by EBV occurs in Infectious
236 Mononucleosis
•• Atypical lymphocytes that are characteristic of infectious
mononucleosis are CD8+ T lymphocytes called DOWNY cells,
that develop in response to the infected B lymphocytes.
•• Reed Sternberg like cell are seen in Infectious mononucleosis,
Complete Review of Pathology
•• Kikuchi disease or ‘histiocytic necrotizing lymphadenitis’ is
benign, recurrent necrotizing lymphadenitis
•• Eosinophilic abscess in lymph node is characteristically seen in
- Kimura’s disease
•• Typhoid (Enteric fever) presents with lymphopenia and not
leukocytosis

Adult T cell lymphoma, Diffuse large B cell lymphoma

NEOPLASTIC PROLIFERATIONS OF WHITE CELLS

ƒƒ Leukemia: Hematological Neoplasms with involvement of bone marrow and peripheral bloodQ
ƒƒ Lymphoma: Hematological Neoplasms where proliferations arise as discrete tissue massesQ usually involving Lymph node,
Spleen, LiverQ

Lymphoid Neoplasms
World Health Organization (WHO) 2008 Classification of Lymphoid Neoplasms

High Yield Facts

•• CD19 is the earliest recognizable marker of B cells & is lost when •• Outside the hematopoietic system, CD34 is expressed on
B cell becomes a plasma cell endothelial cells.
•• CD 34 is the surface glycoproteins that is most often expressed •• CD 45 is found in all hematopoietic cells except erythrocytes
T in human hematopoietic stem cell •• CD 46 is a receptor of pathogen like HHV-6, Streptococci
H •• PAX9 – Marker of B cells
E
Acute Lymphoblastic Leukemia (ALL) ƒƒ Epidemiology:
O ƒƒ Definition:
{{ ALL is the most common cancer of childrenQ, Peak
R {{ Neoplasms of immature B (pre-B) or T (pre-T) cells Incidence: 3rd yrQ
which are referred to as lymphoblasts
{{ Hispanics have the highest incidence of any ethnic group.
Y
ƒƒ Pathogenesis: {{Generalized lymphadenopathy, Hepatosplenomegaly;
{{ T-ALLs have gain-of-function mutations in NOTCH1Q testicular enlargement
{{ B-ALLs have loss-of-function mutations PAX5Q, E2AQ & {{ T-ALL: Mediastinal mass (Superior Mediastinal
EBFQ, or t(12;21)Q involving the genes ETV6 and RUNX1, Syndrome)Q 237
2 genes that are needed in very early hematopoietic {{ CNS features: headache, vomiting, and nerve palsies
precursor. ƒƒ Morphology:
ƒƒ Clinical features: {{ Hypercellular Bone Marrow; > 20% lymphoblastsQ
{{ Abrupt stormy onset

Chapter 9   White Blood Cells and its Disorders

{{ Compared with myeloblasts, lymphoblasts have more
{{ Symptoms related to depression of marrow function:
condensed chromatin, less conspicuous nucleoli &
yy Fatigue due to anemia;
scanty agranular cytoplasm
yy Fever due to neutropenia; and {{ Cytochemistry: Myeloperoxidase (MPO) -ve, Sudan Black
yy Bleeding due to thrombocytopenia B (SBB): -veQ
{{ Marrow expansion and infiltration of the sub- {{ Diagnosis of choice
periosteum: sternal tendernessQ {{ Flow cytometry

Classification of ALL
FAB (French American British) Classification

ALL-subtype L1 L2 L3 (Mature B-cells)Q

Morphology •• Small Homogenous Blasts •• Large heterogeneous blasts •• Large homogenous blasts
of Blasts •• Little Cytoplasm •• One or more nucleoli •• Abundant basophilic cytoplasm
•• Regular Nucleus, •• Prominent cytoplasmic vacuolationQ
•• Small indistinct nucleoli •• Resemble BurkittQ lymphoma
Age group Children Adults Adults
Prognosis GoodQ IntermediateQ PoorQ
Cytochemistry PAS + PAS + PAS-, SBB+Q

L1 L2 L3

High Yield Facts

•• Mature B-cell ALL is an uncommon type of ALLQ (1-2% of ALL
cases) in children.
•• Both B-cell ALL and Burkitt lymphoma are characterized by FAB
L3Q morphology,
•• Mature B-cell ALL is associated with t(8;14) & overexpression of
the c-myc oncogene
•• T-ALL commonly presents with Mediastinal mass (Superior
Mediastinal Syndrome)Q
•• T-ALL are aggressive lymphomas.Q
•• In T-ALL, cells are positive for markers of blasts like- Tdt,Q CD34
& T cell markers CD1, CD2, CD5, CD7Q
•• Response to treatment is the best prognostic marker in ALL

WHO 2018: Classification of ALL

T
ƒƒ B-Lymphoblastic leukemia, Not otherwise specified (NOS)
ƒƒ B-Lymphoblastic leukemia with recurrent cytogenetic abnormality
H
1. t(12;21)ETV6–RUNXI 3.  t (9;22) BCR–ABL1 5.  B cell ALL with hyperdiploidy 7. 
BCR-ABL 1 like ALL (Provisional
E
entitity in 2018 WHO) O
2.  t (v,11)(KMT2A–MLL) 4.  t(5;14) IgH-IL3 6.   B cell ALL t(1, 19)–TCF3 –PBX1 8.   iAMP 21 ALL. R
ƒƒ T-Lymphoblastic leukemia
Y
 Prognostic Factors in Acute Lymphoblastic Leukemia Acute Myeloid Leukemias (AML)
Determinants Favorable Unfavorable ƒƒ Definition:
{{Neoplasms of myeloid cells which are referred to as
238 WBC/uL <10,000 >2,00,000Q myeloblastsQ
Age 2–9 yr <1 y, >10 yQ ƒƒ Clinical features:
{{ Same as ALL but in addition certain types of AML show:
Gender Female MaleQ yy Chloromas (AML M2 > 5 > 4)Q
Complete Review of Pathology

Ethnicity White BlackQ yy Gingival hyperplasia (AML M5 > 4)Q

yy DIC (AML M3)Q
L. node, liver, spleen Absent Massive ƒƒ Predisposing Conditions:
enlargement
Genetic factors Congenital bone Drugs
Testicular AbsentQ PresentQ marrow failure
enlargement syndromes
Central nervous Absent PresentQ •• Down’s syndrome •• Kostmann •• Benzene
system leukemia syndrome

FAB morphologic L1Q L2Q •• Fanconi’s anemia •• Diamond – •• Alkylating

features Early pre–B-cell Pre–B-cell ALL Blackfan anemia agents
ALL Mature B-cell •• Bloom’s syndrome •• Epipodophyl-
Ploidy Hyperdiploidy Hypodiploidy<45 lotoxins
•• Neurofibromatosis •• Ionizing
Cytogenetic markers Trisomy 4, 10, 17Q t(9;22)
type 1 radiation
t(12;21) t(4;11)
•• Klinefelter
Remission states < 14 days > 14 days syndrome
•• Turner syndrome

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Major Subtypes of AML in the WHO Classification 2018
Class Prognosis FAB Subtype Morphology/Comments
I. AML WITH RECURRENT GENETIC ABERRATIONS  
239
a. AML with­balanced translocations
AML with t(8;21)Q RUNX1 – RUNX1T1 Favorable M2Q Auer rods++; abnormal cytoplasmic granules
AML with inv (16) CBFB-MYH II
Q
Favorable M4 abnormal eosinophilic precursorsQ

Chapter 9   White Blood Cells and its Disorders

AML with t(15;17) PML-RARA Intermediate M3 Auer rods +++, high incidence of DICQ
AML with t(9,11) KMT2A-MLL Poor Variable
AML with­ BCR–ABL1 mutation Responds to Rx
b. AML with gene mutations
Favorable
AML with mutated NPM1
Favorable
AML with Biallelic mutation of CEBPA
II. AML WITH MDS-LIKE FEATURES
AML with MDS-like cytogenetic aberrations Poor Variable Associated with 5q-, 7q-, Monosomy 5 and 7Q
III. A
 ML, THERAPY-RELATED
1. Post alkylating agents Very poor Variable 5–10 years after exposure
•• Unbalanced loss of chr. 5 & 7 & loss of p53
2. Post DNA topoisomerase II 1–5 years after exposure
•• Balanced chromosomal translocations
IV. AML, NOT OTHERWISE SPECIFIED (previously FAB)
AML, minimally differentiated PoorQ M0 MPO –VE
AML without maturation Intermediate M1 MPO +ve in >3% of blasts
AML with myelocytic maturation Intermediate M2 myelocytic maturation, Auer Rods ++
AML with myelomonocytic maturation Intermediate M4 Myelocytic and monocytic differentiation MPO +, NSE +Q
AML with monocytic maturation Intermediate M5 Monoblasts and pro-monocytes predominate,
Non-specific esterase (NSE)+Q
AML with erythroid maturation PoorQ M6 >80% erythroid precursors
AML with megakaryocytic maturation PoorQ M7 >50% megakaryocytic blasts
Most common Acute Leukemia in Down syndrome

Diagnosis of AML yy Monocytic stain: Non-specific esterase (NSE) M5Q

ƒƒ Bone marrow Morphology: yy Both MPO/SBB & NSE: M4Q
ƒƒ Diagnosis of choice
{{ > 20% myeloid blasts in the bone marrowQ
{{ Myeloblasts have delicate nuclear chromatin, 2-4 nucleoli, yy Flow cytometry
and moderate cytoplasm with or without Auer rods
High Yield Facts
{{ Auer rods: Most reliable morphological feature of AMLQ

yy Needle-like azurophilic fusiform inclusions in cytoplasm Cytochemical stains Cells stained

of myeloblasts Myeloperoxidase (MPO) MyeloidQ
yy Stain +ve with MPO and Sudan Black BQ
Sudan Black B (SBB) MyeloidQ
yy Seen in AML M2, M3 (also seen in CML blast crisis and
MDS)Q Periodic acid Schiff (PAS) Lymphoid (Block positivity)Q
yy Faggots: bundles of Auer Rods in crisscross patternQ Non-specfic esterase (NSE) MonocytesQ >>Myeloid T
{{ Phi Body: round or oval inclusions in blastsQ Acid phosphatase T-lymphocyteQ
ƒƒ Cytochemistry:
H
Tartarate resistant acid Hairy cell leukemiaQ
{{ Blasts stain positive for:
phosphatase (TRAP) E
yy Myeloid stain: Myeloperoxidase (MPO), Sudan Black B O
(SBB)-M2/3
R
Y
 High Yield Facts
•• Pan B- marker is CD 19Q
240 •• Pan T- marker is CD3Q
•• Memory cells have CD45ROQ
•• CD 71: Transferrin receptors
•• CD95Q is the major receptor for apoptosis
Complete Review of Pathology

•• Cut off for blast counts in AML is < 20% if AML is associated with cytogenetic abnormalities like t(15;17), t(8;21), inv(16)Q
•• AML causing gum hypertrophy/infiltration are AML-M5, M4Q
•• AML causing extramedullary blast proliferations (Chloroms) are AML M2, M4, M5Q
•• AML causing blast infiltrations in skin (leukemia cutis) are AML M5, M4Q
•• Disseminated intravascular coagulation (DIC)Q can be seen in Acute promyelocytic leukemic (APML, M3)

Differences between Myeloblast & lymphoblast in Acute Leukemia

Parametres Myeloblast Lymhoblast

Size Larger (18-20 m) Smaller (10-18 m)
Cytoplasm Moderate and granular Scant and agranular
N/C ratio High Very high
Nuclear chromatin Fine and stippled Coarser
Nucleoli 2–5 prominent 0–2 Inconspicuous
Auer rods Present Absent
Accompanying cells Myelocytes, metamyelocytes, stab and neutrophils Lymphocytes

Origin of peripheral B cell neoplasms

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Peripheral B-Cell Neoplasms ƒƒ Poor prognosis markers:
{{ Rai (stage 3 /4) and Binnet (stage C)
Chronic Lymphocytic Leukemia (CLL)/ Small Lymphocytic {{ High β2 microglobulin
Lymphoma (SLL) {{ Diffuse marrow involvement
241
ƒƒ Clinical criteria: {{ Lymphocyte doubling time (<1 yr)

{{ Absolute clonal lymphocytes >5000/uLQ {{ High LDH

{{ MC leukemia of adults in the Western world. {{ Increased Serum CD23Q

{{ Median age at diagnosis is 60 years; M:F = 2 : 1 {{ Lack of somatic IghVh hypermutationQ

Chapter 9   White Blood Cells and its Disorders

ƒƒ MC mutation–Del 13q. {{ ZAP-70 +ve
{{ CD38 +ve
ƒƒ Cell of origin–Naive B cell.
{{ Presence of NOTCH1 mutationsQ
ƒƒ Peripheral Smear:
{{ Small round lymphocytes with scant cytoplasm ƒƒ Transformations of CLL (poor prognosis):
{{ Diffuse large B-cell lymphoma - Richter syndrome (5% –
(CONVENT girl appearance)Q
{{ Occasional cells have distorted outline called smudge 10%)Q
{{ Large-cell transformation to prolymphocytic leukemia
cellsQ
{{ Rarely Warm type AIHA may develop showing SpherocytesQ (PLL)Q
{{ Acute Leukemia
ƒƒ Morphology of Lymph nodes:
{{ 2nd malignancy- Melanoma and CNS tumorsQ
{{ Diffusely effacedQ by an infiltrate of predominantly small

lymphocytes (6- 12µm) between which lies larger activated
lymphocytes- proliferation centersQ (pathognomonic
for CLL/SLL), which contain mitotically active cells.
{{ Overall CLL has low mitotic rateQ exc in proliferative center
ƒƒ Diagnosis of choice
{{ Immunophenotyping
{{ Dim Surface Ig (usually IgM or IgM and IgD)Q
{{ Pan B-cell markers CD19 + and CD20+Q
{{ CD23+ and CD5+Q
High Yield Facts
•• Rai and Binnet staging system was used for CLL
•• Almost never develops after radiation
•• M.C genetic anomalies in CLL are del 13q14.3Q, 11q, and 17p,
and trisomy 12q.Q
•• Micro-RNAs: miR-15a and miR-16-1 (tumor suppressor
genes): good prognosis in CLLQ
•• CLL with Somatically hypermutated Ig genes have indolent
courseQ
•• CLL with Unmutated Ig genes (naive B-cell origin) have
aggressive courseQ

CLL with smudge cells Lymph node biopsy showing effacement by small lymphocytes

Mantle Cell Lymphoma ƒƒ Presentation:

ƒƒ Definition:
{{ Usual presentation: Lymphadenopathy (with occasional
Tumor arising from mantle zoneQ which surrounds
{{ spill to peripheral blood)Q T
{{ Unusual presentation: Lymphomatoid polyposisQ-
germinal centers H
mucosal involvement of the small bowel or colon
ƒƒ Seen in:
{{ M>F; Most common age: 5th-6th decade
producing polyp-like lesions E
ƒƒ Pathogenesis:
ƒƒ Morphology of lymph node: O
{{ A homogeneous population of small lymphocytes with
{{ t(11;14)Q → overexpression of cyclin D1 → promotes G1-
deeply clefted (cleaved) nuclear contours R
to S-phase progression during the cell cycle.
Y
 ƒƒ Immunophenotype: Diffuse Large B-Cell Lymphoma (DLBCL)
{{ Express high levels of cyclin D1, CD19, CD20, CD45 and
Most common form of NHL in IndiaQ
surface IgQ.
ƒƒ Epidemiology:
242 {{ CD5+veQ and CD23−ve which help to distinguish it from
{{ M>F, Median age =60 yrsQ
CLL/SLL.
ƒƒ Pathogenesis:
{{ Most sensitive marker is SOX II
{{ Pathogenic event is dysregulation of BCL6Q
ƒƒ Prognosis:
{{ 10% – 20% have t(14;18)Q
{{ Poor; Median survival of 3 - 4 years.
Complete Review of Pathology

ƒƒ Morphology:
Follicular Lymphoma {{ Tumor cells have large cell size (4-5 times size of small

Most common form of indolent (low grade) NHL in the West.Q lymphocyte) & diffuse pattern of growth. B4 is involved
ƒƒ Clinical feature late
{{ Presents with painless, generalized lymphadenopathy. ƒƒ Immunophenotype:
ƒƒ Pathogenesis {{ CD19+ and CD20+, CD10+ and BCL6+, surface Ig+Q

{{ Arises from germinal center of B cellsQ ƒƒ Special Subtypes:

{{ Hallmark translocation t(14;18)Q
{{ Mutations in MLL geneQ (histone-methyl transferase) that Immunodeficiency- Primary effusion lymphoma
regulates gene expression (90%) associated large B-cell
ƒƒ Morphology lymphoma
{{ Lymph node: Predominantly nodular or nodular &

diffuse growth pattern with centrocytes (small cleaved •• Severe T-cell •• Malignant pleural effusion
cells) along with centroblastsQ immunodeficiency or ascites in advanced HIVQ
{{ Bone marrow: paratrabecular lymphoid aggregatesQ •• (HIV, allogeneic bone infected patients
ƒƒ Immunophenotype marrow transplantation) •• Co-infection with KSHV/HHV-
{{ Resemble germinal center B cells CD19, CD20, CD10, •• Co-infection with EBVQ 8Q
surface Ig, and BCL6Q •• IHC : CD38, CD30+, CD20 –
{{ CD5 –veQ
{{ BCL2 is expressed in more than 90% of casesQ ƒƒ Prognosis:
ƒƒ Histologic transformation occurs to: {{ Poor prognosis with aggressive course
{{ Diffuse large B-cell lymphoma (DLBCL)
{{ Burkitt’s lymphoma (BL)
Malt Lymphoma (MALToma)
ƒƒ MALT lymphomas express B-cell antigens (CD19 and
CD20) & monotypic surface Ig (IgM without IgD).
ƒƒ MALTomas may be CD43+ but lack other small B-cell
lymphoma markers (CD5, CD10, CD23 & cyclin D1)
•• MALToma of salivary glands in sjogrens & hashimoto thyroiditis
show morphology of marginal zone lymphoma

High Yield Facts

•• Nasal NK/T lymphoma may present with facial swelling/
destruction, so called lethal midline granuloma or
polymorphic reticulosis.
•• Most common ocular lymphoma is B-cell NHL
Follicular lymphoma (Lymph node Biopsy)
•• The most site for extranodal lymphoma is Stomach

Burkitt’s Lymphoma
Pathogenesis MYC geneQ (chr 8) (transcriptional regulator)-characteristic but not specific
Hallmark •• t(8;14) myc; IgH – most characteristicQ
translocations: •• t(2;8) myc ; Ig κ
T •• t(8;22) myc ; λ
H Subtypes/Varieties African (endemic) Sporadic (Non-endemic) Immunodeficiency associated (HIV)
E Site of involvement •• Mandible (M.C)Q •• Ileocecal region(M.C)Q •• Lymph nodes
O •• Abdominal viscera; E.g. •• Peritoneum •• Bone marrow
kidneys, ovaries, adrenals
R
EBV infection 100%Q 20-30% 25-40%
Y Contd...
 Morphology: Tumor: High mitotic indexQ, numerous apoptotic cells, combined with benign macrophages.
•• Macrophages have abundant clear cytoplasm: characteristic “starry sky” pattern.Q
Bone Marrow:
•• Clumped nuclear chromatin with distinct nucleoli, and royal blue cytoplasm containing clear cytoplasmic vacuoles. 243
Immunophenotype Surface IgM+, CD19+, CD20+, CD10+, and BCL6+ Q

Prognosis Burkitt lymphoma is very aggressive but responds well to intensive chemotherapy

Chapter 9   White Blood Cells and its Disorders

Burkitt lymphoma with starry sky pattern Cells showing cytoplasmic vacuoles

Hairy Cell Leukemia ƒƒ Cytochemical markers:

Chronic B-cell leukemia characterized by hairy cells, pancyto-

{{ Tartrate resistant acid phosphatase (TRAP), DBA 44 and
penia and splenomegalyQ Annexin A1.Q
ƒƒ Clinical Features:
ƒƒ Epidemiology:
{{ Infiltration of the bone marrow, liver, and spleen- massive
{{ Median age: 55 years; M:F ratio of 4-5 : 1.
splenomegaly.Q
ƒƒ Pathogenesis: {{ Pancytopenia resulting from marrow involvement and
{{ 90% of cases with activating point mutations in the serine/ splenic sequestration.
threonine kinase BRAF v600EQ (also +ve in melanoma, {{ Atypical mycobacterial infections due to monocytopenia.
LCH and papillary lung Ca)Q
ƒƒ Morphology:
{{ Peripheral smear: Pancytopenia with monocytopenia;
‘Hairy’ tumor cells- Tumor cells with Fine hair like
projections, best recognized under the phase-contrast
microscope.Q
{{ On Electron microscopy: Hairy cells show ribosomal-
lamellar complexesQ
{{ Bone Marrow Aspirate: Dry Tap (due to fibrosis in
marrow)Q
{{ Bone Marrow Biopsy: Tumor nuclei surrounded by zone of
clear cytoplasm giving rise to “honeycomb”Q, “fried eggQ/
chicken wire mesh”Q appearance T
ƒƒ Immunophenotype: H
{{ CD19+ and CD20+, surface Ig +
Characteristic marker: CD103Q along with CD11c, CD25
E
{{ Hairy cell leukemia
O
R
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 High Yield Facts
Infections and Associations with Lymphoma
244 Agent Type of Lymphoma
Epstein Barr virus (EBV) ••  urkitt lymphoma (Africa)
B
••  ost Transplant Lymphoproliferative Disorders
P
•• AIDS–related lymphoma (central nervous system, others)
Complete Review of Pathology

•• Natural killer/T-cell nasal lymphoma

•• Hodgkin lymphoma
Human T-lymphotropic virus I (HTLV-1) Adult T-cell leukemia/lymphoma
Human herpes virus 8 (HHV8) or Kaposi sarcoma–associated •• P rimary effusion lymphoma
herpes virus (KSHV) •• Plasmablastic lymphoma
Helicobacter pylori Gastric MALToma
Hepatitis C virus Splenic marginal zone lymphoma; other B-cell lymphomas
Campylobacter jejuni Immunoproliferative small intestinal disease
Borrelia burgdorferi Primary cutaneous B-cell lymphoma
Chlamydia psittaci Ocular adnexal lymphoma

Clover cells (Adult T cell leukemia/lymphoma) Sezary cell (Peripheral T cell lymphoma)

High Yield Facts Plasma Cell Neoplasms and Related Disorders

•• Clover leaf/flower cells: Adult T cell leukemia/lymphoma Multiple Myeloma
•• Sezary cells: Peripheral T cell lymphoma ƒƒ Definition: Malignant proliferation of plasma cells derived
•• Hallmark/Doughnut cells: Anaplastic large cell lymphoma from a single clone.
ƒƒ Classification and Diagnostic Criteria of Plasma cell
neoplasms

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 245

Chapter 9   White Blood Cells and its Disorders

R9th Latest Update
Myeloma Defining Events (any 1 is sufficient for diagnosing multiple myeloma)
•• ≥ 60% clonal plasma cells
•• Involved/uninvolved free light chain ratio (>100)
•• ≥ focal lesions of > 5 mm in size on (MRI)

Classification of Plasma Cell Neoplasma (WHO 2017)

MGUS Smoldering Myeloma Multiple Myeloma

IgG/A/M MGUS [All criteria must be met] •• Serum monoclonal protein (IgG or IgA) •• Clonal BM plasma cells of ≥10%
•• Serum monoclonal protein (IgG or IgA or ≥3 g/dL or
IgM <3 g/dL AND or •• Biopsy-proven bony or extramedullary
•• Clonal BM plasma cells <10% AND •• Urinary monoclonal protein ≥500 plasmacytoma
•• No myeloma defining events (see below) mg/24 h and/or
•• Clonal BM plasma cells 10% – 60%
AND AND
•• No myeloma defining events or •• 1 or more myeloma defining events as
amyloidosis (no CRAB and no SLIM) as details below
details below ≥1 CRAB feature(s)
OR
≥1SLiM feature(s)
Myeloma defining events are evidence of end organ damage that can be attributed to the underlying plasma cell proliferative disorder, especially
C: Calcium elevation (>11 mg/dL or >1 mg/dL higher than ULN)
R: Renal insufficiency (creatinine clearance < 40 mL/min or serum creatinine >2 mg/dL) T
A: Anemia (Hb <10 g/dL or 2 g/dL < normal)
B: Bone disease (≥1 lytic lesions on skeletal radiography, CT, or PET-CT). H
OR, in the absence of CRAB, any one or more of the following biomarkers or malignancy, referred to here as the
SLiM criteria: SLiM: S = ≥Sixty-percent (≥60%) clonal BM plasma cells; Li=Serum free Light chain ratio involved:
E
uninvolved ≥100; M = >1 focal lesions (≥5 mm each) detected by MRI studies O
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 Lab Diagnosis of Multiple Myeloma ƒƒ Other Investigations:
ƒƒ Peripheral smear: {{ Serum electrophoresis: Monoclonal band (M spike)Q
{{ Anemia: Normocytic, normochromic {{ Immunofixation electrophoresis: Distinguishes Ig class
246 {{ Rouleaux formation with basophilic background staining {{ Serum/Urine free light chain assay: k/λ chains
{{ Few plasma cells may be seen (Plasma cells >20% or {{ Bence jones protein in urineQ : Free light chains which
>2,000/uL → Plasma cell leukemia)Q precipitates at 55-60oC and disappear on heating to 95 oC
ƒƒ Bone marrow: {{ Immunophenotyping: CD 38 +ve, CD138 +ve, cIg +ve,
{{ Diagnostic hallmark: Infiltration of marrow by plasma
Complete Review of Pathology

CD19-veQ
cellsQ {{ Cytogenetics:
{{ Plasmablasts may be present
yy t(11;14)-diagnostic hallmark, good prognosisQ
{{ Mott Cells/Grape cellsQ: Cells with small spherical
yy del 13q, t(4;14), t(14;16): Poor prognosis
inclusions of Immunoglobulins
{{ Flame cells/ThesaurocytesQ: Orange red flame like
{{ Imaging :
peripheral rim yy X-ray (punched out lytic lesions:Q skull,Q spine, ribs,
{{ Inclusion bodies in plasma cells: pelvis);
yy Dutcher body- IntranuclearQ {{ Serum β2 microglobulin: <3.5mg/L indicates good
yy Russel body-IntracytoplasmicQ prognosisQ

Rouleux RBCs Plasma cells Mott cells

High Yield Facts

{{ Mc mutation: MYD88
•• M spike : IgG(most common)Q >A>M>D>E
ƒƒ Clinical features:
•• Free light chains are called Bence-Jones proteins- not detected
{{Anemia, lymphadenopathy, Hepatosplenomegaly &
by urine protein dipsticksQ
•• IL-6Q helps in survival and proliferation of myeloma cell hyperviscosity
proliferation. ƒƒ Immunophenotyping:
{{ CD 138 +, cy IgM+, CD19 +
•• Other growth factors for myeloma cells-IL1 βQ and VEGFQ
•• Most common cytogenetic abnormality in myeloma is 13q->t
(11,14) HODGKIN LYMPHOMA (HL)
•• Osteolytic lesionsQ in bone are due to involvement of RANK-
ƒƒ Characteristics:
LQ (receptor activator of nuclear factor kappa B ligand) →
activates osteoclasts
{{Arises in lymph nodes (M.C cervical region)Q & spreads to
•• POEMSQ: Polyneuropathy, Organomegaly, Endocrinopathy, anatomically contiguous lymphoid tissuesQ
Multiple Myeloma & Skin Changes ƒƒ Clinical features:
{{ Pel Ebstein fever (Intermittent fever every alternate
•• Alkaline Phosphatase levels in multiple myeloma is normal
and not raised, as there is no bone formation and only bone week)Q
lysis. {{ Lymphadenopathy; Affected lymph nodes nodes become

painful with alcohol ingestionQ

T ƒƒ Pathogenesis: Mc mutation: Rel transcription activators
H Waldenstrom Macroglobulinemia
{{ Activation of the transcription factor NF-κB is a common

event in classical HL.

E ƒƒ Definition: {{ Cytokines (e.g., IL-5, IL-10, M-CSF), chemokines (e.g,
{{ Indolent lymphoproliferative disorder characterized
O by Lymphoplasmacytic cell proliferation in marrow with
eotaxin), & other factors (e.g., immunomodulatory factor
galectin-1) that are secreted by Reed-Sternberg cells
R secretion of IgM
Y
ƒƒ Morphology:
{{ Reed-Sternberg cells (R.S cells) surrounded by T lympho- ƒƒ Poor prognostic markers:
cytes in a rosette-like mannerQ {{ Albumin <4.0 g/dL, Hemoglobin <10.5 g/dL, Male sex, 45
{{ Diagnostic Hallmark: Reed-Sternberg cells: (45 µm) years of age or more, Stage IV disease, Leukocytosis at or 247
binucleate cell or single nucleus with multiple nuclear above 15,000/mm3, Lymphocytopenia
lobes.Q

Chapter 9   White Blood Cells and its Disorders

Lymph node biopsy showing Reed Sternberg cell Lacunar cell Popcorn cells

Description of different Subtypes of Hodgkin Lymphoma

Subtype Morphology Immunophenotype Association with EBV Typical Clinical Features
Nodular sclerosis Lacunar cells (clear CD15+, CD30+; usually EBV- MC in WorldQ; M=F;
space around nucleus)Q usually stage I or II; frequent
Fibrous strandsQ & mediastinal involvement;
plasma cellsQ Good prognosisQ
Mixed cellularity Mononuclear cells CD15+, CD30+; 70% EBV+ MC in IndiaQ, stage III or IV;
M > F; biphasic incidence;
Good prognosisQ
Lymphocyte rich Mononuclear cells CD15+, CD30+; 40% EBV+ Uncommon; M > F, Good prognosisQ
Lymphocyte Reticular variant: CD15+, CD30+; 90% EBV+ (Maximum)Q Uncommon; M>F; HIV infectedQ
depletion Poorest PrognosisQ
Lymphocyte Lymphocytic & CD20+, EBV- Uncommon; young males with cervical
predominance Histiocytic (popcorn cell)Q CD15-, C30-; or axillary L. nodes,
Best PrognosisQ

Clinical Staging of Hodgkin’s and Non-Hodgkin’s Lymphomas (Ann Arbor Classification)

Stage Distribution of Disease
I Involvement of a single lymph node region (I) or a single extra-lymphatic organ or site (IE).
II Involvement of two or more lymph node regions on the same side of diaphragm alone (II) or localized involvement of an
extra-lymphatic organ or site (IIE).
III Involvement of lymph node regions on both sides of the diaphragm without (III) or with (IIIE) localized involvement of an
extra-lymphatic organ or site.
IV Diffuse involvement of one or more extra-lymphatic organs or sites with or without lymphatic involvement.
All stages are further divided on the basis of: Absence (A) or Presence of (B) symptoms:Q, Unexplained fever, Drenching night sweats,
and/or, Unexplained weight loss > 10%
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ABVD (Adriamycin, Bleomycine, Vineblastine & Dacarbazine) regimen is standard line of treatmentQ
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 MYELOID NEOPLASMS
Three broad categories of myeloid neoplasia exist:
248 ƒƒ Acute myeloid leukemias (AML): discussed previously
ƒƒ Myelodysplastic syndromes (MDS)
ƒƒ Chronic Myeloproliferative Neoplasms (CMPN)

Myelodysplastic Syndromes
Complete Review of Pathology

ƒƒ Definition:
{{ Group of clonal stem cell disorders characterized by
cytopenias, dysplasias in either lineage, ineffective
erythropoiesis and a high risk of transformation to AML.Q
ƒƒ Cytogenetics
{{ del 5q (MC best prognosis)Q—Adults

{{ Monosomy 5Q, Monosomy 7, del 7q (MC treatment

related MDS; Q both have poor prognosis)Q Pawn Ball megakaryocyte

{{ p53 mutation–aggressive disease
WHO 2017
{{ –y, del 11q–very good prognosis
Chronic Myeloproliferative Neoplasms (CMPN)
ƒƒ Definition:
{{Presence of mutated tyrosine kinasesQ or other acquired
aberrations in signaling pathways that lead to growth
factor independence leading to:
yy Increased proliferation of bone marrow
yy Extra-medullary hematopoiesis
yy Marrow fibrosis and peripheral blood cytopenias
yy Transformation to acute leukemia
We will now discuss the types of CMPN:

Chronic Myelogenous Leukemia (CML)

ƒƒ Characterized by:
{{ BCR-­ABL geneQ (210 kDa in size)
Pseudo-Pelger Huet neutrophil
{{ ABL gene on chr 9q translocates to BCR gene on chr 22q
which activates tyrosine kinaseQ
ƒƒ Cell of origin:
ƒƒ Bone marrow Morphology:
{{ Pluripotent hematopoietic stem cellQ
{{ Cytopenias with features of dysplasia can be seen in either
of the series like: ƒƒ Etiology:
{{ Radiation exposure, No genetic predisposition
Erythroid series Myeloid series Megakaryocytic ƒƒ Epidemiology:
series
{{ M> F; Median age-5th -6th decade
•• Ring •• Hypo or defective •• Micromega- ƒƒ Clinical features:
sideroblastsQ granulation karyocytes {{ Presents with massive splenomegaly, hepatomegaly and
•• Megaloblastic •• Toxic granulations •• Single nuclear
lymphadenopathy.Q
maturation •• Döhle bodies lobes
•• Nuclear budding •• Pseudo- •• Multiple ƒƒ Peripheral smear:
•• Nuclear bridging Pelger-HüetQ separate nuclei {{ Increased TLC (30,000/uL – 10,00,000/uL), myeloid bulgeQ
neutrophils (Pawn ball Meg- (myelocytes and metamyelocytes) and basophilia.Q
T akaryocytes)Q ƒƒ LAP score:
H yy LowQ
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ƒƒ Bone marrow Morphology:
{{ Hypercellular marrow (Not required for diagnosis but for staging)Q
{{ Increased small, dysplastic forms of megakaryocytes.
yy Scattered macrophages with abundant wrinkled, green-blue cytoplasm so-called sea-blue histiocytes/ Pseudo-Gaucher cellsQ 249
ƒƒ Diagnosis of choice
yy Cytogenetics -FISH/PCR

The Philadelphia Chromosome

Chapter 9   White Blood Cells and its Disorders

Band cell Myelocyte Metamyelocyte
Basophil

Neutrophil
Peripheral smear of CML

WHO Diagnostic Criteria for Different Phases of CML (WHO 2017)

Accelerated Phase Blast phase/ blast crisis
•• Blasts 10–19% in blood or marrowQ •• >20% blastsQ (*Wintrobe’s latest 13th ed: >30%)
•• Peripheral blood basophilia ≥ 20%Q •• Clusters of blasts on BM biopsy
•• Newer Cytogenetic clonal evolution •• Extramedullary myeloid tumors (granulocytic sarcomas,
•• Persistent thrombocytopenia (<100 × 109/L) chloromas)Q
•• Persistent thrombocytosis (>1,000 × 109/L) unresponsive to therapy •• Lymphoblasts in any number should be reported as they
•• Increasing splenomegaly & WBC count unresponsive to therapy signify poor prognosis
•• Provisional response to TKI-Tyrosine kinase inhibitors
•• Provisional” response-to-TKI (tyrosine kinase inhibitors) criteria
is added- Occurrence of 2 or more mutations or resistance to
therapy are added

High Yield Facts

Conditions Associated with Abnormal Leukocyte Alkaline Phosphatase (LAP) Scores
High LAP score (>130) Low LAP Score (<15)
•• I nfections (Leukemoid reaction) Q
••  ML
C Q

••  rowth factor therapy

G ••  aroxysmal nocturnal hemoglobinuriaQ
P
•• Myeloproliferative disorders other than CML (ET, PCV, Myelofibrosis)Q ••  ereditary Hypophosphatemic Rickets
H
•• AMLQ •• Myelodysplastic syndromes
•• Hodgkin’s diseaseQ •• Rare infections or toxic exposures
•• Inflammatory disorders
•• Pregnancy,Q oral contraceptives T
•• Stress
•• Drugs (lithium, corticosteroids, estrogen)
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 Polycythemia Vera ƒƒ Diagnosis: Requires all 3 major criteria or first 2 major +
minor criteria
ƒƒ Epidemiology:
{{ Mean age = 60yrs; M:F=1-2:1 Major Criteria Minor Criteria
250 ƒƒ Genetic abnormality:
•• Hemoglobin >16.5 g/dlQ in men, •• Low serum
{{ Most frequent genetic abnormality in PCV is JAK2 V617FQ
>16 g/dL in women or HCT >49% in erythropoietin levelQ
ƒƒ Clinical Features:
men or >48% is woman. Increased
{{ CVS: HypertensionQ, venous or arterial thrombosis,
red cell mass >25% above mean
Complete Review of Pathology

myocardial ischemia or stroke, pruritus after bath

normal predicted value.
{{ CNS: Headache, dizziness. visual disturbances, paraes-
•• Presence of JAK2 mutationQ
thesias •• Hypercellular bone marrow biopsy
{{ Others: Pruritus, erythromelalgia,Q goutQ
with panmyelosisQ

Polycythemia Thrombocytosis

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Essential Thrombocythemia/Primary MYELODYSPLASTIC/
Thrombocytosis MYELOPROLIFERATIVE (MDS/MPN)
ƒƒ Epidemiology NEOPLASMS
251
{{ Mean age = 50-60yrs; M=F
ƒƒ Definition:
ƒƒ Clinical Feature {{ Group of disorders with features of both myeloprolifera-
{{ Microvascular occlusion may lead to transient ischemic
tive and myelodysplastic syndromesQ
attacksQ, digital ischemia with paraesthesia & gangrene.

Chapter 9   White Blood Cells and its Disorders

ƒƒ Includes:
BleedingQ may also be seen, due to platelet function defects {{ Chronic myelomonocytic leukemia (CMML)

ƒƒ Peripheral smear {{ Atypical CML (a-CML)

{{ Thrombocytosis with abnormalities in size, shape & {{ Juvenile myelomonocytic leukemia (JMML)

granularity of platelets
Other
ƒƒ Diagnosis:
{{ All 4 or first 3 major + 1 minor criteria Newer Myeloproliferative Neoplasms (MPNs)
MPN Mutation seen
Major criteria Minor criteria
•• Systemic mastocytosis •• Constitutive c-KIT kinase activation
•• Sustained platelet count ≥4.5 •• Absence of evidence of
•• Chronic eosinophilic •• Constitutive PDGFRα/β kinase
Lakhs/uLQ reactive thrombocytosis
leukemia activation
•• Bone marrow biopsy showing
proliferation of megakaryocytes, •• Stem cell leukemia •• Constitutive FGFR1 kinase activation
•• Exclusion of WHO criteria for PV,
PMF, CML, MDS JUVENILE MYELOMONOCYTIC
•• JAK2 mutationQ, CALR or MPL
mutations LEUKEMIA (JMML)
ƒƒ Definition
Chronic Idiopathic Myelofibrosis/Agnogenic {{It is a childhood mixed MDS/MPD that includes child-
Myeloid Metaplasia (AMM) hood leukemias previously classified as CMML, juvenile
CML, and infantile monosomy 7 syndrome.
ƒƒ Epidemiology:
ƒƒ Diagnostic Criteria:
{{ Mean age: 6th–7th decade; M=F
ƒƒ Hallmark: Genetic Criteria Required Criteria Other criteria
{{ Hallmark of primary myelofibrosis is: obliterative marrow
(Any 1 is (All 4 needed)
sufficient)
fibrosisQ
ƒƒ Peripheral smear: •• NFI mutation •• Peripheral •• Increased hemoglobin
{{ Marrow distortion due to fibrosis leads to the premature
•• CBL mutation blood F for age
(germ line) monocytes > •• Immature granulocytes
release of nucleated erythroid and early granulocyte •• Somatic 1.0 × 109/L in peripheral blood
progenitors (leukoerythroblastosis)Q mutation of •• Blasts + •• Clonal chromosomal
{{ Erythroids damaged in fibrotic marrow results in :Tear KRAS/NRAS/ promonocytes abnormality (i.e.,
drop-shaped RBCs (dacrocytes)Q PTPN11 <20% in blood includes monosomy 7)
ƒƒ Diagnosis requires: All 3 Major + at least 1 minor criteria and marrow •• GM-CSF
•• Absence of hypersensitivity of
Major Criteria Minor Criteria Philadelphia myeloid progenitors in
chromosome or vitro
•• Atypical megakaryocytic hyper- •• LeukoerythroblastosisQ
BCR/ABL fusion •• Hypophosphorylation
plasia, with collagen fibrosisQ •• ↑ LDH
gene od STAT 5 or
•• Exclusion of WHO criteria for PV, •• Anemia •• Splenomegaly Monosomy 7
CML, MDS, or other MPDs •• Palpable splenomegaly
•• JAK2V617F mutationQ, CALR, MPL •• Leucocytosis >11,000 High Yield Facts
•• JMML is the most common MDS/MPD of children
High Yield Facts •• Increased hemoglobin F is seen in JMML T
•• Ph chr discovered by Nowell & Hungerford in 1960 •• JMML is associated with NF1 H
•• Ring sideroblasts are erythroblasts with iron-laden
mitochondriaQ visible as perinuclear granules in Iron/ E
Prussian blue/Perl’sQ staining O
•• Pseudo-Pelger-Hüet neutrophilsQ: bilobed hypogranular
dysplastic neutrophilsQ R
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 LANGERHANS CELL HISTIOCYTOSIS
(LCH) HISTIOCYTOSIS XQ
252 ƒƒ Current classification:
Unifocal (i.e., single-system, single-site disease)
{{

Multifocal (i.e., single-system, multiple-site disease)

{{
{{ Disseminated histiocytosis (i.e., multisystem disease)

ƒƒ Diagnosis: Light microscopy

Complete Review of Pathology

{{ Basic histologic lesion: granulomas, containing histiocytes

or Langerhans cells, mature eosinophils, lymphocytes,

giant cells, neutrophils & plasma cells
{{ The Langerhans cellQ (large mononuclear cells with few

cytoplasmic vacuoles) is the ‘sine qua non’ (essential) of

the diagnostic lesion
ƒƒ Electron microscopy
{{ Birbeck granules (tennis racket appearance)Q Langerhans cells with convoluted nuclei with longitudinal grooves
ƒƒ Immunohistochemistry ("coffee-bean" shaped)
{{ CD1aQ, S-100Q or Langerin (CD 207)Q demonstration on

the surface of LCH cells

ƒƒ Prognosis
{{ LCH may be a self-limiting disease, which may resolve spontaneouslyQ
{{ For most patients with LCH, the prognosis is excellent
{{ Patients with multisystem disease may experience fatal organ failure

High Yield Facts

•• Bone is the most commonly involved organQ
•• Skull is the most commonly involved site in both children and adultsQ
•• Unifocal eosinophilic granuloma of bone is the most common form of the diseaseQ
•• “Punched out” appearance of skeletal lesions is typically seen in LCHQ
•• Pulmonary LCH occurs more commonly in males & is associated with smoking
•• Pneumothorax is seen in 25–40% cases of pulmonary LCH
•• Eosinophilic granuloma:Q bone lesions, with no visceral involvement
•• Letterer-Siwe disease:Q When granulomas involve multiple viscera
•• Hand-Schüller-Christian diseaseQ: Triad of multiple bone lesions, exophthalmos and diabetes insipidus (DI)

Thymoma High Yield Facts

ƒƒ Definition:
{{ Tumors of thymic epithelial cells Post Transplant Lymphoproliferative Disorder (PTLD)
ƒƒ Epidemiology: •• Post-transplant lymphoma occurs due to proliferation of B
{{ Usually seen in adults older than 40 years of age; rare in cells
children; Males = females •• 90% of early (<1 year post-transplant) PTLDs are EBV positive,
ƒƒ Location: when EBV-CTL immunity is lowest
{{ Anterior superior mediastinum, neck, thyroid •• Late (>2 years post-transplant) PTLDs are frequently EBV
ƒƒ Gross Morphology: negative, can be of T-cell origin, and may have a poorer
{{ Lobulated, firm, gray-white masses of up to 15 to 20 cm prognosis.
in size. •• Majority of PTLDs are CD20+, but not all PTLDs are of B-cell
{{ Sometimes have areas of cystic necrosis and calcification. phenotype and not all are EBV positive.
{{ Most are encapsulated, but 25% of the tumors penetrate •• T-cell PTLD tends to occur late, often more than 10 years after
T the capsule & infiltrate perithymic structures transplantation.
H ƒƒ Histology:
{{ Sheets of epithelial cells giving arborizing pattern of
E reactivity along with interspersed lymphoid cells.
O {{ IHC –CK + CD45

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2018 Revision to the World Health Organization Classification of Leukemia & Lymphoma

Category Latest modification Category Latest modification

New Acute AML with RUNX1mutation ALL Early precursor T-ALL –CD7,CD2, 253
Myeloid AML with BCR-ABL 1 mutation CD3 , Myeloid markers+
Leukemia AML with biallelic CEBPA mutations
Subtypes 2016 Familial AML/MDSmultiple types- EBPA,RUNX,GATA
Myeloid Refer to CML in text Essential CALR and MPL mutation is

Chapter 9   White Blood Cells and its Disorders

neoplasms thrombocythemia needed in addition to JAK-2
and Primary mutation
CML myelofibrosis

CNL (chronic CSF3R mutations added Polycythemia Hb cut off reduced to 16.5 gm%
neutrophilic Vera in males and 16 gm% in females
leukemia) or Hematocrit >49% (m) and
48% (f)
MDS Del9q is an MDS related entity only in the absence of Systemic Removed from Chronic
NPM1 mutations mastocytosis myeloproliferative neoplasms
SF3B1 mutation is strongly associated with ringed
sideroblast

WHO 2018 Update

The Cancer Genome Atlas (TCGA) project showing 9 classes of AML
Class 1: Transcription factor fusions Class 6: Chromatin-modifying, genes
e.g. t(8;21), inv(16), and t(15;17) e.g. ASXL1 and EZH2 mutations., fusions, KMT2A-PTD
Class 2: Nucleophosmin 1 Class 7: Myeloid transcription factor genes
NPM1 mutations e.g. CEBPA, RUNX1 mutations
Class 3: Tumor suppressor genes Class 8: Cohesin complex genes
e.g. TP53 and PHF6 mutations e.g. STAG2, RAD21, SMC1, SMC2 mutations
Class 4: DNA methylation-related genes Class 9: Spliceosome-complex genes
DNA hydroxymethylation e.g. TET2 , IDH1 and IDH2 e.g. SRSF2, U2AF1, ZRSR2 mutations
DNA methyltransferases
Class 5: Activated signalling genes
e.g. FLT3, KIT RAS mutation..

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 Image-Based Questions
254

1. 4-year old male presents with fever, bleeding gums and 3. Peripheral smear showing the given figure is likely to be
fatique for 4 days. CBC shows Hb of 8 gm%, TLC 86,000/UL, seen in all except?
Complete Review of Pathology

Platelet count of 25,000/ul. DLC shows Neutrophils 20%,

Lymphocyte 40%, Eosinophils 10%, Basophils 0%, Monocytes
5%, Abnormal cells 25%. Bone marrow aspiration shows cells
as shown in figure 60%. What is your diagnosis?

a. Chronic myeloid leukemia a. Hypergammaglobinemia

b. Chronic lymphoid leukemia b. Severe anemia
c. Acute leukemia c. Multiple myeloma
d. Myelofibrosis d. Hemolytic anemia

2. A 10-year old boy presents to AIIMS OPD with mass in the 4. For which procedure it is used?
abdomen. On imaging the paraaortic LN is enlarged. Biopsy
from the lymph node suggests a pattern as shown in the
figure. What is the underlying abnormality? 

a. Bone marrow examination

b. Liver biopsy
c. Pleural biopsy
d. Lumbar puncture

a. p53 gene mutation 

b. RB gene mutation 
c. Translocation involving BCR-ABL genes 
d. Translocation involving MYC gene

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 5. 40/F presented to Medicine OPD with fever and mucosal
bleeding of 3 days. CBC shows Hb-9.8 gm%, TLC = 15,700/
cumm, Platelet count = 15,000/cumm. Peripheral smear
showed findings as shown in figure. His cytogenetics revealed
t(8;21). What is your diagnosis?
a. AML b. CML
c. MDS d. ALL
6. The most important investigation in the given case to
diagnose if the condition is a neoplasm?
a. JAK-2
b. EPO level
c. PaO2
d. Bone marrow aspiration and biopsy
7. 55/M presented with fatigue and dragging sensation in the
abdomen to AIIMS OPD. He send the patients sample to a
pathologist initially performed hemogram which revealed
Hb = 8gm%, TLC = 1500/cumm, platelet count = 79,000/ 255
cumm. He also reported some bizzare looking cells which
are shown below. Which stain will the pathologist like to do
to diagnose the condition?
Chapter 9   White Blood Cells and its Disorders
a. PAS b. NSE
c. MPO d. TRAP
8. 10 year chid with bilateral cervical lymphadenopathy.
Lymph node biopsy was performed, which showed cells as
given in the figure. Which of the following is true regarding
this condition?
a. Hodgkin lymphoma; EBV and embryo cell
b. NON Hodgkin lymphoma; HIV and Giant B cell
c. TB, Mycobacteria and tiny granuloma
d. Hodgkin lymphoma: EBV and Reed Sternberg cell
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 Answers of Image-Based Questions
256
1. Ans. (c) Acute leukemia
•• The image shows large cells with high N:C ratio, immature chromatin which are blasts. With >20% blasts, the diagnosis is acute
leukemia.
2. Ans. (d) Translocation involving MYC gene
Complete Review of Pathology

•• The arrow marked shows cleared area (stars as macrophages) amidst hugely proliferating tumor cells (sky). This appearance of
starry sky is seen in Burkitts lymphoma having MYC gene translocation.
3. Ans. (d) Hemolytic anemia
•• The smear shows rouleux formation seen in multiple myeloma, severe anemia & cases of hypergammaglobinemia.
4. Ans. (a) Bone marrow examination
•• This is Klima bone marrow aspiration needle for marrow aspiration and biopsy
5. Ans. (a) AML
•• The blasts cells shows Auer rods inside them which are a hallmark of AML.
6. Ans. (a) JAK-2
•• The figure shows increased platelets in smear and increased megakaryocytes in bone marrow. To diagnose this as essential
thrombocythemia (neoplasm); JAK-2 mutation analysis should be done.
7. Ans. (d) TRAP
•• The peripheral smear in the question shows hairy cells which can be diagnosed with TRAP stain.
8. Ans. (d) Hodgkin lymphoma: EBV and Reed Sternberg cell
•• Figure shows Reed Sternberg cells in Hodgkins lymphoma which are EBV infected.

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