Undergraduate Pathology Series 74

3) Bitot spots: Small opaque, frothy, triangular plaques on conjunctiva with keratin debris.
4) Keratomalacia: Softening and destruction of cornea.
5) Total blindness.
Skin: Follicular or papular dermatosis.
Respiratory tract: Secondary pulmonary infections.
Urinary tract: Renal and bladder stones.
Immunity: Increased risk of developing infections such as measles, pneumonia and
infectious diarrhea.

Vitamin D Deficiency
“Concentrations of circulating 25-(OH)-D, less than 20 ng/mL constitute vitamin D
deficiency.”
Causes: 1) Inadequate intake.
2) Limited exposure to sunlight.
3) Renal disorders.
4) Malabsorption syndromes.
Deficiency syndromes: Rickets & osteomalacia

Rickets
“Vitamin D deficiency in growing children causes rickets.”
Age: Most common during first year of life.
Morphology:
1) Overgrowth of epiphyseal cartilage.
2) Persistence of distorted, irregular masses of cartilage.
3) Deposition of osteoid matrix on inadequately mineralized cartilaginous remnants.
4) Disruption of the orderly replacement of cartilage by osteoid matrix.
5) Abnormal overgrowth of capillaries and fibroblasts in the disorganized zone.
6) Deformation of the skeleton.
Manifestations:
1) Nonambulatory stage of infancy:
i) Flattening of occipital bones.
ii) Craniotabes: Parietal bones are soft, and when pressure applied, they will collapse
underneath it.
iv) Frontal bossing and a squared appearance of head.
v) Rachitic rosary: Expansion of the anterior rib ends at the costochondral junctions.
vi) Pigeon breast deformity: Anterior protrusion of sternum.
II) Ambulating child: Lumbar lordosis and bowing of the legs.

Osteomalacia
“Vitamin D deficiency in adults causes osteomalacia.”
Morphology:
1) Deposition of inadequately mineralized osteoid matrix.
2) Presence of excess of persistent osteoid.
C/P: Weak bones with increased risk of fractures, mostly affecting vertebral bodies and
femoral necks.
Refresh Pathology, 5th Edition – Dr. Shiva M.D. 75

Vitamin B Complex Deficiency Syndromes

Vitamin Deficiency Syndromes
Vitamin B1 (thiamine) Dry and wet beriberi, Wernicke-Korsakoff syndrome
Vitamin B2 (riboflavin) Cheilosis, stomatitis, glossitis, dermatitis, corneal
vascularization
Niacin Pellagra (dementia, dermatitis, diarrhea)
Vitamin B6 (pyridoxine) Cheilosis, glossitis, dermatitis, peripheral neuropathy
Vitamin B12 Megaloblastic anemia and degeneration of posterolateral spinal
cord tracts
Folate Megaloblastic anemia, neural tube defects

Vitamin C Deficiency
Causes: 1) Old age.
2) Chronic alcoholism.
3) Erratic & inadequate eating patterns.
Deficiency syndrome: Scurvy.
Manifestations:
Scurvy:
1) Growing children: Bone disease (bowing of limbs and depressed sternum) with inadequate
synthesis of osteoid due to defective collagen.
2) Children & adults: Hemorrhages (bleeding gums, bleeding into skin (perifollicular rash),
periosteum and joints) and healing defects due to defective collagen.
3) Anemia.
Undergraduate Pathology Series 76

9. Diseases of White Blood Cells, Lymph

Nodes, Spleen, and Thymus

MCQs
1) Which of the following is a characteristic feature of Hodgkin lymphoma. (April, 2024)
a) Reed-Sternberg cells b) Hypercellular bone marrow c) Perivascular cuffing d) Auer rods

2) Starry sky pattern is seen in. (April, 2024)

a) Hodgkin lymphoma b) Leukemia c) Kikuchi disease d) Burkitt lymphoma

3) Which of the following is a characteristic feature of multiple myeloma. (April, 2024)

a) Monoclonal gammopathy b) Decreased serum calcium levels
c) Increased bone density d) Normal bone marrow biopsy findings

4) Percentage of blasts in the peripheral blood for diagnosis of acute myeloid leukemia.
(April, 2024)
a) 10% b) 20% c) 30% d) 40%

5) The cytoplasmic inclusions seen in plasma cells in a case of multiple myeloma are.
(Jan. 2024)
a) Howell Jolly bodies b) Russel bodies c) Auer rods d) Siderotic granules

6) Starry sky pattern in the histology of an affected lymph node is classically seen in.
(Jan. 2024)
a) Infectious mononucleosis b) Hodgkin lymphoma
c) Burkitt lymphoma d) Tuberculous lymphadenitis

7) The percentage of blasts in the peripheral blood for a definite diagnosis of acute myeloid
leukemia is. (Jan. 2024)
a) 20% b) 40% c) 10% d) 5%

8) Rouleaux formation of RBCs and increased ESR are classical of. (April, 2023)
a) Polycythemia b) Acute myeloid leukemia c) Multiple myeloma d) Aplastic anemia

9) Blast crisis is a complication of. (April, 2023)

a) Acute myeloid leukemia b) Chronic myeloid leukemia
c) Hodgkin lymphoma d) Acute lymphoblastic leukemia

10) Bence Jones protein in urine can be demonstrated in. (April, 2023)
a) Multiple myeloma b) Acute myeloid leukemia c) Nephrotic syndrome d) Pregnancy
Refresh Pathology, 5th Edition – Dr. Shiva M.D. 77

11) A fifty year male presented with punched out skull lesions on X-ray, rouleaux formation
in peripheral blood and an ESR of 100 mm/hour. The most probable diagnosis is. (Dec. 2022)
a) Acute lymphoblastic leukemia b) Tuberculous meningitis
c) Hodgkin lymphoma d) Multiple myeloma

12) BCR/ABL fusion gene is associated with the pathogenesis of. (Dec. 2022)
a) Acute myeloid leukemia b) Multiple myeloma
c) Acute lymphoblastic leukemia d) Chronic myeloid leukemia

13) The percentage of myeloblasts in a peripheral smear to diagnose acute myeloid leukemia
should be more than. (Dec. 2022)
a) 10 % b) 20 % c) 30 % d) 40 %

14) The anemia associated with leukemia is. (May, 2022)

a) Iron deficiency b) Megaloblastic c) Myelophthisic d) None of the above

15 Marks
1) A 5 year old child was admitted with splenomegaly and lymphadenopathy. Laboratory
findings as follows: Hb 6.8 gm/dl, WBC count 100x109/L, thrombocytopenia. Bone marrow
shows increase in blast cells, which are positive for PAS stain. LDH and serum uric acid
levels are increased. (Jan. 2024)

a) What is the provisional diagnosis and why?

b) Describe the blood and bone marrow picture in this condition.
c) Mention the types as per FAB classification with labelled diagram.
d) Describe the immunophenotypes of this disease.

Ans: Acute Lymphoblastic Leukemia (ALL).

2) A 40 year old male was admitted with easy fatigability, anorexia, weakness, weight loss,
night sweats and dragging sensation in the abdomen due to splenomegaly. His total WBC
count was 2,50,000 cells/mm3. (Dec. 2022)

a. What is the provisional diagnosis and why.

b. Describe the chromosomal abnormality of the disease.
c. Describe the blood and bone marrow picture.
d. Mention various phases of the disease.

Ans: Chronic Myeloid Leukemia (CML).

3) A 35 year old male patient presented with high fever, fatigue, pallor, skin petechiae,
swollen gums and bone pain. His total WBC count is 1,00,000/mm3. (May, 2022)

a) What is the provisional diagnosis.

b) Describe the blood and bone marrow picture of the above case.
c) Classification of the above condition.
d) Discuss the prognosis of the above disease.

Ans: Acute Myeloid Leukemia (AML).

Undergraduate Pathology Series 78

5 Marks
1) Leukemoid reaction. (April, 2023)

10 Marks

1) A 35 year old man was admitted with easy fatigability, anorexia, weakness, weight loss,
night sweats and dragging sensation in the abdomen due to massive splenomegaly. His total
WBC count was 2,00,000 cells/mm3. (Nov. 2020)

a) What is the provisional diagnosis?

b) Describe the blood and bone marrow picture.
c) Describe the chromosomal abnormality of the disease.
d) Mention various phases of the disease.

Ans: Chronic Myeloid Leukemia (CML).

2) A 32 year old man is admitted with history of weakness and dragging sensation on left side
of abdomen. On examination, his liver is enlarged to 3cm below costal margin and spleen is
enlarged to 15cm below costal margin. His TLC is increased to 2,30,00/cumm. (Feb. 2020)

a) What is the possible diagnosis? What is likely to be the differential leukocyte count.
b) What is the diagnostic genetic abnormality in this condition?
c) To which group of diseases, does this entity belong to? Name the other diseases.
d) Give the clinical picture of this disease.

Ans: Chronic Myeloid Leukemia (CML).

3) A 2 year old male presented with fatigue, and breathlessness developing over 1 week. On
examination he had gum bleeding, epistaxis with petechiae, lymphadenopathy and
splenomegaly. CT scan showed presence of mediastinal mass. (July, 2019)

a) Give the possible diagnosis

b) Give the peripheral blood and bone marrow findings
c) Give the cytochemical staining properties
4) What are the prognostic factors

Ans: Acute Lymphoblastic Leukemia (ALL).

4) A 35 year old man admitted with gradual weakness with dragging sensation left side of
abdomen. His liver is 2cm and spleen is 15cm enlarged below costal margin. His Hb is 9.3
gm %, TLC – 2,50,000/cumm and platelet count is 3,80,000/cumm. (July, 2018)

a) What is the probable diagnosis?

b) Give the blood picture and molecular abnormality in this disease.
c) How will you differentiate it from leukemoid reaction?
d) Give five causes of massive splenomegaly.

Ans: Chronic Myeloid Leukemia (CML).

Refresh Pathology, 5th Edition – Dr. Shiva M.D. 79

5) A 3 year old child is admitted with fever and petechial hemorrhages for 2 weeks. On
examination child is pale, no liver/spleen enlargement. Cervical lymph nodes are enlarged.
TLC – 50, 000/cumm. Peripheral smear shows blast cells. (Feb. 2017)

a) What is the probable diagnosis?

b) What is the bone marrow picture in this disease?
c) Enumerate the various prognostic factors.
d) Tabulate the differences between lymphoblast and myeloblast.

Ans: Acute Lymphoblastic Leukemia (ALL).

6) A male child aged 8 years presented with fever, fatigue, generalized lymphadenopathy,
bone pain, petechial hemorrhages over the skin, pallor, enlarged testes and features of
meningism. (Jan. 2014)

a) What is the provisional diagnosis?

b) Describe blood and bone marrow picture.
c) Other investigations to confirm the diagnosis.
d) Discuss the prognosis of the same.

Ans: Acute Lymphoblastic Leukemia (ALL).

7) A 35 year old male was admitted with easy fatigability, anorexia, weakness, weight loss,
night sweats and dragging sensation in the abdomen due to massive splenomegaly. His total
WBC count was 2,00,000 cells/mm3. (July, 2013)

a) What is the provisional diagnosis?

b) Describe the blood and bone marrow picture.
c) Describe the chromosomal abnormality of the disease.
d) Mention various phases of the disease.
Ans: Chronic Myeloid Leukemia (CML).

8) A 4 years old male child presented with fatigue, fever, epistaxis, bleeding gums, bone pain
and CNS manifestations from meningeal involvement. Physical examination revealed
petechiae and ecchymoses of skin and mucous membranes, generalized lymphadenopathy
and testicular enlargement. The Leukocyte and differential counts were abnormal. (Jan. 2012)

a) What is the provisional diagnosis?

b) Discuss various main laboratory investigations to make a final diagnosis.
c) Describe peripheral blood and bone marrow picture.
d) Discuss molecular pathogenesis of the disease.
Ans: Acute Lymphoblastic Leukemia (ALL).

9) A 35 year old male patient presented with high fever, fatigue, pallor, skin petechiae,
swollen gums and bone pains. His total WBC count was 1,00,000/ ul. (Aug. 2009)

a) What is the provisional diagnosis?

b) Describe the blood and bone marrow picture of the above case.
c) Discuss the prognosis of this disease.
Ans: Acute Myeloid Leukemia (AML).
Undergraduate Pathology Series 80

10) 45 year old male presented with weakness, fatigue, weight loss, night sweats and
dragging sensation in the abdomen caused by massive splenomegaly. (Feb. 2009)

a) What is the provisional diagnosis?

b) What blood investigations should be done to confirm the diagnosis? Describe the
peripheral smear findings.
c) Which chromosomal abnormality is seen in this condition?

Ans: Chronic Myeloid Leukemia (CML).

11) A 40 year male was admitted with easy fatigability, weakness, weight loss and night
sweats. On examination, massive splenomegaly was noted. Total leukocyte count was 275,
000/ul. (Sep/Oct. 2007)
a) What is the possible diagnosis?
b) Describe the chromosomal abnormality of the disease.
c) Describe the peripheral blood smear and bone marrow findings of the same.

Ans: Chronic Myeloid Leukemia (CML).

12) A 2 year old child presented with fatigue, fever, epistaxis, bleeding gums and bone pain.
On examination, generalized lymphadenopathy and hepatosplenomegaly was noted. Total
leukocyte count was 150,000/ul. (May, 2007)

a) What is the probable diagnosis?

b) Describe the cytogenetics of the disease.
c) Describe the peripheral blood smear and bone marrow findings of the same.
d) Describe the prognostic factors of the disease.

Ans: Acute Lymphoblastic Leukemia (ALL).

13) 36 year old female came with swollen gums, fatigue and weight loss. She gives history of
repeated upper respiratory tract infections. On examination pallor, fever and
hepatosplenomegaly present. (May, 2006)

a) What is the provisional diagnosis?

b) Mention various investigations to make a final diagnosis.
c) Emphasize on the peripheral blood and bone marrow picture.

Ans: Acute Myeloid Leukemia (AML).

14) A 30 years old male patient came with moderate anemia, easy fatigability, weakness,
weight loss, anorexia, dragging sensation in the abdomen due to extreme splenomegaly.
Chromosomal analysis revealed the presence of Philadelphia chromosome. (April/May 2004)

a) What is the provisional diagnosis?

b) Describe the laboratory investigations to make a final diagnosis.
c) Describe the blood and bone marrow picture of the disease.

Ans: Chronic Myeloid Leukemia (CML).

Refresh Pathology, 5th Edition – Dr. Shiva M.D. 81

4 Marks

1) Lab diagnosis of chronic myeloid leukemia. (Oct. 2023)

2) Laboratory diagnosis of chronic myeloid leukemia. (May, 2022)
3) WHO classification of Acute Myeloid Leukemia. (Aug. 2021)
4) Lab diagnosis of chronic myeloid leukemia. (Feb. 2019)
5) Classify chronic myeloproliferative disorders. Give blood picture and diagnostic tests
in a case of chronic myeloid leukemia. (July, 2017)
6) Leukemoid reaction. (July, 2016)
7) Cytochemistry in differentiation of acute leukemias. (Jan. 2016)
8) FAB classification of Acute Myeloblastic Leukemia (AML). (Jan. 2015)
9) Tabulate the differences between leukemoid reaction and chronic myeloid leukemia.
(July/Aug. 2014)
10) Blood picture and bone marrow findings in CML. (Aug. 2010)
11) Multiple myeloma. (Oct. 2006)
12) Leukemoid reaction. (March/April 2005)

2 Marks

1) Russel bodies. (March, 2021)

2) Write four clinical and lab features of multiple myeloma. (Feb. 2020)
3) Variants of Reed Sternberg cell. (Feb. 2019)
4) Mention four clinical features of acute lymphoblastic leukemia. (July, 2017)
5) Name four subtypes of Hodgkin disease. (July, 2016)
6) Name any four myeloproliferative disorders. (July, 2015)
7) Draw a diagram of Reed-Sternberg cell. (July/Aug. 2014)
8) Mention 4 morphologic characteristics of a myeloblast. (Jan. 2013)
9) Myeloblast of AML 3. (March, 2010)
10) Juvenile chronic myeloid leukemia. (March/April, 2008)

High-Yield Topics
Leukemoid reaction CML
CLL AML
ALL Multiple myeloma
Polycythemia Vera Hodgkin lymphoma
Burkitt lymphoma
Undergraduate Pathology Series 82

Lymphadenopathy
Causes of generalized lymphadenopathy:
1) Infections: Infectious mononucleosis; Measles; HIV; TB; Syphilis.
2) Malignancies: Leukemias; Lymphomas; Metastatic cancers.
3) Storage disorders: Niemann-Pick disease; Gaucher disease.
4) Autoimmune disorders: SLE; Rheumatoid arthritis.
5) Drug reactions: Phenytoin; Allopurinol.

Splenomegaly
Causes of massive splenomegaly: CML, myelofibrosis, polycythemia vera, essential
thrombocythaemia, indolent lymphomas, hairy cell leukaemia, β-thalassaemia major, malaria,
visceral leishmaniasis, Gaucher disease.

Acute Lymphoblastic Leukemia/Lymphoma (ALL)

*Most common cancer of children.
*Leading cause of cancer deaths in children.
Cell of origin: Precursor B or T cells.
Age: <15 yrs.
Sex: Boys>Girls.
Types: B-ALLs (MC) & T-ALLs.
Genetic alterations: 1) T-ALLs: Gain of function mutations in NOTCH 1 gene.
2) B-ALLs: Loss of function mutations in PAX5, E2A, and EBF genes.
3) Hyperploidy is common.
Pathogenesis: Genetic aberrations block the maturation of lymphoid progenitors with their
proliferation and survival.
French American British (FAB) Classification:1) L1 2) L2 3) L3
C/P: 1) Fatigue and weakness; Recurrent infections with fever; Bleeding manifestations.
2) Bone pain; Generalized lymphadenopathy, splenomegaly, hepatomegaly, and testicular
enlargement.
3) Headache, vomiting and nerve palsies with CNS involvement.
Inv.: 1) Peripheral smear: i) Anemia, neutropenia and thrombocytopenia.
ii) Total leukocyte count is variable with many lymphoblasts.
2) Bone marrow: Hypercellular marrow showing many lymphoblasts with interspersed
macrophages imparts a ‘starry sky’ appearance.
*Lymphoblast: Immature cells having scant agranular basophilic cytoplasm and nuclei with
delicate and finely stippled chromatin and small nucleoli. The nuclear membrane is often
deeply subdivided, imparting a convoluted appearance.
i) L1: Blasts are small, homogeneous with scanty cytoplasm and indistinct nucleoli.
ii) L2: Blasts are large, heterogeneous with moderate cytoplasm and 1-2 nucleoli.
iii) L3: Blasts are large, homogeneous with moderate basophilic cytoplasm having prominent
vacuoles and 1-2 prominent nucleoli.
3) Cytochemistry: Lymphoblasts are myeloperoxidase negative and PAS positive.
4) Immunophenotyping:
i) B-ALL: Positive for CD19, CD20, CD21, CD22, CD10 and cytoplasmic heavy chain.
ii) T-ALL: Positive for CD2, CD3, CD5, and CD7.
Refresh Pathology, 5th Edition – Dr. Shiva M.D. 83

Prognosis: I) Worse prognosis with 1) Age < 2 yrs.

2) Presentation in adolescence or adulthood. 3) Peripheral blood blast counts >100,000/uL.
II) Favorable prognosis with 1) Age between 2 and 10 yrs. 2) A low white cell count.
3) Hyperdiploidy. 4) Presence of a t(12;21). 5) Trisomy of chromosomes 4, 7, and 10.

Acute Myeloid Leukemia (AML)

“A tumor of hematopoietic progenitors with the accumulation of immature myeloid blasts in
the marrow.”
Cell of origin: Hematopoietic progenitor cells.
Age: >60yrs (MC).
Genetic alterations:
1) Balanced chromosomal translocations such as t(8;21), inv(16) and t(15;17) are associated
with AML arising de novo in patients with no risk factors.
2) Deletions or monosomies involving chromosomes 5 and 7 are associated with AML that
follow MDS or exposure to DNA-damaging agents.
Pathogenesis: Genetic aberrations block the maturation of myeloid progenitors with their
proliferation and survival.
WHO Classification
I) AML with genetic aberrations (e.g., t(8;21); inv(16))
II) AML with MDS-like features
With prior MDS
AML with multilineage dysplasia
AML with MDS-like cytogenetic aberrations
III) AML, Therapy-related
IV) AML, Not Otherwise Specified
AML, minimally differentiated
AML without maturation
AML with myelocytic maturation
AML with myelomonocytic maturation
AML with monocytic maturation
AML with erythroid maturation
AML with megakaryocytic maturation
French American British (FAB) Classification
M0: AML, minimally differentiated
M1: AML without maturation
M2: AML, with maturation
M3: Acute promyelocytic leukemia
M4: Acute myelomonocytic leukemia
M5: Acute monocytic leukemia
M6: Acute erythroleukemia
M7: Acute megakaryocytic leukemia

C/P: 1) Fatigue and weakness; Recurrent infections with fever; Bleeding manifestations.
2) DIC may be seen in AML with t(15;17).
3) Gingival swelling or skin infiltration (leukemia cutis) may be seen in AML with
monocytic differentiation.
4) Occasionally, a localized soft tissue mass (myeloblastoma, granulocytic sarcoma or
chloroma) may be seen.
Undergraduate Pathology Series 84

Inv.: 1) Peripheral smear: i) Anemia, neutropenia, and thrombocytopenia.

ii) Total WBC count is variable with many myeloid blasts.
iii) Blasts are entirely absent in aleukemic leukemia.
2) Bone marrow: Hypercellular with many myeloid blasts (20% or more is diagnostic).
*Myeloblast: Immature cells having basophilic cytoplasm with fine azurophilic granules and
nuclei with delicate chromatin, and two to four nucleoli. Auer rods are needle-like
azurophilic granules, seen prominently in AML with the t(/15;17).
*Monoblast: Immature cells having abundant basophilic cytoplasm that may contain vacuoles
or few granules and eccentric and round nucleus with delicate chromatin and prominent one
or more nucleoli.
3) Cytochemistry: i) Myeloblasts are myeloperoxidase positive and PAS negative.
ii) Monoblasts are nonspecific esterase (NSE) positive, myeloperoxidase negative and PAS
negative.
Prognosis: 1) Good for AMLs with the t(15;17).
2) Bad for AMLs following MDS or genotoxic therapy or occur in older adults (>60 yrs).

Myeloproliferative Disorders (MPD)

Chronic myeloid leukemia; Polycythemia vera; Essential thrombocythemia; Primary
myelofibrosis; Systemic mastocytosis.

Chronic Myeloid Leukemia (CML)

“A Myeloproliferative disorder, characterized by the presence of a BCR-ABL fusion gene.”
Origin: Pluripotent hematopoietic stem cell.
Age: 50-60 yrs.
Genetic alterations:
1) Reciprocal t(9;22) translocation, designated as Philadelphia chromosome is most common.
2) t(9;22) leads to fusion of portions of the BCR gene on chromosome 22 and the ABL gene
on chromosome 9 generating BCR-ABL fusion gene.
Pathogenesis: Genetic aberrations drive the proliferation of granulocytic & megakaryocytic
progenitors, and also cause abnormal release of immature granulocytic forms into the blood.
Phases: Chronic (majority), accelerated and blastic.
I) Chronic phase: Remains stable for 3 to 5 yrs and is responsive to chemotherapy.
C/P: 1) Fatigue, weakness, weight loss and anorexia.
2) Splenomegaly, mild hepatomegaly and lymphadenopathy.
Inv.:
1) Peripheral smear:
i) Anemia, leucocytosis (>100,000/μl) with shift to left having few myeloblasts (<10%) and
thrombocytosis.
ii) Eosinophilia and basophilia (<20%) are noted.
2) Bone marrow: i) Hypercellular with elevated myeloid and megakaryocytic series of cells.
Erythroid series is either unaffected or may show mild suppression.
ii) Sea-blue histiocytes (scattered macrophages with abundant wrinkled green-blue
cytoplasm) with increased deposition of reticulin.
3) Karyotyping: Detects the BCR-ABL fusion gene.
II) Accelerated phase: Basophils (>20%) and blast cells (10 to 19%) increase in number and
shows no response to therapy.
Refresh Pathology, 5th Edition – Dr. Shiva M.D. 85

III) Blast phase: Transformation to an acute leukemia like picture having >20% blasts in
peripheral blood or bone marrow with or without a preceding accelerated phase. In 70% of
cases, blasts are of myeloid origin (myeloid blast crisis) and in the reminder the blasts are of
pre-B cell origin (lymphoid blast crisis).

Juvenile Myelomonocytic Leukemia (Juvenile

Chronic Myelomonocytic Leukemia)
*Grouped under myelodysplastic/myeloproliferative (MDS/MPD) neoplasms.
Age: <4yrs (MC).
Associations: Neurofibromatosis 1 (NF1).
Genetic alterations: Monosomy 7 may be associated. The Philadelphia (Ph) chromosome
and the BCR―ABL1 fusion gene are absent.
C/P: Failure to thrive, pallor, fever, hepatosplenomegaly, lymphadenopathy, skin rashes and
bleeding manifestations.
Inv.: i) Peripheral smear: Anemia, leukocytosis with neutrophilia and monocytosis and
thrombocytopenia; Few myeloblasts and nucleated red cells are noted.
ii) Bone marrow: Hypercellular marrow with increased myeloid series of cells.

Leukemoid Reaction
“Refers to the presence of markedly increased total leukocyte count (>50,000/μl) with
immature cells in peripheral blood resembling leukemia.”
Causes: Severe bacterial infections (pneumonia); Severe hemorrhage; Severe acute
hemolysis; Burns; Metastatic tumors of bone marrow.
Bone marrow: Hypercellular with increased myeloid series of cells.
Peripheral smear: Leukocytosis (>50,000/μl) with neutrophilia having shift to left.
Myeloblasts are usually absent. Basophilia is not seen.
C/P: Features of underlying disease.
Differential diagnosis: CML.

Chronic Myelogenous Leukemia Vs Leukemoid

Reaction
Feature CML Leukemoid reaction
Nature Neoplastic Reactive
Clinical picture Splenomegaly Features of underlying disease
Total leukocyte count >100,000/μl >50,000/μl
Myeloblasts Common Uncommon
Basophilia Present Absent
Eosinophilia Present Absent
Toxic granules in neutrophils Absent Present
LAP Score Low High
Philadelphia chromosome Present Absent
Undergraduate Pathology Series 86

Multiple Myeloma (Plasma Cell Myeloma)

*Most common plasma cell neoplasm.
Age: 65-70 yrs.
Sex: M>F
Origin: Post-germinal centre B cell.
Genetic alterations: Chromosomal translocations that fuse the IGH locus on chromosome 14
to proto-oncogenes such as the cyclin D1 gene.
Pathogenesis: Tumor cells and stromal cells of marrow produce cytokines (IL-6) which
mediate proliferation and survival of myeloma cells.
C/P: i) Skeletal: Pathologic fractures and chronic pain.
*Bones affected: Vertebral column (MC), ribs, skull, pelvis, femur, clavicle and scapula.
ii) Neurologic: Confusion, weakness, lethargy, constipation, and polyuria.
iii) Renal dysfunction (myeloma kidney).
iv) Recurrent bacterial infections.
v) Amyloidosis.
Inv.: i) Peripheral smear: Normocytic normochromic anemia; Rouleaux formation;
Moderate leukopenia; Thrombocytopenia.
*Plasma cell leukemia: Tumor cells within the peripheral circulation (rare).
ii) Bone marrow: a) Increased number of plasma cells.
b) Plasmablasts with vesicular nuclear chromatin and a prominent single nucleolus or bizarre,
multinucleated cells may be found.
c) Flame cells with fiery red cytoplasm or Mott cells with multiple grapelike cytoplasmic
droplets may be seen.
c) Globular inclusions such as Russel bodies or Dutcher bodies may be found in some cells.
**Russel bodies: Large homogeneous eosinophilic inclusions that represent marked
accumulation of newly synthesized immunoglobulins in the RER of some plasma cells.
iii) Blood: Increased levels of immunoglobulins; Hypercalcemia.
iv) Urine: Increased levels of light chains (Bence Jones proteins).
v) Radiology: Punched-out defects.
vi) Serum or urine electrophoresis: Abnormal protein spikes.
*The most common monoclonal Ig (M protein) is IgG.

Hodgkin Lymphoma (HL)

“Arises in a single node or chain of nodes and spreads first to anatomically contiguous
lymphoid tissues.”
WHO Classification: Nodular sclerosis; Mixed cellularity; Lymphocyte-rich; Lymphocyte
depletion; Nodular lymphocyte predominance.
Classic forms: Nodular sclerosis; Mixed cellularity; Lymphocyte-rich; Lymphocyte
depletion.
Genetic alterations: Mutations that activate transcription factor NF-kB in classic forms.
Risk factor: EBV infection in classic forms.
Types
I) Nodular sclerosis: Most common.
Age: Young adults.
Sex: M=F
EBV association: Uncommon.
Refresh Pathology, 5th Edition – Dr. Shiva M.D. 87

Morphology: Lymph node: Circumscribed nodules with bands of collagen; Background with
T cells, eosinophils, plasma cells and macrophages; R-S Cells: Lacunar type.
C/P: Painless lymphadenopathy; No systemic signs.
Stage: I or II

II) Mixed cellularity

Age: Young adults and older adults (>55yrs).
EBV association: 70%
Morphology: Lymph node: Diffuse effacement with T cells, eosinophils, plasma cells and
macrophages; R-S cells: Both diagnostic and mononuclear variants.
C/P: Painless lymphadenopathy with systemic signs (night sweats, fever, and weight loss).
Stage: III or IV

III) Lymphocyte rich

Age: Older adults.
Sex: M>F
EBV association: 40%
Morphology: Lymph node: Diffuse effacement with reactive lymphocytes;
R-S cells: Diagnostic and mononuclear variants.
C/P: Painless lymphadenopathy; No systemic signs.
Stage: I or II

IV) Lymphocyte depletion: Least common.

Age: Older adults.
Sex: M>F
Risk factors: HIV infection.
EBV association: 90%
Morphology: Lymph node: Paucity of lymphocytes and relative abundance of R-S cells;
R-S cells: Diagnostic and pleomorphic types.
C/P: Painless lymphadenopathy with systemic signs (night sweats, fever, and weight loss).
Stage: III or IV

V) Lymphocyte predominant
Age: <35 yrs.
Sex: M>F
Sites: Cervical and axillary lymph nodes.
EBV association: Absent.
Morphology: Lymph node: Nodular infiltration with small lymphocytes and macrophages;
R-S cells: Lymphohistiocytic (L&H) variants (popcorn cells).
C/P: Painless lymphadenopathy; No systemic signs.
Stage: I or II

Spread: Lymph nodes are involved first, then spleen, liver and finally bone marrow and
other tissues.

Reed-Sternberg cells (R-S cells)

“Neoplastic giant cells, essential for the diagnosis of Hodgkin lymphoma.”

Origin: Germinal center or post-germinal center B cells.
Undergraduate Pathology Series 88

Role: R-S cells of classical forms secrete various factors that induce the accumulation of
reactive lymphocytes, macrophages, and granulocytes.
Morphology:
Diagnostic R-S cells: Large cells having multiple nuclei or a single nucleus with multiple
nuclear lobes, each with a large inclusion-like nucleolus and abundant cytoplasm.
Variants:
1) Mononuclear variants: Contain a single nucleus with a large inclusion like nucleolus.
2) Lacunar variants: Contain folded or multilobate nucleus with abundant pale cytoplasm,
often disrupted during sectioning. Seen with nodular sclerosis type.
3) Lymphohistiocytic (L&H) variants: Contain polypoid nuclei with inconspicuous
nucleoli and moderately abundant cytoplasm. Seen with lymphocyte predominance type.
Mummification: Death of R-S cells in classical forms of Hodgkin lymphoma in which, they
shrink and become pyknotic.

Clinical Staging (Ann Arbor Classification)

*Involves physical examination, radiologic imaging of the abdomen, pelvis, and chest and
biopsy of the bone marrow.
*Important for prognosis and to guide therapy.
Stage I – Involvement of a single lymph node region or a single extralymphatic organ or site.
Stage II – Involvement of two or more lymph node regions on the same side of the
diaphragm alone or localized involvement of an extralymphatic organ or site.
Stage III – Involvement of lymph node regions on both sides of the diaphragm without or
with localized involvement of an extralymphatic organ or site.
Stage IV – Diffuse involvement of one or more extralymphatic organs or sites with or
without lymphatic involvement.
All stages are further divided on the basis of the absence (A) or presence (B) of systemic
manifestations (fever, night sweats and/or weight loss).
Inv.: FNAC and biopsy of involved tissues.

Burkitt Lymphoma
“Very aggressive tumor of mature B cells that usually arises at extranodal sides.”
Cell of origin: Germinal center B-cell.
Types: 1) African (endemic) Burkitt lymphoma.
2) Sporadic (nonendemic) Burkitt lymphoma.
3) HIV-associated Burkitt lymphoma.
Age: Endemic and sporadic: Children or young adults.
Risk factor: EBV infection (Endemic >HIV-associated>Sporadic).
Genetic alterations: Increased MYC protein levels with translocations of the MYC proto-
oncogene on chromosome 8 (MC: t(8;14)), promote growth and division of cells.
Morphology: 1) Affected sites are effaced by a diffuse infiltrate of intermediate sized
lymphoid cells with round to oval nuclei, coarse chromatin, several nucleoli and a moderate
amount of cytoplasm.
2) High mitotic index and numerous apoptotic cells.
3) Interspersed phagocytes with abundant clear cytoplasm give ‘starry sky’ pattern.
C/P: 1) Endemic type: Mass involving the mandible and of abdominal viscera (kidneys,
ovaries and adrenal glands).
2) Sporadic type: Mass involving ileocecum or peritoneum.
Refresh Pathology, 5th Edition – Dr. Shiva M.D. 89

10. Red Blood Cell Disorders

MCQs
1) What is the primary defect in sickle cell anemia. (April, 2024)
a) Defective hemoglobin synthesis b) Abnormal RBC morphology
c) Reduced RBC production d) Increased RBC destruction

2) Definitive indication for bone marrow aspiration. (April, 2024)

a) Aplastic anemia b) Sickle cell anemia c) Thalassemia d) Spherocytosis

3) Increased number of hypersegmented neutrophils are seen in the peripheral blood in. (Jan.
2024)
a) Iron deficiency anemia b) Megaloblastic anemia
c) Severe bacterial infections d) Aplastic anemia

4) FIGLU test is done in the diagnosis of. (Jan. 2024)

a) Acute myeloid leukemia b) Iron deficiency anemia
c) Megaloblastic anemia d) Polycythemia

5) The definite indication for bone marrow aspiration is. (Jan. 2024)
a) Aplastic anemia b) Sickle cell anemia c) Thalassemia d) Spherocytosis

6) The normal percentage of reticulocytes in adults is. (Jan. 2024)

a) 2-6% b) 8-10% c) 10-20% d) 0.2-2%

7) Sickle cell anemia can be confirmed by this test. (Jan. 2024)

a) Osmotic fragility test b) Schilling test
c) Sodium metabisulphite reduction test d) Benzidine test

8) The anticoagulant used for Westergren method of ESR is. (Jan. 2024)
a) EDTA b) Heparin c) Double oxalate d) Trisodium citrate

9) Electrophoresis is used in the diagnosis of. (April, 2023)

a) Spherocytosis b) Iron deficiency anemia c) Aplastic anemia d) Sickle cell anemia

10) Cabot rings in RBCs are seen in. (April, 2023)

a) Megaloblastic anemia b) Spherocytosis c) Sickle cell anemia d) Thalassemia

11) A dry tap in a bone marrow aspiration is usually seen in cases of. (Dec. 2022)
a) Hemolytic anemia b) Aplastic anemia
c) Iron deficiency anemia d) Metastatic deposits in bone

12) Coombs test is used in the diagnosis of. (Dec. 2023)

a) Erythroblastosis fetalis b) Beta thalassemia
c) Megaloblastic anemia d) Chronic myeloid leukemia