pathology histopathology exam md residency

1. Pre-leukemia
Dr. Akshay Agarwal
Moderator : Dr. Sangeeta Sharma

2. Introduction
Pre-leukemia are a group of disorders that most
commonly present with cytopenia(s) and has a
tendency to progress into acute leukemias unless
attended to clinically.
These include Myeloproliferative syndromes,
Marrow failure syndromes and congenital defects.

3. Disorders implicated in the
Pathogenesis of AML
Marrow Failure Syndromes Congenital Defects
Myelodysplastic Syndrome Down’s Syndrome
Fanconi’s Anemia Bloom Syndrome
Shwachman-Diamond Syndrome Monosomy 7 syndrome
Amegakaryocytic Thrombocytopenia Klinefelter Syndrome
Blackfan-Diamond Syndrome Turner Syndrome
Kostmann Agranulocytosis Neurofibromatosis
Familial Aplastic Anemia Congenital Dysmorphic syndromes
Dyskeratosis Congenita

4. Myelodysplastic Syndrome
• Derived from 2 words:
• Myelo – the Myeloid series
• Dysplastic – dysplasia meaning disordered
growth

5. Dysplastic features of
Erythroid series
• Megaloblastosis
• Karyorrhexis
• Nuclear irregularity
• Fragmentation or multinucleation
• Ring Sideroblasts
• Cytoplasmic Vacuoles
• PAS positivity

7. Iron stain

8. Dysplastic features of
Granulocytic series
• Hypogranular neutrophil
• Pseudo-Pelger Huet anomaly
• Bizzare segmented neutrophils

12. Dysplastic features of
Megakaryocytic series
• Micromegakaryocytes
• Non lobated or multiple nuclei

15. • The myelodysplastic syndromes (MDSs) are
disorders caused by a clonal expansion of
hematopoietic stem cells in which maturation is
abnormal (dysplastic) and production ineffective,
resulting in many cells being destroyed before they
reach the systemic circulation. Anemia typically
occurs, often accompanied by thrombocytopenia
and/or neutropenia. Some cases develop from
exposure to ionizing radiation or cytotoxic
chemotherapy, usually with alkylating agents, and in
these circumstances the bone marrow is
characteristically hypocellular and partially fibrotic

16. Classification
Sr.
No.
Disease Blood findings Bone marrow findings
1 Refractory cytopenias with unilineage dysplasia
(RCUD)
Uni / bi-cytopenias
No or rare blasts (<1%)
Unilineage dysplasia: >
10% of the cells in one
myeloid lineage
<5% blasts
<15% of erythroid
precursors are ring
sideroblasts
2 Refractory anemia with ring siderblasts (RARS) Anemia
No blasts
>15% of erythroid
precursors are ring
sinderblasts
Erythroid dysplasia only
<5% blasts
3 Refractory cytopenia with multilineage
dysplasia
(RCDM)
Cytopenia(s)
No or rare blasts
No Auer rods
<1 x 109/L monocytes
Dysplasia in >10% of the
cells in >2 myeloid
lineages
<5% blasts
No auer rods
+/- 15% ring sideroblasts

17. Sr.
No.
Disease Blood findings Bone marrow findings
4 Refractory Anemia with excess blasts -1
(RAEB-1)
Cytopenia
<5% blasts
No auer rods
<1 x 109/L monocytes
Unilineage or
multilineage dysplasia
5-9% blasts
No auer rods
5 Refractory Anemia with excess blasts -2
(RAEB -2)
Cytopenia
5-19% blasts
+/- auer rods
<1 x 109/L monocytes
Unilineage or
multilineage dysplasia
10-19% blasts
+/- auer rods
6. Myelodysplastic syndrome – unclassified
(MDS-U)
Cytopenia
<1% blasts
Unequivocal dysplasis
in ,10% cells
<5% blasts
7. MDS associated with isolated del (5q) Anemia
Normal to increased
platelet count
No or rare blasts
Normal to increased
megakaryocytes with
hypolobated nuclei
<5% blasts
Isolated del(5q)
No auer rods

18. Fanconi’s Anemia
• Autosomal recessive
• FA is the result of a genetic defect in a cluster of
proteins responsible for a DNA repair.

19. • As a result, the majority of FA patients develop
cancer, most often acute myelogenous leukemia
in 33%, and 90% develop bone marrow failure by
the age of 40.
• Most commonly M4 (Myelomonocytic) and M5
(monocytic)

20. • Significant risk of solid tumors like
• Hepatic tumors
• Squamous cell carcinoma
• 28% calculated risk by the age 40

21. Cell and Molecular Biology
• FA cells characteristically display a high frequency of
spontaneous chromosomal breakage and
hypersensitivity to DNA cross-linking agents.
• A subset of patients also present with biallelic
mutations in BRCA2 gene
• BRCA2 protein is important in the repair of DNA
damage.
• Thus, cells lacking BRCA2 inaccurately repair
damaged DNA and are hypersensitive to DNA
crosslinking agents.

22. Signs and Symptoms
• During childhood, short stature and skin pigmentation,
including café au lait spots, may become apparent.
• The first sign of a hematologic problem is usually
petechiae and bruises, with later onset of pale
appearance, feeling tired, and infections.
• Somatic abnormalities such as Skeletal (absent
thumbs, radial hypoplasia, scoliosis), genitourinary (
inferitility, horseshoe kidneys) , gastrointestinal,
cardiac and neurological may be present

23. Bilateral thumb hypoplasia

24. Treatment
• Administration of oxymetholone, corticosteroids
can show response in upto 70% patients but
many will become refractory after variable time
• Hematopoietic stem cell transplant is the
treatment of choice.

25. Dyskeratosis Congenita
• X-linked recessive, autosomal dominant and
autosomal recessive forms
• Bone marrow failure develops below the age of
20 years; 80-90% will develop bone marrow
abnormalities by age 30 yrs.

26. Cell and Molecular Biology
• Peripheral blood and bone marrow metaphases from
patients show unbalanced chromosomal
rearrangements in the absence of any clastogenic
agents
• Chromosome/genomic instability
• Defect in DKC1 gene leading to defective ribosome
production
• Hematopoietic progenitor studies have shown
reduced numbers of all progenitors.

27. Signs and Symptoms
• Characterized by the mucocutaneous triad of
abnormal skin pigmentation, nail dystrophy and
mucosal leucoplakia
• Bone marrow failure is the principal cause of
early mortality with an early predisposition to AML
• Non-cutaneous lesions such as short stature,
pulmonary disease, esophageal strictures have
been documented.

28. Treatment
• Transient successful responses to
granulocyte/macrophage colony-stimulating
factor, Granulocyte colony-stimulating factor and
erythropoietin have been reported
• Steroid oxymetholone
• Hematopoietic Stem cell transplant

29. Shwachman-Diamond
Syndrome
• Shwachman–Diamond syndrome is characterized
by an autosomal recessive mode of inheritance.
The gene that is mutated in this syndrome lies on
the long arm of chromosome 7 at cytogenetic
position 7q11
• rare congenital disorder characterized by
exocrine pancreatic insufficiency, bone marrow
dysfunction, skeletal abnormalities, and short
stature. After cystic fibrosis (CF), it is the second
most common cause of exocrine pancreatic
insufficiency in children.

30. Cell and Molecular biology
• The SDS gene is on 7q11.22 which is mutated in
90% patients.
• Its importance in indicated in RNA metabolism
and ribosome biogenesis.

31. Hematological
abnormalities
• Neutropenia - Low neutrophil counts leave patients at
risk of developing severe recurrent infections that
may be life-threatening.
• Anemia and thrombocytopenia may also occur. Bone
marrow is typically hypocellular, with maturation
arrest in the myeloid lineages that give rise to
neutrophils, macrophages, platelets and red blood
cells.
• Patients may also develop progressive marrow failure
or transform to acute myelogenous leukemia.

32. Treatment
• G-CSF
• Incidence of myelodysplasia and transformation
to AML is seen in 15-25%
• Particularly AML with erythroid differentiation: M6

33. Blackfan-Diamond
Syndrome
• Most pedigrees suggest an autosomal dominant
mode of inheritance with incomplete penetrance.
Approximately 10–25% of DBA occurs with a
family history of disease.
• Inherited pure red cell aplasia is a congenital
erythroid aplasia that usually presents in infancy.
• DBA causes anemia, without substantially
affecting the other blood

34. Diagnostic criteria
• Normochromic macrocytic Anemia
• Reticulocytopenia
• Normocellular bone marrow with selective
deficiency of erythroid precursors
• Decreased leukocyte counts with normal to
increased platelet counts
• Elevated erythrocyte deaminase activity

35. Kostmann Agranulocytosis
• Kostmann disease is a form of severe congenital
neutropenia which is a rare autosomal recessive
condition in which severe chronic neutropenia is
detected soon after birth.

36. Diagnosis
• An absolute neutrophil count chronically less than 500/mm3,
usually less than 200/mm3, is the main sign of Kostmann's.
• Other elements include the severity of neutropenia, and other
normal findings (hemoglobin, platelets)
• Isolated neutropenia in infants can occur in viral infections,
autoimmune neutropenia of infancy, bone marrow suppression
from a drug or toxin, hypersplenism, and passive placental
transfer of maternal IgG
• The bone marrow usually shows early granulocyte precursors,
but myelopoietic development stops at the promyelocyte and/or
myelocyte stage, so that few maturing forms are seen.

37. Bloom Syndrome
• are autosomal recessive disorder characterized
by short stature, caused by mutations in the BLM
gene leading to mutated DNA helicase protein
formation.

38. Signs and Symptoms
• short stature and a rash on the face
• moderate immune deficiency, characterized by
deficiency in certain immunoglobulin classes and
apparently leading to recurrent pneumonia and ear
infections.
• low birth weight
• Hypogonadism is characterized by a failure to
produce sperm, hence infertility in males, and
premature cessation of menses (premature
menopause)

39. • Thank you