Di Guglielmo syndrome

Table of Contents

Introduction

Di Guglielmo syndrome is a rare and aggressive hematological malignancy involving the erythroid (red blood cell) precursor cells.
It is a form of acute myeloid leukemia (AML) and is commonly referred to as erythroleukemia.
The disorder is characterized by uncontrolled proliferation of immature erythroblasts in the bone marrow.
Normal blood cell production is suppressed, leading to bone marrow failure.
It results in severe anemia, often accompanied by leukopenia and thrombocytopenia (pancytopenia).
In the FAB classification, it is classified as AML M6.
Di Guglielmo syndrome is most commonly seen in elderly patients and often develops secondary to myelodysplastic syndromes or prior chemotherapy.
It is considered a clinically aggressive leukemia with poor prognosis.
Early diagnosis is essential due to its rapid progression and severe clinical consequences.

Historical Background

Described by Giovanni Di Guglielmo, an Italian pathologist.
Initially recognized as a malignant disorder of erythropoiesis.
Later incorporated into leukemia classifications due to its aggressive nature.
In the FAB classification, it is labeled as AML M6 (Erythroleukemia).

Definition

Di Guglielmo syndrome is an acute leukemia characterized by excessive proliferation of immature erythroid precursor cells in the bone marrow, often associated with myeloblasts, resulting in bone marrow failure.

Classification

FAB Classification

AML M6 – Erythroleukemia

WHO Classification (Conceptual Understanding)

Considered under acute myeloid leukemia with erythroid predominance
Recognized as a biologically aggressive entity
Pure erythroid leukemia is separated due to its distinct behavior

Subtypes of Di Guglielmo Syndrome

1. Erythroid/Myeloid Type (M6a)

Erythroid precursors > 50% of total marrow cells
Myeloblasts ≥ 20% of non-erythroid cells
More common subtype

2. Pure Erythroid Leukemia (M6b)

Almost complete replacement of marrow by immature erythroblasts
Minimal or absent myeloblasts
Extremely aggressive with very poor prognosis

Pure erythroid leukemia is considered one of the most malignant leukemias.

Etiology and Risk Factors

The exact cause is unknown, but strong associations include:

Secondary leukemia following:
- Myelodysplastic syndrome (MDS)
- Aplastic anemia
Prior chemotherapy or radiotherapy
Exposure to:
- Benzene
- Ionizing radiation
Genetic instability
Elderly age group (commonly affected)

Most cases arise as transformation from pre-existing marrow disorders.

Pathogenesis

(Initiation → Cellular Transformation → Marrow Infiltration → Disease Evolution)

Initiating Event (Stem Cell Injury)

The disease begins with genetic damage to a pluripotent hematopoietic stem cell in the bone marrow.
This damage may be primary or secondary (after MDS, chemotherapy, or radiation exposure).
The affected stem cell acquires a selective growth advantage.

Genetic and Molecular Alterations

Mutations occur in genes regulating:
- Cell cycle control
- DNA repair
- Differentiation pathways
Common abnormalities include:
- Complex karyotypes
- Chromosome 5q and 7q deletions
- TP53 mutations
These alterations disrupt normal erythroid maturation.

Lineage Commitment Shift

The mutated stem cell shows preferential commitment toward the erythroid lineage.
Instead of producing mature red cells, differentiation is arrested at the erythroblast stage.
Immature erythroid precursors begin to accumulate abnormally.

Clonal Expansion of Abnormal Erythroblasts

The abnormal erythroid precursors undergo uncontrolled clonal proliferation.
These cells are:
- Morphologically abnormal
- Functionally ineffective
In some cases, myeloblasts also proliferate, producing the erythroid–myeloid subtype.

Replacement of Normal Marrow Architecture

Expanding malignant erythroblasts replace normal hematopoietic tissue.
Normal production of RBCs, WBCs, and platelets becomes progressively suppressed.
Bone marrow becomes hypercellular but nonfunctional.

Failure of Differentiation and Apoptosis Control

Normal apoptotic pathways fail to eliminate abnormal cells.
Immature cells survive longer and continue dividing.
This leads to ineffective erythropoiesis and marrow exhaustion.

Disease Progression

Persistent clonal dominance causes:
- Pancytopenia
- Bone marrow failure
In advanced stages, abnormal erythroid cells spill into the peripheral blood.
The disease progresses rapidly with aggressive clinical behavior.

End result: Pancytopenia with severe marrow dysfunction

Pathophysiology

Pathophysiology of Di Guglielmo Syndrome

(Cause → Cellular Events → Systemic Effects → Clinical Outcome)

Marrow-Level Disturbance

The bone marrow becomes overloaded with immature erythroid precursor cells.
These cells multiply rapidly but fail to mature into functional red blood cells.
Although the marrow appears hypercellular, it is functionally ineffective.

Failure of Effective Erythropoiesis

Immature erythroblasts dominate the marrow.
Normal RBC production is markedly reduced.
Result: Severe anemia despite increased cellularity.

Suppression of Other Blood Cell Lines

Excess erythroid cells physically crowd out normal precursors.
This leads to:
- ↓ White blood cell production → leukopenia
- ↓ Platelet production → thrombocytopenia

Imbalance Between Production and Destruction

High turnover of abnormal cells increases:
- LDH
- Uric acid
This creates metabolic stress on the body.

Systemic Hypoxia and Compensation

Reduced RBCs cause tissue hypoxia.
The body responds by:
- Increasing heart rate
- Increasing cardiac output
Clinically manifests as fatigue, breathlessness, and palpitations.

Immune and Hemostatic Failure

Leukopenia reduces immune defense → recurrent infections.
Thrombocytopenia impairs clot formation → bleeding and petechiae.

Progressive Bone Marrow Failure

Continuous ineffective hematopoiesis leads to:
- Pancytopenia
- Dependence on transfusions
In advanced disease, abnormal cells enter circulation.

End-Stage Physiological Consequence

Multi-lineage marrow failure
Systemic metabolic burden
Rapid clinical deterioration if untreated

Clinical Features

Symptoms Due to Anemia

Fatigue and weakness
Pallor
Dyspnea on exertion
Palpitations

Symptoms Due to Leukopenia

Recurrent infections
Fever
Poor wound healing

Symptoms Due to Thrombocytopenia

Petechiae
Easy bruising
Epistaxis
Gum bleeding

General/Systemic Features

Weight loss
Fever of unknown origin
Hepatosplenomegaly (variable)

Clinical presentation often mimics severe anemia or MDS, delaying diagnosis.

Laboratory Findings

Peripheral Blood Findings

Severe anemia
- Usually normocytic or macrocytic
Reduced hemoglobin level
Leukopenia or leukocytosis
- Often leukopenia due to marrow suppression
Thrombocytopenia
Presence of nucleated red blood cells (NRBCs)
Circulating immature erythroblasts
Marked anisopoikilocytosis
Reticulocyte count is usually low (ineffective erythropoiesis)

Key clue: Severe anemia with circulating erythroblasts

Bone Marrow Examination

Bone Marrow Aspiration / Biopsy

Hypercellular marrow
Erythroid precursors > 50% of total nucleated cells
Marked erythroid hyperplasia
Megaloblastoid changes in erythroblasts
Multinucleated and dysplastic erythroid cells
Suppression of normal myeloid and megakaryocytic lines
Increased myeloblasts in erythroid–myeloid type (M6a)

Diagnostic hallmark of the disease

Cytochemical Staining

PAS (Periodic Acid–Schiff):
- Strong block positivity in erythroblasts
Myeloperoxidase (MPO):
- Positive in myeloblasts (if present)
- Negative in pure erythroid leukemia

PAS positivity helps differentiate from other leukemias

Immunophenotyping (Flow Cytometry)

Erythroid Markers (Positive)

CD71 (transferrin receptor)
Glycophorin A
CD36

Myeloid Markers (Variable)

CD13
CD33
CD117

Confirms erythroid lineage involvement

Cytogenetic & Molecular Findings

Complex karyotype
Deletions of chromosome 5q and 7q
TP53 mutations
Monosomal karyotype (poor prognosis)

Associated with aggressive disease and poor outcome

Biochemical Findings

↑ Lactate dehydrogenase (LDH)
↑ Uric acid (high cell turnover)
Possible electrolyte imbalance (tumor lysis risk)

Coagulation Profile

Prolonged bleeding time (due to thrombocytopenia)
Increased risk of hemorrhage

These abnormalities are associated with poor prognosis.

Differential Diagnosis

Condition	Key Difference
Megaloblastic anemia	No malignant blasts
Myelodysplastic syndrome	Less aggressive, lower blast count
Other AML subtypes	Predominant myeloid lineage
Aplastic anemia	Hypocellular marrow

Treatment

Management follows AML protocols:

Definitive Treatment

Intensive combination chemotherapy
Hematopoietic stem cell transplantation (selected patients)

Supportive Care

RBC and platelet transfusions
Broad-spectrum antibiotics
Management of infections
Nutritional support

Pure erythroid leukemia responds poorly to therapy.

MCQs

1. Di Guglielmo syndrome is also known as:

A. Myeloblastic leukemia
B. Lymphoblastic leukemia
C. Erythroleukemia
D. Megaloblastic anemia

2. Di Guglielmo syndrome belongs to which leukemia group?

A. Acute lymphoblastic leukemia
B. Chronic myeloid leukemia
C. Acute myeloid leukemia
D. Chronic lymphocytic leukemia

3. In FAB classification, Di Guglielmo syndrome is:

A. M2
B. M4
C. M6
D. M7

4. The primary cell lineage involved in Di Guglielmo syndrome is:

A. Lymphoid
B. Myeloid
C. Erythroid
D. Megakaryocytic

5. Di Guglielmo syndrome was first described by:

A. Virchow
B. Ehrlich
C. Di Guglielmo
D. Hooke

6. The most common age group affected is:

A. Children
B. Adolescents
C. Young adults
D. Elderly

7. Di Guglielmo syndrome commonly develops secondary to:

A. Iron deficiency anemia
B. Myelodysplastic syndrome
C. Thalassemia
D. Hemophilia

8. The hallmark of Di Guglielmo syndrome is:

A. Lymph node enlargement
B. Predominant erythroid proliferation
C. Plasma cell excess
D. Megakaryocyte hyperplasia

9. Which bone marrow finding is diagnostic?

A. Hypocellular marrow
B. Normal cellularity
C. Hypercellular marrow with erythroid predominance
D. Fatty marrow

10. Percentage of erythroid precursors required for diagnosis is:

A. >10%
B. >30%
C. >50%
D. >80%

11. The pure erythroid leukemia subtype is:

A. M6a
B. M6b
C. M5
D. M7

12. In erythroid–myeloid type, myeloblasts are:

A. Absent
B. <5%
C. ≥20% of non-erythroid cells
D. >50%

13. Peripheral blood commonly shows:

A. Polycythemia
B. Pancytopenia
C. Thrombocytosis
D. Leukocytosis only

14. The most prominent clinical feature is:

A. Jaundice
B. Severe anemia
C. Hypertension
D. Edema

15. PAS stain in erythroblasts shows:

A. Negative reaction
B. Diffuse positivity
C. Block positivity
D. Ring positivity

16. PAS positivity helps identify:

A. Lymphoid lineage
B. Myeloid lineage
C. Erythroid lineage
D. Megakaryocytic lineage

17. Myeloperoxidase (MPO) is positive in:

A. Erythroblasts
B. Myeloblasts
C. Lymphoblasts
D. Plasma cells

18. Common erythroid marker in immunophenotyping is:

A. CD3
B. CD20
C. CD71
D. CD41

19. Glycophorin A is a marker of:

A. Myeloid cells
B. Lymphoid cells
C. Erythroid cells
D. Platelets

20. Cytogenetic abnormality commonly associated is:

A. t(9;22)
B. del(5q)
C. t(15;17)
D. t(8;21)

21. TP53 mutation indicates:

A. Good prognosis
B. Viral infection
C. Poor prognosis
D. Drug resistance only

22. Di Guglielmo syndrome results in:

A. Leukocytosis only
B. Isolated anemia
C. Bone marrow failure
D. Splenic rupture

23. Elevated LDH indicates:

A. Liver damage
B. High cell turnover
C. Renal failure
D. Iron deficiency

24. Uric acid levels are increased due to:

A. Reduced excretion
B. Cell lysis
C. Dehydration
D. Diet

25. The reticulocyte count is usually:

A. Increased
B. Normal
C. Decreased
D. Variable

26. Which of the following is a differential diagnosis?

A. Megaloblastic anemia
B. Sickle cell anemia
C. Iron overload
D. Polycythemia vera

27. Megaloblastoid changes are seen in:

A. WBCs
B. Platelets
C. Erythroblasts
D. Lymphocytes

28. Bone marrow cellularity in Di Guglielmo syndrome is:

A. Hypocellular
B. Normocellular
C. Hypercellular
D. Fatty

29. Which cell type is suppressed?

A. Erythrocytes
B. All hematopoietic lineages
C. Only lymphocytes
D. Only granulocytes

30. Thrombocytopenia causes:

A. Hypertension
B. Infections
C. Bleeding tendency
D. Polycythemia

31. Leukopenia leads to:

A. Anemia
B. Fever and infections
C. Bleeding
D. Thrombosis

32. The disease progression is:

A. Slow
B. Benign
C. Aggressive
D. Self-limiting

33. Treatment follows protocols of:

A. ALL
B. CML
C. AML
D. Aplastic anemia

34. Definitive treatment option in selected patients:

A. Splenectomy
B. Bone marrow transplantation
C. Iron therapy
D. Steroids alone

35. Supportive therapy includes:

A. Chemotherapy only
B. Blood transfusions
C. Surgery
D. Radiation alone

36. Prognosis of pure erythroid leukemia is:

A. Excellent
B. Good
C. Fair
D. Poor

37. Disease often evolves from:

A. Thalassemia
B. Iron deficiency anemia
C. Myelodysplastic syndrome
D. Sickle cell disease

38. Peripheral blood shows nucleated RBCs due to:

A. Increased erythropoiesis
B. Marrow stress
C. Marrow infiltration
D. Hemolysis

39. Which enzyme helps differentiate erythroid cells?

A. ALP
B. PAS
C. AST
D. ALT

40. Bone marrow failure leads to:

A. Polycythemia
B. Pancytopenia
C. Leukemoid reaction
D. Thrombocytosis

41. The most aggressive subtype is:

A. M6a
B. M6b
C. M3
D. M5

42. Common clinical triad includes anemia, infection, and:

A. Jaundice
B. Bleeding
C. Hypertension
D. Edema

43. Which lineage shows dysplasia?

A. Only lymphoid
B. Only myeloid
C. Predominantly erythroid
D. Megakaryocytic

44. The marrow appears active but ineffective due to:

A. Hypoplasia
B. Ineffective erythropoiesis
C. Iron deficiency
D. Hemorrhage

45. Di Guglielmo syndrome is best described as:

A. Chronic disorder
B. Benign marrow condition
C. Acute malignant disorder
D. Autoimmune disease

46. A key biochemical marker of tumor burden is:

A. Creatinine
B. LDH
C. Calcium
D. Sodium

47. The condition is often misdiagnosed as:

A. Iron deficiency anemia
B. Megaloblastic anemia
C. Polycythemia
D. Hemolytic anemia

48. The disease affects hematopoiesis by:

A. Enhancing maturation
B. Arresting differentiation
C. Increasing RBC lifespan
D. Improving oxygenation

49. Which organ is primarily affected?

A. Spleen
B. Liver
C. Bone marrow
D. Lymph node

50. The overall survival in Di Guglielmo syndrome is:

A. Long-term
B. Excellent
C. Short
D. Normal

Answer Key