Myelodysplastic syndrome pathophysiology: Difference between revisions

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{{Myelodysplastic syndrome}}
{{Myelodysplastic syndrome}}
{{CMG}}
{{CMG}}; {{AE}} {{NM}}
 
==Overview==
==Overview==
Myelodysplastic syndrome comprises a heterogeneous group of clonal [[bone marrow]] disorders.<ref name="Librepathology2">Cytogenetics of myelodysplastic syndromes. Librepathology (2015). http://librepathology.org/wiki/index.php/Myelodysplastic_syndromes. Accessed on December 8, 2015</ref> Cytogenetic abnormalities involved in the pathogenesis of myelodysplastic syndrome include isolated deletion of 5q, monosomy 7, and monosomy 8.<ref name="Librepathology2">Cytogenetics of myelodysplastic syndromes. Librepathology (2015). http://librepathology.org/wiki/index.php/Myelodysplastic_syndromes. Accessed on December 8, 2015</ref> Myelodysplastic syndrome is associated with [[Fanconi syndrome]], [[Diamond-Blackfan syndrome|Diamond-Blackfan anemia]], and [[Shwachman-Diamond syndrome]].<ref name="Librepathology1">Associations of myelodysplastic syndromes. Librepathology (2015). http://librepathology.org/wiki/index.php/Myelodysplastic_syndromes. Accessed on December 8, 2015</ref> There are no characteristic findings of myelodysplastic syndrome on gross pathology. On microscopic histopathological analysis, [[dyserythropoiesis]], dysgranulopoiesis, and dysmegakaryocytopoiesis are findings of myelodysplastic syndrome.<ref name="Librepathology2">Histologic features of myelodysplastic syndromes. Librepathology (2015). http://librepathology.org/wiki/index.php/Myelodysplastic_syndromes. Accessed on December 8, 2015</ref>


==Pathophysiology==
==Pathogenesis==
MDS is thought to arise from [[mutation]]s in the [[hematopoietic stem cell|multi-potent bone marrow stem cell]], but the specific defects responsible for these diseases remain poorly understood.  [[Cellular differentiation|Differentiation]] of blood precursor cells is impaired, and there is a significant increase in levels of cell death [[apoptosis]] in bone marrow cells. Clonal expansion of the abnormal cells results in the production of cells which have lost the ability to differentiate. If the overall percentage of bone marrow [[Myeloblasts|blasts]] rises over a particular cutoff (20% for [[Myelodysplastic syndrome#WHO classification|WHO]] and 30% for [[Myelodysplastic syndrome#French-American-British (FAB) classification|FAB]]) then transformation to [[acute myeloid leukemia|leukemia]] (specifically [[acute myelogenous leukemia]] or AML) is said to have occurred. The progression of MDS to [[acute myeloid leukemia|leukemia]] is a good example of the ''[[Knudson hypothesis|multi-step theory of carcinogenesis]]'' in which a series of mutations occur in an initially normal cell and transform it into a [[cancer|cancer cell]].  The mechanism involved was initially thought to be an increase in apoptosis but, as the disease progresses, more cytogenetic damage occurs.  This eventually heralds a decrease in apoptosis leading to leukemia (showing abnormal clones with point mutations in Nras and AML1). 
Myelodysplastic syndrome comprises a heterogeneous group of clonal bone marrow disorders characterized by:<ref name="Corrêa de Souzade Souza Fernandez2014">{{cite journal|last1=Corrêa de Souza|first1=Daiane|last2=de Souza Fernandez|first2=Cecília|last3=Camargo|first3=Adriana|last4=Apa|first4=Alexandre Gustavo|last5=Sobral da Costa|first5=Elaine|last6=Bouzas|first6=Luis Fernando|last7=Abdelhay|first7=Eliana|last8=de Souza Fernandez|first8=Teresa|title=Cytogenetic as an Important Tool for Diagnosis and Prognosis for Patients with Hypocellular Primary Myelodysplastic Syndrome|journal=BioMed Research International|volume=2014|year=2014|pages=1–10|issn=2314-6133|doi=10.1155/2014/542395}}</ref>
 
*Various degrees of [[pancytopenia]]
While recognition of leukemic transformation was historically important (see [[Myelodysplastic syndrome#History|History]]), a significant proportion of the [[morbidity]] and [[death|mortality]] attributable to MDS results not from transformation to [[acute myeloid leukemia|AML]] but rather from the [[cytopenia]]s seen in all MDS patients. While [[anemia]] is the most common [[cytopenia]] in MDS patients, given the ready availability of [[blood transfusion]] MDS patients rarely suffer injury from severe [[anemia]]. However, if an MDS patient is fortunate enough to suffer nothing more than [[anemia]] over several years, they then risk [[iron overload#secondary iron overload|iron overload]]. The two most serious complications in MDS patients resulting from their [[cytopenia]]s are bleeding (due to lack of [[platelet]]s) or infection (due to lack of [[white blood cell]]s).
*Morphological and functional abnormalities of hematopoietic cells
 
*Increased risk of transformation into [[acute myeloid leukemia]]
The recognition of [[epigenetic]] changes in [[DNA]] structure in MDS has explained the success of two of three commercially available medications approved by the US FDA to treat MDS.  Proper [[DNA methylation]] is critical in the regulation of proliferation genes, and the loss of [[DNA methylation]] control can lead to uncontrolled cell growth, and [[cytopenias]].  The recently approved  DNA methyltransferase inhibitors take advantage of this mechanism by creating a more orderly [[DNA methylation]] profile in the [[hematopoietic stem cell]] [[nucleus]], and thereby restore normal blood counts and retard the progression of MDS to [[acute leukemia]].
 
Some authors have proposed that the loss of [[mitochondrial]] function over time leads to the accumulation of DNA [[mutation]]s in hematopoietic stem cells, and this accounts for the increased incidence of MDS in older patients.  Researchers point to the accumulation of [[mitochondrial]] [[iron]] deposits in the [[ringed sideroblast]] as evidence of [[mitochondrial]] dysfunction in MDS.<ref name="pmid12406866">{{cite journal |author=Cazzola M, Invernizzi R, Bergamaschi G, ''et al'' |title=Mitochondrial ferritin expression in erythroid cells from patients with sideroblastic anemia |journal=Blood |volume=101 |issue=5 |pages=1996–2000 |year=2003 |pmid=12406866 |doi=10.1182/blood-2002-07-2006}}</ref>


==Genetics==
Cytogenetic abnormalities involved in the pathogenesis of myelodysplastic syndrome include:<ref name="Librepathology2">Cytogenetics of myelodysplastic syndromes. Librepathology (2015). http://librepathology.org/wiki/index.php/Myelodysplastic_syndromes. Accessed on December 8, 2015</ref>
*Isolated deletion of 5q
*Isolated deletion of 17p
*Monosomy 7
*Monosomy 8
==Associated Conditions==
Myelodysplastic syndrome is associated with:<ref name="Librepathology1">Associations of myelodysplastic syndromes. Librepathology (2015). http://librepathology.org/wiki/index.php/Myelodysplastic_syndromes. Accessed on December 8, 2015</ref>
*[[Fanconi syndrome]]
*[[Diamond-Blackfan syndrome|Diamond-Blackfan anemia]]
*[[Shwachman-Diamond syndrome]]
==Gross Pathology==
There are no characteristic findings of myelodysplastic syndrome on gross pathology.
==Microscopic Pathology==
On microscopic histopathological analysis, characteristic findings of myelodysplastic syndrome include:<ref name="Librepathology2">Histologic features of myelodysplastic syndromes. Librepathology (2015). http://librepathology.org/wiki/index.php/Myelodysplastic_syndromes. Accessed on December 8, 2015</ref>
*[[Dyserythropoiesis]] (abnormal red blood cell formation)
*Dysgranulopoiesis (abnormal granulocyte formation)
*Dysmegakaryocytopoiesis (abnormal megakaryocyte formation)
====Dyserythropoiesis====
=====Nuclear Features=====
*Nuclear budding
*Intranuclear bridging (nuclei fail to separate post-division)
*Multinucleation
*Megablastoid changes (may be difficult to observe)
*[[Karyorrhexis]] (nuclear fragmentation)
=====Cytoplasmic Features=====
*[[Sideroblastic anemia|Ring sideroblasts]] (red blood cells are surrounded by a ring of iron)
*Vacuolization
====Dysgranulopoiesis====
=====Nuclear Features=====
*Nuclear hypolobation (pseudo Pelger-Huët)
*Nuclear hypersegmentation
=====Cytoplasmic Features=====
*Cytoplasmic hypogranulation
*Pseudo-Chediak-Higashi granules
*Small cytoplasmic size
====Dysmegakaryocytopoiesis====
=====Nuclear Features=====
*Micromegakaryoctes with hypolobated nuclei
*Non-lobated nuclei of any size
*Multiple widely separated nuclear lobes
==Immunohistochemistry==
On immunohistochemistry, characteristic findings of myelodysplastic syndrome include:
*CD34 positive- (myeloid) progenitor/precursor cells
*CD117 positive- (myeloid) progenitor/precursor cells, mast cells
*Tryptase positive- mast cells, immature basophils
*CD61 positive- megakaryocytes
*CD42b positive- megakaryocytes
*CD20 positive- B cells
*CD3 positive- T cells
*Glycophorin A positive- erythroid cells
*Glycophorin C positive- erythroid cells
==References==
==References==
{{reflist|2}}
{{reflist|2}}
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Latest revision as of 13:36, 12 April 2018

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Nawal Muazam M.D.[2]

Overview

Myelodysplastic syndrome comprises a heterogeneous group of clonal bone marrow disorders.[1] Cytogenetic abnormalities involved in the pathogenesis of myelodysplastic syndrome include isolated deletion of 5q, monosomy 7, and monosomy 8.[1] Myelodysplastic syndrome is associated with Fanconi syndrome, Diamond-Blackfan anemia, and Shwachman-Diamond syndrome.[2] There are no characteristic findings of myelodysplastic syndrome on gross pathology. On microscopic histopathological analysis, dyserythropoiesis, dysgranulopoiesis, and dysmegakaryocytopoiesis are findings of myelodysplastic syndrome.[1]

Pathogenesis

Myelodysplastic syndrome comprises a heterogeneous group of clonal bone marrow disorders characterized by:[3]

Genetics

Cytogenetic abnormalities involved in the pathogenesis of myelodysplastic syndrome include:[1]

  • Isolated deletion of 5q
  • Isolated deletion of 17p
  • Monosomy 7
  • Monosomy 8

Associated Conditions

Myelodysplastic syndrome is associated with:[2]

Gross Pathology

There are no characteristic findings of myelodysplastic syndrome on gross pathology.

Microscopic Pathology

On microscopic histopathological analysis, characteristic findings of myelodysplastic syndrome include:[1]

  • Dyserythropoiesis (abnormal red blood cell formation)
  • Dysgranulopoiesis (abnormal granulocyte formation)
  • Dysmegakaryocytopoiesis (abnormal megakaryocyte formation)

Dyserythropoiesis

Nuclear Features
  • Nuclear budding
  • Intranuclear bridging (nuclei fail to separate post-division)
  • Multinucleation
  • Megablastoid changes (may be difficult to observe)
  • Karyorrhexis (nuclear fragmentation)
Cytoplasmic Features

Dysgranulopoiesis

Nuclear Features
  • Nuclear hypolobation (pseudo Pelger-Huët)
  • Nuclear hypersegmentation
Cytoplasmic Features
  • Cytoplasmic hypogranulation
  • Pseudo-Chediak-Higashi granules
  • Small cytoplasmic size

Dysmegakaryocytopoiesis

Nuclear Features
  • Micromegakaryoctes with hypolobated nuclei
  • Non-lobated nuclei of any size
  • Multiple widely separated nuclear lobes

Immunohistochemistry

On immunohistochemistry, characteristic findings of myelodysplastic syndrome include:

  • CD34 positive- (myeloid) progenitor/precursor cells
  • CD117 positive- (myeloid) progenitor/precursor cells, mast cells
  • Tryptase positive- mast cells, immature basophils
  • CD61 positive- megakaryocytes
  • CD42b positive- megakaryocytes
  • CD20 positive- B cells
  • CD3 positive- T cells
  • Glycophorin A positive- erythroid cells
  • Glycophorin C positive- erythroid cells

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 Cytogenetics of myelodysplastic syndromes. Librepathology (2015). http://librepathology.org/wiki/index.php/Myelodysplastic_syndromes. Accessed on December 8, 2015
  2. ↑ 2.0 2.1 Associations of myelodysplastic syndromes. Librepathology (2015). http://librepathology.org/wiki/index.php/Myelodysplastic_syndromes. Accessed on December 8, 2015
  3. ↑ Corrêa de Souza, Daiane; de Souza Fernandez, Cecília; Camargo, Adriana; Apa, Alexandre Gustavo; Sobral da Costa, Elaine; Bouzas, Luis Fernando; Abdelhay, Eliana; de Souza Fernandez, Teresa (2014). "Cytogenetic as an Important Tool for Diagnosis and Prognosis for Patients with Hypocellular Primary Myelodysplastic Syndrome". BioMed Research International. 2014: 1–10. doi:10.1155/2014/542395. ISSN 2314-6133.


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