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1354 Part X: Malignant Myeloid Diseases Chapter 87: Myelodysplastic Syndromes 1355

Erythroblasts may resemble megaloblasts that have nuclear-cytoplasmic but all clonal myeloid diseases, including AML, chronic myelogenous
maturation asynchrony, nuclear fragmentation, or cytoplasmic nuclear leukemia, and CMML may have within their spectrum of expression
remnants. The asynchrony is manifest morphologically by nuclear occasional cases with intense myelofibrosis. Like numerous other
immaturity with prominent euchromatin in cells with more advanced epiphenomena that occur in the expression of hematopoietic stem cell
cytoplasmic maturation. This pattern is referred to as megaloblastoid diseases, extending the general classifications is not warranted.
erythropoiesis (see Fig. 87–3I). Erythroid aplasia seen in occasional Increased angiogenesis is a feature of MDS. Microvessel den-
cases results in a hypocellular marrow. 220 sity increases with more advanced stages of the disease. Mast cell
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Pathologic sideroblasts may be identified when the marrow is frequency and mast cell tryptase activity are highly correlated with
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stained with Prussian blue stain (see Fig. 87–3J and K). The sideroblasts microvessel density. Circulating endothelial cells are also increased
include erythroblasts with an increased number and size of siderosomes in concentration in patients with MDS and their concentration is cor-
(cytoplasmic ferritin-containing vacuoles), referred to as intermediate related with marrow neoangiogenesis (microvessel density). 276
sideroblasts, or erythroblasts with mitochondrial iron aggregates that
take the form of a partial or complete circumnuclear ring of iron glob-
ules, referred to as ring sideroblasts. Macrophage iron often is increased. THERAPY-RELATED MYELODYSPLASTIC
Ring sideroblasts are uncommon or present only in very low propor- SYNDROMES
tions in clonal myeloid disorders other than RA.
Therapy-related MDS are increasing in frequency as the use of inten-
Granulopoiesis sive chemotherapy and radiation increases in other solid tumors and
Granulocytic hyperplasia is frequent. 228,234,260,261 Marrow monocytes may lymphoma. 277–284 These cases have a poor prognosis and are not included
be increased in number. Abnormalities of granulocytes include hypogran- in either the original IPSS or the revised IPSS-R. Cellular abnormalities
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ulation, a monocytoid appearance of neutrophilic granulocytes, and the of chromosomes 5, 7, and 8 are common in these cases. MDS following
acquired Pelger-Huët nuclear abnormality of neutrophils. 232,263 Progranu- breast cancer is associated with older age, presence of other cancers, and
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locytes and myelocytes may be increased. The proportion of blast cells is multiple first-degree relatives with cancer. As compared to patients
not increased in clonal hemopathies that are categorized as RA (defined with myeloma or germ cell tumors, patients with lymphoma under-
as <5 percent); although, a blast percentage of greater than 2 percent going autologous stem cell transplantation have a higher incidence of
should be considered oligoblastic leukemia and is recognized as having treatment-related MDS. In this group, pretransplantation therapy, total-
prognostic risk. Marrow biopsy may show abnormal localized immature body irradiation, and other transplantation-related factors play a role, as
precursors (ALIPs), 264,265 which are clusters of immature myeloid, CD34+ do inherited polymorphisms in genes governing drug metabolism and
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cells located centrally rather than subjacent to the endosteum. These DNA repair. Therapy-related MDS has been reported after high-dose
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clusters of atypical cells are present in almost all cases of oligoblastic leu- melphalan for myeloma treatment, particularly in patients treated with
kemia where blast cells compose 3 percent or more of nucleated mar- lenalidomide. 288
row cells (RAEBs) and in approximately one-third of patients with RA, Accelerated telomere shortening precedes development of ther-
suggesting these patients have a disorder closely approaching oligoblastic apy-related myelodysplasia after autologous transplantation for
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leukemia. Patients with this abnormality are more prone to develop overt lymphoma. Treatment-related MDS is managed as are de novo cases
AML. Vascular endothelial growth factor and its receptor are expressed of MDS, but are very refractory to treatment. AHSCT can result in
on cells forming ALIP clusters and have been proposed as providing an long-term disease-free survival, but most patients with therapy-related
autocrine loop to promote leukemia progenitor cell formation. The MDS are not candidates because of advanced age, comorbidities, or the
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number of plasma cells may be slightly increased. Marrow basophilia or inability to control the primary cancer. 290
eosinophilia occurs in approximately one in seven patients and is associ-
ated with a higher probability of evolution to AML. 268
DIAGNOSTIC CRITERIA FOR
Thrombopoiesis MYELODYSPLASTIC SYNDROMES
Megakaryocytes are present in normal or increased numbers. 234,260,261
Micromegakaryocytes (dwarf megakaryocytes) may occur. 261,269,270 The current diagnostic criteria for MDS are well defined, but can be dif-
Megakaryocytes with unilobed or bilobed nuclei may be increased, and ficult to apply in practice. Many diagnostic elements, such as the extent
hypersegmented and hyposegmented megakaryocytes may be present of dysplasia in the marrow and the quantification of blasts, are subjec-
(see Fig. 87–3L). Clusters of megakaryocytes may be seen. Megakary- tive measures associated with high rates of interobserver variability. 291,292
ocytes may be distributed laterally from their usual parasinusoidal Current guidelines require a blast proportion of 5 percent or greater in
location. 271 the marrow as definitive evidence for MDS absent other criteria and
this threshold distinguishes RAEB from other MDS subtypes. However,
Fibrosis and Angiogenesis more than 2 percent marrow blasts is abnormal and likely evidence of
An increase in reticulin and collagen fibers of varying degree is common oligoblastic leukemia. This lower threshold is recognized as prognos-
(approximately 15 percent of cases), especially in oligoblastic myeloge- tically adverse in the IPSS-R. Even when dysplasia is clearly present,
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nous leukemia. When fibrosis is prominent, the disorder can resemble benign and potentially reversible causes of morphologic abnormalities
primary myelofibrosis, although, in contrast to the latter, splenomegaly must be excluded (Table 87–3). The presence of acquired chromoso-
usually is not marked and mutations of CALR, JAK2, or MPL, genes fre- mal abnormalities is indicative of clonal hematopoiesis and can aid in
quently truncated in primary myelofibrosis and ET, are extremely rare. the diagnostic evaluation. Specific karyotypes found more commonly
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Because primary myelofibrosis is an oligoblastic leukemia with striking in patients with MDS serve as presumptive evidence of the disorder in
dysmorphogenesis of cells, some confusion in classification with other patients with clinically meaningful cytopenias and insufficient dyspla-
fibrotic clonal myeloid disorders may occur. Marrow fibrosis is cor- sia to meet the morphologic criteria for diagnosis. Somatic mutations,
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related with higher blast counts and poor-risk cytogenetics. Some which are more frequent than chromosomal abnormalities may soon be
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physicians have proposed a category of myelofibrotic myelodysplasia, formally used in this manner to aid the diagnosis of MDS.

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