Pathology of Myelodysplastic Syndromes Associated With Isolated Del (5q)

This article focuses on the features of myelodysplastic syndromes (MDS) associated with isolated del(5q) as they relate to pathology. MDS with del(5q) continues to be "the only cytogenetic or molecular genetic abnormality that defines a specific MDS subtype." ^[1] ​ ^[2]

MDS with isolated del(5q) is one of a group of clonal disorders of myeloid stem cells that are characterized by ineffective hematopoiesis, manifested in morphologic dysplasia of hematopoietic precursors and characterized by one or more peripheral blood cytopenias. In patients with MDS with isolated del(5q), the morphologic dysplasia is most evident as an increase in the number of small, hypolobated megakaryocytes, as seen in the following image.

Pathology of Myelodysplastic Syndromes Associated With Isolated Del (5q). Normocellular bone marrow with increased numbers of small, hypolobated megakaryocytes. In this case, granulocytes and erythroid precursors show normal maturation (bone marrow aspirate, Wright-Giemsa, ×1000).

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Affected patients typically present with marked macrocytic anemia with or without other cytopenias and a normal or increased platelet count in the peripheral blood. Thus, its features comprise macrocytic anemia, unilineage erythroid dysplasia, thrombocytosis, and elevated hypolobulated micromegakaryocytes. ^[3] This form of MDS is defined in part by the presence of deletion in the long arm of chromosome 5 (del(5q)) as the sole cytogenetic abnormality. The 2016 revision to the World Health Organization (WHO) classification of MDS updated the category of MDS with del(5q) to include cases with an additional cytogenetic abnormality (excluding monosomy 7 and excluding del(7q)). ^{[1, 3, 4, 5]} ​ In cases of MDS with isolated del(5q), there are less than 5% blasts in the bone marrow and less than 1% blasts in the peripheral blood. In addition, Auer rods are absent. ^[6] Progression to acute myeloid leukemia (AML) is less common in MDS with isolated del(5q) than in other forms of MDS. ^[7]

Del(5q) is one of the most frequent abnormalities identified in MDS, ^[8] including many cases of MDS associated with previous chemotherapy or with other cytogenetic abnormalities. ^[9] In cases in which the patient has received previous chemotherapy, MDS in which del(5q) is the sole abnormality should be classified as a therapy-associated myelodysplastic syndrome (t-MDS). The prognosis for patients with t-MDS is not as favorable as the prognosis for patients with MDS with isolated del(5q). If additional cytogenetic abnormalities are present and the patient has no history of chemotherapy, the disease should be classified on the basis of morphologic parameters.

As with other forms of MDS, MDS with isolated del(5q) is predominantly a disease of elderly persons; the median age of patients at the time of presentation is between 65 and 70 years. As described in van den Berghe et al's original series ^[10] and as defined by the World Health Organization (WHO) classification of tumors of hematopoietic and lymphoid tissues, ^[3]

See also Pediatric Myelodysplastic Syndromes, Pathology of Acute Myeloid Leukemia With Myelodysplasia-Related Changes, Pathology of Therapy-Related Myeloid Neoplasms (t-MNs), Pathology of Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN), and Pathology of Acute Myeloid Leukemia Not Otherwise Specified (AML NOS).

In general, patients with myelodysplastic syndrome (MDS) typically present with features associated with their cytopenia(s), such as fatigue, easy bleeding or bruising, or infection. Patients with MDS with isolated del(5q) typically present with persistent anemia that has no other identifiable cause. The neutrophil count is usually normal, and the number of platelets may be normal or even increased. The anemia often progresses to transfusion dependence. Transformation to acute leukemia is uncommon in patients with this subtype of MDS, but patients sometimes succumb to complications related to transfusion-associated hemosiderosis. ^[11] In addition, patients with isolated del(5q) who require red blood cell transfusion during their disease course appear to be at higher risk of death from cardiovascular disease. ^[12]

Until relatively recently, there were limited therapeutic options capable of altering the course of MDS. However, the use of lenalidomide, a thalidomide analogue, has improved outcomes in MDS patients, particularly those with del(5q). Lenalidomide use leads to complete morphologic and cytogenetic remission in a significant number of cases. ^[13]

Patients with MDS with isolated del(5q) present with a striking macrocytic anemia and usually have normal or increased numbers of platelets in the peripheral blood. Leukocytopenia may be present; however, the number of granulocytes is typically normal. Bone marrow aspirates show predominantly megakaryocytic dysplasia with many small, hypolobated megakaryocytes (see the images below).

Pathology of Myelodysplastic Syndromes Associated With Isolated Del (5q). Small, hypolobated megakaryocytes are typical of myelodysplastic syndrome with isolated del(5q) (bone marrow aspirate, Wright-Giemsa, ×1000).

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Pathology of Myelodysplastic Syndromes Associated With Isolated Del (5q). Normocellular bone marrow with trilineage hematopoiesis, including many megakaryocytes. Scattered hypolobated forms are present (bone marrow biopsy specimen, hematoxylin-eosin, ×1000).

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Erythroid hypoplasia may be present. Erythroid and granulocytic dysplasia, if present, is generally mild. The bone marrow biopsy and clot sections generally show normocellular or mildly hypercellular bone marrow with numerous small megakaryocytes, sometimes forming clusters. ^[14] Although some early case series included patients with blast counts greater than 5%, ^[15] such cases are better classified as either myelodysplastic syndrome with excess blasts (5-19% blasts) or acute leukemia (20% or more blasts).

There are no specific immunophenotypic findings associated with myelodysplastic syndrome (MDS) with isolated del(5q). However, immunohistochemical studies that assess for the presence of CD61 or factor VIII on bone marrow core biopsy specimens or clot sections may reveal the small, hypolobated megakaryocytes associated with this disease. Immunohistochemical studies for CD34 should reveal that few (< 5%) mononuclear cells are immunoreactive.

Flow cytometric analysis may be of value in establishing a diagnosis of MDS. However, its utility in specifically establishing a diagnosis of MDS with isolated del(5q) has not been demonstrated.

As its name implies, in cases of myelodysplastic syndrome (MDS) with isolated del(5q), cytogenetic studies demonstrate a deletion of the long arm of chromosome 5 (del(5q)) as the sole cytogenetic abnormality. In patients with myelodysplasia, deletions of 5q show considerable heterogeneity. Several genes localized to the long arm of chromosome 5q influence hematopoiesis and could be involved in the pathogenesis of the syndrome.

Research aimed at delineating the specific chromosomal bands or genes that give rise to this form of MDS (the so-called common deleted region) have narrowed the region involved to band 5q32-5q33 ^[16] in the 5q- syndrome. A distinct region at 5q31 is frequently found to be deleted in patients who have del(5q) associated with other chromosomal abnormalities or who have previously undergone chemotherapy. ^[13]

A gene involving ribosome biogenesis, RPS14, has been implicated in the pathogenesis of this syndrome, although this defect alone may not be sufficient to fully account for the spectrum of clinical and pathologic changes seen in the disease. ^[17] It is possible that the phenotype of MDS in patients with del(5q) is influenced by deletion of multiple genes in this chromosome region. ^[18]

For patients with myelodysplastic syndrome (MDS) with isolated del(5q), prognoses had been considered to vary widely. In cases that fit the classic description of 5q- syndrome, the prognosis was described as favorable, with prolonged median survival and a lower rate of transformation to acute myeloid leukemia (AML), as compared with other forms of MDS. The presence of granulocytic dysplasia had been shown to be an independent adverse prognostic factor. ^[19]

Relatively more recent studies indicate the MDS with del(5q) has a similar prognosis regardless of whether it occurs in isolation or with another low-risk cytogenetic aberration. ^{[1, 4]} The prognostic category remains good for patients with MDS and chromosomal categories of del(5q) as well as those with double aberrations that include del(5q). Although the median survival time in the good prognostic category is 48.5 months, ^{[1, 3, 5]} patients with isolated del(5q) generally have a median survival of 9 years and their condition rarely leads to development of AML. ^[3]

In a 2023 report from the European MDS registry that analyzed 2008-2019 data regarding the cause of death and excess mortality in those with lower-risk MDS, individuals with isolated del(5q) who required red blood cell transfusion during their disease course were at greater risk of fatal cardiovascular disease. ^[12]

The use of the immunomodulatory drug lenalidomide (an analogue of thalidomide) has been promising in the treatment of MDS, particularly MDS with del(5q). ^{[20, 21, 22]} Benefits have been seen in patients with del(5q) as the sole abnormality, as well as in patients with del(5q) in association with other cytogenetic abnormalities. In over half of the patients with MDS with del(5q) who were treated with lenalidomide, transfusion independence was achieved, and a subset of patients exhibited a complete cytogenetic response.

However, a study by Mallo et al revealed the importance of a low baseline platelet count, karyotypic complexity, and TP53 mutational status for response to lenalidomide treatment. ^[22] In general, TP53 mutations are associated with aggressive disease in MDS; those with del(5q) appear to have a poorer response to lenalidomide. ^{[1, 2, 3]} Thus, it is recommended that patients with MDS with isolated del(5q) undergo evaluation for TP53 mutation to identify a potential adverse prognostic subgroup. ^{[1, 2, 5]}