In 1974, Van den Berghe et al. reported a group of three patients with refractory anemia and interstitial deletion of the long arm of chromosome 5. Such cases were later recognized as the “5q- syndrome”. Features of the syndrome included macrocytic anemia, low-normal leukocyte counts, and normal to elevated platelet counts. The BM showed erythroid hypoplasia, hypolobulated megakaryocytes, and a blast count <15% [7]. According to the French–American–British (FAB) cooperative group classification criteria, most of the patients with these characteristics pertain to the group of patients with refractory anemia [10].

It was not until the 2001 edition of the WHO classification that the 5q- syndrome was recognized as a unique and well-defined MDS subtype [11]. In addition to previously described characteristics of this syndrome, in this classification, the blast count threshold was redefined to <5%, and the absence of Auer roads was considered to define 5q- syndrome patients. In 2008, the subtype “MDS with isolated del(5q)” was introduced and the term 5q- syndrome remained restricted to a subset of cases within this category that presented with macrocytic anemia, normal or elevated platelet count, BM erythroid hypoplasia, and a blast count <5% in BM and <1% in peripheral blood (PB) [12]. In the 2017 WHO classification, these cases remained within the MDS with isolated del(5q) subtype. Additionally, the diagnosis of this subtype can be established even if there is one additional cytogenetic abnormality besides the del(5q), unless this abnormality is monosomy 7 or del(7q) [1,13]. This is based on data showing that there is no adverse effect of one chromosomal abnormality in addition to the del(5q) in such patients [14].

As mentioned previously, the overview of the next WHO classification has recently been published [2]. In this new proposal, MDS with isolated del(5q) has been renamed as “myelodysplastic neoplasm with low blast and isolated del(5q)” (abbreviated MDS-5q). The diagnostic criteria have not changed, and it is stated that although an SF3B1 or TP53 mutation (not multi-hit) may potentially alter the biology and/or prognosis of the disease, the presence of such mutations does not per se override the diagnosis of this entity. Regarding the ICC proposal for the classification of MDS, MDS with isolated del(5q) has been retained with no changes from the revised fourth edition of the WHO classification, although the name has been simplified to “MDS with del(5q)”. Similarly to the new WHO proposal, the ICC also specifies that TP53 mutations are admitted in this MDS subtype unless a multi-hit state is detected [8].

It is important to remark that although del(5q) is the most frequent cytogenetic alteration in MDS and is present in roughly 20% of cytogenetic abnormal cases, only about 5% are classified in the MDS-5q category. Features such as higher blast count, alterations in chromosome 7, or a multi-hit TP53 state impact disease prognosis and would reclassify these remaining patients into other, more aggressive, disease subtypes [2,8,15].

The changes in terms and inclusion criteria over time are produced as a consequence of the advances in technology and discoveries, which directly impact our knowledge and the management of this disease (Figure 1).

Conventional cytogenetics (CC) constitutes the gold standard for the genetic diagnosis and prognosis of MDS. However, fluorescence in situ hybridization (FISH) of 5q31 could be useful in cases without evidence of del(5q) by CC. When the presence of MDS-5q is suspected and/or if the cytogenetic study shows no metaphases or an aberrant karyotype with chromosome 5 is involved (no 5q deletion), it is recommended to perform FISH analysis [16,17]. Figure 2 shows the genetic studies available for the diagnosis and characterization of MDS-5q. During follow-up, genetics studies will be adapted to each patient, considering their comorbidities. A new BM aspiration, and the corresponding genetic study, will be performed on suspicion of disease evolution and no response to treatment. In the case of clonal evolution, the approach can be decided according to the general patient status.

The karyotype is a prognostic variable included in the International Prognostic Scoring System (IPSS) and the revised edition of the IPSS (IPSS-R) [18,19]. Del(5q) alone has always been considered a good prognostic variable and, in the IPSS-R, a concomitant cytogenetic alteration has been included. This change was based on a scoring system proposed by Schanz et al. based on an international data collection of 2902 patients [15]. Deletion 5q is a classical alteration detected in around 15–20% of MDS patients, with half being isolated, around 17% having an additional alteration, and 36% being part of a complex karyotype [3]. The prognostic impact of the accompanying abnormalities in del(5q) is difficult to determine because double abnormalities are highly variable. In 2011, Mallo et al. published an international collaborative study including a large series of del(5q) patients to determine the prognostic impact of adjunct prognostic abnormalities. The multivariate analysis showed that karyotype complexity was one of the main prognostic factors together with platelet count and BM blasts [14]. The good prognosis of del(5q) with one accompanying alteration was included in the MDS with the del(5q) category of the 2017 WHO classification, excluding cases harboring a chromosome 7 alteration [1].

4. Prognostic Impact of Somatic Mutations in MDS-5q