||9861/3 AML with mutated NPM1; AML with mutated CEBPA; Acute myeloid leukaemia, NOS
||9874/3 AML with maturation
||9867/3 Acute myelomonocytic leukaemia
||9983/3 Refractory anaemia with excess blasts
|| Isochromosome 4p10 results in the loss of the long arm (4q) and duplication of the short arm (4p) of one chromosome 4 leading to partial 4q monosomy and partial 4p trisomy.
This rare abnormality has been reported in different phenotypes of solid tumors (adenocarcinoma, squamous cell carcinoma, melanoma, leiomyosarcoma, astrocytoma, medulloblastoma), usually in complex karyotype, and in various types of haematological disorders: Acute Myeloid Leukaemia (AML), Myelodysplastic Syndromes (MDS), Hodgkin and non Hodgkin lymphoma, myeloma.
Whereas in solid tumors or lymphoid neoplasia this abnormality is observed as a part of complex karyotypes, in myeloid malignancies it is only reported as an isolated supernumerary i(4p), except for one case with a double supernumerary i(4)p (Soriani et al., 2010), assuming the fact that the gain of isochromosome 4p may be a sufficient event for the pathogenesis of myeloid neoplasia. To date, only 7 cases have been documented in myeloid neoplasms, all reported either in AML or MDS (Hagemeijer et al., 1981; Hoo et al., 1995; Chen et al., 1999; Soriani et al., 2010; Desangles et al., 2014; Richebourg et al., 2016).
According to literature, there is a male predominance since 6 of the 7 cases are male patients and, among AML cases, it seems there is an association with a monocytic differentiation of blast cells.
Because of its rarity, no specific prognosis significance is associated with the presence of a supernumerary isochromosome 4p in myeloid malignancies.
|| +i(4p) G- banding - Courtesy Steven Richebourg|
|| Acute Myeloid Leukemia, Myelodysplastic syndrome|
|Phenotype / cell stem origin
|| 7 cases are available. The WHO/FAB classification was: RAEB-T/RAEB-2 : 2 cases, M4-AML : 3 cases, M2-AML : 1 case, NOS-AML : 1 case|
Table 1: Cases of i(4)(p10) reported in myeloid neoplasms (M : male; F : Female; CR : complete remission)
|Epidemiology|| +i(4p) as sole cytogenetic aberration represents less than 1% of cases of myeloid malignancies. The median age is 60 years old (32-79), the M/F sex ratio is 6:1|
|Clinics|| Supernumerary i(4p) cases can be divided into 2 distinct subgroups based on the presentation : AML and MDS. AML cases fit into the FAB classification of M2 or M4 AML, except for one case with no bone marrow evaluation. The 2 MDS cases fit into the 2008 WHO classification of RAEB-2 (Swerdlow et al., 2008).|
|Cytology|| No particular cytologic feature is associated with the presence of a supernumerary i(4p). The median white blood cell count is 6.95 (2.7-49). Thrombocytopenia is reported in 5 of the 7 cases. Among AML cases, it seems there is an association with a monocytic differentiation: indeed three of the four precedent AML cases were classified into acute myelomonocytic leukemia (Hagemeijer et al., 1981; Hoo et al., 1995; Soriani et al., 2010) and in one case, despite the absence bone marrow evaluation and the absence of peripheral monocytosis, the expression of CD4 and CD11c on blast cells demonstrated by flow cytometry was consistent with this observation (Richebourg et al., 2016). No specific morphologic feature is described in MDS cases. |
Cytometry No common phenotype arises from the 3 cases with phenotypic data published.
|Genes|| The 2 AML cases with molecular characterization demonstrate the same profile with the presence of NPM1 mutation and the absence of FLT3-ITD mutation (NPM1+/FLT3-ITD-).|
|Treatment|| Therapeutic data are available for 3 of the 5 AML cases: the patients received idarubicine + cytarabine based induction chemotherapy followed either by no consolidation or consolidation by chemotherapy or autologous peripheral blood stem cell transplantation. |
Therapeutic data are available for one of the two MDS cases: the patient received azacytidine and achieved transfusion independence.
|Prognosis|| 100% of AML patients with follow up data achieved a complete remission. Only 1 case of relapse is reported, 1 year after the diagnosis. Interestingly, this case presented a double supernumerary i(4p) at diagnosis, which could be considered as a clonal evolution and may have had an impact on the risk of relapse. |
Since no specific prognostic significance is attached to the presence of supernumerary i(4p), this abnormality should be included into the intermediate cytogenetic subgroups according to the ELN (Döhner et al., 2010) and R-IPSS (Greenberg et al., 2012) classifications for AML and MDS respectively.
| A group of previously not recognized cytogenetic abnormalities in myeloid hematological malignancies|
| Chen Z, Richkind K, Roherty S, Velasco J, Lytle C, Brothman AR, Sandberg AA|
| Cancer Genet Cytogenet 1999 Sep;113(2):162-5|
| Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European LeukemiaNet|
| Döhner H, Estey EH, Amadori S, Appelbaum FR, Büchner T, Burnett AK, Dombret H, Fenaux P, Grimwade D, Larson RA, Lo-Coco F, Naoe T, Niederwieser D, Ossenkoppele GJ, Sanz MA, Sierra J, Tallman MS, Löwenberg B, Bloomfield CD; European LeukemiaNet|
| Blood 2010 Jan 21;115(3):453-74|
| Increased expression of fibroblast growth factor receptor 3 in CD34+ BCR-ABL+ cells from patients with chronic myeloid leukemia|
| Dvorak P, Dvorakova D, Doubek M, Faitova J, Pacholikova J, Hampl A, Mayer J|
| Leukemia 2003 Dec;17(12):2418-25|
| Revised international prognostic scoring system for myelodysplastic syndromes|
| Greenberg PL, Tuechler H, Schanz J, Sanz G, Garcia-Manero G, Solé F, Bennett JM, Bowen D, Fenaux P, Dreyfus F, Kantarjian H, Kuendgen A, Levis A, Malcovati L, Cazzola M, Cermak J, Fonatsch C, Le Beau MM, Slovak ML, Krieger O, Luebbert M, Maciejewski J, Magalhaes SM, Miyazaki Y, Pfeilstöcker M, Sekeres M, Sperr WR, Stauder R, Tauro S, Valent P, Vallespi T, van de Loosdrecht AA, Germing U, Haase D|
| Blood 2012 Sep 20;120(12):2454-65|
| Cytogenetic follow-up of patients with nonlymphocytic leukemia|
| Hagemeijer A, Hählen K, Abels J|
| II Acute nonlymphocytic leukemia|
| Supernumerary isochromosome 4p in ANLL-M4 myelomonocytic type is associated with favorable prognosis|
| Hoo JJ, Gregory SA, Jones B, Szego K|
| Cancer Genet Cytogenet 1995 Feb;79(2):127-9|
| Double supernumerary isochromosome 4p in acute myelomonocytic leukemia|
| Soriani S, Marbello L, Colosimo A, Scarpati B, Grillo G, Cesana C|
| Leuk Res 2010 Dec;34(12):e342-4|