9. Systemic mastocytosis (SM) with an excess of mast cells.
Of these disorders, CML is distinctive in that practically all cases have a BCR - ABL1 gene fusion that is present in almost all cells at diagnosis, and usually produces the Philadelphia chromo- some ( see Subheading 3). In all the other disorders, chromosom- ally abnormal clones are seen much more rarely; are usually present in a much lower proportion of the dividing cell population; and the abnormalities are much less disease-specifi c.
CMML is deemed to be one of the myelodysplastic syndromes (MDS) and therefore will not be described further in this chapter.
Excluding CML, the other disorders are collectively known as the myeloproliferative neoplasms (MPN, formerly called myelo- proliferative disorders). The predominant cell type that gives each MPN its name can change during the course of a disease, so, for example, PV can progress to PMF . And in addition to all these being serious disorders in their own right, there is also the further risk of transformation to acute myeloid leukemia in a small propor- tion of cases.
For chromosome studies of MPN, a bone marrow aspirate is necessary, as a blood sample is very unlikely to be informative. The only exception is PMF, in which the replacement of bone marrow by fi brotic tissue results in extramedullary hematopoiesis and this may result in clonal cells being in circulation. An aspirate is also best for CML, though at diagnosis up to 50 % of blood samples have produced divisions for chromosome study in the author’s laboratory. A blood sample is very unlikely to be informative in CML once treatment has started.
For more information than can be included in this chapter, the reader is referred to the online Mitelman database of chromosome aberrations and gene fusions in cancer [ 1 ], and the summaries in the online Atlas of genetics and cytogenetics in oncology and hematology [ 2 ], the World Health Organization (WHO) classifi - cation of tumors of hematopoietic and lymphoid tissues [ 3 ], and the publication by Heim and Mitelman [ 4 ]. All of these are slightly out of date, however, and the classifi cation of MPN has changed in recent years, so the next edition of the WHO publication should be consulted when it is published, for an update on the current understanding of these disorders.
2 Chromosome Studies in MPN
Chromosome studies in malignancy generally have two principal functions: to aid in diagnosis, and to indicate prognosis. MPN are a group of chronic disorders that can resemble relatively benign disorders, often secondary or reactive, so confi rming the diagnosis can be important. However, chromosomally abnormal clones are relatively rare in some kinds of MPN, occurring in about 15 % of PV, and 7 % of ET. Therefore, confi rming a diagnosis of these MPN is better done in other ways: for example, molecular tech- niques using multiplex polymerase chain reaction (PCR) for muta- tions in genes such as JAK2 , CALR , and MPL will give an informative result in over 90 % of cases. Additionally, PCR for BCR - ABL1 fusion is useful to distinguish between ET and CML. For these reasons, many cytogenetics laboratories no longer offer a routine diagnostic service for PV and ET; it is more effi cient to reserve chromosome studies for those rare cases where PCR has not been informative and the clinician still seeks diagnostic clarifi cation.
Although the incidence of cytogenetics abnormalities at diagnosis of PV is low (15 %), it does increase as the disease progresses, and in advanced, treated disease it has reached 80 % in some series. The most common abnormality at diagnosis is an interstitial deletion of the long arms of a chromosome 20 [ 5 ], and this was the second abnormality, after the Ph chromosome to be historically associated with a hematologic malignancy. The other common abnormalities, as listed in Table 1 , are +8, +9, gain of 1q and deletion of 13q. Two of these abnormalities are illustrated in Fig. 1 . Progression of PV to other diagnoses, such as PMF or AML, often involves the acqui- sition of further abnormalities, especially gain of 1q if not already present, but also deletion of 5q, 7q, or 17p.
It can be clinically diffi cult to distinguish between ET and CML, and so excluding the presence of the Ph chromosome or a BCR -
ABL1 fusion is diagnostically useful. In addition, if a del(5q13~q35) is detected , or any abnormality involving the MECOM gene at band 3q26.2, then a diagnosis of MDS becomes likely.
The same common abnormalities occur in ET as in PV [ 6 ] but at a lower incidence. ET is a relatively benign disease, with few cases progressing to overt leukemia; this is often associated with the acquisition of abnormalities such as deletion of 7q or 17p.
Unusual abnormalities can occur in ET as in all other disorders;
Figure 2 illustrates the common gain of 1q in a patient with ET , but arising from a translocation that is unusual in myeloid disorders.
2.1 Polycythemia Vera (PV)
2.2 Essential
Thrombocythemia (ET)
Table 1
Principal recurrent chromosome abnormalities in common myeloproliferative neoplasms
Diagnosis PV ET PMF HES SM
Approximate prevalence of visible, clonal chromosome abnormalities
15 % 5–7 % 30–50 % 15 % 35 %
Trisomy 1q X X X
del(7)(q21~36) X X X
Trisomy 8 X X X X
Trisomy 9 X X X X
del(13)(q13~q21) X X X
del(17)(p11~13) X X
i(17q) X X
del(20)(q11.2q13.1) and del(20)(q11.2q13.3) X X X X
Other See text See text
PV Polycythemia vera, ET Essential thrombocythemia, PMF Primary myelofi brosis, HES Hypereosinophilic syndrome, SM Systemic mastocytosis
Fig. 1 A karyogram showing 47,XY,+9,der(21)t(1;21)(q21;q22). This clone is from a patient with JAK2 +ve polycythemia vera. It has the gain of a chromosome 9 (trisomy 9) that is one of the most common fi ndings in this disorder. In addition, there is an unbalanced translocation between chromosomes 1 and 21 that has resulted in gain of the long arm of the chromosome 1 (+1q). Translocations resulting in +1q occur in a wide variety of malignancies
In PMF it is technically diffi cult to get an adequate bone marrow aspirate for a chromosome study but if material is obtained then an abnormal clone can be found in 30–40 % of cases, rising to 50 % and more in those with advanced disease.
Unlike other types of MPN, some chromosome abnormalities found at diagnosis of PMF do have a clear prognostic signifi cance.
Inversion of 3q, loss of a chromosome 5 or a 7, deletion of their long arms (5q-, 7q-), gain of a chromosome 8, translocations involving 11q, deletion of 12p, or any complex clone (Fig. 3 ) are regarded as high risk; other single abnormalities (the commonest being deletion from the long arm of chromosome 13 or 20) are standard risk [ 7 ].
Most common in PMF, but also occurring in other myeloid disorders, is an unbalanced whole arm translocation der(1;7) (q10;p10) , which in the presence of two normal #1 chromosomes results in a combination of two common abnormalities: gain of an extra copy of the long arms of chromosome 1 and loss of the long arms of a chromosome 7 (Fig. 4 ).
Twenty-three percent of cases of this rare disorder have been reported to have a chromosomally abnormal clone. The abnormalities have been much the same as those reported to occur in other MPN, with no one abnormality being specifi c for CNL, or 2.3 Primary
Myelofi brosis ( PMF )