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Keywords:

  • isochromosome 17q;
  • myelodysplastic syndrome;
  • chronic myeloproliferative disorder;
  • pseudo-Pelger-Huet neutrophils

Abstract

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. References

A clinicopathologic study was performed on 15 patients with haematological malignancies in which isochromosome 17q [i(17q)] was the sole structural chromosome abnormality identified in bone marrow. The data indicated that an isolated i(17q) is associated with a distinct type of mixed chronic myeloproliferative/myelodysplastic disorder with an aggressive clinical course. The patients ranged in age from 37 to 83 years (median 60) with a M:F ratio of 3:1. All cases were chronic myeloid disorders with mixed proliferative and dysplastic features, making classification difficult. 11 patients tested for BCR/ABL gene fusion were normal. A low bone marrow blast count (<5%) at presentation was a typical finding. All cases had severe myeloid dysplasia which included non-segmented neutrophils and an increase in the monocyte/macrophage lineage. Fluorescence in situ hybridization (FISH) analysis of one case showed the i(17q) to involve all myeloid lineages, but not the lymphocytes. For cases with complete follow-up (n = 11) the median survival was 2.5 years (range 0.83–5.25) and 64% progressed to AML prior to death. The following features were identified which defined the haematological disorder associated with an isolated i(17q): (1) adult patient, (2) chronic myeloid disorder with clonal involvement of all myeloid lineages, (3) mixed chronic myeloproliferative/myelodysplastic features, (4) severe hyposegmentation of neutrophil nuclei, (5) prominence of the monocyte/macrophage lineage, (6) high risk for progression to AML, and (7) median survival of 2.5 years.

There are a growing number of haematological disorders being identified in which a specific cytogenetic abnormality is associated with a characteristic collection of clinical and histologic features. Examples of these ‘cytogenetic syndromes’ include t(9;22)(q34;q11) (Champlin, 1985), t(15;17) (Rowley, 1990), inv(16)(p13q22) (Bitter et al, 1984), 5q− (Sokel et al, 1975) and, in children, monosomy 7 (Sieff et al, 1981). It is presumed that these cytogenetic abnormalities give clues to the underlying molecular defects producing the phenotypes seen, and several of these disorders are now understood at the molecular level. It is probable that future disease classifications will be based on genetic abnormalities, and that this will improve our ability to give accurate prognoses and develop more effective treatment strategies.

We questioned whether an isolated isochromosome 17q [i(17q)] in haematological disorders is associated with distinctive clinical and morphologic features. The formation of an i(17q) results in loss of the p arm and duplication of the q arm, leaving the affected cell with a single copy of 17p, and three copies of 17q (Fig 1). i(17q) has been reported in solid tumours (Biegel et al, 1989; Kakati et al, 1976; Oshimura & Sandberg, 1975) as well as in various types of haematological diseases: acute and chronic myeloid leukaemia (Borgstrom et al, 1982; Engel et al, 1975; Mitelman et al, 1973), acute and chronic lymphoid leukaemias (Nowell & Finan, 1977), and Hodgkin's and non-Hodgkin's lymphoma (Kaneko et al, 1982; Mark, 1977). Although i(17q) is the most common isochromosome seen in malignant haematological diseases (Mitelman, 1988), it is usually part of a complex karyotype, and is rarely seen as a sole anomaly.

image

Figure 1. . Partial karyotype of an isolated i(17q) (from case 4 of this study). Left: Chromosome 17 pair with normal (N) and rearranged [i(17q)] chromosomes. Each p and q arm is labelled. Right: A schematic of the same chromosome pair showing the approximate location of the breakpoint for isochromosome formation at 17p11.2 ([LEFTWARDS ARROW]), and location of probes used in FISH analysis for i(17q) mutation in this paper. Red probe is at 17p13.3 (R). Green probe is at 17q21.1 (G).

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In this paper we present findings from a clinicopathologic study of 15 patients with haematological malignancies in which i(17q) was the sole structural chromosome abnormality identified. Our findings indicate that an isolated i(17q) does produce a distinct haematological disorder which may represent a new cytogenetic syndrome.

METHODS

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. References

Cytogenetic karyotype files from the Mayo Clinic (1985–97) were searched for haematological cases that had i(17q) as the only structural chromosome abnormality. 36 cases were identified (representing approximately 1% of all myeloid cases); 15 had sufficient material available for review and are reported here. For each case the patient record was reviewed for pertinent clinical information, and the peripheral blood smear, bone marrow aspirate smear and bone marrow biopsy were analysed. For most cases bone marrow aspirates were cytochemically stained for iron, α-naphthyl butyrate esterase and chloroacetate esterase, and bone marrow biopsies were stained for reticulin and CD68 (PGM1) (Li et al, 1996). Cytogenetic analysis was done on bone marrow aspirates using standard methods. Fluorescence in situ hybridization (FISH) for identification of BCR/ABL gene fusion (Dewald et al, 1993) was performed in 11 cases with material available. In one case (case 9) the peripheral blood smear was studied for the presence of i(17q) using FISH as follows: the slide was stained with Wright-Giemsa and digital images of individual cells were taken before the slide was destained for 16 h with methanol. The slide was then treated sequentially with 2× sodium saline citrate (1 h at 37°C), 0.005% pepsin/0.01 n HCl (10 min at 37°C), phosphate-buffered saline (21°C for 5 min), 1% formaldehyde (21°C for 5 min), phosphate-buffered saline (21°C for 5 min) and an alcohol dilution series (70–85–100% each for 2 min). The slide was then incubated at 80°C for 3 min and a hybridization mixture added (7 μl hybridization mix, 2 μl H2O, 1 μl probe), before being coverslipped, sealed, and incubated for 16 h at 37°C. The coverslip was then removed, the slide washed in 0.4× sodium saline citrate (70°C for 2 min), and an anti-fade agent added. The same cells that had been previously photographed were then identified using a fluorescence microscope and new digital images were taken. The probe used was from Vysis Incorporated (Downers Grove, Ill.) and contained a DNA fragment directly labelled with rhodamine (red) that binds the Miller-Dieker locus at 17p13.3, and a DNA fragment fragment directly labelled with FITC (green) that binds the retinoic acid receptor alpha locus at 17q21.1 (Fig 1).

RESULTS

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. References

Clinical (1, 2Tables I and II)

Table 1. Table I. Clinical information and classification for patients with an isolated i(17q). LTF, lost to follow-up. ND, not done.* Death from surgical complications while disease chronic.† Increase in total WBCs and/or platelets in peripheral blood.‡ Decrease in total WBCs and/or platelets in peripheral blood.Thumbnail image of
Table 2. Table II. Blood and bone marrow features of patients with an isolated i(17q). ®, Ringed sideroblasts. ND, not done.* Bone marrow smear contained only peripheral blood, therefore no marrow differential count is included.† Hyposegmented nuclei.‡ Small, mononuclear.Thumbnail image of

The patients ranged in age from 37 to 83 years (median 60 years). 11 patients were male and four were female. All patients presented with abnormalities of the complete blood count (CBC): 14 with anaemia, 12 with leucocytosis, one with leucopenia, four with thrombocytosis, and eight with thrombocytopenia. 10 patients had organomegaly. All cases were classified as chronic myeloid malignancies at initial presentation, although case 15 had subsequently evolved to acute myeloid leukaemia (AML) prior to evaluation at our institution.

Bone marrow

The bone marrow was 100% cellular in 13/15 cases; the remaining two had <10% cellularity with extensive bone marrow fibrosis. Granulocytic hyperplasia with dysgranulopoiesis was a prominent and consistent finding in all cases. In each case we observed severely dysplastic pseudo-Pelger-Huet (PPH) neutrophils with hyposegmentation of nuclei such that many were non-segmented (Fig 2), although the classic bilobed ‘pince-nez’ variety was also present. The non-segmented PPH cells in each case ranged from few to all of the neutrophils. Other manifestations of neutrophil dysplasia included hypogranularity, ringed nuclei, and giant metamyelocytes. The blast count ranged from 0 to 5% in the 14 chronic cases, and was 40% in the one case which was acute at the time of our review.

image

Figure 2. . Dysplastic cells observed in cases of isolated i(17q) including a hypogranular, non-segmented PPH neutrophil (left) and a cell of ‘mixed’ neutrophil/monocyte lineage (right).

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Each case had an increase in the monocyte/macrophage cell lineage, and many had immature monocytes which were difficult to identify by Wright-Geimsa staining. When available, cytochemical staining with α-naphthyl butyrate esterase allowed for recognition of these cells and a combined α-naphthyl butyrate esterase/chloroacetate esterase stain showed four cases to have dysplastic cells with hybrid monocyte-granulocyte features (Fig 2). In 10 cases the bone marrow biopsies were stained with a monocyte/macrophage-associated monoclonal antibody, CD-68 (PGM1); in nine of these there was increased staining of both monocytes and macrophages (the remaining case was severely hypocellular and difficult to interpret).

Dysplasia was noted in other cell lines also. Each case had dysplastic small mononuclear megakaryocytes; some also had large bizarre multinucleated forms. In the two cases with hypocellular marrows, dysplasia of the megakaryocyte line was the most striking feature. In many cases dysplastic nucleated red blood cells including ringed sideroblasts were seen in small numbers (i.e. <15% of RBC precursors). Hypogranulated basophils and eosinophils were also noted in some cases.

Peripheral blood (Table II)

Examination of the peripheral blood smear was informative and essential to the evaluation process. In all cases the spectrum of cell types identified in the peripheral blood reflected that seen in the bone marrow smear. However, the number of peripheral cells did not always correlate with the bone marrow cellularity, as several cases with ‘packed’ bone marrows presented with cytopenias, and the two cases with hypocellular marrows presented with elevated blood counts.

In each case the same dysplastic features seen in the bone marrow were present in the peripheral blood. Granulocytic dysplasia was mostly manifested as hypogranular and PPH neutrophils. Immature and dysplastic monocytes were present and could be easily confused with neutrophil precursors. Two cases had a dimorphic population of RBCs. Dysplastic platelets were seen in most cases as hypogranular or giant forms.

A granulocytic ‘left shift’ was present in 13 cases. The blast count in the chronic cases ranged from 0 to 6%, and was 69% in the one acute case. All cases had a monocytosis; 14/15 had a peripheral monocyte count >1 × 109/l, and the remaining case had a relative monocytosis in a background of severe pancytopenia. Eight cases had basophilia (range 2–12%), and three cases had eosinophilia (range 7–18%).

Cytogenetics/FISH

An i(17q) was the only structural cytogenetic abnormality identified in all cases (Table III). Four cases had additional numerical abnormalities: case 12 had trisomy 13, case 6 had −Y, case 15 had monosomy 7 at presentation and subsequently developed an additional del 6, and case 1 evolved to include +19, −21 and −22. This aneuploidy did not appear to alter the phenotypes of these cases, as they were similar to the remaining cases. 11 patients were tested for the BCR/ABL gene fusion by FISH and were normal, thus eliminating a masked Philadelphia chromosome of chronic myelogenous leukaemia as a diagnostic consideration.

Table 3. Table III. Cytogenetic analysis of bone marrow in patients with isolated i(17q). Cases that were studied more than once have karyotypes listed in chronological order. All cases contained i(17q) as the only structural abnormality. Cases 1, 6, 12 and 15 contained additional numerical abnormalities.Thumbnail image of

For one case (no. 9), the peripheral blood smear was studied using FISH to identify individual cells containing i(17q) (Fig 3), and 150 cells were examined in total. All lymphocytes observed (small and large) contained two normal number 17 chromosomes, whereas all myeloid cells observed contained an i(17q). The myeloid cells examined included blasts, PPH neutrophils, hybrid neutrophil/monocyte cells, monocytes, basophils, eosinophils and a megakaryocyte.

image

Figure 3. . Fluorescence in situ hybridization (FISH) analysis for i(17q) abnormality in peripheral blood from case 9. Probe locations are shown in Fig 1. Normal cells contain two p and two q arms (signals seen as two red and two green), whereas cells containing i(17q) have one p and three q arms (signals seen as one red and three green). (a, above) Left: A lymphocyte (1), a PPH neutrophil (2), and a basophil (3). Right: The corresponding FISH study showing i(17q) in the neutrophil and basophil. (b, below) Above: a ‘normal-appearing’ monocyte (A), a non-segmented neutrophil (B), and a blast (C). Below: The corresponding FISH study showing i(17q) in all three cells.

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Survival and progression of disease (Table I)

A complete record from diagnosis to death due to disease was available for 11/15 patients. Of the remaining patients, one remained alive at the time of writing, one patient died as a complication of surgery, and two were lost to follow-up. Survival was considered as the time from initial diagnosis of a chronic myeloid disorder to death from disease. A survival curve for the initial 11 patients is shown in Fig 4. By standard Kaplan-Meier analysis, the median survival was 2.5 years (range 0.83–5.25 years). 82% of the patients were dead by 4 years. 7/11 patients (64%) with complete follow-up progressed to AML before death.

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Figure 4. . Survival curve for patients with isolated i(17q). The single patient who remained alive at the time of writing is not shown. Two patients were lost to follow-up and are indicated by points not associated with steps in the curve.

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Classification (Table I)

Each case was clearly a chronic myeloid malignancy at presentation; however, further separation into a chronic myeloproliferative disorder (CMPD) or myelodysplastic syndrome (MDS) was difficult in all cases. Therefore we attempted to determine which chronic myeloid process was ‘dominant’ by selecting what we felt to be the most pertinent and prominent clinical and cell morphology features in each case. Features favouring CMPD included organomegaly, an elevated WBC count, and a hyperplastic fibrotic bone marrow. MDS features included cytopenias and prominent pan-dysplasia in association with a hypercellular marrow. The best descriptive diagnosis in these cases was often either CMPD with excessive dysplasia or MDS with excessive fibrosis. 14/15 cases could also have been accepted as chronic myelomonocytic leukaemia (CMML) if the standard criteria were used (i.e. peripheral blood monocyte count >1 × 109/l); however, only five of the cases had a striking monocytosis with counts >5 × 109/l. Case 15 was seen at our institution as AML, FAB-M2, although previous material (not available for our review) had been reported as ‘MDS vs CMPD’. Case 14 also had concurrent mast cell disease present in the bone marrow, confirmed by a tryptase immunoperoxidase stain.

DISCUSSION

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. References

The presentation of patients with an isolated i(17q) does not easily fit into the accepted classification scheme for haematological malignancies. It is a disease of adult patients, and presents as a chronic myeloid disorder with mixed CMPD/MDS features including severe hyposegmentation of neutrophil nuclei and a prominence of the monocyte/macrophage lineage. The patients have a high risk for progression to AML and a relatively short median survival.

To our knowledge, this report is the largest series which reviews patients with haematological diseases and i(17q) as the sole structural abnormality. Fewer than 50 other cases have been described in the English medical literature, and the results are difficult to compare because of case selection and inconsistent reporting of clinical and histologic information. Previous series, however, have suggested that isolated i(17q) cases are chronic myeloid abnormalities that have a high rate of progression to AML (Becher et al, 1990; Sole et al, 1993; Weh et al, 1990).

Several morphological features were common to all of our cases. Each had a population of severely dysplastic non-segmented PPH-type neutrophils which, in our experience, is uncommon in either MDS or CMPD. Other studies have shown an association between severely hyposegmented PPH neutrophils and heterozygous loss of 17p (the so-called 17p− syndrome) (Fugazza et al, 1996; Jary et al, 1997; Lai et al, 1995; Pedersen & Kerndrup, 1990; Sessarego & Ajmar, 1987). In these studies the majority of cases contained complex phenotypes, adding extra variables to the evaluation of a phenotype associated with a single abnormality. Our study supports the association of PPH neutrophils with 17p loss using cases without additional identifiable structural chromosome abnormalities. One could also speculate that it is not 17p loss, but rather the presence of the 17q arm in triplicate, that causes the neutrophil phenotype seen in our i(17q) cases. We feel that this is not the case for two reasons: (1) PPH neutrophils are not seen in trisomy 17 (Sessarego & Ajmar, 1987) and (2) in studies of the 17p− syndrome, PPH neutrophils were seen in cases where 17p was lost by a variety of mechanisms, many of which did not result in additional copies of 17q. In our study, peripheral blood cells from a single case were examined by FISH for the presence of i(17q), and all hyposegmented neutrophils observed contained the abnormality. There were, unfortunately, no normally segmented neutrophils present for evaluation in this case.

Another consistent morphologic feature in our isolated i(17q) cases was an increase in the monocyte/macrophage lineage. Many patients also had a population of mononuclear cells which were difficult to classify by Wright-Giemsa stain and these were shown to be either dysplastic monocytes, or cells of mixed monocyte/neutrophil lineage which exhibit a combined butyrate esterase/chloroacetate esterase cytochemical staining pattern. The FISH analysis done in one of our cases revealed that all monocytes observed were part of the i(17q) clone, including both the obviously dysplastic forms and, surprisingly, those that appeared normal on the Wright-Geimsa stain.

In the case available for investigation by FISH analysis, all myeloid cell lines observed contained the abnormal i(17q) and appeared to be part of the neoplastic clone, whereas none of the lymphocytes were affected. This reinforces the finding that the isolated i(17q) mutation is a clonal abnormality affecting an early myeloid stem cell.

Chronic myeloid malignancies are historically divided into two broad categories: (1) chronic myeloproliferative disorders, characterized by proliferation of one or more myeloid cell lines with elevated blood counts, enlarged spleen and fibrotic marrow, and (2) myelodysplastic syndromes, characterized by dysplasia of one or more myeloid cell lines with associated cytopenias. Some patients, however, have disorders that defy traditional classification, as they clearly have features overlapping both entities. All 15 of our isolated i(17q) cases exhibited a mixture of myeloproliferative and myelodysplastic characteristics, making classification difficult.

‘Mixed’ disorders have been inconsistently recognized, but have recently received attention in the literature as some authors have attempted to define morphologic subsets of disorders within this group (Neuwirtova et al, 1996; Oscier, 1996; Singh et al, 1994). Typical attempts at diagnoses have included BCR-negative chronic myeloid leukaemia (CML), atypical CML, and CMML. Criteria have been proposed using morphologic features to separate ‘mixed’ cases into these categories (Neuwirtova et al, 1996; Oscier, 1996), although it is evident that significant overlap between CMPD and MDS remains. None of our cases could be strictly classified using the criteria stated in these studies. In addition, the prognostic significance of these proposed classifications remains to be determined. Mixed cases where the predominant features are myelofibrosis, no organomegaly, and dysplasia have also been reported (Pagliuca et al, 1989; Sultan et al, 1981). The fact that organomegaly was identified in the majority of the isolated i(17q) cases, and that i(17q) was not identified in a series of cases with MDS and fibrosis (Pagliuca et al, 1989), highlights the probable heterogenous origin of cases with mixed MDS/CMPD features. Therefore we feel that the mixed MDS/CMPD category is a collection of disorders, with isolated i(17q) cases representing a distinct subset within this group. It seems likely that accurate classification within this difficult diagnostic category will require knowledge of the molecular defects involved. To accurately define and diagnose a ‘cytogenetic syndrome’, however, it is important to have methods with sufficient sensitivity to detect the DNA rearrangements, especially in less than optimal specimens such as fibrotic bone marrows. Should classic genetics on bone marrow aspirates, biopsies or peripheral blood fail to identify an abnormality in cases highly suspicious for isolated i(17q) by morphology, interphase FISH can easily be performed on peripheral blood or bone marrow with excellent sensitivity.

From a clinical standpoint, the aim of accurate classification is to predict a clinical course and provide an indication of prognosis. The prognosis of the ‘mixed’ chronic myeloid malignancies as a group is not known. Based on a small number of patients, Shepherd et al (1987) suggested that these disorders have an overall worse prognosis than the average CMPD or MDS. The survival in our group of isolated i(17q) cases was uniformly poor (median 2.5 years) when compared with CML (median ~5 years) (Kantarjian et al, 1993) and MDS with similar blast counts (CMML): median 3 years, refractory anaemia (RA): median 5 years, and RA with ringed sideroblasts (RARS): median 6 years) (Greenberg et al, 1997). In addition, our isolated i(17q) cases had a high rate of progression to AML, greater than that seen for MDS with similar numbers of blasts in the chronic phase (Group, 1988). Among the isolated i(17q) cases, both the patients who underwent transformation to AML and those who remained in chronic phase had similar survivals.

The underlying molecular defect (or defects) that produce the isolated i(17q) phenotype is unknown. Several studies have provided evidence that i(17q) forms by breakage of the proximal p arm (at 17p11.2) with re-joining of the two centromere-containing chromatids, and subsequent inactivation of one centromere (Pasquali et al, 1982; Shi et al, 1994; Testa & Cohen, 1986). It is known that the 17p breakpoint is heterogenous, and it could be that this simply reflects normal heteromorphism in that region. It is also possible, however, that the breakpoint contains important genetic material which, when disrupted, results in either activation of an oncogene or loss of a tumour-suppressor gene.

Another theory for the isolated i(17q) phenotype is that loss of material more distal to the breakpoint on 17p is the main abnormality. Only a few genes on this arm have been thoroughly investigated with respect to neoplasia. Among them is the tumour-suppressor gene, p53, which is located at 17p13.1 and codes for a nuclear phosphoprotein important for regulating the death of abnormal cells via apoptosis (Chang et al, 1995). Most feel that inactivation of both p53 alleles is required to produce an abnormal phenotype, although there is also some evidence that heterozygosity for p53 may still confer a selective growth advantage (Nakai et al, 1995). The role of p53 in haematological tumours is poorly defined, as many studies have addressed this issue with varying results (Cesarman et al, 1992; Gandini et al, 1994; Lai et al, 1995; Nakai et al, 1992; Schutte et al, 1993). Whether p53 function is retained in isolated i(17q) cases is unknown. In any event, it is unlikely to be the sole genetic defect in these cases, because many haematological neoplasms have loss of p53 and do not have the features seen in our cases, such as PPH neutrophils. In addition, isolated i(17q) cases are strictly myeloid abnormalities, although p53 loss has also been identified in lymphoid malignancies. A search of the literature revealed a single case of isolated i(17q) that was investigated for p53 abnormalities and was found to be normal (Lai et al, 1995). The same study, however, looked at a series of MDS and AML cases with 17p− and found a direct correlation between p53 loss and the incidence of PPH cells. The significance of this for isolated i(17q) cases is unclear, and further work is needed to clarify whether the p53 gene plays any role in the i(17q) phenotype. There are numerous studies (investigating both haematological and solid tumours) which have concluded that there must be other important tumour-suppressor genes on 17p (Saxena et al, 1992; Schutte et al, 1993; White et al, 1996). It is evident, therefore, that more work is required to identify the gene (or genes) which are responsible for the isolated i(17q) phenotype seen in haematological disorders.

The findings from this study indicate that an isolated i(17q) does indeed produce a distinct haematological disorder with a unique constellation of morphologic features that is associated with an aggressive clinical course and relatively short survivals. The study of these patients exemplifies the importance of cytogenetic analysis in furthering our understanding and classification of the chronic myeloid malignancies.

Acknowledgements

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. References

Sincere thanks to Mark Law, Bill Wyatt, Amy Juneau and Dr P. Greipp for their excellent technical assistance.

References

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. References
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