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Soft tissue sarcoma at the turn of the millennium
Nijhuis, Paulus Henricus Antonius
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Chapter 6
67
Chapter 6
Prognostic relevance of cytogenetic changes in
soft tissue sarcomas
Nijhuis P.H.A.1, Hoekstra H. J.1, Plaat B.E.C.2, van der Graaf W.T.A.3, Sluiter W.J.4,
Molenaar W.M.2, van den Berg E.5
1.Department of Surgical Oncology, Groningen University Hospital, Groningen, The Netherlands 2. Department of
Pathology, Groningen University Hospital, Groningen, The Netherlands 3. Department of Medical Oncology,
Groningen University Hospital, Groningen, The Netherlands 4. Department of Internal Medicin, Groningen
University Hospital, Groningen, The Netherlands 5. Department of Medical Genetics, University of Groningen,
Groningen, The Netherlands
submitted
68
Prognostic relevance of cytogenetic changes in soft tissue sarcomas
Chapter 6
Introduction
The prognosis of soft tissue sarcomas (STS) largely depends on tumor-specific characteristics, as histological (sub) type, tumor grade, size and site [1-3]. In recent years, significant
progress has been made in identifying chromosomal abnormalities in solid tumors.
Characteristic cytogenetic alterations have been demonstrated in several STS, and often
have diagnostic relevance [4-7]. Well-known rearrangements include the translocation t(11;
22)(q24; q11.2-12) in Ewing’s sarcoma and primitive neuroectodermal tumors, t(12;16) (q13;
p11) in myxoid liposarcomas (MXLPS), t(X;18)(p11.2; q11.2) in synovial sarcomas, and
t(2;13)(q35- 37;q14) in alveolar rhabdomyosarcomas [7-9]. Most studies deal with the specific
chromosomal rearrangements within histological tumor types and refer to their diagnostic
relevance, whereas only a few report on prognosis of such aberrations [10-14].
The present study analyzes the prognostic significance of cytogenetic changes observed
in soft-tissue sarcomas, using a computer-assisted cytogenetic analysis [13]. A database
was constructed, which permits the detection of statistically significant, non-random
chromosomal aberrations and allows direct comparison of different karyotypes. Special
attention was paid to cytogenetic differences between metastatic and non-metastatic STS
and between patients who died of the disease and who did not.
Materials and methods
For this study, material for cytogenetic analysis was obtained from consecutive STS specimens submitted for pathologic examination at the Department of Pathology of the
Groningen University Hospital from 1984- 1993. All STS were reviewed by a pathologist
with special interest and experience in STS (WMM), and histopathologically classified
according to the criteria described by Enzinger and Weiss [6]. Cytogenetic analysis was
performed at the department of Medical Genetics at the University of Groningen. The
criteria for inclusion in the current study were 1) a (reviewed) histological diagnosis of a
primary or locally recurrent malignant mesenchymal tumor, located in the soft tissues,
which had not been previously treated with radiotherapy and/or chemotherapy, 2) a successful karyotype, and 3) the availability of complete clinical follow-up. Mesenchymal
proliferations of parenchymal organs were excluded.
For genetic analysis, part of the tissue specimen was minced with scalpels, incubated in a
collagenase-DNAse solution and cultured in RPMI 1640 supplemented with 16% FCS,
glutamine and antibiotics. After short-term culture, cells were harvested, chromosomes
were G-banded using trypsin/pancreatin, and karyotypes were described according to the
ISCN 1995 Guidelines for Cancer [15]. If more than one tumor per patient was described, it
was decided to use the karyotype of one tumor, preferably the primary tumor, to avoid
overrepresentation.
The database consisted of four main parts related to the described karyotype: 1) patient’s
characteristics, 2) histopathological data, 3) gain and loss of chromosomal material, and 4)
structural rearrangements. After interpretation of the karyotype, the gains and losses of
chromosomal material were entered, as described by Plaat et al [13]. Each chromosome was
divided according to the ideogram at 400 bands level as described by the ISCN, in such a
Chapter 6
Prognostic relevance of cytogenetic changes in soft tissue sarcomas
69
way that the net gains and losses in 1p11-13 were summarized in 1p1, changes in 1p21-22
were summarized in 1p2, etc. In case of loss in a particular region a –1 was entered. If the
same region was lost in both chromosomes, a –2 was entered. Similarly, if gain occurred in
one of the chromosomal regions a +1 was entered, etc. Only changes as compared to the
constitutional karyotype were evaluated.
Data were analyzed for the number of tumors with gains or losses in a particular chromosomal region, and the mean change in chromosomal material per chromosomal region.
Mean change in chromosomal material in each of the 86 chromosomal regions was
expressed as a chromosomal change ratio (CCR), which was defined as the change in a
specific chromosomal region as compared to a normal diploid karyotype. Only full abnormal
karyotypes were used for the analysis of the over- or under representation of chromosomes
or chromosomal regions. In the analysis of over- or under representation, markerchromosomes were not included, because of the fact that these are structurally rearranged
chromosomes, in which no part can be identified. Chromosomal changes were compared
between patients with metastasizing STS and those with STS that had not metastasized,
and between patients with no evidence of disease and patients who had died from their
disease. Graphs were constructed to visualize the change in chromosomal material, and
the differences between selected groups.
To identify chromosomal regions with significant gains or losses, 95% confidence intervals (CI) were determined. Survival curves were calculated by the method of Kaplan and
Meier. Cox’s proportional hazards regression model was used to assess the importance of
specific chromosomal alterations in overall and metastasis-free survival. A P-value <0.05
was considered statistically significant.
Results
Patients
Forty-three patients met the inclusion criteria, 23 males and 20 females (53% and 47%,
respectively), with a mean age of 45 (range 2-81) years. Most STS (n=38) were primary
tumors (88%), the others (n=5) were local recurrences (12%). Liposarcoma (LPS) was the
most common histological type (n=20, 47%), followed by synovial sarcoma (n=5, 12%),
malignant fibrous histiocytoma (MFH) (n=4, 9%), and rhabdomyosarcoma (n=2, 5%) [Table
1].
Table 2 presents the patients’ status of disease after a median and mean follow-up of 55 and
Table 1. Distribution according to histopathology (n=43).
Histopathology
Liposarcoma
Synovial sarcoma
Sarcoma nos
Malignant fibrous histiocytoma
Rhabdomyosarcoma
Others
Sarcoma nos: sarcoma with no other specification
n
20
5
5
4
2
7
70
Prognostic relevance of cytogenetic changes in soft tissue sarcomas
Chapter 6
Table 2. Clinical status at follow-up.
Primary STS
Local recurrence
Total
AWD
DOC
DOD
NED
Total
(34-195; 95; 116)1
(85) 1
(2-238; 34; 50) 1
(22-145; 71; 79) 1
(2-238; 55; 73) 1
3
3
6
1
1
15
1
16
19
1
20
38
5
43
AWD: Alive with disease; DOC: Dead of other cause:DOD: Dead of disease; NED: No evidence of
disease.
1
Follow-up in months (range; median; mean).
73 months, respectively (range 2-238 months). Twenty patients (47%) showed no evidence
of disease, after a median and mean follow-up of 71 and 79 months, respectively (range 22145 months). Sixteen patients had died from their disease (37%), after a median and mean
follow-up of 34 and 50 months, respectively (range 2-238 months). Fourteen of these sixteen
patients died from distant metastatic disease; the other two from irresectable local
recurrences. One patient had died from a cerebral hemorrhage. Six patients (14%) were
alive with recurrent disease, two of which had pulmonary metastases, whereas the other
four (all retroperitoneal liposarcomas) had local recurrences. The mean and median
metastasis free period in the metastasis group was 15 and 28 months, respectively, with a
range of 0-128 months. The lung was the most common site of distant failure (n=13, 81%),
followed by bone (n=3, 19%), liver (n=2, 13%), and soft tissues (n=1, 6%).
Chromosomal loss and gain
Construction of 95% confidence intervals (CI) revealed no statistically significant loss or
gain of chromosomal material, expressed as chromosomal change ratio (CCR). Although
not statistically significant, notable loss was seen in the chromosomal regions 15p, 21p,
and 22q. Notable gain in chromosomal material was observed in region 7p1, 7p2, and
7q1 [Fig. 1].
The difference in CCR between patients still alive without evidence of disease, and patients who died from (recurrent) disease, is presented in Fig. 2. At univariate analysis,
overall survival was influenced negatively by gain of chromosomal material in region
1q1-4, and by loss of chromosomal material in region 18q1-2, 14p, 18p, 10q1, Yp, Yq1, 2q23, 12p, 9p2, 17p, 17q1-2, and 4p (Table 3). At stepwise backward multivariate analysis,
chromosomal gain in 1q (RR 38.7, P<0.001), and loss in 4p (RR 6.3, P=0.002) were the
only negative prognostic factors regarding overall survival. Survival curves according to
chromosomal change in the significant regions are presented in Fig. 3 a- c.
The difference in CCR between patients who developed metastases during follow-up
(n=16) and patients without distant metastases (n=27) is presented in Fig. 4. At univariate
analysis, significant poor prognostic factors regarding distant relapse were gain of
chromosomal material in region 1q1-2, and loss in regions 18p, 18q1-2, 10q1, 2q2-3, Yp,
Yq, 10q2, 14p, and 22p (Table 4). At stepwise backward multivariate analysis, chromosomal loss in 18p (RR 8.3, P<0.001) remained the only significant negative prognostic
factor regarding metastasis-free survival (Fig. 5). Furthermore, there was a strong
association between loss in 18p and gain in 1q in patients with the shortest survival.
Chapter 6
Prognostic relevance of cytogenetic changes in soft tissue sarcomas
71
Figure 1. Mean CCR with 95% Confidence Interval of all cases
Figure 2. Mean CCR in patients with no evidence of disease (NED) versus patients who died of the
disease (DOD)
72
Prognostic relevance of cytogenetic changes in soft tissue sarcomas
Chapter 6
Table 3. Overall Survival: statistically significant chromosomal changes at
univariate analysis.
Chromosomal Change
Gain of 1q1
Loss of 14p
Loss of 18p
Gain of 1q3
Gain of 1q2
Loss of 10q1
Gain of 1q4
Loss of Yp
Loss of Yq
Loss of 2q2
Relative Risk (RR)
7.7
6.3
6.3
6.3
5
5.6
4.4
5.6
5.6
5
P-value
<0.001
<0.001
<0.001
0.001
0.006
0.009
0.01
0.01
0.012
0.013
Chromosomal Change
Loss of 2q3
Loss of 12p
Loss of 18q2
Loss of 9p2
Loss of 17p
Loss of 17q1
Loss of 18q1
Loss of 4p
Loss of 17q2
Figure 3a. Overall survival and gain in chromosome 1q
Figure 3b. Overall survival and loss in chromosome 4p
Relative Risk (RR)
P-value
5
3
4.8
2.2
2.2
2.2
7.7
3
2.1
0.013
0.016
0.029
0.037
0.037
0.037
0.044
0.045
0.045
Chapter 6
Prognostic relevance of cytogenetic changes in soft tissue sarcomas
73
Figure 3c. Overall survival and loss in chromosome 18p
Figure 4. Mean CCR in patients with metastasizing STS versus STS that did not metastasize
Table 4. Metastasis-Free Survival survival: statistically significant chromosomal
changes at univariate analysis.
Chromosomal Change
Gain of 1q1
Loss of 18p
Loss of 10q1
Loss of 10q2
Loss of 2q2
Loss of 2q3
Loss of Yp
Relative Risk (RR)
9.7
8.3
5.9
4.2
4.5
4.5
4.5
P-value
<0.001
<0.001
0.005
0.014
0.015
0.015
0.02
Chromosomal Change
Loss of Yq
Loss of 14p
Loss of 22p
Loss of 18q2
Gain of 1q2
Loss of 18q1
Relative Risk (RR)
P-value
4.5
3.3
2.2
4.2
5.9
6.3
0.02
0.025
0.031
0.037
0.048
0.049
74
Prognostic relevance of cytogenetic changes in soft tissue sarcomas
Chapter 6
Figure 5a. Metastasis-free survival and loss in chromosome 18p
Figure 5b. Metastasis-free survival and gain in chromosome 1q
Discussion
Cytogenetic analysis has demonstrated that both benign and malignant tumors often have
characteristic chromosomal aberrations and that the karyotype may be important in
diagnosis and treatment [5,7,16,17]. STS often reveal a very complex karyotype due to a
large number of chromosomal abnormalities [13]. As all these chromosomal changes, either
alone or in combination, might be responsible for certain steps in oncogenesis, it is very
difficult to relate these changes to the oncogenetic process. Another problem is the difficulty
to interpret and compare different studies, as most of them have presented karyotypes in
such a way that comparison and statistical analysis is hardly possible. To overcome this
problem, we started a database in which all karyotypes are interpreted and entered in a
uniform fashion, which makes a computer-assisted analysis of large groups of karyotypes
possible, as described by Plaat et al. [13]. Data from the database were linked to clinical
outcome to determine the prognostic importance of shared cytogenetic abnormalities.
In the present series, overrepresentation of STS with balanced translocations (especially
the myxoid and round-cell liposarcoma subtype, characterized by the t(12;16) (q13;p11)
Chapter 6
Prognostic relevance of cytogenetic changes in soft tissue sarcomas
75
translocation) seems to be of minor importance, as such translocations do not result in
net gain or loss of chromosomal material.
Correlation between cytogenetic alterations and prognosis has been documented in other
human malignancies [18-22]. For STS, however, hardly any data exist on the prognostic
relevance of specific chromosomal aberrations [23-25]. In the present study, univariate
analysis of involved chromosomal changes revealed many regions with chromosomal
alterations as negative prognostic factors. Several studies have identified cytogenetic bands
in these regions involved in human tumor development and progression. Specific information on STS, on the other hand, is very scanty.
In the present study, chromosomal gain in 1q1 was the most important negative prognostic factor regarding survival. A relation between alterations at the long arm of chromosome 1 and human malignancies has been demonstrated in various tumor types,
suggesting the existence of oncogenes (breast cancer [26], prostate cancer [27], and endometrium cancer [28]), as well as tumor suppressor genes (breast cancer [26]) and
medulloblastoma [29]). In liposarcomas, there are indications that amplification of genes
located at 1q21-24, often with concomitant gain in 12q14-21, plays a significant role in
development and progression [30]. Furthermore, the long arm of chromosome 1 is a
region of particular interest with regard to metastasis, as it harbors the KiSS-1 metastasis-suppressor gene at 1q32, which has been identified as a metastasis-suppressor gene
in malignant melanoma and breast cancer [31]. However, as gain of chromosomal material at the long arm of chromosome 1 was a negative prognosticator for metastasis-free
survival, it seems very unlikely that this metastasis-suppressor gene is involved in the
metastatic process of STS.
The other negative prognostic factor regarding survival, loss in 4p, was surprising, as
there is only very limited information on its role in human malignancies [32,33]. In their
search for the human homologue of the SH3BP2 protein in bladder cancer, Bell et al.
identified an interesting gene at 4p16.3 that is a potential negative regulator of the Abl
gene [34], a proto-oncogene that has been related to differentiation and apoptosis inhibition in chondrosarcoma [35]. The association between high malignancy grade, a wellknown negative prognostic factor regarding disease-specific survival, and low amounts
of apoptosis in STS [36], might further support a potential role of SH3BP2 and Abl genes
in STS prognosis.
At univariate analysis, aberrations in many other chromosomal regions were related to
survival. Because of the magnitude of genes, located at these regions, and the fact that we
did not investigate specific gene products, it is impossible to predict which chromosomal bands and which genes will be involved, although some regions (9p, chromosome
17, and 18p) are very intriguing. The negative prognostic importance of loss in region
9p2 was not unexpected, as this region contains the p16 (CDKN2A/ IKN4A) and p15
(CDKN2B/ IKN4B) genes, which act as negative regulators of proliferation of normal
cells. Deletions or mutations of these CDK (cyclin-dependent kinase)- 4 and 6 inhibitors
lead to unchecked cell growth, which has been demonstrated in many human cancer
types [18,21,37]. In Ewing’s sarcoma, Wei et al. demonstrated that p16 deletion was a very
strong negative prognostic factor (P<0.001) [37]. In Wilms’ tumors, loss of p16 also seems
76
Prognostic relevance of cytogenetic changes in soft tissue sarcomas
Chapter 6
to be of prognostic importance, as it correlates with advanced tumor stage [39]. In STS,
however, the prognostic impact of both p16 and p15 alterations remains contradictory.
Orlow et al. reported a significant relation between p16 deletions or alterations and poor
survival in 46 STS (P=0.036 and 0.005, respectively), with alteration of the IKN4A/B
gene being the only statistically significant predictor for poor survival when controlling
for tumor grade and size (P=0.03) [40]. Yao and Meye investigated the role of the p16
gene status and expression in STS, and reported a low frequency of deletions and
mutations of this gene in STS, in contrast to Simons et al., who demonstrated a loss of
9p21 in 55% of MFH [42-44]. Moreover, Yao et al. suggested that CDK4 might act as an
oncogene in STS, which is in contrast to findings in other human malignancies where
CDK4 acts as a tumor suppressor gene [41]. In the present study, however, loss of region
9p2 is a statistically significant negative prognostic factor (P=0.037), suggesting the
location of a STS suppressor gene in this region.
The prognostic importance of chromosomal loss at the short arm of chromosome 17 is
very interesting, as some important tumor suppressor genes are located there. TP53,
located at 17p13.1, is the most common tumor suppressor gene, altered in many malignancies. A study from the Memorial Sloan Kettering Cancer Center demonstrated that
17p deletions and p53 mutations were common events in adult STS [44]. Dei Tos et al.
demonstrated a 30% incidence of p53 aberrations in myxoid and round cell liposarcoma
[45]. However, these studies did not provide any information on the prognostic importance of the p53 alteration. In a series of 113 bone and soft tissue sarcomas, Mousses
reported p53 alterations at different frequencies in various sarcomas; furthermore, these
alterations were not associated with prognosis [46]. As p53 expression was not examined
in the present study, we can not be sure whether this gene product is responsible for the
poor prognosis in patients with loss of the short arm of chromosome 17, or whether
other suppressor genes at 17p are involved, as has been reported in sporadic breast cancer [47].
Besides chromosomal loss at the short arm of chromosome 17, also loss at its long arm
had prognostic importance. One of the genes that might contribute to this is the protooncogene c-erbB-2, at band 17q21.1. Although a correlation between loss of 17q and a
high degree of amplification of c-erbB-2 has been demonstrated in human breast cancer
[48], no reports on its prognostic importance in STS are available.
Loss of the short arm of chromosome 18 (18p1) was another important negative prognostic factor, both in metastasis-free and overall survival, suggesting the location of (a) putative suppressor gene(s). In the literature, there is some evidence for the presence of
tumor suppressor genes on the short arm of chromosome 18, involved in breast carcinoma, NSCLC, and brain tumors [49]. Apart from that, information on the role of 18p in
human malignancy is extremely scarce.
Except for retroperitoneal STS, survival in STS has been related directly to metastasis. In
human malignancies in general, and in STS in particular, the cytogenetic base for metastasis remains obscure. As reports revealing possible clues are awaited, the finding
that loss of 18p was the only statistically significant negative prognostic factor regarding
metastasis-free survival is very interesting, as it suggests the location of a putative (sarcoma-) metastasis suppressor gene.
Chapter 6
Prognostic relevance of cytogenetic changes in soft tissue sarcomas
77
The computer-assisted approach, used in the present study, is valuable in the analysis of
large groups of complex karyotypes to detect common chromosomal alterations. The
strong association between gain in the long arm of chromosome 1 and loss in the short
arm of chromosome 18 in patients with the shortest survival has not been reported before, and its importance in STS prognosis remains unclear.
In conclusion, the present study provides indications for correlations between cytogenetic changes and metastasis and prognosis in STS. Some of these findings confirm
earlier reports, whereas many are novel in STS, and need to be confirmed in additional
studies. The strong association between alterations in the long arm of chromosome 1
and the short arm of chromosome 18 in non-survivors is very challenging and may have
prognostic value in STS.
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Prognostic relevance of cytogenetic changes in soft tissue sarcomas
Chapter 6