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Osteosarcoma of the jaw bones
Nt. J. Oral Maxillofac. Surg. 1997,"26." 191-197 Printedin Denmark. Allr@hts reserved
Copyright9
1997
InternationalJournalof
Oral 8c Maxillofacial Surgery ISSN 0901-5027
0ncology
0steosarcoma of the jaw bones Long-term follow up of 48 cases
Robert J. J. van Es 1, Ronaid B. Keus2, Isaac van der Waal a, Ronald Koole a, Albert Vermey 3 1Department of Oral and Maxillofacial Surgery, University Hospital Utrecht; 2Department of Radiotherapy, the Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam; aOn behalf of the Dutch Head and Neck Oncology Cooperative Group (NWHHT), The Netherlands
R. J. J. van Es, R. B. Keus, I. van der Waal, R. Koole, A. Vermey. Osteosarcoma of the jaw bones. Long, term follow up o f 48 cases. Int. J. Oral Maxillofac. Surg. 1997; 26." 191-197. 9 Munksgaard; i997 Abstract. To evaluate the incidence and treatment results.of osteosarcoma of the j~iw (OSJ) in the Netherlands, data from 48 patients with a histologically proven diagnosis of osteogenic Sarcoma Of the maxilla or mandible were retrospectively analysed. Patient files, covering the period from 1964 to 1992, were obtained fr6in all university hospitals in the Netherlands and the Netherlands Cancer institute. The incidence of OSJ in the Netherlands is estimated to be at least 0.14 per 1 000 000. The overall 10-year survival was 59%. D i s t a n t metastasis occurred in 21% and local recurrences in 31% of the cases. Survival was significantly better in case of radical surgery and small tumoui:s. Long-term survival after treatment of OSJ was good if complete surgical excision was achieved. Radiotherapy should only be considered to prevent local recurrence if surgery is not complete. The possible benefit of current chemotherapy in preventing metastatic disease is still questionable. Since other malignant neoplasms associated with OSJ occurred in 17% of the cases, lifelong follow up is mandatory for the detection of these second primary malignancies.
Accepted for publication 14 December 1996
It is generally believed that osteosarcomas of the jaw bones (OSJ) behave differently from long-bone osteosarcomas (LOS) and have a markedly better prognosis4,5,21. Recent publications concerning larger groups of patients, however, refute this optimism. Long-term survival is reported to be less than 35%, mainly due to local recurrence2,6,1~ Using multi-agent chemotherapy, long-term survival of osteosarcomas of the extremities is presently reported to be approximately 45% 24'25, For this reason, multi-agem chemotherapy is recommended following radical surgery of OSJ as well. The purpose of this study was to
Working Group on Bone Tumours"has existed since 1953. In 1971 the "Dutch Working Group on Jaw Tumours" was formed. working closely together with the-former. Histology of all material was verified by pathologists from one of the two groups. Material obtained before 1982 was published earlier by BRAS3. All osteosarcomas, occurring in the mandible and maxilla were included in this study. If.involvementof the maxillary bone was less than about 50%. however, it was excluded because the characteristics of osteosarcomas in other craniofacial .bones are reported to be different from OSJ 16'2~ Forty-eight cases were collected and an~tlysed. The data are summarized in Table 1. Completeness of excisionwas based on the histology of the resection specimen. Only if
evaluate the incidence and treatment results of OSJ in the Netherlands. The Dutch Head and Neck Oncology Cooperative Group (NWHHT) retraced the histories of all patients with OSJ, treated in different university hospitals in the Netherlands over a period of 29 years, and analysed the data retrospectively.
Material and methods Patient material All university hospitals and the hospital of the Netherlands Cancer Institute were invited to participate in this retrospective analysis. The patient material covered the period 1964-1992. In the Netherlands. the "Dutch
Key words: osteosareoma; oncology; epidemiology; craniofacial bones; treatment results.
van E s et al.
192
Table 1. Osteosarcoma of the jaw: clinical data of reported patients Case No.
Year sex
age
Died of disease or alive with 1 F 39 4 M 19 5 M 29 7 F 26 9 F 59 10 M 26 12 F 72 13 M 44 17 M 45 18 M 23 22 M 42 24 M 72 31 35 36 40 42 44 46
M M M F M M M
45 26 34 63 17 55 28
site disease Dr D Dm Dr Xm X-Z1 Xr X-Z1 Dr Dr Dr X-Er D1 X-Z1 Xr Dr X1 X-E1 Dr
Pa
Rmrks
2 H L H M/H H H 3 H M/H 3 I -
# # # ## # ##
# ##
N o evidence of disease or died of other cause 2 M 25 X-Z1 3 6 8 11 14 15 16 19 20 21 23 25 26 27 28 29 30 32 33 34 37 38 39 41 43 45 47 48
M M M M F M F M M M M M M M F F F M M M M F M F M F M F
25 43 31 55 29 31 25 15 30 40 56 12 71 46 49 65 15 18 30 75 17 57 28 35 11 45 21 19
X X1 Dm Dr Xr Xm X1 Xr DI Dr X1 X1 D1 Xr DI X1 X-FI X1 Dr D1 D1 Xr Xr Xr Xl X1 Xm D1
** 1 L 3 I/H H 1 1 1 -
*
** **
1/L L H L L 3 M/L L H H -
# # *
## **
Local recurrence
Metastasis
Follow up
Hosp
Treatment
year, m o n t h (therapy)
year, m o n t h (therapy)
year, m o n t h
64G 65U 66AL 67R 70A 71AL 73L 73R 76U 77G 80U 81AL
Sp S? Srt R S? Sp+R Sn R Srt+Ch Ch+R St+Ch Sd+R
0,2/0,5(R) 0,6 immediately 1(S)/4(S)/5(S)/13(S) immediately 0,2(R) 0,4(S)/5,6(S) -
0,5 lung(Ch) 0,6 lung lung 0,4(R) -
D O D 4,2 D O D 0,9 D O D 0,7 D O D 1,0 D O D 14 DOD, 1,4 D O D 0,11 D O D 6,6 D O D 1,11 D O D 0,3 D O D 5,9 D O D 1,2
83R 85N 86A 88G 90AL 90A 92U
St+Ch Sd+Ch Sp Sp+R Ch+Sp+R Sp Srt
0,6(S+R) immediately 0,3 0,5 1,3(Ch) 1,2(S)/2,2(S) 0,7(S)
64G
Sp
64U 66AL 69G 72G 74AL 75A 76U 78U 80AL 80G 80N 81A 82G 82U 82U 83U 83N 84G 84A 84M 87A 88N 88U 89G 90A -90A 92A 92A
Sn R+St Ch+R+Sn Ch+R+St R+St S? R+St+Ch St+Ch Srt/ Ch+St Srt st St St St Srt Srt Ch+St St " Ch+R+St Sn St Sn Ch+St+Ch St Sp+R St St
0,2(St+R)/ 0,4(R+Ch+R) 1,0(Ch+St+Ch) -
0,4 0,1 3,9 0,8 1,1 -
rib / vertebra lung pelvis / femur cervic lymphnd lung/liver/skeleton
0,3 lung 0,6 lung -
DOD DOD DOD DOD DOD AWD DOD
-
N E D 29
-
NED DOC NED NED NED NED NED NED NED NED DOC NED NED NED DOC NED NED NED NED NED NED NED NED NED NED NED NED NED
2,1 lung(S) 2,7 lung(S)
1,2 1,0 0,9 0,8 2,1 2,6 0,11
6,lost 11,10 24 12,1 18,10 11 12,6 13,11 10,8 12,8 4,7 11,7 11,7 10,2 4,10 10,6 9,7 9,1 8;11 8,3 5,10 4,11 5,10 4,8 2,4 2,6 0,9 0,3
Sex: M =male, F=female; Age: at time of diagnosis 9Site: X=maxilla, D=Mandible, E = E t h m o i d , Z = Z y g o m a , F=frontal; l=left, r=right, m=midline. Pa: Histopathology: Grade: L=Low, I=Intermediate, H = H i g h ; Mitosis: l=few, 2=intermediate, 3 = m a n y Remarks (case number): 9 14 after 10 years: Postirradiation-sarcoma of parotid followed by parotidectomy, after 13.5 years: basalioma of cheek 9 32 Developed diffuse encephalopathia with epilepsia (probably cisplatinum-induced). 9* 6 Bronchial carcinoma after 10.4 years, treated by pneumectomia 9* 20 Philadelphia chromosome positive, developed chronic myeloid leukemia after 10.8 years 9* 23 Intrapulmonary and skelettal lesions after 4.4 years, presumed bronchal carcinoma, not histologically verified. 9* 45 synchronous axillary non-Hodgkin l y m p h o m a # 9 First and second resection initially misdiagnosed as fibrous dysplasia # 10 Poly-ostotic fibrous dysplasia # 13 osteosareoma ex fibrous dysplasia # 18 fibrous dysplasia removed at age 16; 6 years before diagnosis of OSJ # 27 osteosarcoma ex Pagetiform sclerosis, M Paget not proven # 29 osteosarcoma ex fibrous dysplasia # 40 Ambonese, fibrous dysplasia diagnosed at age 51; 1 f years before diagnosis of OSJ ## 17 Previous radiotherapy (tuberculosis age 10; 35 years before) ## 24 Previous chemotherapy (multiple myeloma; 1.5 years before) ## 43 Previous chemotherapy (abdominal Burkitt-iymphoma age 6; 4 years before) ## 44 Previous chemo- and radiotherapy (fibrosarcoma cheek age 48; 7 years before) Hospital: N = N i j m e g e n , L=Leiden, M = M a a s t r i c h t , U = U t r e c h t , G = G r o n i n g e n , A = A m s t e r d a m - V U , A L = A n t h o n i e v.Leeuwenhoek; R = R o t t e r d a m Year: Ranking of cases according to the year in which diagnosis OSJ was established Treatment: S=Surgery: Sr:repeat resection, Sp:partial resection, Sd:total removal dubious; St:total removal; S n = n a r r o w margins S?=margin-status unknown R = Radiotherapy ; C h = C h e m o t h e r a p y Follow up: D O D = d i e d of disease, N E D = n o evidence of disease, D O C = d i e d of other cause, A W D = a l i v e with disease.
Osteosarcoma o f the jaw bones the pathologist claimed total surgical removal, was the excision considered to be complete. In all other cases, excision was considered to be not complete. From 1975 on, different types of chemotherapy were used in the participating h0spitals, largely according to the ROSEN protocolTM. Data analysis
As uncertainty exists whether tumour histology of OSJ (type, grade, mitotic index) corresponds with survival 11b,21, we tried to correlate survival with tumour volume. Information on tumour dimensions was available in 33 cases, A tumour volume (box with frame a . b" c) was estimated, based on the following: if only one dimension ('a') was available, then a=b=c; if two dimensions ('a' and 'b') were available, then c = b and b < a . Following data analysis, two g r o u p s , one with a " s m a l l " ( < = 5 0 cc, n=17) and one with a "large"(>50c, n=16) volume, were arbitrarily defined (Table 2).
Statistical analysis included Chisquare or Fisher's exact test and Kaplan-Meier curves. Differences between curves were analysed with the log-rank test, regarding P-values below 0.05 as statistically significant. The Cox proportional hazard test was used to analyse interaction between t u m o u r volume and completeness of excision. Results Epidemiology
A t the time of diagnosis, age ranged from l l to 75 years (median: 31 years). O f the 48 patients, 34 (71%) were male and 14 (29%) female. The peak frequency of OSJ for males was in their third decade. In females the i n c i d e n c e 0 f OSJ was evenly distributed among different decades (Fig. 1). Twenty-eight tum o u r s (58%) were localized in the maxilla and 20 (42%) in the mandible. Four tumours (8%) occurred in the midline. Assuming that participating hospitals covered about 80% of the cases*, the inci-
Table 2. Duration of symptoms (n=31), turnout dimensions and estimated volume (n=33) Case
Symptoms (weeks)
Dimensions (cm)
14 19 08 20 23 34 41 6 27 28 29 31 32 39 11 5 18 22 24 30 38 12 35 26 42 46 40 21
52 6 28 5 40 6 8 12 >300 4 500 6 8 20 12 8 4 52 28 6 4 75 24 25 25 12
1.7• 1.5 3 • 1.5 3.5• 2 3.5• 3•215 4• 2.5 3.5•215 3 3• 3 3 4.5x2.5 5?<2.5 3x4 6•215 4 4• 4 6x3.5 4?<5 5?44.5 5• 5 5.5 7x6•
1
4
6
16 2 7 10
6 8 10 16
6 7 8 10
Volume (cc) 2 3 7 7 8 8 15 16 16 26 27 27 27 27 28 31 36 54 64 64 64 74 80 101 125 125 166 210 216 216 343 512 1000
193
dence of OSJ in the Netherlands is estimated to be at least 0.14 per 1000000. D u r a t i o n of symptoms varied from 4 to 500 weeks, and tumour dimensions from 2.5 to 1000 cc. Disease-specific survival was significantly better in case of "small" tumours (P=0.015) (Fig. 2). Previous radiotherapy
Possible tumour induction by previous radiotherapy to the region 11c was found in 2 out of 48 cases (4%) (case nos. 17 and 44, respectively 7 and 35 years before diagnosis). Dysplastic bone
Dysplastic bone was found in 7 out of 48 cases (15%), of which one had a proven polyostotic disease. Two patients with fibrous dysplasia had a recurrent t u m o u r at the primary site more than five years after initial treatment. Survival
Recurrent t u m o u r was seen in 22 out of 48 patients ( 4 6 % ) . Twelve patients (25%) had a recurrent t u m o u r locally and six patients (13%) a recurrent- tum o u r at distant sites, whereas four patients (8%) had both local and distant recurrences. During follow up, 18 out of 48 patients (38%) died of the disease, of w h o m three died more than five years after initial treatment. The overall disease-free ,survival was 65% after five years and 59% after ten years. Recurrent tumour at the primary site
Recurrence at the primary site was seen in 16 out of 48 patients (33%), of w h o m only two survived. O f these 16 patients, 3 out of 16 suffered from local recurrence despite complete excision (two patients even had chemotherapy combined with surgery), 3 out of 16 patients had no initial surgery at all, and in 10 out of 16the resection was not complete. O f the 24 patients who were free of disease at the primary site and were followed for more than two years, 18 out
* In the period 1989-1992, 14 osteosarcomas of all carniofacial bones were registered at the Netherlands Cancer Registry. Based on the distribution patterns of Huvos 11", the jaws alone would account for about 71%, that is 10 cases. In the same period, participating hospitals reported 8 cases, which is about 80% of all OSJ.
van E s et aL
194
a local recurrence. The 12 other cases did not receive radiotherapy and recur, rence developed in nine of them. If the excision was not complete, adding postoperative radiotherapy to the surgery indicated a trend showing better local control (P=0.29), but not improved survival (P=0.45).
c~
o
co
~
Distant metastasis
Gender
Men Women
O
10~19
20-29
30-39
40-49
50-59.
60-69
70~79
Age
(years)
Fig. 1. Osteosarcoma of the jaw in the Netherlands. Distribution of age at diagnosis and
gender (n=48).
of 24 excisions were complete. Four had narrow margins, in one completeness of excision was unknown, and only one patient had a debulking with adjuvant radiotherapy. Of these 24 patients, 16 out of 24 received surgery as monotherapy. The difference in survival between completely and not completely excised cases was significant (P=0.012; Fig. 3), also when corrected for tumour volume (P=0.017; Fig. 4).Ten-year survival following resection of large tumours was
69% when excision was complete; but dropped to 13% if excision was not complete. Interdiction between these two parameters li.e. tumour volume and completeness of excision) could not be established. In 18 cases, completeness of exclston could not be verified: partial excision in eight cases, dubious margins in two, narrow margins in five, completeness unknown in three (Table 1). Of these 18 cases, six did receive postoperative radiotherapy, of which three developed
p : 0.017
Metastatic disease occurred in 10 out of 48 patients (21%). The lung was involved in eight of these cases, the skeleton in three, the liver in one and neck nodes in one case. All these patients died of the disease except one, who undei'went pulmonary resection twice (case no. 21). Of the six patients having metastasis with local disease controlled, four had cfiemotherapy as part of their initial therapy. One patient suffered from possible iatrogenic damage from chemotherapy (case no. 32: encephalopathia with epilepsia), one from possible iatrogenic damage of radiotherapy (case no. 14: parotid sarcoma and basal cell carcinoma). Other malignant neoplasms
Eight patients (17%) had other neoplasms associated with OSJ, of which four originated from the haematopoietic system. Three patients Icase nos. 24, 43 and 44) were treated with chemotherapy for previous neoplastic disease (respectively 1.5, 4 and 7 years before the diagnosis of OSJ). Five patients (case nos. 6, 14, 20, 23 and 45) developed other turnouts during the follow up.
eO d
Discussion
1 LI
~5
t
Lt
Q
L----] L .
.
.
.
.
.
.
L. . . . .
9
I L. . . . . . . . . . . . . .
C~
Volume <~50 cc
0 C~
I
L
I
I
2
4
6
8
..... 10
Time (years) Fig. 2. Disease-free survival rates according to tumour volume.
> 50 cc
Although we are aware that the calculated incidence is inaccurate, its estimation of at least 0.14 corresponds well with a 5% share xb of all 42-84 osteosarcomas per year occurring in the Dutch population of approximately 15 million people 25. It is higher than the 0.02 in Japan as reported by TANZAWA et al. 23, but probably lower then the 0.7 in the US as suggested by GARRINGTON et al. 8. A male preponderance of OSJ in our population [7:3) is comparable to a US populatio n described by CLA~K et al. 4 and MARK et al. 13 (about 2:1), but different from reports from Germany 1~ and Italy2 (about 1:i) or Japan 23
Osteosarcoma of the jaw bones O
-~,
p = o.o12 k........
O
~5 O
Excision O
.....
5
10
Not complete Complete
20
15
Time (years)
Fig. 3. Disease-free survival rates comparing complete and not complete excision.
p = 0.017
I
. . . . . . . . . . . . .
s
Volume > 50 cc oniy: Excision o o
.... I
I
q
I
2
4
6
8
Not complete Complete
10 Time (years)
Fig. 4. Disease-free survival rates in case of large turnout volume, comparing complete and not complete excision.
(1:1.5). A maxillo-mandibular ratio of about 3:2 is comparable with a l:l ratio found by others 4,6,1~ Different ratios, ranging from 2:323 to 3:72, might also be explained by different criteria used in excluding tumours of the maxilla with extension to other facial bones. The uniform age distribution of OSJ in females is in contrast with previous reports 4,11b , 2 3 An extensive analysiS concerning differences between behaviour o f OSJ versus LOS was presented by SI~OOTWE~&
M~LLER21. As LOS occurs at a lower mean age, one of the explanations for the better prognosis of OSJ is an increase in host resistance to the tumour with advancing age 3;21. This assumption is, however, in contrast with the findings Of SMEELEet al. 22. They report better survival of patients under 35 years of age. In our study, no age-related difference in survival could be demonstrated (Fig. 5)i Previous reports from our country indicated a 5-year survival of 41-
195
69% 3,21,22. The favourable lO-year disease-free survival of 59% in this group is probably based on a comparatively low rate of local recurrences: 33% in this study versus 50-95% local recurrences reported by others 2'10'13'23'24. Distant metastases occurred in 21% in this material, which is comparable to the figures found in the literature. The importance of complete surgical resection was already mentioned by CLARK et al. 4 and is further stressed by others 11b'21'22. In cases of large tumours, however, urging multi-piece resection, thorough histological assessment of completeness of excision is difficult. Tumour dimensions exceeding 10 cm and previous surgery elsewhere might explain the high rate of local recurrences and mortality mentioned by DELGADO et al. 6, despite the fact that 43% of their excisions were claimed to be complete, Recurrent tumour at the primary site more than five years after initial treatment in two patients with fibrous dys~plasia (case nos. 9 and 13) is remarkable and could possibly be eXplained by the occurrence of new primaries. The parameter tumour volume in this study was only used as a crude to01 to compare different dimensions available in the patient files. The positive influence of small tumour-size on survival was already suggested~bY BEI~TONI et al. 2, whether this parameter is more relevant than tumour histology remains unclear. If excision is histologically complete, surgery alone seems sufficient. Adjuvant irradiation should be considered if excision is not complete. The beneficial effect of radiotherapy on local control or survival has not reached significance in this study, probably because of the few cases involved. Of the 32 patients with local tumour control, six developed metastatic disease; though four of these six patients received chemotherapy according 'to one of ROSEN'S schemeslS; This, as well as possible toxicity and persistent cerebral dysfunction is, should b e taken into account when considering the possible benefit of "neo-adjuvant" chemotherapy for OSJ. However, the issue of preventing metastatic disease following local cure, deserves full attention, and agents which modify multidrug resistance might prove to be useful 1. As advocated for metastatic LOS 19, thoracotomy and pulmonary resection Should also be considered in
van Es et al.
196
._ ffJ
..c
p = 0.60
-i
o
-'L_ 2 .....
,~
L
L.....
. I
o
Age
--0
2
4
6
8
3t.25 yrs > 31.25 yrs
1:0
Time ( y ~ s )
Fig. 5. Disease-free survival rates comparing patients younger and older than the median age.
case of isolated pulmonary metastatis (case no. 21). A relation between previous irradiation of a malignancy and development of osteosarcomas (case no.44), as well as tile development of secondary malignancies following irradiation and/ or chemotherapy for osteosarcomas (case no. 14), are well known 11a,11c'12. The possible role of previous chemotherapeutic agents in the carcinogenic process of osteosarcomas (case nos. 24, 43 and 44), was mentioned by NEWTON et al. 14. As suggested by others 7;ala,14, genetic predisposition may play a role in patients with an osteosarcoma as part of a multiple malignancy syndrome. Whether a case of Li-Fraumenti syndrome was among this material could not be established. SMEELEet al. 22 drew attention to the association between n o n - H o d g k i n l y m p h o m a and second primaries (case no. 45). Chromosomal abnormalities (case no. 20) have been found in patients with osteosarcomas 11a and recently attention has been focused on the retinoblastoma and p53 suppressor genes 9. This high incidence of second primaries justifies a high degree of alertness during the follow up of patients cured from an osteosarcoma of the jaw. Acknowledgments. We would like to thank the following members of the Dutch Head and Neck Oncology Cooperative Group (NWHHT), who participated in this study:
Institution (number of patients)
Investigator
Free University Hospital Amsterdam (11) University Hospital Utrecht (11) University Hospital Groningen (10) The Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital Amsterdam (7) University Hospital Nijmegen (4) University Hospital Rotterdam (3) University Hospital Leiden (1) University Hospital Maastricht (1)
I. van der Waal R. Koole A. Vermey E J. M. Hilgers
I. Bruaset R E M. Knegt A . G . L . van der Mey J . M . H . van der Beek
References
1. BALDINI N, SCOTLANDI K, BARBANTIBR~DANO G, et al. Expression of P-glycoprotein in high-glade osteosarcomas in relation to clinical outcome. N Engl J Med 1995: 333: 1380-5. 2. BERTONI F, DALLERA P, BACCHINI P, MARCHETTIC, CAMPOBASSIA. The Istituto Rizzoli-Beretta experience with osteosarcoma of the jaw. Cancer 1991: 68: 1555-63. 3. BRAS J. Sarcomen van de kaak. Thesis. Free University Amsterdam: Zeldenthuls BV, 1982 [in Dutch]. 4. CLARKJL, UNNI KK, DAHLINDC, DEVINE KD. Osteosarcoma of the jaw. Cancer 1983: 51: 2311-6.
5. DAHLIN DC. Malignant bone tumors: improvement in survival. Mayo Clin Proc 1988: 63: 414-5. 6. DELGADO R, MAAFS E, ALEEIRAN A, et al. Osteosarcoma of the jaw. Head Neck 1994: 16: 246-52. 7. GARDNER GM, STEINIGER JR. Family cancer syndrome: a study of the kindred of a man with osteogenic sarcoma of the mandible. Laryngoscope 1990: 100: 1259-63. 8. GARRINGTON GE, SCOEIELDHH, CORNYN J, HOOKERSIR.Osteosarcoma of the jaws. Cancer 1967: 20: 377-91. 9. HANSENME Molecular genetic considerations in osteosarcoma. Clin Orthop 1991: 270: 237-46. 10. HERMAbrNA, Z6LLER J. Zur Klinik und Therapie des osteogenen Sarkoms im Kieferbereich. Dtsch Z Mund Kiefer Gesichtschir 1990: 14: 180-6. 11. Huvos AG. (a) Osteogenic sarcoma: 5: 85-91. (b) Osteogenic sarcoma of the craniofacial bones: 7: 179-200. (c) Radiation as an oncogenic agent in sarcoma of bone: 9: 223-51. In: Hovos AG. Bone tumors. 2nd ed. Philadelphia: WB Saunders, 1991. 12. VAN DER LAAN BF, BARISG, GREGORRT, HILGERSF J, BALMAJ. Radiation induced tumors of the head and neck. J Laryngol Otol 1995: 109: 346-9. 13. MARK RJ, SERCARZJA, TRAN L, DODD LG, SELCH M, CALCATERRAT. Osteogenic sarcoma of the head and neck. Arch Otolaryngol Head Neck Surg 1991: 117: 761-6. 14. NEWTON WA, MEADOWSAT, SHIMADAH, BUNIN GR, VAWTERGF. Bone sarcomas as second malignant neoplasms following childhood cancer. Cancer 1991: 67: 193201. 15. NICHOLSONHa, MVLVIHILL JJ. Late effects of therapy in survivors of childhood and adolescent osteosarcoma. Cancer Treat Res 1993: 62: 45-8. 16. NORA, FE, UNNI KK, PRITCHAP,D DJ, DAHLIN DC. Osteosarcoma of extragnathic craniofacial bones. Mayo Clin Proc 1983: 58: 268-73. 17. PRATT CB, CHAMPIONJE, FLEMINGID, RAo B, KUMARAPM, EVANs'WE, GREEN AE, GEORGES. Adjuvant chemotherapy for osteosarcoma of the extremity. Cancer 1990: 65: 439-445. 18. ROSEN G, TAN C, SANMANEECHAIA, BEATTIEEJ, MARCOVER, MURPHYML. The rationale for multiple drug chemotherapy in the treatment of osteogenic sarcoma. Cancer 1975: 35: 936-45. 19. ROSEN G, HOLMES EC, FORSCHERCA, LOWENBRAUNS, ECKARDTJ J, EILBERFR. The role of thoracic surgery in the management of metastatic osteogenic sarcoma. Chest Surg Clin N Am 1994: 4: 75-83. 20. SALVATIM, CIAPETTAP, RACO A. Osteosarcomas of the skull. Cancer 1993: 71: 2210-6. 21. SLOOTWEGP J, MOLLERH. Osteosarcoma
Osteosarcoma o f the j a w bones of the jaw bones. J Max-Fac Surg 1985: 13: 158-66. 22. SMEELELE, VAN DER WAL JE, VAN DIEST PJ, VAN DER WAALI, SNOW GB. Radical surgical treatment in craniofacial osteosarcoma gives excellent survival. A retrospective cohort study of 30 patients~ Oral Oncol Eur J Cancer 1994: 30B: 374-6. 23. TANZAWAH, UCHIYAMAS, SATOK. Statistical observation of osteosarcoma of the maxillofacial region in Japan. Oral
Surg Oral Med Oral Pathol 1991: 72: 444-7. 24. VE~E DS, BORGES AM, AGGRAWAL K, BALASUBRAMANIAM G, PARIKH DM, BHASER B. Osteosarcoma of the craniofacial bones. J Cranio Max-Fac Surg 1991: 19: 90-3. 25. VETHRPH. Osteosarcoma, current management, local control and survival statistics - The Netherlands. Clin Orthop 1991: 20: 67-71.
Address:
R. J. J. van Es Department of Oral and Maxillofacial Surgery University Hospital Utrecht Huispostnummer GO5.129 Postbus 85500 3508 GA Utrecht The Netherlands
197
Copyright9
1997
InternationalJournalof
Oral 8c Maxillofacial Surgery ISSN 0901-5027
0ncology
0steosarcoma of the jaw bones Long-term follow up of 48 cases
Robert J. J. van Es 1, Ronaid B. Keus2, Isaac van der Waal a, Ronald Koole a, Albert Vermey 3 1Department of Oral and Maxillofacial Surgery, University Hospital Utrecht; 2Department of Radiotherapy, the Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam; aOn behalf of the Dutch Head and Neck Oncology Cooperative Group (NWHHT), The Netherlands
R. J. J. van Es, R. B. Keus, I. van der Waal, R. Koole, A. Vermey. Osteosarcoma of the jaw bones. Long, term follow up o f 48 cases. Int. J. Oral Maxillofac. Surg. 1997; 26." 191-197. 9 Munksgaard; i997 Abstract. To evaluate the incidence and treatment results.of osteosarcoma of the j~iw (OSJ) in the Netherlands, data from 48 patients with a histologically proven diagnosis of osteogenic Sarcoma Of the maxilla or mandible were retrospectively analysed. Patient files, covering the period from 1964 to 1992, were obtained fr6in all university hospitals in the Netherlands and the Netherlands Cancer institute. The incidence of OSJ in the Netherlands is estimated to be at least 0.14 per 1 000 000. The overall 10-year survival was 59%. D i s t a n t metastasis occurred in 21% and local recurrences in 31% of the cases. Survival was significantly better in case of radical surgery and small tumoui:s. Long-term survival after treatment of OSJ was good if complete surgical excision was achieved. Radiotherapy should only be considered to prevent local recurrence if surgery is not complete. The possible benefit of current chemotherapy in preventing metastatic disease is still questionable. Since other malignant neoplasms associated with OSJ occurred in 17% of the cases, lifelong follow up is mandatory for the detection of these second primary malignancies.
Accepted for publication 14 December 1996
It is generally believed that osteosarcomas of the jaw bones (OSJ) behave differently from long-bone osteosarcomas (LOS) and have a markedly better prognosis4,5,21. Recent publications concerning larger groups of patients, however, refute this optimism. Long-term survival is reported to be less than 35%, mainly due to local recurrence2,6,1~ Using multi-agent chemotherapy, long-term survival of osteosarcomas of the extremities is presently reported to be approximately 45% 24'25, For this reason, multi-agem chemotherapy is recommended following radical surgery of OSJ as well. The purpose of this study was to
Working Group on Bone Tumours"has existed since 1953. In 1971 the "Dutch Working Group on Jaw Tumours" was formed. working closely together with the-former. Histology of all material was verified by pathologists from one of the two groups. Material obtained before 1982 was published earlier by BRAS3. All osteosarcomas, occurring in the mandible and maxilla were included in this study. If.involvementof the maxillary bone was less than about 50%. however, it was excluded because the characteristics of osteosarcomas in other craniofacial .bones are reported to be different from OSJ 16'2~ Forty-eight cases were collected and an~tlysed. The data are summarized in Table 1. Completeness of excisionwas based on the histology of the resection specimen. Only if
evaluate the incidence and treatment results of OSJ in the Netherlands. The Dutch Head and Neck Oncology Cooperative Group (NWHHT) retraced the histories of all patients with OSJ, treated in different university hospitals in the Netherlands over a period of 29 years, and analysed the data retrospectively.
Material and methods Patient material All university hospitals and the hospital of the Netherlands Cancer Institute were invited to participate in this retrospective analysis. The patient material covered the period 1964-1992. In the Netherlands. the "Dutch
Key words: osteosareoma; oncology; epidemiology; craniofacial bones; treatment results.
van E s et al.
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Table 1. Osteosarcoma of the jaw: clinical data of reported patients Case No.
Year sex
age
Died of disease or alive with 1 F 39 4 M 19 5 M 29 7 F 26 9 F 59 10 M 26 12 F 72 13 M 44 17 M 45 18 M 23 22 M 42 24 M 72 31 35 36 40 42 44 46
M M M F M M M
45 26 34 63 17 55 28
site disease Dr D Dm Dr Xm X-Z1 Xr X-Z1 Dr Dr Dr X-Er D1 X-Z1 Xr Dr X1 X-E1 Dr
Pa
Rmrks
2 H L H M/H H H 3 H M/H 3 I -
# # # ## # ##
# ##
N o evidence of disease or died of other cause 2 M 25 X-Z1 3 6 8 11 14 15 16 19 20 21 23 25 26 27 28 29 30 32 33 34 37 38 39 41 43 45 47 48
M M M M F M F M M M M M M M F F F M M M M F M F M F M F
25 43 31 55 29 31 25 15 30 40 56 12 71 46 49 65 15 18 30 75 17 57 28 35 11 45 21 19
X X1 Dm Dr Xr Xm X1 Xr DI Dr X1 X1 D1 Xr DI X1 X-FI X1 Dr D1 D1 Xr Xr Xr Xl X1 Xm D1
** 1 L 3 I/H H 1 1 1 -
*
** **
1/L L H L L 3 M/L L H H -
# # *
## **
Local recurrence
Metastasis
Follow up
Hosp
Treatment
year, m o n t h (therapy)
year, m o n t h (therapy)
year, m o n t h
64G 65U 66AL 67R 70A 71AL 73L 73R 76U 77G 80U 81AL
Sp S? Srt R S? Sp+R Sn R Srt+Ch Ch+R St+Ch Sd+R
0,2/0,5(R) 0,6 immediately 1(S)/4(S)/5(S)/13(S) immediately 0,2(R) 0,4(S)/5,6(S) -
0,5 lung(Ch) 0,6 lung lung 0,4(R) -
D O D 4,2 D O D 0,9 D O D 0,7 D O D 1,0 D O D 14 DOD, 1,4 D O D 0,11 D O D 6,6 D O D 1,11 D O D 0,3 D O D 5,9 D O D 1,2
83R 85N 86A 88G 90AL 90A 92U
St+Ch Sd+Ch Sp Sp+R Ch+Sp+R Sp Srt
0,6(S+R) immediately 0,3 0,5 1,3(Ch) 1,2(S)/2,2(S) 0,7(S)
64G
Sp
64U 66AL 69G 72G 74AL 75A 76U 78U 80AL 80G 80N 81A 82G 82U 82U 83U 83N 84G 84A 84M 87A 88N 88U 89G 90A -90A 92A 92A
Sn R+St Ch+R+Sn Ch+R+St R+St S? R+St+Ch St+Ch Srt/ Ch+St Srt st St St St Srt Srt Ch+St St " Ch+R+St Sn St Sn Ch+St+Ch St Sp+R St St
0,2(St+R)/ 0,4(R+Ch+R) 1,0(Ch+St+Ch) -
0,4 0,1 3,9 0,8 1,1 -
rib / vertebra lung pelvis / femur cervic lymphnd lung/liver/skeleton
0,3 lung 0,6 lung -
DOD DOD DOD DOD DOD AWD DOD
-
N E D 29
-
NED DOC NED NED NED NED NED NED NED NED DOC NED NED NED DOC NED NED NED NED NED NED NED NED NED NED NED NED NED
2,1 lung(S) 2,7 lung(S)
1,2 1,0 0,9 0,8 2,1 2,6 0,11
6,lost 11,10 24 12,1 18,10 11 12,6 13,11 10,8 12,8 4,7 11,7 11,7 10,2 4,10 10,6 9,7 9,1 8;11 8,3 5,10 4,11 5,10 4,8 2,4 2,6 0,9 0,3
Sex: M =male, F=female; Age: at time of diagnosis 9Site: X=maxilla, D=Mandible, E = E t h m o i d , Z = Z y g o m a , F=frontal; l=left, r=right, m=midline. Pa: Histopathology: Grade: L=Low, I=Intermediate, H = H i g h ; Mitosis: l=few, 2=intermediate, 3 = m a n y Remarks (case number): 9 14 after 10 years: Postirradiation-sarcoma of parotid followed by parotidectomy, after 13.5 years: basalioma of cheek 9 32 Developed diffuse encephalopathia with epilepsia (probably cisplatinum-induced). 9* 6 Bronchial carcinoma after 10.4 years, treated by pneumectomia 9* 20 Philadelphia chromosome positive, developed chronic myeloid leukemia after 10.8 years 9* 23 Intrapulmonary and skelettal lesions after 4.4 years, presumed bronchal carcinoma, not histologically verified. 9* 45 synchronous axillary non-Hodgkin l y m p h o m a # 9 First and second resection initially misdiagnosed as fibrous dysplasia # 10 Poly-ostotic fibrous dysplasia # 13 osteosareoma ex fibrous dysplasia # 18 fibrous dysplasia removed at age 16; 6 years before diagnosis of OSJ # 27 osteosarcoma ex Pagetiform sclerosis, M Paget not proven # 29 osteosarcoma ex fibrous dysplasia # 40 Ambonese, fibrous dysplasia diagnosed at age 51; 1 f years before diagnosis of OSJ ## 17 Previous radiotherapy (tuberculosis age 10; 35 years before) ## 24 Previous chemotherapy (multiple myeloma; 1.5 years before) ## 43 Previous chemotherapy (abdominal Burkitt-iymphoma age 6; 4 years before) ## 44 Previous chemo- and radiotherapy (fibrosarcoma cheek age 48; 7 years before) Hospital: N = N i j m e g e n , L=Leiden, M = M a a s t r i c h t , U = U t r e c h t , G = G r o n i n g e n , A = A m s t e r d a m - V U , A L = A n t h o n i e v.Leeuwenhoek; R = R o t t e r d a m Year: Ranking of cases according to the year in which diagnosis OSJ was established Treatment: S=Surgery: Sr:repeat resection, Sp:partial resection, Sd:total removal dubious; St:total removal; S n = n a r r o w margins S?=margin-status unknown R = Radiotherapy ; C h = C h e m o t h e r a p y Follow up: D O D = d i e d of disease, N E D = n o evidence of disease, D O C = d i e d of other cause, A W D = a l i v e with disease.
Osteosarcoma o f the jaw bones the pathologist claimed total surgical removal, was the excision considered to be complete. In all other cases, excision was considered to be not complete. From 1975 on, different types of chemotherapy were used in the participating h0spitals, largely according to the ROSEN protocolTM. Data analysis
As uncertainty exists whether tumour histology of OSJ (type, grade, mitotic index) corresponds with survival 11b,21, we tried to correlate survival with tumour volume. Information on tumour dimensions was available in 33 cases, A tumour volume (box with frame a . b" c) was estimated, based on the following: if only one dimension ('a') was available, then a=b=c; if two dimensions ('a' and 'b') were available, then c = b and b < a . Following data analysis, two g r o u p s , one with a " s m a l l " ( < = 5 0 cc, n=17) and one with a "large"(>50c, n=16) volume, were arbitrarily defined (Table 2).
Statistical analysis included Chisquare or Fisher's exact test and Kaplan-Meier curves. Differences between curves were analysed with the log-rank test, regarding P-values below 0.05 as statistically significant. The Cox proportional hazard test was used to analyse interaction between t u m o u r volume and completeness of excision. Results Epidemiology
A t the time of diagnosis, age ranged from l l to 75 years (median: 31 years). O f the 48 patients, 34 (71%) were male and 14 (29%) female. The peak frequency of OSJ for males was in their third decade. In females the i n c i d e n c e 0 f OSJ was evenly distributed among different decades (Fig. 1). Twenty-eight tum o u r s (58%) were localized in the maxilla and 20 (42%) in the mandible. Four tumours (8%) occurred in the midline. Assuming that participating hospitals covered about 80% of the cases*, the inci-
Table 2. Duration of symptoms (n=31), turnout dimensions and estimated volume (n=33) Case
Symptoms (weeks)
Dimensions (cm)
14 19 08 20 23 34 41 6 27 28 29 31 32 39 11 5 18 22 24 30 38 12 35 26 42 46 40 21
52 6 28 5 40 6 8 12 >300 4 500 6 8 20 12 8 4 52 28 6 4 75 24 25 25 12
1.7• 1.5 3 • 1.5 3.5• 2 3.5• 3•215 4• 2.5 3.5•215 3 3• 3 3 4.5x2.5 5?<2.5 3x4 6•215 4 4• 4 6x3.5 4?<5 5?44.5 5• 5 5.5 7x6•
1
4
6
16 2 7 10
6 8 10 16
6 7 8 10
Volume (cc) 2 3 7 7 8 8 15 16 16 26 27 27 27 27 28 31 36 54 64 64 64 74 80 101 125 125 166 210 216 216 343 512 1000
193
dence of OSJ in the Netherlands is estimated to be at least 0.14 per 1000000. D u r a t i o n of symptoms varied from 4 to 500 weeks, and tumour dimensions from 2.5 to 1000 cc. Disease-specific survival was significantly better in case of "small" tumours (P=0.015) (Fig. 2). Previous radiotherapy
Possible tumour induction by previous radiotherapy to the region 11c was found in 2 out of 48 cases (4%) (case nos. 17 and 44, respectively 7 and 35 years before diagnosis). Dysplastic bone
Dysplastic bone was found in 7 out of 48 cases (15%), of which one had a proven polyostotic disease. Two patients with fibrous dysplasia had a recurrent t u m o u r at the primary site more than five years after initial treatment. Survival
Recurrent t u m o u r was seen in 22 out of 48 patients ( 4 6 % ) . Twelve patients (25%) had a recurrent t u m o u r locally and six patients (13%) a recurrent- tum o u r at distant sites, whereas four patients (8%) had both local and distant recurrences. During follow up, 18 out of 48 patients (38%) died of the disease, of w h o m three died more than five years after initial treatment. The overall disease-free ,survival was 65% after five years and 59% after ten years. Recurrent tumour at the primary site
Recurrence at the primary site was seen in 16 out of 48 patients (33%), of w h o m only two survived. O f these 16 patients, 3 out of 16 suffered from local recurrence despite complete excision (two patients even had chemotherapy combined with surgery), 3 out of 16 patients had no initial surgery at all, and in 10 out of 16the resection was not complete. O f the 24 patients who were free of disease at the primary site and were followed for more than two years, 18 out
* In the period 1989-1992, 14 osteosarcomas of all carniofacial bones were registered at the Netherlands Cancer Registry. Based on the distribution patterns of Huvos 11", the jaws alone would account for about 71%, that is 10 cases. In the same period, participating hospitals reported 8 cases, which is about 80% of all OSJ.
van E s et aL
194
a local recurrence. The 12 other cases did not receive radiotherapy and recur, rence developed in nine of them. If the excision was not complete, adding postoperative radiotherapy to the surgery indicated a trend showing better local control (P=0.29), but not improved survival (P=0.45).
c~
o
co
~
Distant metastasis
Gender
Men Women
O
10~19
20-29
30-39
40-49
50-59.
60-69
70~79
Age
(years)
Fig. 1. Osteosarcoma of the jaw in the Netherlands. Distribution of age at diagnosis and
gender (n=48).
of 24 excisions were complete. Four had narrow margins, in one completeness of excision was unknown, and only one patient had a debulking with adjuvant radiotherapy. Of these 24 patients, 16 out of 24 received surgery as monotherapy. The difference in survival between completely and not completely excised cases was significant (P=0.012; Fig. 3), also when corrected for tumour volume (P=0.017; Fig. 4).Ten-year survival following resection of large tumours was
69% when excision was complete; but dropped to 13% if excision was not complete. Interdiction between these two parameters li.e. tumour volume and completeness of excision) could not be established. In 18 cases, completeness of exclston could not be verified: partial excision in eight cases, dubious margins in two, narrow margins in five, completeness unknown in three (Table 1). Of these 18 cases, six did receive postoperative radiotherapy, of which three developed
p : 0.017
Metastatic disease occurred in 10 out of 48 patients (21%). The lung was involved in eight of these cases, the skeleton in three, the liver in one and neck nodes in one case. All these patients died of the disease except one, who undei'went pulmonary resection twice (case no. 21). Of the six patients having metastasis with local disease controlled, four had cfiemotherapy as part of their initial therapy. One patient suffered from possible iatrogenic damage from chemotherapy (case no. 32: encephalopathia with epilepsia), one from possible iatrogenic damage of radiotherapy (case no. 14: parotid sarcoma and basal cell carcinoma). Other malignant neoplasms
Eight patients (17%) had other neoplasms associated with OSJ, of which four originated from the haematopoietic system. Three patients Icase nos. 24, 43 and 44) were treated with chemotherapy for previous neoplastic disease (respectively 1.5, 4 and 7 years before the diagnosis of OSJ). Five patients (case nos. 6, 14, 20, 23 and 45) developed other turnouts during the follow up.
eO d
Discussion
1 LI
~5
t
Lt
Q
L----] L .
.
.
.
.
.
.
L. . . . .
9
I L. . . . . . . . . . . . . .
C~
Volume <~50 cc
0 C~
I
L
I
I
2
4
6
8
..... 10
Time (years) Fig. 2. Disease-free survival rates according to tumour volume.
> 50 cc
Although we are aware that the calculated incidence is inaccurate, its estimation of at least 0.14 corresponds well with a 5% share xb of all 42-84 osteosarcomas per year occurring in the Dutch population of approximately 15 million people 25. It is higher than the 0.02 in Japan as reported by TANZAWA et al. 23, but probably lower then the 0.7 in the US as suggested by GARRINGTON et al. 8. A male preponderance of OSJ in our population [7:3) is comparable to a US populatio n described by CLA~K et al. 4 and MARK et al. 13 (about 2:1), but different from reports from Germany 1~ and Italy2 (about 1:i) or Japan 23
Osteosarcoma of the jaw bones O
-~,
p = o.o12 k........
O
~5 O
Excision O
.....
5
10
Not complete Complete
20
15
Time (years)
Fig. 3. Disease-free survival rates comparing complete and not complete excision.
p = 0.017
I
. . . . . . . . . . . . .
s
Volume > 50 cc oniy: Excision o o
.... I
I
q
I
2
4
6
8
Not complete Complete
10 Time (years)
Fig. 4. Disease-free survival rates in case of large turnout volume, comparing complete and not complete excision.
(1:1.5). A maxillo-mandibular ratio of about 3:2 is comparable with a l:l ratio found by others 4,6,1~ Different ratios, ranging from 2:323 to 3:72, might also be explained by different criteria used in excluding tumours of the maxilla with extension to other facial bones. The uniform age distribution of OSJ in females is in contrast with previous reports 4,11b , 2 3 An extensive analysiS concerning differences between behaviour o f OSJ versus LOS was presented by SI~OOTWE~&
M~LLER21. As LOS occurs at a lower mean age, one of the explanations for the better prognosis of OSJ is an increase in host resistance to the tumour with advancing age 3;21. This assumption is, however, in contrast with the findings Of SMEELEet al. 22. They report better survival of patients under 35 years of age. In our study, no age-related difference in survival could be demonstrated (Fig. 5)i Previous reports from our country indicated a 5-year survival of 41-
195
69% 3,21,22. The favourable lO-year disease-free survival of 59% in this group is probably based on a comparatively low rate of local recurrences: 33% in this study versus 50-95% local recurrences reported by others 2'10'13'23'24. Distant metastases occurred in 21% in this material, which is comparable to the figures found in the literature. The importance of complete surgical resection was already mentioned by CLARK et al. 4 and is further stressed by others 11b'21'22. In cases of large tumours, however, urging multi-piece resection, thorough histological assessment of completeness of excision is difficult. Tumour dimensions exceeding 10 cm and previous surgery elsewhere might explain the high rate of local recurrences and mortality mentioned by DELGADO et al. 6, despite the fact that 43% of their excisions were claimed to be complete, Recurrent tumour at the primary site more than five years after initial treatment in two patients with fibrous dys~plasia (case nos. 9 and 13) is remarkable and could possibly be eXplained by the occurrence of new primaries. The parameter tumour volume in this study was only used as a crude to01 to compare different dimensions available in the patient files. The positive influence of small tumour-size on survival was already suggested~bY BEI~TONI et al. 2, whether this parameter is more relevant than tumour histology remains unclear. If excision is histologically complete, surgery alone seems sufficient. Adjuvant irradiation should be considered if excision is not complete. The beneficial effect of radiotherapy on local control or survival has not reached significance in this study, probably because of the few cases involved. Of the 32 patients with local tumour control, six developed metastatic disease; though four of these six patients received chemotherapy according 'to one of ROSEN'S schemeslS; This, as well as possible toxicity and persistent cerebral dysfunction is, should b e taken into account when considering the possible benefit of "neo-adjuvant" chemotherapy for OSJ. However, the issue of preventing metastatic disease following local cure, deserves full attention, and agents which modify multidrug resistance might prove to be useful 1. As advocated for metastatic LOS 19, thoracotomy and pulmonary resection Should also be considered in
van Es et al.
196
._ ffJ
..c
p = 0.60
-i
o
-'L_ 2 .....
,~
L
L.....
. I
o
Age
--0
2
4
6
8
3t.25 yrs > 31.25 yrs
1:0
Time ( y ~ s )
Fig. 5. Disease-free survival rates comparing patients younger and older than the median age.
case of isolated pulmonary metastatis (case no. 21). A relation between previous irradiation of a malignancy and development of osteosarcomas (case no.44), as well as tile development of secondary malignancies following irradiation and/ or chemotherapy for osteosarcomas (case no. 14), are well known 11a,11c'12. The possible role of previous chemotherapeutic agents in the carcinogenic process of osteosarcomas (case nos. 24, 43 and 44), was mentioned by NEWTON et al. 14. As suggested by others 7;ala,14, genetic predisposition may play a role in patients with an osteosarcoma as part of a multiple malignancy syndrome. Whether a case of Li-Fraumenti syndrome was among this material could not be established. SMEELEet al. 22 drew attention to the association between n o n - H o d g k i n l y m p h o m a and second primaries (case no. 45). Chromosomal abnormalities (case no. 20) have been found in patients with osteosarcomas 11a and recently attention has been focused on the retinoblastoma and p53 suppressor genes 9. This high incidence of second primaries justifies a high degree of alertness during the follow up of patients cured from an osteosarcoma of the jaw. Acknowledgments. We would like to thank the following members of the Dutch Head and Neck Oncology Cooperative Group (NWHHT), who participated in this study:
Institution (number of patients)
Investigator
Free University Hospital Amsterdam (11) University Hospital Utrecht (11) University Hospital Groningen (10) The Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital Amsterdam (7) University Hospital Nijmegen (4) University Hospital Rotterdam (3) University Hospital Leiden (1) University Hospital Maastricht (1)
I. van der Waal R. Koole A. Vermey E J. M. Hilgers
I. Bruaset R E M. Knegt A . G . L . van der Mey J . M . H . van der Beek
References
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Address:
R. J. J. van Es Department of Oral and Maxillofacial Surgery University Hospital Utrecht Huispostnummer GO5.129 Postbus 85500 3508 GA Utrecht The Netherlands
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