=20 Osteosarcoma =96 = current concept=20 review

=20 Prof.A.Devadoss, = Department of Orthopaedics, Institute of = Orthopaedic=20 Research and =20 Accident Surgery, Madurai

=20 Primary malignant bone tumours are rare. The two most common types, = osteosarcoma=20 and Ewing=92s Sarcoma have a peak incidence in the second decade of life = and an=20 annual incidence of two and 0.8 per million population respectively = ¹=20 In our Country though we have no Bone Tumour Registry the incidence is = almost=20 the same in the Authors experience and experience of other Orthopaedic = Surgeons=20 also.

=20 Most of our patients come to us with primary malignant tumour = very late=20 after having had native treatment or missed by the General Practitioner = or by=20 Junior Orthopaedic Surgeons. = These=20 tumours are so rare that most doctors will see only a few patients with = symptoms=20 from an undiagnosed primary bone tumour during their whole working = life. Most general practitioners = therefore=20 have little or no experience with these primary malignant tumours, but = they are=20 the first doctors consulted in the initial phase of the=20 disease.

Osteosarcoma

=20 Early recognition and treatment is important in all malignant=20 diseases. In recent = decades there=20 has been a remarkable increase in survival rates of both patients with=20 osteosarcoma and those with Ewing=92s Sarcoma = ^2.

=20 Bjorn Widhe and Torulf Widhe from Sweden ³ studied the initial symptoms = and clinical=20 features in Osteosarcoma and Ewing=92s Sarcoma in 102 and 61 patients=20 respectively. They came = to a=20 conclusion that an initial symptom of Both O.S and E.S. was pain, which = was=20 intermittent and often related to strain but not infrequently felt at=20 night. A history of = trauma was=20 common, but the clinical course often diverged from what was expected = from=20 trauma. The clinical = course of=20 osteosarcoma and particularly of Ewing=92s Sarcoma was not steadily = progressive,=20 but intermittent, who often misled the Doctor into believing that the = condition=20 was temporary and tubbed as post traumatic strain. The most important clinical = feature was=20 a palpable mass which was noted in more than one-third of the patients = at the=20 first visit. This finding = emphasizes that a thorough physical examination is absolutely=20 necessary.

=20 The author also strongly believe that physical examination must = be=20 carefully done and also any swelling and pain coming on little late = after=20 injury, the surgeon must always keep bony tumour in the back of his mind = as=20 differential diagnosis.

=20 In this article I have attempted to review the most common = primary=20 malignant tumours of bone ie. Osteosarcoma only.

=20 Osteosarcoma is a highly malignant spindle. Cell sarcoma of bone = in which=20 the malignant cells produce osteoid ⁴. It is the most common = primary=20 malignant tumour of bone. However, and increased prevalence has been = reported in=20 families affected with = Li-=20 Fraumeni = Syndrome⁵ and in patients who have had=20 retinoblastoma⁶, have undergone radiation therapy⁷ or = have Paget=92s=20 disease ⁸

=20 75% of cases of primary osteosarcoma occur between the ages of = ten to=20 twenty five years. Second peak in 60-70 of years due its association = with=20 Paget=92s disease of bone. Its most common location are the distal femoral = metaphysis ( 35%), the Proximal tibial metaphysis ( 20%) and the Proximal Humeral Metaphysis = (10%), all =20 areas of rapid skeletal growth. Boys are slightly more affected than girls. = Occasionally=20 the tumour is found in the diaphysis of long bones and more rarely, in = the flat=20 bones.

Clinical=20 features

=20 Pain is the most common complaint occurring in 85% of patients=20 ³ . It is probably due to micro fractures through the = involved areas=20 of the bone or in severe cases, due to compression or stretching of = adjacent=20 anatomic structures. Pain = is=20 exacerbated by games or any other intensive activity and only 21% of = patients=20 have pain at night ³. = History of Trauma may be present of 50% of patients. A palpable or visible mass = will be=20 present in 40% of cases. = Sometimes=20 they present with limping, weakness, diminished range of movements in = the=20 associated joint, venous engorgement, oedema and striae. Elevated serum lactate = dehydrogenase and=20 alkaline phosphatase levels have been associated with poorer prognosis.=20 ^9,10

Plain=20 x-ray appearance

Destructive=20 lesion of the metaphysis of a long bone. =20 Mixture of lytic and blastic areas but may be exclusively one or = the=20 other. Usually has an = extra osseous=20 soft tissue mass with fluffy irregular densities indicative of = neoplastic bone=20 formation. Codmans = Triangle of=20 reactive periosteal new-bone formation is seen at the proximal and = distal=20 cortical margins of the tumour. =20 However these are not specific for = osteosarcoma.

=20 MRI, Bone Scientigraphy and CT Scan of Lungs are useful in = staging the=20 disease. It is beyond the = scope of=20 this review article.

Pathology

Gross=20 examination of an osteosarcoma specimen most often reveals or soft = tissue mass=20 originating in the medullary canal and extending beyond the cortex. Inner part of the mass is = heavily=20 minaralised than the=20 periphery.

=20 Microscopically frankly malignant cells producing osteoid. These cells are pleomorphic = and exhibit=20 mitotic activity. = Pathologist must=20 be informed about the clinical and radiographic findings of the = case. Otherwise the pathologist may = mistake=20 the reactive bone of fracture callus or periosteal new bone for that = produced by=20 the malignant cells of osteosarcoma or vice versa.

Osteosarcoma=20 variants

Because=20 of the variations of osteosarcoma, the Orthopaedic Surgeon sometimes = misses the=20 diagnosis in the early phase of the disease. The primary type of = osteosarcoma=20 include high grade central (classic variety), low grade central, Juxta = cortical=20 or surface and telengiectatic varieties. The secondary type include post = irradiation sarcoma, Pagets disease, dedifferentiation from fibrous = dysplasia=20 and bone infarcts. The classic high grade central osteosarcoma does not = pose a=20 difficult diagnostic challenge. The surface type of variants of = osteosarcoma=20 include periosteal, parosteal and high grade surface tumours. Periosteal = osteosarcoma is most commonly found in the diaphysis of long bones = especially=20 Femur and Tibia. = Radiographically=20 it appears as a variably calcified mass in a saucer shaped defect in the = cortex=20 of a long bone. = Histologically, it=20 is composed of intermediate grade malignant cells including osteoid in=20 predominant chondroid back-ground. =20 It occurs in adolescence and has a metastatic rate between the = paraosteal=20 osteosarcoma and that of the conventional osteosarcoma. The treatment is wide excision = and the=20 role of chemotherapy is unclear¹¹. However in the Authors = experience of 2=20 cases of periosteal osteosarcoma of femur and tibia, local excision and=20 chemotherapy has given fairly good survival rate of more than 5=20 years.

Paraosteal=20 osteosarcoma is common in the distal femoral metaphysis in its popliteal = surface=20 and have a lobulated radiodense =93pasted on=94 appearance in the = X-ray. There is an apparent cleavage = plane=20 between the bone and the tumour. = Usually occurs in the age group between 20-40 years. Biopsy reveals a low grade = fibrous=20 stroma with tumour osteoid and bone formation ¹² wide = excision=20 without chemotherapy low grade tumours gives a survival rate of 93%=20 .¹³

High-grade=20 surface osteosarcoma is not a common tumour, occurs in the = 2^nd and=20 3^rd decade. =20 Histologically looks the same as classic osteosarcoma. Wide surgical excision and = chemotherapy=20 is thought to be beneficial. Telengiectatic osteosarcoma is a high-grade = osteosarcoma which is more destructive in the x-ray. It is similar to classic high = grade=20 osteosarcoma in its behaviour, treatment and outcome. = Secondary=20 osteosarcomas are associated with Pagets disease of bone or in a bone = that had=20 undergone irradiation. = Both have a=20 poor prognosis.

Treatment=20 of osteosarcoma

=20 Lot of improvement has taken place in the treatment of = osteosarcoma. Before 1970, Amputation or=20 disarticulation was the treatment of choice. Large proportion died of secondaries by 1=20 year.

=20 Modern therapy for osteosarcoma begins with accurate clinical = staging the=20 final step of which is biopsy ¹⁴. The current standard of = treatment is=20 multiagent pre-operative (neoadjuvant) chemotherapy combined with wide = resection=20 or amputation followed by postoperative (neo adjuvant) chemotherapy.=20

=20 Rosen et al¹⁵ showed a reasonable increase in survival = of=20 patients treated with neo adjuvant chemotherapy there are lot of factors = that=20 help with neo adjuvant chemotherapy

1. = ;=20 Prevents=20 the development of resistant clones in a tumour with rapid doubling = time.=20 Postponing the institution of chemotherapy until after surgery might = allow=20 spontaneous mutations to = occur,=20 resulting in resistant clones.

2. = ;=20 Preoperative chemotherapy would = kill the=20 microscopic metastasis already present in the majority of=20 patients

3. = ;=20 Neo=20 adjuvant chemotherapy may also shrink the primary tumour and sterilse = the=20 microscopic tumour foci = in the=20 reactive zone around it, facilitating resection and increasing the = chance for=20 limb- Sparing surgery.

4. = ;=20 It also=20 allows time for surgical planning, the fabrication for a custom = made tumour=20 prosthesis or the procurement of allograft tissue for=20 transplantation.

5. = ;=20 Neoadjuvant=20 chemotherapy induces necrosis in the primary tumour, and the amount of = necrosis=20 serves as an extremely important prognostic indicator for long = -term = survival.

=20 Because of the above theoretical =20 advantages, most protocols =20 include neoajuvant chemotherapy . The drugs that are most = commonly used=20 in combination for the treatment for the osteosarcoma are Doxorubicin = high dose=20 of Methotrexate, cisplatin and , most recently ifosfamide^=20
16.

Surgical=20 management will be successful only when we attain wide surgical margins. = Limb=20 sparing resection or amputation can be done. Rougraff et al ¹⁷ reported that there does not = to be any significant = difference in long term survival between = patients who=20 undergo amputation and those who have a limbs sparing procedure provided that wide margins are obtained.

=20 In modern times many of our patients are not willing for = amputation and=20 may be willing for limb sparing resection . However to do limb sparing = resection=20 there are some criteria, wide margin can be obtained without sacrificing = so much=20 tissue that the remaining limb is non functional . Usually the = determining the=20 factor is the ability to spare major nerves. Major vessels need to be = preserved=20 or reconstructed. There = must be=20 adequate soft tissue coverage to prevent infection and good function . = The=20 overall reconstruction should function as well as or better than an = appropriate=20 prosthesis after an amputation.

The=20 following are available for reconstruction of the skeletal defect,=20 osteoarticular allo graft, intercalary allograft, a metal endoprosthesis, an allograft - prosthesis = composite,=20 arthrodesis, rotation = plasty and=20 free vascularised fibular transfer. Provisor et al ¹⁸ and Glasser et al = ¹⁹ proved that the current = management=20 protocols provide long term survival rates of between 60% and 80% for patients, without = clinically=20 apparent metastatic disease at =20 presentation. Bacci et al ²⁰ reported that patients who have = clinically apparent metastasis at presentation fare considerably worse with five = year=20 survival rates of 10% and 20%. When =20 pulmonary metastasis develop after completion of therapy and the=20 metastatis can be resected, five year =20 survival rate of 20% to 40% =20 can be expected as per Ward=20 et al ²¹.

Prognosis=20 in = osteosarcoma

Very=20 often the parents will ask the surgeon regarding the=20 prognosis.

It is=20 better to be frank about that the prognosis in these cases . The usual = questions=20 the parents will asks as whether my son or daughter will be again normal = . The=20 predictive factor is the presence of absence of detectable metastatic = disease at=20 presentation . As mentioned, the survival rate for patients who have = metastatis=20 at the time of = presentation is between 10% and 20%. Patients = who have=20 tumors with a good response to chemotherapy ( >90% = tumour=20 necrosis ) have a considerably better long-term survival rate = than those=20 who have tumour with a poor response. (<90% tumour = necrosis)¹⁶=20 Other poor prognostic variables reported in the literature include elevated serum lactate dehydrogenase and alkaline = phosphates=20 levels ^8,9.

Molecular=20 and genetic considerations of osteosaracoma

Chromosomal=20 abnormalities

Chromosomal=20 abnormalities are common in osteosarcoma. =20 Approximately 70% of osteosarcomas will show some chromosomal = abnormality=20 including gains and losses. =20 Consistantly idendified abnormalities include a gain of = chromosome 1;=20 loss of chromosomes 9,13 and 17; partial loss of chromosomes 6q and=20 rearrangements involving chromosomes of 11, 19 and 20=20 ²².

=20 Some of these abnormalies are consistant with the syndromes that = are=20 associated with osteosarcoma. For instance, the Rb gene for = retinoblastoma maps=20 to chromosome 13q and p53 for Li-Fraumeni maps to 17p. Loss of these chromosomal = regions could=20 create defects similar to those for patients who have the genetic=20 mutation.

=20 In normal cells, shortening of telomeres at the ends of = chromosomes is=20 responsible for its senescence. Tumour cells escape normal senescence by = abnormally maintaining telomere length. =20 There are two mechanisms to maintain telomere length as the = chromosome=20 duplicates. The first = uses a=20 telomerase, which lengthens the telomere, and the second is a = recombination=20 based method using the alternative lengthening of telomere (ALT) = pathway. About 50% of osteosarcomas are = dependent=20 on the ALT pathway to evade senescence ^20. the ALT pathway is associated = with more=20 chromosomal instability, which may explain the large variations of = chromosomal=20 defects associated with osteosarcoma. =20 In an animal model, a telomerase pathway was associated more = closely with=20 metastatic potential ^20. =20 Therefore, the telomere maintenance mechanisms may function as an = early=20 marker for more aggressive disease.

Oncogenes

=20 The effect of oncogenes on tumorigenesis is different from that = of tumour=20 suppressors in that mutation of a normal proto-oncogene to an oncogene = confers a=20 gain of function, as opposed to a loss, driving the cell toward a = malignant=20 phenotype. C-myc is a=20 proto-oncogene transcription factor found to be over expressed in many = human=20 cancers. C-fos is another = transcription factor implicated in many cell =96processes including = cell-cycle=20 progression. It is also = involved in=20 osteoblast and chondrocyte differentiation Gamberri et al ^{23 =}studied=20 both C-myc and C-fos were shown to be overexpressed in osteosarcoma, = especially=20 in pulmonary metastasis.

=20 Her 2/erb B-2 is a cellular proto-oncogene that encodes the human = epidermal growth factor receptor-2 (Her 2). Overexpression of this = oncogene induces=20 malignant transformation of rodent fibroblasts and has been implicated = in=20 decreased survival of patients with breast carcinoma. Gorlick et al=20 ²² and Onda et al ²⁴have recently studied that=20 overexpressions in approximately 40% of the osteosarcomas and a = correlation with=20 decreased event-free survival and histological response to neo-adjuvant=20 chemotherapy. With the = development=20 of additional prospective studies, the presence of the Her 2/erb B-2 = receptor=20 eventually may emerge as a significant prognostic indicator. It may also become a treatment = target,=20 with use of recombinant anti Her 2 monoclonal antibody tumours positive = for=20 overexpression.

=20

=20 The MDRI (Multidrug resistance) gene codes for an adenosine = triphosphate=20 dependent cellular efflux pump (p-glycoprotein) that actively transports = doxorubicin (among other drugs) out of the cell. It would make sense that cells = overexpressing MDRI would be relatively resistant to doxorubicin, an = important=20 agent in the treatspent of osteosarcoma ²⁵. Although the logic behind the = theory=20 that MDRI confers a resistant phenotype upon osteosarcoma cells is = attractive,=20 its true effect remains somewhat = controversial.

Angio-genesis

=20 In cancer therapy Anti-angiogenesis has become a very interesting = topic=20 in recent times. = Anti-angiogenic=20 agents have been shown to inhibit tumour regression in mouse models=20 ^26. Kaya et al = ²⁷ demonstrated expression of vascular endothelial growth = factor=20 (VEGF) in seventeen (63%) of twenty seven osteosarcomas. They also correlated this = expression=20 with a high prevalence of pulmonary metastasis, suggesting that = expression of=20 VEGF may play a role in the metastatic cascade of osteosarcoma. From their findings there are = two drugs=20 currently on trial for Anti angiogenesis. =20 Anti-vascular endothelial growth factor receptor inhibitor are = the drugs=20 that may will prove advantageous in the treatment of=20 osteosarcoma.

=20 In conclusion, the classic high grade osteosarcoma in young adult = in the=20 metaphysis must be diagnosed early. =20 The general practitioners who sees these patients must be = educated to=20 diagnose them early. With = the=20 modern technology of MRI, CT and bone scans it is possible to diagnose = these=20 cases very early. Early = diagnosis=20 carries a 93% good prognosis with neo-adjuvant chemotherapy and Limb = sparring=20 surgeries.

=20 In the near future, molecular analysis may very well help to = stratify=20 patients with osteosarcoma into relative risk groups (molecular staging) = allowing more tailored treatment regimens. =20 In addition, we hope that, with further progress, highly = selective=20 targets for osteosarcoma without the substantial morbidity of current = cytotoxic=20 chemotherapy will be idendified.

=20

References

1.=20 =20 Larsson .S.E. and Lorentgen .R =96 The incidence of Malignant = Primary =20 bone =20 tumours in relation to age, sex and site. A study of osteogenic =20 sarcoma, =20 chondrosarcoma and Ewing=92s Sarcoma diagnosed in Sweden =20 from 1958 to =20 1968 =96 JBJS 56B(3):536-540,1974. =20

2.=20 =20 Arudt, C.A.S., and Erist .W.M., Common musculo skeletal tumours = of =20 childhood and adolescence. =20 Nev England J.Med. 341:342-352.1999

3.=20 =20 Bjorn Widhe and Torulf Widhe =20 JBJS Vo.82.A.No.5 666-674

4.=20 =20 Mirra JM. Bone Tumours. =20 Clinical, radiologic and pathologic =20 correlations,- =20 Philadelphia Lea = and Febiger=20 1989

5. =20 Evans .S.C., Loyano.G =96 The Li- Fraumeni Syndrome, an inherited =20 susceptibility to cancer. Mol.Med.Today 1997 3:=20 390-5

6.=20 =20 Dukel IJ, Gerold WL, Rosenfield NS, Strong EW, Abramson DH =20 Ghasim.F. =20 Outcome of patients with a history of bilateral =20 retinoblastoma = treated for a=20 =20 second malignancy . The Memorial Sloan =96 Kettering experience. Med. =20 Paediatric Oncol .1998 30: 59-62

7.=20 =20 Sheppard DG, Lipshity H1. Post radiation sarcoma: a review of the clinical =20 and imaging features in 63 cases. (Clin .Radiology =96 2001 56:22 = -9).

8.=20 =20 Hadfipavlon.A,Lander.P.,SrolovityH,EnkerIP:Malignant =20 transformationin =20 Paget disease of bone =96cancer 1992: 70 : 2802 =96 = 8

9.=20 =20 Bacci G Ferrari S Sangiorgi L., Picci.P, Casadel R, Corlandi = MIantorna D,=20 Battistini .A , Zanone .A Prognostic significance of = serum =20 lactate dehydrogenase in patients with osteosarcoma of the = extremities=20 J.Chemotherapy 1994 6:2004-10

10.=20 = Bacci G,=20 Picci.P, Orlandi .M, Avella =20 M, Manfrine M. Pignatti.G, Dallari.D, Manduchi.R, Prognostic = value =20 of serum Alkaline phosphatase in osteosarcoma, Tumouri 1987, 73=20 331-6.

11 Rivs GD, = Pritchord DJ,=20 Unni KK, Beabout JW, ECkardt JJ, Periosteal

=20 Osteosarcoma, clinical Orthopaedics. 1987,=20 219-299-307

12. Okada, Frassica F.J., = Sim F.H.,=20 Beabout J.W., Bond J.R., Unni K.K.,

Parosteal Osteosarcoma. = A=20 clinicopathological study. JBJS

= Am.1994:76:366-78

13. Sheth DS, Yasko AW, = Raymond A.K.,=20 Ayala AG., Carrasco C.H.,

Benjamin R.S., Jaffe.N., = Murray=20 .JA., - Conventional and de- =20

=20 differentiated parosteal osteosarcoma. Diagnosis, Treatment = and

=20 outcome. Cancer. 1996:78:2136-45.

14. =20 Peabody=20 TD., Gibbs c.P., Simon M.A., Current Concept review.

= Evaluation=20 and staging of musculoskeletal neoplasms. JBJS Am. 1998

=20 80.1204-18

15. =20 Rosen=20 .G, Marcone RC., Caparros .B., Nirenberg .A., Kosloff.C., Huvos AG., = Primary=20 osteogenic sarcoma and reationale for preoperative chemotherapy and = delayed=20 surgery. Cancer 1979:43,=20 2163-77

16. =20 Winklerk,=20 Beron.G., Delling.G, Heise V., Kabisch.H., Purfurst.C., Berger.J, = Ritter.J.,=20 Jurgens.H, Gerein.V et al. =20 Neoadjuvant chemotherapy of osteosarcoma results of a randomized=20 co-operative trial (COSS-82) with salvage chemotherapy based on = histological=20 tumour response. J.Clinical Oncology. 1988; = 6:329-37.

17. =20 Rougraft=20 BT., Simon MA., Kneisl JS., Greenberg DB., Mankin HJ, Limb salvage = compared with=20 amputation for osteosarcoma of the distal end of the femur. A long term oncological, = functional and=20 quality of life study. = JBJS Am.1994=20 76:649-56.

18. =20 Provisor=20 AJ., Ettinger LJ., Nachman JB, Krailo MD., Makley JT., Yuris EJ, Huvos = AG., Betcher DL., Baun ES, Kisker = CT., Miser=20 JS. Treatment of non = metastatic=20 osteosarcoma of the extremity with preoperative and postoperative=20 chemotherapy. A report = from the=20 children=92s cancer group. = Journal of=20 Clinical Oncology. =20 1997:15:76-84

19. =20 Glasser=20 DB, Lane JM, Huvos AG., Marcove RC., Rosen G., Survival, prognosis and=20 therapeutic response in osteogenic sarcoma. The Memorial Hospital = experience=20 Cancer. =20 1992:69:698-708.

20. =20 Bacci.G.,=20 Mercuri.M., Briccoh.A., Ferrari.S., Bertoni .F., Donati .D., Monti.C.,=20 Zanoni.A., Forni.C., Manfrini.M., Osteogenic sarcoma of the = extremity=20 with detectable lung metastasis at presentation. Results of treatment of 23 = patients with=20 chemotherapy followed by simultaneous resection of primary and = metastatic=20 lesions. Cancer=20 1997:79:245-54.

21. =20 Ward=20 WG, Mikaclian .K, Dorey-F., Mirra J.M, Sassoom.A., Holmes EC, Eilbert = FR.,=20 Eckardi JJ. Pulmonary = metastasis of=20 stage IIB extremity osteosarcoma and subsequent pulmonary metastasis. = J.Clinical=20 Oncology 1994:12:1849-58

22. =20 Gorlick.R.,=20 Anderson.P, Andrulis I et al. =20 Biology of childhood osteogenic sarcoma and potential targets for = therapeutic development meeting summary. =20 Clinical cancer Research 2003; 9-5442-53

23. =20 Gameri.G.,=20 Benassi MS., Bohling J., Ragaryyini .P., Molendini.L, Sollaryyo MR, = Pompetts F.,=20 MErli.M, Magagnoli .G., Balladelli.A., Picci.P., C-Myc and C-fos in = human=20 osteosarcoma prognostic value in MRNA and protein expression. Oncology=20 1998:55:556-63

24. =20 Gorlick=20 .R., Huvos AG., Helles .G., Aledo.A., Beardsley GP., Healey JH., Meyers=20 P.A., Expression of HER = 2/erb B-2=20 correlates with survival in Osteosarcoma. J.Clin.Oncology =96 1999:17 = 2781-8.=20

25. Onda .M., Matsuda .S, = Higaki.S., Lijina=20 .T., Fukushima .J., Yokokura

.A., = Kojima.T.,=20 Horiuchi.H., Kurakova T., Yamanoto.T., Erb B-2

= expression is=20 correlated with poor prognosis for patients with

= osteosarcoma=20 cancer. =20 1996:77:71-8