Thirty-seven COSS patients pretreated assuming a tumor diagnosis distinct from osteosarcoma were identified. The erroneous diagnosis had been benign in 29/37 (78%; bone cyst 8 (aneurysmatic 7, unspecified 1), giant cell tumor of bone 6, bone forming and fibro-osseous tumors 8 (osteoblastoma 6, ossifying fibroma 1, osteoid osteoma 1), chondroid lesions 4 (chondromyxoidfibroma 2, chondroblastoma 1, synovial chondromatosis 1), fibrolipoma 1, and not clear 2). Malignancies were assumed in 8/37 (22%; chondrosarcoma 6 (conventional 5, mesenchymal 1), malignant giant cell tumor 1, carcinoma of unknown primary (CUP) 1) cases.
The study cohort consisted of 14/37 (38%) males and 23/37 (62%) females. None of the affected patients was reported to suffer from a known tumor predisposition syndrome or had a history of prior malignancy. The median age at the first (incorrect) diagnosis was reported as 19.7 (range: 2.7–60.4) years. Twenty-three (62%) tumors were located in the limbs (tibia 9 (proximal 6, distal 2, diaphysis 1), femur 7 (distal 5, diaphysis 1, proximal 1), fibula 3 (all proximal), humerus 3 (proximal 2, distal 1), foot 1). Eleven (30%) tumors affected the axial skeleton (pelvis 8, ribs 2, clavicle 1), three (8%) were located craniofacially (base of skull 1, maxilla 1, mandibula 1). Primary metastases, to distant bones, were only reported for one (3%) tumor, the one assumed as CUP.
All patients had been subjected to a diagnostic biopsy or primary surgery. In total, 36/37 (97%) received an operation intended to remove the lesion. Radiotherapy or chemotherapy was administered to one (3%) patient each. In total, 35/37 (95%) of all patients were considered cured by first-line therapy.
The correct diagnosis of osteosarcoma was finally made at the second disease manifestation in 22/37 (59%), the third in 11 (30%), the fourth in two (5%), and the fifth and sixth in one (3%), patient each. By then, it was a correct assumption in 9/22 (41%) and an unexpected finding in 13/22 (59%) among 22/37 (59%) with appropriate information. The latency period from the first incorrect diagnosis to the diagnosis of osteosarcoma was reported as 8 months (range: 1 month – 14.1 years). It was longer than one year in 15/37 (42%) and longer than five years in 2/37 (5%) affected patients. Patients were 22.1 (5.4–60.4) years old when the osteosarcoma diagnosis was made.
Information about the osteosarcoma subtype was available for 31/37 (84%) patients. Among these, 9/31 (29%) tumors each were considered osteoblastic and chondroblastic, 6/31 (19%) teleangiectatic, and 5/31 (16%) fibroblastic. One tumor each (3%) was classified as undifferentiated pleomorphic sarcoma-like and osteoblastoma-like. The absolute size of the primary tumor at time of correct diagnosis was only known for 12/34 (35%) of osteosarcomas with local involvement. In these, it was a median of 6 (1.6–13) cm. Its relative size in relation to the involved bone was known for 13/34 (38%) of these and was reported as less than one third of the involved bone in 11/13 (85%) and more in 2/13 (15%). At the time of the osteosarcoma diagnosis, 31/37 (84%) affected patients still had localized disease, 3/37 (8%) metastases only, and 3/37 (8%) had both a local recurrence and metastases. Metastases involved the lungs in four/37 (11%), distant bones in one/37 (3%), and both in one/37 (3%). They consisted of more than one lesion in all but one case, a solitary lung metastasis.
Among patients with involvement of the primary site at correct diagnosis, treatment included surgery of this site in 32/34 (94%) tumors. In the subgroup of 20/21 (95%) operated extremity primaries, it was reported as ablative in 12/20 (60%), limb-salvage procedures were performed in 8/20 (40%). Local radiotherapy of 40, 51, and 71 Gy was given to 3/37 (8%) patients, all as an adjunct to surgery. As a result of local therapy, a complete macroscopic remission of all disease sites was achieved in 31/37 (84%), one of these with known microscopic residuals.
All 37/37 (100%) patients proceeded to chemotherapy. Its duration was reported for 34/37 (92%) and lasted a median of 252 (range: 18–609) days. The use of pre- and postoperative chemotherapy was documented for 17/37 (46%) patients, that of postoperative chemotherapy only in 19/37 (51%). One further patient was known to have received preoperative chemotherapy, but postoperative therapy was unknown. Drugs used were documented for all 37/37 (100%) and included doxorubicin in all 37/37 (100%), high-dose methotrexate and cisplatin in 34/37 (92%), and ifosfamide in 29 (78%) patients. A variety of further drugs were administered to 8 (22%), including one case of autologous bone marrow transplantation. No patient was known to have received targeted or immunotherapy. Data on tumor response to preoperative chemotherapy was available for 13/37 (35%) patients. In these, it was good in 4/13 (31%) and poor in 9/13 (69%).
Median follow-up from osteosarcoma diagnosis was 4.3 (range: 0.3–32.1) years for all patients and 15.7 (0.3–32.1) years for survivors. The corresponding event-free observation period was 2.1 (one day − 32.1) years. During this period, 21/37 (57%) patients developed in an event as defined (six without surgical remission (including one without disease progression after radiotherapy), ten metastatic, three local, two combined, one death of unknown causes), 16/37 (43%) remained event-free. There were no secondary malignancies. At last follow up, 18/37 (49%; 16 1st, 1 2nd complete remission, one with irradiated tumor residual) patients were still alive and 19/37 (51%; five without ever having achieved a remission, ten 1st, three 2nd recurrence, one death of unknown causes while in first remission) had died.
Median overall survival from osteosarcoma diagnosis for all 37 patients was 85.7% (standard error: 5.9%) at 2, 50.2% (8.6%) at 5, 47.1% (8.6%) at 10, and 43.2% (8.7%) at 15 years. The corresponding values for event-free survival were 57.8% (8.3%) at 2, 42.6% (8.5%) at 5 and 10, and 38.3% (8.6%) at 15 years, respectively (Fig. 1). Results by presenting and therapeutic variables are given in table 1.