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Background and Purpose: Metastases engaging the acetabulum result in significant disability. We investigated the outcome after curettage and reconstruction of the defect with a protrusio cage, retrograde screws, and a cemented total hip arthroplasty., Patients and Methods: We retrospectively identified 70 consecutive patients who were surgically treated for metastatic disease of the acetabulum between 1995 and 2012 using the above technique. The type of primary tumor, extent of the disease, degree of acetabular erosion, and type of implant used were identified. Patient and implant survival, complications, and functional outcome were recorded., Results: There were no mortalities in the perioperative period (30 days after surgery). Median overall patient survival was 12 months. Prosthesis survival was 92% at 1 year and 89% at 5 years. One third of the patients suffered a complication, the most frequent one being dislocation. The functional outcome was good. Multiple skeletal or visceral metastases and specific types of cancer were associated with poor patient survival., Interpretation: Reconstruction of metastatic acetabular defects using a protrusio cage stabilized with retrograde screws and a cemented total hip arthroplasty is a safe procedure that provides efficient relief of symptoms. Patients with extensive disease, especially when diagnosed with specific types of cancer, have a very poor prognosis. The complication rate is substantial, the most frequent being dislocation. However, revision surgery is seldom required and prosthesis survival is high.

Tartrate-resistant acid phosphatase (TRAP) exists in human serum as two major isoforms, monomeric 5a and proteolytically processed enzymatically active 5b. The 5b isoform is secreted by osteoclasts and has recently been advocated as a serum marker for bone metastasis in breast cancer patients. The 5a isoform, on the other hand, is not bone-derived and has been proposed to be a marker of activated macrophages and chronic inflammation. In this study, expression of TRAP protein and enzymatic activity in bone metastases from different primary sites was examined. TRAP activity was high in bone metastases from prostate cancer, intermediate in breast cancer, and low in lung and kidney cancers. The partially purified TRAP from breast cancer bone metastasis samples exhibited the enzymatic characteristics of purple acid phosphatase. Both 5a and 5b isoforms were expressed in bone metastases of different histogenetic origins, i.e. prostate, breast, lung and kidney, and also a novel previously unreported 42 kDa variant of the TRAP 5a isoform was identified in bone metastases. This novel TRAP 5a isoform was absent in human bone, indicating that the 42 kDa variant is specific to metastatic cancer tissue. Immunohistochemistry revealed that metastatic cancer cells were the predominant source of TRAP 5a, whereas tumor-associated macrophages and occasionally multinucleated giant cells in the tumor stroma preferentially expressed the proteolytically processed TRAP 5b variant. Our results indicate the presence of a previously unstudied variant of monomeric TRAP 5a in cancer cells, which may have functional and diagnostic implications. Moreover, the presence of TRAP-positive macrophages in bone metastases could, together with cancer cells and osteoclasts, contribute to the elevated levels of serum TRAP activity observed in patients with bone metastases.

Background: The purpose of this study was to evaluate late effects and symptom complaints in long-term survivors (>5 years) of Extremity Bone Sarcoma (EBS survivors). The results were compared with findings in age- and gender-matched individuals from the general population (NORMs)., Patients and Methods: Among 155 EBS survivors approached, 133 (86%) were included, and 110 of them (83%) attended an outpatient examination. Health status was evaluated by a mailed questionnaire concerning demographic and current health issues, and physical examinations at the outpatient clinic. Age- and gender-adjusted normative controls were drawn from participants of the Health Study of Nord-Trøndelag County (HUNT 2)., Results: Median age at follow-up was 29 (15-57) years. Median follow-up was 12 (6-22) years. Of EBS survivors 42% had > or =1 somatic disease, 33% had ototoxicity and 13% had reduced renal function. EBS survivors were more likely to have heart disease (odds ratio [OR], 7.9; 95% confidence interval [95% CI], 2.5-25.3; P = 0.001), hypertension (OR, 3.4; 95% CI, 1.1-10.1; P = 0.03) and thyroid disease (OR, 3.0; 95% CI, 1.1-8.3; P = 0.04) compared to NORMs. EBS survivors reported more diarrhoea (29% vs. 19%, P = 0.02), palpitations (23% vs. 13%, P = 0.01) and shortness of breath (11% vs. 5%, P = 0.01) than NORMs., Conclusions: EBS survivors have poorer health status compared to age- and gender-matched controls. Long-term follow-up of these patients is therefore mandatory., (Copyright 2009 Wiley-Liss, Inc.)

Results from four consecutive trials, conducted from 1982 by members of the Scandinavian Sarcoma Group, are reviewed. A total of 330 classical osteosarcoma patients were enrolled. In all trials chemotherapy was based on the three active drugs, methotrexate, doxorubicin and cisplatinum and for the latter trials also ifosfamide. Post-operative chemotherapy was stratified by histological response to up-front treatment.

We evaluated the long-term functional outcome in 118 patients treated for osteosarcoma or Ewing's sarcoma in the extremities a minimum of five years after treatment. We also examined if impaired function influenced their quality of life and ability to work. The function was evaluated according to the Musculoskeletal Tumor Society (MSTS) score and the Toronto Extremity Salvage Score (TESS). Quality of life was assessed by using the Short Form-36 (SF-36). The mean age at follow-up was 31 years (15 to 57) and the mean follow-up was for 13 years (6 to 22). A total of 67 patients (57%) initially had limb-sparing surgery, but four had a secondary amputation. The median MSTS score was 70% (17% to 100%) and the median TESS was 89% (43% to 100%). The amputees had a significantly lower MSTS score than those with limb-sparing surgery (p < 0.001), but there was no difference for the TESS. Tumour localisation above knee level resulted in significantly lower MSTS scores and TESS (p = 0.003 and p = 0.02, respectively). There were no significant differences in quality of life between amputees and those with limb-sparing surgery except in physical functioning. Of the patients 11% (13) did not work or study. In multivariate analysis, amputation, tumour location above the knee and having muscular pain were associated with low physical function. We conclude that most of the bone tumour survivors managed well after adjustment to their physical limitations. A total of 105 are able to work and have an overall good quality of life.

We retrospectively studied local recurrence of giant cell tumour in long bones following treatment with curettage and cementing in 137 patients. The median follow-up time was 60 months (3 to 166). A total of 19 patients (14%) had at least one local recurrence, the first was diagnosed at a median of 17 months (3 to 29) after treatment of the primary tumour. There were 13 patients with a total of 15 local recurrences who were successfully treated by further curettage and cementing. Two patients with a second local recurrence were consequently treated twice. At the last follow-up, at a median of 53 months (3 to 128) after the most recent operation, all patients were free from disease and had good function. We concluded that local recurrence of giant cell tumour after curettage and cementing in long bones can generally be successfully treated with further curettage and cementing, with only a minor risk of increased morbidity. This suggests that more extensive surgery for the primary tumour in an attempt to obtain wide margins is not the method of choice, since it leaves the patient with higher morbidity with no significant gain with respect to cure of the disease.

A consecutive series of 47 chondrosarcomas was reviewed to identify the most useful criteria for cytological diagnosis, and grading in comparison to histology grade. This series includes 39 evaluable cases, including 2 patients with Ollier's disease and 2 with extraskeletal chondrosarcomas. Eight cases were excluded because of lack of histologic confirmation (3). nondiagnostic cytology (4). and one inconclusive histologic diagnosis. The cytologic diagnosis of these tumors was based on the identification of chondrocytes and a chondromyxoid stroma. The chondrocytes often showed double nuclei (34/39) and macronucleoli (20/39). Nuclear atypia in terms of distinct variation in size was less common (16/39). Cytoplasmic granules and vacuoles were often seen (34/39 and 29/39, respectively). In smears, chondroid fragments and a chondromyxoid background were seen in a majority of cases (36/39 and 30/39, respectively). By grade, concordance with histology was present in 4/7 grade I tumors, 26/29 grades II-III, and 5/5 grade IV, respectively., (Copyright 2003 Wiley-Liss, Inc.)

The European Musculo Skeletal Oncology Society (EMSOS) has carried out a retrospective review of patients over the age of 40 years with osteosarcoma. 481 patients from 12 centres or multicentric groups were included. 42 patients had osteosarcoma arising in Paget's disease, median survival was 9 months. Patients with axial or metastatic tumours also did badly whilst 41 patients with radiation-induced osteosarcoma had a prognosis paralleling conventional osteosarcoma matched for patient age and site of the tumour. 238 patients had high grade non-metastatic osteosarcoma and had a survival of 46% at 5 years. Older patients had less chemotherapy and fared worse. Osteosarcoma in the elderly is a curable condition and warrants intensive treatment with chemotherapy and surgical resection.

Background: The objective of this article was to assess the occurrence of symptomatic bone metastases in a defined population of patients with breast carcinoma and to characterize the clinical outcome with reference to surgical treatment for pathologic fracture or neurologic deficit., Methods: The authors identified all patients in the Stockholm Breast Cancer Database (population base 1.8 million) with a diagnosis of bone metastases during 1989--1994. These cases were linked with the Stockholm County Council Hospital Discharge Diagnosis Registry that includes information on in-patient care and discharge diagnoses. This enabled us to identify patients who had undergone surgical treatment for their bony metastases at any of the six departments of orthopedics in the region, or who had been treated at the one department of neurosurgery., Results: Six hundred forty-one patients with breast carcinoma presented with symptomatic skeletal metastasis during 1989--1994, and 107 (17%) were operated on. Metastases were located in long bones (77), spine (14), and pelvis (6). The median survival postoperatively was 6 months. The total reoperation rate was 0.12. Hip screws and glide-screw plates were associated more often with failure as was location in the distal femur. Pain decreased postoperatively in 77% of the patients, and function improved in 65%., Conclusions: One in 10 patients with breast carcinoma developed symptomatic bone metastases, and one-fifth of these patients required surgery for pathologic fracture or neurologic deficit. There was a high failure rate in those hospitals in which few patients were operated on., (Copyright 2001 American Cancer Society.)

Diagnosis of skeletal lymphoma and myeloma by radiology and fine needle aspiration cytology From 1986 to 1998, all patients referred to Karolinska Hospital because of a skeletal destruction of unknown origin routinely underwent radiographic examination and fine needle aspiration cytology (FNAC). Among these, there were 83 patients with solitary lesions of the bone diagnosed and treated for myeloma (plasmacytoma) or non-Hodgkin's lymphoma. Review of the series showed that myeloma could not be distinguished radiographically from lymphoma. Nor could low and high grade lymphoma lesions be discriminated by radiographic appearance. The diagnostic utility of plain radiography in the two conditions seems to be confined to the mere detection of a destructive bone lesion and visual guidance for FNAC. The latter aspect, however, is crucial for the application of FNAC to bone lesions. Review of the cytologic specimens obtained by FNAC showed that they allowed a conclusive diagnosis in all 40 myeloma cases and in 41 of 43 lymphoma cases. In 32 of the 40 myeloma cases, the FNAC material could be used for immunocytochemistry, which disclosed kappa or lambda light chain restriction, corroborating the cytomorphological diagnosis. Thirty-eight lymphomas were characterized immunologically and in 35, a light chain restriction could be demonstrated. Our results show that the use of FNAC in the diagnosis of primary myeloma and lymphoma of bone obviates the need for other diagnostic modalities, including open biopsy. A combined approach based on radiology and FNAC, performed as an out-patient procedure, offers rapid and accurate diagnosis of myeloma and lymphoma among patients with radiographically unclassified destructive bone lesions.

We have previously shown that cytological diagnosis based on fine-needle aspiration biopsy (FNAB) is a safe and efficient method for the discrimination between benign, primary malignant and metastatic bony lesions. We have now studied metastatic lesions to assess the diagnostic accuracy and to ascertain whether FNAB allows identification of the primary lesion. Between 1990 and 1997, 447 patients were referred for diagnosis of skeletal lesions of unknown type. Of these 119 proved to have metastatic disease, either myeloma or lymphoma. Nine were excluded leaving 110 consecutive patients with metastatic carcinoma (80), myeloma (16) or lymphoma (14). FNAB gave a correct diagnosis in 102 of the 110 patients (93%). In eight it was inconclusive. It correctly diagnosed 15 of 16 patients with myeloma, 12 of 14 with lymphoma, and 75 of 80 with metastatic carcinoma. Furthermore, the site and type of malignancy were correctly suggested in two-thirds of patients with metastatic carcinoma. Overall, only seven open biopsies were carried out. We conclude that time-consuming and costly investigations can be reduced by choosing FNAB as the initial diagnostic method for skeletal lesions of unknown origin. The choice of radiological examinations, laboratory tests and surgical biopsies can be determined by using FNAB.

DNA copy number changes were studied by comparative genomic hybridization (CGH) in 50 chondrosarcoma samples from 45 patients. Mean number of genetic aberrations in primary tumors was 4.8 +/- 1.8. The most frequently gained regions were 20q12-qter (37%), 20q (32%), 8q24.1-qter (27%), 20p (24%), and 14q24-qter (24%). Losses were 5.5 times less frequent than gains and observed mainly at Xcen-q21, 6cen-q22, and 18cen-q11.2 (11% each). Recurrent and metastatic tumors showed a mean of 4.0 +/- 2.2 aberrations per sample. The most frequently gained regions were chromosome 7 (4 cases), 5q14-q32 (4 cases), 6p (3 cases), and 12q (3 cases). Losses of DNA sequences were 3.4 times less frequent than gains. Histological tumor grade was significantly associated with metastasis-free survival (P = .002) and overall survival (P = .003), being the strongest prognostic factor tested. A statistically significant correlation was found between gain at 8q24.1-qter and shorter overall survival (P = .01) but not with local recurrence or metastasis-free survival. Gain at 14q24-qter was associated with a trend to shorter overall survival (P = .05) but neither with an increased risk for local recurrence nor with metastasis-free survival. In a multivariate analysis, only the tumor grade associated with overall survival (P = .02). In a multivariate analysis together with the tumor grade, gain at 8q24.1-qter did not retain its significance (P = .44), indicating that this imbalance is not an independent prognostic factor.

In an effort to learn more about malignant fibrous histiocytoma (MFH) of bone and its prognosis with different treatment approaches, the European Musculo-Skeletal Oncology Society (EMSOS) initiated a retrospective survey among its members. Data requested included patient and treatment variables and outcome. The information on all patients with histologically proven, primary, localized osseous extremity MFH was analyzed if surgical tumor removal was performed and disease status was documented for at least one follow-up date. 125 such patients were evaluable (74 male, 51 female; median age 34 years; tumor site femur 81, tibia 26, humerus 12, other 6). Local treatment was surgery only (110) or surgery plus radiotherapy (15). Chemotherapy was used in 97/125. On last follow-up, 85 patients remained in remission, 33 had developed metastases, 6 a local recurrence, and 1 a combined relapse. With a median follow-up of 3.9 years for patients at risk, actuarial 5-year disease-free survival was 59%. In univariate analyses, younger age and the use of chemotherapy were associated with a more favorable outcome, as was limb-salvage surgery. 23 of 66 tumors with information on response to preoperative chemotherapy responded well (> 90% necrosis). Among these 23, only one relapsed.

This study was based on 192 patients treated surgically for 228 metastatic lesions of the long bones from 1986 through 1995. The survival rate was 0.3 at 1 year after surgery. The surgical treatment consisted of resection and reconstruction of the involved bone (18), intralesional curettage (133), or stabilization only (77). Reconstruction was achieved by an endoprosthesis in 54 cases, by an osteosynthetic device in 162, by cement only in 10. In two cases no reconstruction was performed. The local failure rate was 11% and the median time to failure was 8 months. Local failure was most frequent in patients with kidney cancer (24%) and in diaphyseal and distal femoral lesions (20%). Among 162 operations involving osteosynthetic devices, 22 (14%) were failures as compared with one of 54 (2%) endoprostheses. Sixty percent of the patients received preoperative or postoperative radiotherapy. Five of the six patients who had surgery for local tumor progression had not received radiotherapy. Eight of 10 nonunions and all five patients who developed a stress fracture had been treated with radiotherapy. It is concluded that endoprosthetic reconstructions are preferable to osteosynthetic devices. The skeletal complications associated with radiotherapy may be circumvented by the use of endoprostheses.

Unlabelled: Technetium-99m-MIBI was initially developed for heart studies but it can also be used to depict tumors, predict multidrug resistance and evaluate chemotherapy. Recently, 99mTc-tetrofosmin, which exhibits similar physical properties, has been launched for heart studies. Tumor uptake and prediction of multidrug resistance have also been reported regarding the latter tracer. A comparison of these two tracers regarding the detectability of musculoskeletal sarcoma has been made., Methods: Twenty patients with musculoskeletal sarcoma of the extremities or pelvis underwent planar examination after the administration of 99mTc-MIBI and 99mTc-tetrofosmin with an interval of 2-7 days. The tumor activity was compared with one ipsilateral and one contralateral background region., Results: There was a small, but not significant, difference in favor of 99mTc-MIBI with regard to both background regions., Conclusion: Technetium-99m-MIBI and 99mTc-tetrofosmin can both be used to visualize musculoskeletal sarcomas. The choice may depend on which agent is used routinely for myocardial studies in the laboratory.

The use of gamma camera scintigraphy with technetium-99m hexakis-2-methoxyisobutylisonitrile (99mTc-MIBI) for assessment of the response of high-grade osteosarcoma to preoperative chemotherapy was evaluated. Twelve patients with osteosarcoma of the extremities underwent planar examination with 99mTc-MIBI before and after preoperative chemotherapy according to the recommendations of the Scandinavian Sarcoma Group. After calculating a quotient for the tumour and the average activity of both extremities and correcting for background activity, the change in uptake between the two examinations was assessed. This was compared with histological examination of the ultimately resected specimen in 11 patients and progressive clinical disease in one. All the 11 tumours undergoing histological examination showed cellular necrosis of between 50% and 100% as well as a reduced uptake of 99mTc-MIBI, while the single progressive tumour showed an increased uptake. There was a correlation between the reduction of radiopharmaceutical uptake and the histological response in the entire series, while the variation was too large to allow conclusions in individual patients. This variation may have biological reasons or may be due to the planar imaging technique, which only allows semiquantitative evaluation. The technique reflects response to therapy but is not yet clinically applicable for the identification of poor responders, which would serve as a basis for alteration of the chemotherapy regimen. In order to evaluate whether such a role could be fulfilled, further studies using single-photon emission tomography with correction for attenuation and scattering of photons are necessary.

In 12 patients with acetabular metastases, we reconstructed the hip with a support ring, cement, and Charnley prosthesis with a 22 mm head. There were no immediate postoperative deaths or cardiovascular complications. Dislocations occurred in 5 patients, 1 of whom required open reduction. At follow-up, 3 patients were alive 11, 15, and 18 months after surgery. 9 patients died after 8 (2-13) months. All patients obtained relief from pain, became ambulatory and were discharged to their homes. 1 patient had rapid disease progression with pathologic fracture and cranial dislocation of the support ring. Among the remaining 11 patients, the hip has not again caused pain or limited function. There were no signs of loosening, except in the patient with fracture of the hemipelvis. Remineralization was observed in 2 breast cancer patients after chemotherapy. Hip reconstruction can restore painless function until death in cancer patients with severe destruction of the acetabulum.

We evaluated the diagnostic accuracy of fine-needle aspiration biopsy in a prospective study of 300 patients with previously undiagnosed bone lesions. Patients with suspected local recurrence of a primary bone tumour or a metastatic lesion of a previously diagnosed malignancy were excluded. Fine-needle aspiration biopsy was performed under radiological control as an outpatient procedure. The series was grouped into three major categories: 1) benign bone lesions including infections; 2) primary malignant bone tumours; and 3) metastases including lymphomas and myelomas. We compared the cytological diagnosis with the final diagnosis as assessed by histological examination and/or the clinical and radiological features. Material considered conclusive for cytological diagnosis was obtained from 251 of the 300 patients. Of the 49 failures, there were 24 aspirates with insufficient cellular yield and 25 in which a diagnosis could not be made although the cytological material was adequate in quantity. Most of the inconclusive aspirates (36/49) were obtained from benign bone lesions. The diagnosis was correct in 239 (95%) of the 251 cases providing adequate cytological material. There were eight (3%) falsely benign diagnoses, one (0.3%) falsely malignant, and three cases in which we were unable to differentiate between sarcoma and a metastasis. Chondrosarcoma (2/12) gave the greatest diagnostic difficulty and Ewing's sarcoma the least (0/9). There were no decisive errors of treatment. All falsely benign or malignant diagnoses were questioned, and led to open biopsy since they did not correlate with the clinical and radiological features. Our study suggests that fine-needle aspiration biopsy is a valid option for the diagnosis of bone tumours. It is a simple outpatient procedure which gives sufficient cytological material for the correct diagnosis in 80% of cases. As with histological analysis of material from open biopsy, the cytological assessment must agree with the clinical and radiological findings.

We analyzed the clinical course in 40 patients with enchondroma and 40 with low-grade chondrosarcoma of the extremities after a median follow-up of 7 years. 13 patients with enchondroma and 2 with chondrosarcoma had only open biopsy and they had no signs of further progression of the lesions. Among 23 patients with enchondroma and 23 with chondrosarcoma who were treated by intralesional curettage, 3 had local recurrences. The 10-year local recurrence rate was 0.04 in the enchondroma group and 0.09 in the chondrosarcoma group. There were no metastases. The results imply that enchondroma and low-grade chondrosarcoma of the extremities should be treated with limited surgery. The morbidity associated with en bloc resection and reconstruction can apparently be obviated without jeopardizing the limb or survival.

We assessed the survival after surgery in 153 patients with extremity metastases and 88 with spinal metastases. The survival rate for the whole series of 241 patients was 0.30 at 1 year, 0.15 at 2, and 0.08 at 3 years. The 1-year survival rate was the same for the extremity metastases group and the spinal group. Univariate analysis showed that 1-year survival was related to metastatic load, site of primary tumor, and presence of pathologic fracture. Multivariate regression analysis showed that pathologic fracture, visceral or brain metastases, and lung cancer were negative prognostic variables. Solitary skeletal metastases, breast and kidney cancer, myeloma, and lymphoma were positive variables. A prognostication model based on these variables stratified the patients into 3 groups with a 1-year survival ranging from 0.5 to 0.0. These prognostic variables can be used for differentiating the treatment of cancer patients with pathologic fracture or epidural compression.

Between 1971 and 1991 we treated 98 patients with giant-cell tumours, 15 of whom presented with a pathological fracture. They were most common around the knee (12). Nine fractures were intra-articular. The tumours were treated by curettage and acrylic cementing (10), excision and endoprosthesis (1), excision and allograft (1), curettage and autologous graft (2) or by resection of the fibular head (1). Four patients had local recurrence, three of whom were cured by repeat curettage and cementing. Pathological fracture through a giant-cell tumour is not a contraindication to treatment by curettage and acrylic cementing.

During the period from 1971 to 1990 all osteosarcoma patients referred to the Karolinska Hospital without signs of metastases received human leukocyte interferon (IFN) as adjuvant treatment. Patients referred between 1985 and 1990 were given more intensive human leukocyte IFN treatment, i.e. a standard dose of 3 MU s.c. daily for 3-5 years. These 19 patients, all followed for 5 years, were included in a pilot study which entailed patients with central localization where radical surgery was not feasible. Metastases developed in 9 patients, of whom 3 had local recurrences. Sixty-three percent are free of disease at 5 years. Side-effects were negligible and long-term toxicity practically non-existent. It is suggested that a randomized multicenter IFN trial should be instituted on patients with poor prognosis receiving chemotherapy and/or that IFN treatment should be combined with other therapeutic modalities--irradiation, chemotherapy or anti-angiogenic substances--in osteosarcoma.

Thirty-three osteosarcomas (OS) were analyzed cytogenetically. Clonal chromosome changes were detected in 17 cases. Six tumors had chromosome numbers in the diploid range, 6 in the triploid range, 1 in the tetraploid range and 1 in the pentaploid range, while 3 tumors had multiple clones with different ploidy levels. Including the present 17 tumors, a total of 27 OS with clonal aberrations have been reported. The recognizable structural rearrangements in these 27 tumors clustered to chromosome arms 1p, 1q, 3p, 3q, 7q, 11p, 17p and 22q. Chromosome bands 1q11, 1q21, 1q42 and 7q11 were the most frequently rearranged, and the most common numerical rearrangements were -3, -10, -13 and -15. Supernumerary ring chromosomes, in 2 tumors as the sole change, were found in all 3 parosteal OS, which is in agreement with the findings in 1 previously reported parosteal OS. The association between ring formation and parosteal morphology represents the first cytogenetic-morphologic entity among OS.

An update of the adjuvant trial on osteosarcoma in Sweden comparing patients receiving natural interferon (IFN) alpha with a high-dose chemotherapy group and a nonadjuvant group is presented. The overall survival for the IFN group is 49%, for the chemotherapy group 54%, and for the nonadjuvant group 35%. Trial evaluation was complicated by group differences with respect to various clinicopathologic features of prognostic significance. The role of IFN in the treatment of osteosarcoma can still not be established.

Microspectrophotometric DNA analysis of archival bone tumor tissue is often impeded by previous acid demineralization, which destroys Feulgen DNA stainability. To find an alternative to acid for prospective DNA studies of bone tumors in tissue sections, Feulgen stainability of fresh osteosarcoma specimens after demineralization in neutral EDTA was investigated. The reliability of DNA analysis of weakly Feulgen-stained sections from archival tissue was also studied. Demineralization of four fresh specimens in EDTA slightly reduced Feulgen DNA stainability compared to nondemineralized preparations but did not affect the determination of ploidy level. Hydrolysis tests of one diploid and one hyperploid osteosarcoma showed that the staining relationship between control and tumor cells was not altered by EDTA pretreatment. For DNA studies of bone tumors requiring demineralization, EDTA offers a means of retaining nuclear Feulgen stainability. In 22 archival osteosarcoma specimens of varying Feulgen stainability, three different upper limits of light transmission (75, 85, and 95%) were applied to test the significance of background disturbances in relation to nuclear stain intensity. The relationship between the median total extinction of the control and tumor cell populations was not significantly affected by altering the upper transmission limit except in four poorly stained lesions. The control cells of these four specimens exhibited a median total extinction less than one-third of the maximum encountered. The results suggest that weakly stained archival specimens can be tested for selecting those appropriate for ploidy determination.

The aim of the present study was to establish an upper limit of diploidy for microspectrophotometric (MSP) DNA measurements in sections of mesenchymal tissue analyzing DNA data of a large number of normal cell populations. The reliability of this upper limit of diploidy for discriminating between diploid and hyperploid bone sarcomas was tested by analyzing the same tumors by MSP in imprint preparations and flow cytometry (FCM). The median DNA value of control cells in tissue sections was given arbitrary value of DNA index (DI) 1.0, denoting the diploid DNA content. The proportion of cells with DNA values exceeding DI 1.25 (greater than DI 1.25) was determined for each normal cell population. The maximum percentage of cells with DNA values exceeding DI 1.25, encountered by analysis of 91 normal cell populations in tissue sections, was 31%. This percentage was set as an upper limit of diploidy. Hence, tumors with a higher percentage of cells greater than DI 1.25 were classified as hyperploid. When we applied this criterion, 31 of 36 sarcomas analyzed by MSP in tissue sections were hyperploid, which was in complete agreement with FCM and MSP in imprints of the same tumors. Apart from discriminating between diploid and hyperploid tumors, an attempt was made to determine peak DNA values of sarcomas analyzed in tissue sections. Peak DNA values, as defined by a minimum of 30% of the cells within a class width of DI 0.25, could be determined for 23 of 36 tumors. These peak DNA values correlated well with corresponding peaks obtained by FCM.(ABSTRACT TRUNCATED AT 250 WORDS)

The relationship between cytochemical features and histomorphology in osteosarcoma, and the clinical significance of DNA content were investigated by microspectrophotometry (MSP) of tissue sections and flow cytophotometry (FCM) of cell suspensions. MSP of tissue sections entails the methodological error of determining the DNA content of sectioned cell nuclei. By analyzing 184 normal mesenchymal cell populations, an upper limit of diploidy (normal DNA content) was deduced. Applying this upper limit for 42 sarcomas, 6 were diploid and 36 hyperploid. Comparative analysis of the same lesions by MSP of imprint preparations and by FCM disclosed complete agreement in ploidy classification (diploid versus hyperploid). Retrospective MSP analysis of bone tumors is often impeded by previous demineralization in acid, which destroys DNA. EDTA as an alternative was found to slightly reduce Feulgen DNA stainability of osteosarcomas, but did not affect tumor ploidy determination. Hence, EDTA offers a means of retaining DNA stainability of bone tumors requiring demineralization. MSP analysis of different histologic areas, and comparative FCM analysis of biopsy and surgical specimens, dislosed that individual osteosarcomas are cytochemically uniform despite morphologic heterogeneity. Hence, a single tumor sample for DNA analysis can be relied upon as representative for the tumor as a whole. In a consecutive series of 83 osteosarcoma patients treated by surgery and adjuvant Interferon, the 7-year survival rate was 0.44. MSP DNA analysis gave no significant prognostic information. Multivariate analysis identified 3 risk factors for tumor related death, i.e., male sex, proximal tumor location, and histologic grade IV. In a prognostication model, the 7-year survival rates, for patients with 0, 1, 2, or 3 risk factors, were 0.80, 0.59, 0.42, and 0.13, respectively. Hence, it is possible to identify subgroups of high grade osteosarcoma patients with different prognosis. In a study of 166 primary bone tumors, the applicability of DNA analysis for differential diagnostic purposes was investigated. The series included high grade osteosarcomas, parosteal osteosarcomas and benign bone tumors, which may be mixed up histologically with osteosarcoma. Out of 166 tumors, 149 (90%) were histologically noncontroversial, whereas 17 (10%) posed diagnostic difficulties. In the diagnostically noncontroversial group, all benign tumors and parosteal osteosarcomas were diploid, whereas 97 of 102 osteosarcomas were hyperploid. Hence, hyperploidy seems to be a characteristic feature of high grade osteosarcoma.(ABSTRACT TRUNCATED AT 400 WORDS)

The DNA content of osteosarcomas, and of giant cell tumors, osteoblastomas, aneurysmal bone cysts, and fibrous dysplasias was determined by cytophotometry. Of 158 tumors, 141 were histologically noncontroversial, whereas 17 posed diagnostic difficulties. In the noncontroversial group, all 41 benign tumors had a diploid (normal) DNA content. Ninety-two of 96 high-grade osteosarcomas were hyperploid (increased DNA content). The four analyzed low-grade parosteal osteosarcomas were diploid. Among 17 diagnostically controversial cases, nine were primarily diagnosed and treated as benign. Three of these patients, nevertheless, exhibited a malignant clinical course and two had local recurrence. All five proved to have hyperploid tumors. The four nonrecurrent lesions were diploid. Of eight patients primarily evaluated as malignant, one died and two developed local recurrence. These three patients had hyperploid tumors. Among the five nonrecurrent lesions, two were hyperploid and three diploid. In the diagnostically controversial group, recurrence or death was consistently related to hyperploidy. The present study shows that the vast majority of high-grade osteosarcomas are hyperploid. Benign bone tumors, which may be mixed up histologically with osteosarcoma, are diploid. Routine DNA analysis of primary bone tumors, as an adjunct to histopathologic assessment, can be employed to obtain diagnostic confirmation. In cases presenting histopathologic difficulties, ploidy determination may provide decisive diagnostic information.

The DNA content of osteosarcomas, and of giant cell tumors, osteoblastomas, aneurysmal bone cysts, and fibrous dysplasias was determined by cytophotometry. Out of 158 tumors, 141 were histologically noncontroversial, whereas 17 posed diagnostic difficulties. In the noncontroversial group all 41 benign tumors had a diploid (normal) DNA content. Ninety-two of 96 high-grade osteosarcomas were hyperploid (increased DNA content). The four analyzed low-grade parosteal osteosarcomas were diploid. Among 17 diagnostically controversial cases, nine were primarily diagnosed and treated as benign. Three of these patients, nevertheless, exhibited a malignant clinical course and two had local recurrence. All five proved to have hyperploid tumors. The four nonrecurrent lesions were diploid. Of eight cases primarily evaluated as malignant, one died and two developed local recurrence. These three patients had hyperploid tumors. Among the five nonrecurrent lesions, two were hyperploid and three diploid. Hence, in the diagnostically controversial group, recurrence or death was consistently related to hyperploidy. The current study shows that the vast majority of high-grade osteosarcomas are hyperploid. Benign bone tumors, which may be mixed up histologically with osteosarcoma, are diploid. Routine DNA analysis of primary bone tumors, as an adjunct to histopathologic assessment, can be employed to obtain diagnostic confirmation. In cases presenting histopathologic difficulties, ploidy determination may provide decisive diagnostic information.

In a retrospective study of 83 osteosarcoma patients treated by surgery and adjuvant interferon from 1971 to 1986, the clinical course was related to different clinicopathologic features and tumor DNA content. DNA analysis was feasible in 60 cases. Four tumors were diploid and 56 hyperploid. The 7-year survival rate, estimated by life-table analysis, was 0.44 for the whole series. Multivariate analysis disclosed that male sex, proximal tumor location, and histologic Grade IV were independent risk factors--all approximately of equal strength. DNA analysis did not provide prognostic information, except for tumors with extreme abnormality of the DNA content, which was associated with a very poor prognosis. A prognostication model was created, based on the number of risk factors present. The 7-year survival rate for patients with none, one, two, or three risk factors was 0.80, 0.59, 0.42, and 0.13, respectively. The estimated 7-year rate of local recurrence was 0.29: 0.07 after ablative surgery and 0.54 after local surgery. Among patients who were free of metastasis 1 year after diagnosis, local recurrence reduced the 7-year survival rate from 0.86 to 0.48. In high-grade osteosarcoma, conventional clinicopathologic features and local tumor control remain the most important prognostic factors.