Gary D. Bos

20q11.1 amplification in giant‐cell tumor of bone: Array CGH, FISH, and association with outcome

The goal of this study was to identify recurrent regions of genomic gain or loss in giant‐cell tumor of bone (GCTb). Array comparative genomic hybridization (aCGH) was performed for 20 frozen tumor samples of GCTb. A separate subset of 59 GCTb with outcome data was used for validation. The most frequent region of change identified by aCGH was gain of a 1‐Mbp region at 20q11.1. In the validation arm of 59 cases the minimal common region of copy number gain at 20q11.1, seen in 54% of the samples, was BAC clone RP11‐4O9, which contained the genes TPX2 and BCL2L1. For most cases, amplification was restricted to the mononuclear component and was not present in the multinucleated giant cells. Southern blot for TPX2 and BCL2L1 identified the former as the gene with the highest level of amplification for these two proposed candidate genes of importance. Immunohistochemistry for TPX2 expression correlated with amplification, while BCL2L1 expression was not identified. Kaplan–Meier curves for progression‐free survival showed a statistically significant difference for cases with 20q11.1 amplification (P = 0.0001). Univariate analysis involving Cox proportional hazards models did not show a significant difference for initial treatment type (curettage versus resection) (P = 0.575), age (≤50 vs. >50) (P = 0.543), or sex (P = 0.268), but did correlate with 20q11.1 amplification (P = 0.001). By multivariate analysis, it was found that 20q11.1 amplification (P = 0.001) was the only factor to reach statistical significance. 20q11.1 amplification can be used as a marker of prognostic importance in GCTb. We propose TPX2 as a candidate oncogene in the core‐amplified region at 20q11.1.

MYC Amplification and Polysomy 8 in Chondrosarcoma: Array Comparative Genomic Hybridization, Fluorescent In Situ Hybridization, and Association With Outcome

PURPOSE To identify recurrent regions of genomic gain or loss in chondrosarcoma in a clinically relevant and statistically valid fashion. MATERIALS AND METHODS Array comparative genomic hybridization (CGH) results of 15 frozen tumor samples of high-grade chondrosarcoma for chromosome 8 are presented. A separate subset of 116 cartilaginous tumors with outcome data was used for validation. RESULTS Array CGH identified gain at 8q24.12-q24.13, the region of the MYC (c-Myc) oncogene, as a frequent change in high-grade chondrosarcoma. In the validation arm of 116 cartilaginous tumors, MYC was frequently amplified in G2 (15%), G3 (20%), and dedifferentiated (21%) chondrosarcomas. No amplification was identified in samples of enchondroma and grade 1 chondrosarcoma. In samples without MYC amplification, polysomy 8 was a frequent finding in grade 1 (18%), grade 2 (31%), grade 3 (80%), and dedifferentiated (29%) chondrosarcomas, but was not found in any samples of enchondroma. MYC protein expression was identified in all samples with amplification, but was also frequent in the remaining samples without amplification or polysomy 8. Kaplan-Meier survival curves for overall survival showed a statistically significant difference for patients with MYC amplification or polysomy 8 (P = .034). Univariate analysis involving Cox proportional hazards models showed that grade (P = .003), polysomy 8 (P = .045), and MYC amplification (P = .053) correlated with shorter overall survival. By multivariate analysis, grade of chondrosarcoma (P = .026) was the only factor to reach statistical significance. CONCLUSION MYC amplification and polysomy 8 can be used as markers of prognostic importance in chondrosarcoma. Molecular targeting of MYC expression may have therapeutic potential in the future for subsets of chondrosarcoma.

The cytopathology of soft tissue mxyomas: ganglia, juxta-articular myxoid lesions, and intramuscular myxoma.

We studied the practicality of issuing a cytologic diagnosis of myxoma/juxta-articular myxoid lesion/ganglion (MJG) by reviewing all fine-needle aspiration (FNA) biopsy specimens of soft tissue masses in our files with diagnoses of myxoma, myxoid cyst, myxoid lesion, ganglion, or ganglion cyst. The control group was soft tissue aspirates with abundant myxoid stroma. Of 39 cases with a cytologic diagnosis of soft tissue MJG, 15 had subsequent tissue biopsy or complete resection of the mass; 24 had clinicoradiologic follow-up. All cases except 1 (fat necrosis) were diagnosed correctly as benign myxoid lesions. We grouped MJG aspirates into 3 subtypes based on clinicoradiologic features: soft tissue ganglion/ganglion cyst (12 cases), juxta-articular myxoid lesion (16 cases), and intramuscular myxoma (11 cases). MJG aspirates showed few, subtle cytopathologic differences among subtypes. They characteristically had a viscous, gelatinous quality when expressed from the needle onto the glass slide. The typical smear contained a film of paucicellular, often finely granular, myxoid stroma, that contained few cells, usually macrophages or bland spindle cells. Control group aspirates always contained cellular components that allowed distinction from MJGs. The cytopathologic diagnosis of MJG lesions is accurate; FNA biopsy can be used to subtype MJGs into 3 categories when clinicoradiologic features are known.

Foot Tumors: Diagnosis and Treatment

Several large clinical series have demonstrated that benign and malignant tumors occur in the foot and ankle at a much higher rate than previously thought. Vigilance is warranted in investigating any foot mass, including those with an apparently indolent course. Although tumors in the foot tend to produce symptoms relatively early because of the foots compact structure, many tumors are initially misdiagnosed. Given the comparatively small size of the anatomic compartments in the foot, tumors often present outside the original compartment, making timely diagnosis essential. Major treatment errors can be avoided if physicians consider the potential for malignancy when evaluating all foot masses. A high index of suspicion, an organized approach to diagnosis, and evaluation of and adherence to the basic principles of treatment of musculoskeletal neoplasms increase the likelihood of acceptable results.

Selective drug resistant human osteosarcoma cell lines.

Chemotherapy in combination with surgery has been shown to be effective for the control of osteosarcoma. Development of resistance to chemotherapeutic agents is a recurring clinical problem. To investigate this phenomena, human osteosarcoma cells, TE-85, were exposed to increasing doses of Taxol or Taxotere during a 9-month period. Highly resistant subclones (TE-85TXL; TE-85TXR, respectively) were developed. Chemosensitivities are presented for TE-85 cell line and these new lines to Taxol, Taxotere, doxorubicin, cisplatin, and topotecan. Drug concentrations that inhibited cell growth by 50% compared with untreated cells were determined. The TE-85TXL cells showed resistance greater than 1000-fold to Taxol and Taxotere and 60-fold to doxorubicin. The TE-85TXR cells showed resistance greater than 1000-fold to Taxol, 800-fold to Taxotere, and 90-fold to doxorubicin. There was little cross resistance to topotecan and enhanced sensitivity to cisplatin. The role of P-170 glycoprotein in Taxol and Taxotere resistance was explored. Coincubation with verapamil, to block the actions of P-170 glycoprotein, partly reversed resistance to Taxol, Taxotere, and doxorubicin in both cell lines. Anti-P-170 glycoprotein antibodies revealed positive staining in TE-85TXL and TE-85TXR cell lines. Flow cytometry revealed reduced accumulation of doxorubicin in resistant cells. These data indicate that a human osteosarcoma cell line will develop resistance to Taxol and Taxotere, which is mediated in part by the P-170 glycoprotein.

Lower-Extremity Local Flaps

&NA; Some soft‐tissue defects of the lower extremities can be covered reliably with local flaps. Five such flaps—the tensor fascia lata, gastrocnemius, soleus, posterior tibial artery fasciocutaneous, and dorsalis pedis flaps—are described. If the indications for each flap are understood and the vascular pedicle is carefully preserved, these flaps can be used to provide relatively simple and reliable coverage of selected soft‐tissue defects on the lower extremities. However, the indications must not be overextended in an attempt to avoid a free‐tissue transfer. The gastrocnemius flap is most often used. It reliably covers common defects about the knee and the proximal tibia. A skin graft is required for the gastrocnemius flap, as well as the soleus flap, which covers the midportion of the tibia. The soleus requires deeper dissection of the calf for elevation. The tensor fascia lata flap and the more recently described posterior tibial artery fasciocutaneous flap are relatively easy to raise, but there are fewer orthopaedic indications for their use. The dorsalis pedis cutaneous flap is technically more demanding, but it can be used to cover difficult defects around the ankle.

MANAGEMENT OF METASTATIC DISEASE OF OTHER BONES

Metastases to the scapula and distal sites on the upper and lower extremities are infrequent. Although these metastases tend to occur in patients with advanced disease, a distal metastasis is occasionally the sole metastatic location. Distal metastases do not pose an immediate threat to a patients life; however, they may cause significant pain and disability. Appropriate management can considerably enhance function, quality of life, and, occasionally, survival. Seven cases of distal metastasis are presented in this article with discussion of operative and nonoperative approaches to management.