Vascular pattern in enchondroma and chondrosarcoma: clinical and immunohistologic study.

INTRODUCTION: Although cartilaginous tumors have low microvascular density, vessels are important for the provision of nutrition so that the tumor can grow and generate metastasis. The aim of this study was to assess the value of the vascular pattern classification as a prognostic tool in chondrosarcomas (CSs) and its relation with vascular endothelial growth factor (VEGF) expression. MATERIALS AND METHODS: This was a retrospective study of 21 enchondromas and 57 conventional CSs. Clinical data and outcome were retrieved from medical files. CSs histologic grades (on a scale of 1 to 3) were determined according to the World Health Organization classification. The vascular pattern (on a scale of A to C) was assessed through CD34, according to Kalinski. CD105 and VEGF were also evaluated. RESULTS: Poor outcome was significantly associated with vascular pattern groups B and C. Higher vascular pattern were 6.5 times more frequent in moderate-grade and high-grade CSs than in grade 1 CS. On multivariate analysis, a clear correlation was found between VEGF overexpression and B/C vascular patterns. Only 18 (benign and malignant) tumors stained for CD105. DISCUSSION: The results point to the use of the vascular pattern classification as a prognostic tool in CSs and to differentiate low-grade from moderate-grade/high-grade CSs. Vascular pattern might be also used to complement histologic grade, VEGF immunostaining, and microvascular density, for indicating a patient's prognosis. Low-grade CSs develop under low neoangiogenesis, which conforms to the slow growth rate of these tumors.

Analysis of angiogenic factors and cyclooxygenase-2 expression in cartilaginous tumors- clinical and histological correlation.

OBJECTIVES: To study the role of angiogenesis and cyclooxygenase-2 expression in cartilaginous tumors and correlate these factors with prognosis. INTRODUCTION: For chondrosarcoma, the histological grade is the current standard for predicting tumor outcome. However, a low-grade chondrosarcoma can follow an aggressive course-as monitored by sequential imaging techniques-even when it is histologically indistinguishable from an enchondroma. Therefore, additional tools are needed to help identify the biological potential of these tumors. The degree of angiogenesis that is induced by the tumor could assist in this task. Angiogenesis can be quantified by measuring the expression of vascular endothelial growth factor and CD34, and cyclooxygenase-2 can induce angiogenesis by stimulating the production of proangiogenic factors. METHODS: In total, 21 enchondromas and 58 conventional chondrosarcomas were studied by examining the clinical and histopathological findings in conjunction with the immunostaining markers of angiogenesis and cyclooxygenase- 2 expression. RESULTS: The significant variables that were associated with poor outcome were 1) higher-grade chondrosarcomas, 2) tumors that developed in flat bones, and 3) over-expression of CD34 (with a median count that was higher than 5.9 vessels in 5 high power fields). Moreover, CD34 expression (measured using the Chalkley method) revealed significantly higher microvessel density in flat bone chondrosarcomas. DISCUSSION: Previous studies have shown a positive correlation between Chalkley microvessel density and histological grade; however, in our sample, we found that the former is predictive of the outcome. Chondrosarcomas in flat bones have been shown to correlate with a poor prognosis. We also found that CD34 microvessel density values were significantly higher in flat-bone chondrosarcomas. This could explain-at least in part-the more aggressive biological course that is taken by these tumors. CONCLUSIONS: These results provide evidence that CD34 microvessel density in chondrosarcomas can be helpful in predicting patient outcome and may add to our understanding of chondrosarcoma pathogenesis.

Analysis of angiogenic factors and cyclooxygenase-2 expression in cartilaginous tumors: clinical and histological correlation

OBJECTIVES: To study the role of angiogenesis and cyclooxygenase-2 expression in cartilaginous tumors and correlate these factors with prognosis. INTRODUCTION: For chondrosarcoma, the histological grade is the current standard for predicting tumor outcome. However, a low-grade chondrosarcoma can follow an aggressive course-as monitored by sequential imaging techniques-even when it is histologically indistinguishable from an enchondroma. Therefore, additional tools are needed to help identify the biological potential of these tumors. The degree of angiogenesis that is induced by the tumor could assist in this task. Angiogenesis can be quantified by measuring the expression of vascular endothelial growth factor and CD34, and cyclooxygenase-2 can induce angiogenesis by stimulating the production of proangiogenic factors. METHODS: In total, 21 enchondromas and 58 conventional chondrosarcomas were studied by examining the clinical and histopathological findings in conjunction with the immunostaining markers of angiogenesis and cyclooxygenase- 2 expression. RESULTS: The significant variables that were associated with poor outcome were 1) higher-grade chondrosarcomas, 2) tumors that developed in flat bones, and 3) over-expression of CD34 (with a median count that was higher than 5.9 vessels in 5 high power fields). Moreover, CD34 expression (measured using the Chalkley method) revealed significantly higher microvessel density in flat bone chondrosarcomas. DISCUSSION: Previous studies have shown a positive correlation between Chalkley microvessel density and histological grade; however, in our sample, we found that the former is predictive of the outcome. Chondrosarcomas in flat bones have been shown to correlate with a poor prognosis. We also found that CD34 microvessel density values were significantly higher in flat-bone chondrosarcomas. This could explain-at least in part-the more aggressive biological course that is taken by these tumors. CONCLUSIONS: These results provide evidence that CD34 microvessel density in chondrosarcomas can be helpful in predicting patient outcome and may add to our understanding of chondrosarcoma pathogenesis.

[Angiogenesis in cartilage tumors]. / Angiogenese in Knorpeltumoren.

In contrast to normal cartilage, which is avascular, angiogenesis is characteristic of cartilage tumors. In this review, we outline the basic principles of angiogenesis with regard to recent findings on differential morphological and molecular aspects of angiogenesis in cartilage tumors, including enchondromas, conventional chondrosarcomas and dedifferentiated chondrosarcomas. Furthermore, we describe the effects of hypoxia and interleukin-1ß on angiogenic signaling in chondrosarcoma cells.

C-propeptides of procollagens I alpha 1 and II that differentially accumulate in enchondromas versus chondrosarcomas regulate tumor cell survival and migration.

Chondrogenic tumors that exhibit benign or malignant behaviors synthesize variable amounts of cartilage-like extracellular matrix. To define the regulators of these phenotypes, we performed a proteomic comparison of multiple human chondrogenic tumors, which revealed differential accumulation of the C-propeptides of procollagens Ialpha1 and II (PC1CP and PC2CP) in malignant versus benign tumors, respectively. Expression patterns of PC1CP correlated with levels of tumor vascularization, whereas expression patterns of PC2CP suggested its susceptibility to immobilization within the extracellular matrix. Prompted by these observations, we investigated the functions of recombinant PC1CP and PC2CP in the extracellular matrix in soluble or immobilized states. Each induced beta1 integrin-mediated chondrocyte adhesion by distinct domains and efficacies, suggesting that they initiated distinct signaling pathways. Indeed, immobilized PC2CP, but not PC1CP, induced apoptosis of primary chondrocytes and EAhy926 endothelial cells. In contrast, soluble PC1CP, but not PC2CP, induced the migration of EAhy926 cells and increased vascular endothelial growth factor (VEGF) and CXCR4 expression in chondrocytes. Soluble PC2CP also increased VEGF expression, but along with a more pronounced effect on CXCR4 and matrix metalloproteinase 13 expression. Our findings suggest that PC1CP favors angiogenesis and tumor progression, but that PC2CP acts in a more complex manner, exerting antitumor and antiangiogenic properties through apoptosis induction when immobilized, but progression and metastasis when soluble. In summary, the relative levels of PC1CP and PC2CP and their interactions within the extracellular matrix contribute to tumor progression, angiogenesis, and metastasis in chondrogenic tumors.

Heterogeneity of angiogenesis and blood vessel maturation in cartilage tumors.

Cartilage tumors have a special angiogenic phenotype, with blood vessels arranged predominantly in pericartilage fibrous septa and relatively low microvessel density (MVD), except in dedifferentiated chondrosarcomas. To further elucidate angiogenesis in cartilage tumors, we used double-labeling immunohistochemistry to determine microvessel pericyte coverage index (MPI) and proliferating capillary index (PCI), referring to blood vessel maturation and angiogenic activity in enchondromas, conventional chondrosarcomas, and dedifferentiated chondrosarcomas. Altogether, we found high MPIs (>70%) especially in dedifferentiated chondrosarcomas but without a correlation to the grade of malignancy. PCI was significantly higher in conventional chondrosarcomas grades II and III than in enchondromas, chondrosarcomas grade I, and dedifferentiated chondrosarcomas. Thus, PCI positively correlated with the previously reported differential expression of vascular endothelial growth factor (VEGF)-A in cartilage tumors. Altogether, cartilage tumors exhibit a heterogeneous but predominantly mature angiogenic phenotype with differential proliferative activity.

Differential expression of VEGF-A and angiopoietins in cartilage tumors and regulation by interleukin-1beta.

BACKGROUND: Vascular endothelial growth factor (VEGF)-A and angiopoietin (Ang)-1 and Ang-2 are key factors in angiogenic signaling. In this study the expression of these factors was identified in cartilage tumors. As interleukin (IL)-1beta has been found to be an indispensable factor in angiogenic signaling, we further analyzed the effect of IL-1beta on the expression of VEGF-A, Ang-1, and Ang-2 using a previously established cell culture model. METHODS: Surgical specimens of enchondromas, conventional chondrosarcomas, and dedifferentiated chondrosarcomas were obtained from 72 patients. VEGF-A, Ang-1, and Ang-2 mRNA expression was detected by conventional and quantitative reverse transcription polymerase chain reaction (PCR). VEGF-A expression was also detected by immunohistochemistry or Western blot. RESULTS: Differential expression of VEGF-A, Ang-1, and Ang-2 was clearly demonstrated in cartilage tumors. VEGF-A expression was positively correlated with the tumor type. Higher VEGF-A expression levels were detected in conventional chondrosarcomas Grades II and III (using a 3-tier grading system) than in dedifferentiated chondrosarcomas (P < .05). A typical pattern of VEGF-A isoforms was identified, including VEGF(121), VEGF(145), VEGF(165), and VEGF(189). Ang-1 presented as a low-level transcript with slightly elevated levels in chondrosarcomas (P < .05). Highly variable Ang-2 expression levels were detected in solitary cases of conventional chondrosarcomas. IL-1beta regulated VEGF-A and Ang-1 expressions in a dose-dependent manner. Whereas low IL-1beta concentrations increased VEGF-A and Ang-1 transcription, high IL-1beta concentrations had the opposite effect. IL-1beta did not activate Ang-2 expression. CONCLUSIONS: Angiogenic signaling in cartilage tumors is variable and at least partly regulable by IL-1beta. The findings are of therapeutic relevance, either as a desired effect or a side effect in medical treatment.

Pathologic neovascularization in cartilage tumors.

Tumor-induced angiogenesis is necessary to sustain radial growth of tumors. Increased microvascularity has been correlated with increased metastatic potential in breast, gastrointestinal, and gynecologic tumors, but has not been well studied in cartilaginous tumors. Grade II and Grade III chondrosarcomas have increased metastatic potential compared with Grade I tumors. One reason for this may be pathologic neovascularization. The purpose of the current study was to quantify the microvessel density of cartilage tumors. Seven Grade III, 17 Grade II, and eight Grade I chondrosarcomas, and 22 benign cartilage tumors were examined. Specimens were stained with antiCD34 antibody. Microvessel densities then were determined by direct counting and estimated using the Chalkley technique. Microvessel densities for Grade III and Grade II chondrosarcomas were 45.9 and 46.2 per high-power field and for Grade I and benign tumors the microvessel densities were 9.3 and 10.3. Microvessel densities of the aggressive tumors (Grades III and II) were greater than the microvessel densities of the nonaggressive tumors (Grade I and benign). Chalkley estimates confirmed the results. Microvascularity in cartilage tumors correlates with their biologic aggressiveness and seems promising as a variable to help with histopathologic grading and as a target for new treatment modalities.

Microvasculature and VEGF expression in cartilaginous tumors.

We examined the microvasculature and VEGF expression in 26 cartilaginous lesions (CL) including 5 enchondromas, 9 grade 1 chondrosarcoma (CS), 6 grade 2 CS, 4 grade 3 CS, 1 mesenchymal, and 1 myxoid chondrosarcoma. The degree of neovascularization was measured by counting microvessels on H&E and factor VIII related antigen immunostained slides. Vessels were divided into pericartilage vessels (PCV) and intracartilage vessels (ICV). PVC comprised vessels around the lobules or invading the lobules but themselves surrounded by noncartilaginous stroma (ie, fibrous stroma); ICV consisted of those vessels present inside the tumoral nodules and in direct apposition with malignant cells or tumoral stroma. A direct correlation was seen between histological type and grade of CS and pericartilage vessels. In contrast, ICV were found only in higher-grade CS. No enchondromas and only 1 of 9 grade 1 CS had ICV. This patient had Ollier's disease. All but 2 of the grade 2 CS showed ICV (average, 20.5). The exceptions were predominantly grade 1 CS with focal grade 2 areas and extensive areas of necrosis. All but 1 grade 3 CS had ICV, the exception being a case of metastatic CS to the lung. Malignant chondrocytes of high-grade lesions stained strongly for vascular endothelial growth factor (VEGF), a potent angiogenic factor. The only high-grade tumors that did not express VEGF did not show ICV either. Enchondromas and grade 1 CS, most without ICV, did not express VEGE In summary, PCV are present in all categories of tumoral cartilage and the number increases with histological grade; ICV are found in high-grade lesions, and the exceptions show extensive necrosis; VEGF expression by malignant chondrocytes is seen in high-grade lesions almost exclusively, and among these in those lesions that showed intracartilage vessels. It is possible that PCV are involved in supporting tumor growth, whereas ICV might be involved in the acquisition of metastatic potential by cartilage tumors. VEGF expression is strongly associated with the presence of ICV.

Adjuvant arterial embolization in the treatment of benign primary bone tumors in children.

This report presents an initial clinical experience with arterial embolization as adjuvent therapy in the surgical treatment of selected benign primary bone tumors in childhood. Embolization was dramatically effective in 4 children with spinal or pelvic vascular tumors. This technique facilitated local surgical resection and/or curettage. No child had evidence of local recurrence. Three of the 4 children had spinal cord or nerve root compression resulting in various degrees of paralysis prior to surgery. All treated patients had complete recovery from their paralysis. There were no complications of embolization or surgery. The treatment of benign primary bone tumors of the spine and pelvis is immeasurably improved by the adjuvant arterial embolization procedure. The immediate surgical treatment of these difficult tumors now becomes feasible with the greatly diminished blood flow resulting from embolization.

[The role of glomi (arteriovenous anastomoses) in the pathomechanisms of solitary enchondromas (author's transl)]. / Die Rolle der Glomi (arterio-venöse Anastomosen) im Pathomechanismus solitärer Enchondrome.

The author performed the histlologic examination of 62 solitary enchondromas located in the short tubular bones of the hand and the feet. In 25 cases the thinned cortical bone and its periosteum covering the lesion could be examined, too. Comparison with the controls revealed that the glomi (arteriovenous anastomoses) in the periosteum, or close to it were open in 1 case, strongly contracted in 9 cases, and closed in 15 cases. It is shown throughout the whole material that the pathologic tissue of the enchondromas has a poor vascular supply. In 14 out of 62 cases the septa amoung the cartilaginous lobes were filled with blood. In the vicinity of these, however, a regular osteoblastic ossification sets in. The above results lead to the conclusion that in the pathomechanism of the enchondromas the local hypoxaemia induced by functional disturbance of the glomi plays an important role in the proliferation of the bradytrophic cartilaginous tissue.