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1 Department of Medical Imaging, Ultrasonography Unit, Institut Gustave Roussy,
39 rue Camille Desmoulins, 94805 Villejuif, France.
2 Department of Biostatistics, Institut Gustave Roussy, 94805 Villejuif,
France.
3 Department of Medicine, Institut Gustave Roussy, 94805 Villejuif,
France.
4 Department of Surgery, Institut Gustave Roussy, 94805 Villejuif, France.
5 Department of Pathology, Institut Gustave Roussy, 94805 Villejuif,
France.
Received April 2, 2001;
accepted after revision December 6, 2001.
Address correspondence to N. Lassau.
Abstract
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SUBJECTS AND METHODS. Sixty-nine histologically proven melanomas in 67 patients were prospectively studied before surgical resection. A morphologic study was performed with a 20-MHz probe. The maximal thickness of tumors was measured and compared with the Breslow index. A color Doppler sonographic analysis of neovascularization was performed with a 13-MHz probe to depict intratumoral vessels.
RESULTS. Of the 69 melanomas, 65 were depicted on sonography. Tumor thickness ranged from 0.26 to 8.0 mm as measured by sonography and from 0.15 to 8.0 mm according to the Breslow index. Sonographic measurements correlated strongly with the Breslow index (r > 0.96). Surgical reexcision was necessary in 33 tumors with a Breslow index exceeding 1 mm, but reexcision could have been avoided in 31 of these cases had the initial surgical planning been based on high-frequency sonographic measurements. Among the 62 patients studied with color Doppler sonography, intratumoral vessels were depicted on color Doppler sonography in 21 melanomas, all of which were thicker than 2 mm. The median follow-up was 40 months. Eleven patients developed metastases, and all except one had a vascularized melanoma. In the univariate analyses, neovascularization visualized with sonography and the Breslow index were both significantly linked to the occurrence of metastases (p < 0.0001). In the multivariate Cox proportional hazards regression analysis, neovascularization was the only significant parameter.
CONCLUSION. This study confirms that prognostic value of angiogenesis evaluated with color Doppler sonography could be used to identify melanomas with a high metastatic potential.
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The risk of metastasis is related to the Breslow index, which is considered to be the most accurate prognostic factor. During the first year, the metastasis rate after excision is less than 1% in tumors with a Breslow index of less than 0.76 mm, and it reaches 33% in tumors with a Breslow index greater than 4 mm [2].
Several studies [3,4,5] have shown the accuracy of sonography in the preoperative evaluation of melanoma thickness. We have also shown that color Doppler sonography can be used to study intratumoral vascularization and that vessels visualized with color Doppler sonography are significantly correlated with parameters evaluated after immunochemical studies are performed using anti-factor VIII antibody [3]. Thus we considered that color Doppler sonography could be used to evaluate angiogenesis and neovascularity and that it would be useful for the preoperative evaluation of melanomas.
The purpose of this study was to confirm the effectiveness of high-frequency sonography in the preoperative assessment of melanomas so that surgical resection can be adapted accordingly and reexcision thereby avoided. We also studied the prognostic value of angiogenesis evaluated with high-frequency and color Doppler sonography compared with that of the Breslow index in determining the metastatic potential of melanomas.
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We used an AU 5 Idea Sonograph (Esaote-Biomedica, Genoa, Italy) with two very-high-frequency probes (a 20-MHz annular probe with an axial resolution of 80 µm and lateral resolution of 100 µm and a 13-MHz linear electronic probe with an axial resolution of 200 µm and lateral resolution of 400 µm) with pulsed and color Doppler sonography (Doppler frequency, 7 MHz). Standard sonographic gel was used to separate the probe face from the skin surface and to prevent flattening of the melanoma. The focal zone was adapted according to the position of the tumor in the superficial tissue.
A sonographic morphologic study was performed for each tumor to analyze the structural sonographic pattern—delineation of the margins and echogenicity compared with the adjacent cutaneous tissue (hypoechoic or hyperechoic)—and to measure tumor thickness on the workstation screen using electronic calipers (accurate to the nearest 0.01 mm). The maximal thickness of the lesion was determined by measuring from the skin surface to the deepest point of the posterior margin. After surgical resection, tumors were analyzed histologically to determine the Breslow index. The pathologist was unaware of the thickness of the lesion as measured by sonography.
Sonographically determined tumor thickness was compared with the corresponding Breslow index measured at histology. The linear relationship between the Breslow measurement and sonographic measurement was estimated, and Pearson's correlation coefficient was used for correlation studies.
To search for intratumoral vessels in 60 visible melanomas (58 patients), we used color Doppler sonography with a pulse repetition frequency of 750 Hz, an imaging frequency of 9-16 images per sec, a 50-Hz acoustic filter, and a power of 75%. Quantification of the number of vessels per tumor was performed by obtaining multiple cross-sections of the tumors. Tumors with more than one vessel were those for which several pixels corresponding to tumor vessels were not contiguous. Contiguity between vessels was assessed across all sections. For four patients with tumors not seen at sonography, the number of vessels was considered equal to zero. Neovascularization was considered abundant when two or more vessels were visualized.
Follow-up examinations were scheduled every 3 months during the first 2 years and every 6 months thereafter. The prognostic value of the Breslow index and of neovascularization was based on the occurrence of metastases and tested by log-rank tests in univariate analyses and by the Cox proportional hazards regression model in a multivariate analysis. In the two patients with two melanomas each, we used the findings of the thickest melanoma for our analyses.
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On color Doppler sonography, vessels were not seen in the 40 melanomas of less than 2 mm in thickness. Vessels were visualized in 21 melanomas exceeding 2 mm in thickness (Fig. 3). In 13 cases, neovascularization was considered abundant (Fig. 4). The association between vascularization and the Breslow index was highly significant (p <10-4); the mean Breslow index was equal to 0.71 mm (range, 0.15-2.1 mm) in nonvascularized tumors, 3.7 mm (range, 2-6.2 mm) in tumors with one visible vessel, and 5.1 mm (range, 2-8 mm) in tumors with abundant vascularization. The median follow-up of the 62 patients was 40 months (range, 4-62 months). Eleven patients developed metastases. All but one had a vascularized melanoma. Both neovascularization (absent, one vessel, or two or more vessels) and the Breslow index (<1 mm, 1-4 mm, or >4 mm) were found to be significantly associated with metastases (p <0.0001 in both) (Table 1 and Figs. 5 and 6). In the multivariate Cox proportional hazards regression analysis, neovascularization was the only parameter significantly linked to metastases (p < 0.0001).
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At present, melanomas are treated by initial surgical resection based on clinical features. After the histologic analysis, reexcision may be deemed necessary according to the maximal tumor thickness (Breslow index). High-frequency sonographic measurement of tumor thickness is as accurate as histologic measurement and has the added advantage of being performed before surgery, thus allowing complete excision during the first (and only) surgical procedure. High-frequency sonography improves treatment of melanomas by saving time, limiting pain, and reducing costs. In our series, findings from preoperative sonography could have allowed surgical planning to be adapted and reexcision avoided in 31 melanomas of more than 1 mm in thickness.
Tumor growth is dependent on the development of neovessels [11]. Before the growth of tumor blood vessels, cell nutrients are delivered by passive diffusion. Rapid tumor expansion is dependent on the emergence of new capillary blood vessels that vascularize the tumor [12]. Angiogenesis may be an important factor in metastasis from cutaneous malignant melanomas [13, 14]. The second aim of our study was to investigate tumor vascularity to determine its prognostic value and to compare its value with that of the Breslow index, which is currently considered the most important prognostic factor. Blood flow was studied for the first time in vivo in 20 melanomas by Srivastava et al. [15] using 10-MHz continuous Doppler sonography. Those researchers found more abundant tumor vascularity in patients with regional or systemic spread than among patients who remained free of cancer for 2 years. However, their technique does not permit direct visualization of the blood flow. Several studies have shown that color Doppler sonography can visualize vessels in melanomas or in cutaneous metastases of melanomas [16,17,18]. In our study, vessels were detected in melanomas more than 2 mm thick. We have shown [3] that intratumoral vessels can be visualized directly with high-frequency and color Doppler sonography and that spectra can be recorded with pulsed Doppler sonography. The correlation with three histologic parameters (microvessel density, the number of vessels measuring > 100 mm in diameter, and the diameter of the largest vessel) showed that color Doppler sonography can visualize vessels of more than 100 µm and thus evaluate neoangiogenesis in vivo [19, 20]. Our study shows that color Doppler sonography allows evaluation of neovascularization in melanomas and confirms the relationship between the thickness of the melanoma and the importance of neovascularization. No vessels were visualized in lesions with a thickness of less than 2 mm, whereas at least one vessel was visible in all tumors more than 2 mm thick. Most (10/13) tumors with at least two vessels were thicker than 4 mm.
Srivastava et al. [21] noted that melanomas 0.76-4.0 mm in thickness that had an increased vascular area seen at histology were more likely to metastasize than tumors having comparable thickness but significantly less neovasculature. Barnhill and Levy [22], who specifically studied the vascular histologic aspect of melanomas with a very low metastatic potential in theory (<1.0 mm thick), showed that melanomas associated with angiogenesis had a poorer prognosis than those without angiogenesis.
Our results confirm that color and pulsed Doppler sonography can be used before surgery to evaluate angiogenesis and its corollary tumor aggressiveness. Vessels identified on color Doppler sonography could be indicative of tumors with a high metastatic potential. In the univariate prognostic analyses, the Breslow index and the abundance of vascularization are equivalent (p < 0.001). However, in the multivariate analysis, only vascularization is selected, which suggests that the prognostic importance of vascularization is greater than that of the Breslow index. This observation must be confirmed in a larger and independent series. A key factor might be the rate of intratumoral blood flow, which is related to the hemodynamic functionality of the vessels. Abundant vascularity, detectable with color Doppler sonography, corresponds to the phase of rapid tumor growth and is correlated with the rate of metastasis. New treatment procedures, such as isolated limb perfusion with tumor necrosis factor and melphalan, could be proposed, thus adapting treatment as soon as neovessels are visualized. These new procedures would have to be critically evaluated and compared with the standard procedures in prospective randomized trials.
Contrast agents can also be used with sonography to improve tumor vessel detection [23]. Ongoing studies are investigating higher frequencies (40-100 MHz) for better tissue characterization and vessel detection with contrast enhancement [24].
This study confirms that high-frequency sonography is a simple, reliable, noninvasive method for accurate preoperative measurement of the thickness of melanomas. Surgical planning could be adapted according to this measurement. The angiogenesis evaluated with color Doppler sonography could be used to select melanomas with a high metastatic potential.
Acknowledgments
We are grateful to Lorna Saint Ange for editing.
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