Comparison of Color Flow Doppler Sonography (CFDS) and Immunohistologic Detection of Microvessels for the Assessment of the Malignancy of Thyroid Nodules

Abstract

The assessment of tumor vascularization by color flow Doppler sonography (CFDS) has been suggested for the distinction between benign and malignant thyroid nodules. Our objective was to investigate if the CFDS results reflect the percentage of histologically determined microvessels in adenomas (As), adenomatous nodules (ANs), and papillary carcinomas (PCs). Tissue sections from 10 adenomas, 8 ANs and 13 PC and surrounding tissue of 10 PCs and 2 benign nodules were immunostained for CD34. A computerized image analysis was used to determine the microvessel density in four hot spots and ten systematically selected fields. Preoperatively CFDS was performed and classified according to Frates et al. We found a consistent percentage increase of CD34 stained microvessels in PCs (83 and 96%) as compared to adenomas and ANs (38 and 49%) determined by the hot spot analysis and systematic field analysis. A ROC analysis on the basis of the histologically determined number of microvessels demonstrated 70% microvessels as an optimal cut point for the diagnosis of PC with the highest sensitivity of 92% and highest specificity of 89%. The analysis of the CFDS-classification IV for the distinction between PCs and adenomas and ANs showed a sensitivity of 62% with a specificity of 100%. The lower sensitivity of the CFDS classification as compared with the immunohistologic determination of the microvessel density indicates that the CFDS classification detects the pathognomonic intranodular microvessels only incompletely. The higher CFDS specificity is most likely due to the detection of other vascular aspects of malignancy in addition to intranodular microvessels.

Key words

thyroid - papillary carcinoma - CD34 - hot nodules - cold nodules - color flow Doppler sonography

References

• 1 Gharib H, Goellner JR. Fine-needle aspiration biopsy of the thyroid: an appraisal.  Ann Intern Med. 1993;  118 282-289
• 2 Gharib H. Fine-needle aspiration biopsy of thyroid nodules: advantages, limitations, and effect.  Mayo Clin Proc. 1994;  69 44-49
• 3 Appetecchia M, Solivetti FM. The association of colour flow Doppler sonography and conventional ultrasonography improves the diagnosis of thyroid carcinoma.  Horm Res. 2006;  66 249-256
• 4 Frates MC, Benson CB, Charboneau JW, Cibas ES, Clark OH, Coleman BG, Cronan JJ, Doubilet PM, Evans DB, Goellner JR, Hay ID, Hertzberg BS, Intenzo CM, Jeffrey RB, Langer JE, Larsen PR, Mandel SJ, Middleton WD, Reading CC, Sherman SI, Tessler FN. Management of thyroid nodules detected at US: Society of Radiologists in Ultrasound consensus conference statement.  Radiology. 2005;  237 794-800
• 5 Fobbe F, Finke R, Reichenstein E, Schleusener H, Wolf KJ. Appearance of thyroid diseases using colour-coded duplex sonography.  Eur J Radiol. 1989;  9 29-31
• 6 Frates MC, Benson CB, Doubilet PM, Cibas ES, Marqusee E. Can color Doppler sonography aid in the prediction of malignancy of thyroid nodules?.  J Ultrasound Med. 2003;  22 127-131
• 7 Miyakawa M, Onoda N, Etoh M, Fukuda I, Takano K, Okamoto T, Obara T. Diagnosis of thyroid follicular carcinoma by the vascular pattern and velocimetric parameters using high resolution pulsed and power Doppler ultrasonography.  Endocr J. 2005;  52 207-212
• 8 Papini E, Guglielmi R, Bianchini A, Crescenzi A, Taccogna S, Nardi F, Panunzi C, Rinaldi R, Toscano V, Pacella CM. Risk of malignancy in nonpalpable thyroid nodules: predictive value of ultrasound and color-Doppler features.  J Clin Endocrinol Metab. 2002;  87 1941-1946
• 9 Shimamoto K, Endo T, Ishigaki T, Sakuma S, Makino N. Thyroid nodules: evaluation with color Doppler ultrasonography.  J Ultrasound Med. 1993;  12 673-678
• 10 Sasano H, Suzuki T. Pathological evaluation of angiogenesis in human tumor.  Biomed Pharmacother. 2005;  59 (S 02) S334-S336
• 11 Vermeulen PB, Gasparini G, Fox SB, Toi M, Martin L, McCulloch P, Pezzella F, Viale G, Weidner N, Harris AL, Dirix LY. Quantification of angiogenesis in solid human tumours: an international consensus on the methodology and criteria of evaluation.  Eur J Cancer. 1996;  32A 2474-2484
• 12 Weidner N. Intratumor microvessel density as a prognostic factor in cancer.  Am J Pathol. 1995;  147 9-19
• 13 Newman JS, Bree RL, Rubin JM. Prostate cancer: diagnosis with color Doppler sonography with histologic correlation of each biopsy site.  Radiology. 1995;  195 86-90
• 14 Taylor KJ, Ramos I, Carter D, Morse SS, Snower D, Fortune K. Correlation of Doppler US tumor signals with neovascular morphologic features.  Radiology. 1988;  166 57-62
• 15 Caruso G, Attard M, Caronia A, Lagalla R. Color Doppler measurement of blood flow in the inferior thyroid artery in patients with autoimmune thyroid diseases.  Eur J Radiol. 2000;  36 5-10
• 16 Clark KJ, Cronan JJ, Scola FH. Color Doppler sonography: anatomic and physiologic assessment of the thyroid.  J Clin Ultrasound. 1995;  23 215-223
• 17 Martinoli C, Derchi LE, Rizzatto G, Solbiati L. Power Doppler sonography: general principles, clinical applications, and future prospects.  Eur Radiol. 1998;  8 1224-1235
• 18 Rago T, Vitti P, Chiovato L, Mazzeo S, De Liperi A, Miccoli P, Viacava P, Bogazzi F, Martino E, Pinchera A. Role of conventional ultrasonography and color flow-doppler sonography in predicting malignancy in ‘cold’ thyroid nodules.  Eur J Endocrinol. 1998;  138 41-46
• 19 Rubin JM, Bude RO, Carson PL, Bree RL, Adler RS. Power Doppler US: a potentially useful alternative to mean frequency-based color Doppler US.  Radiology. 1994;  190 853-856
• 20 Spiezia S, Cerbone G, Colao A, Assanti AP, Picone GM, Lombardi G. Usefulness of power Doppler in the diagnostic management of hypoechoic thyroid nodules.  Eur J Ultrasound. 1997;  6 165-170
• 21 Castagnone D, Rivolta R, Rescalli S, Baldini MI, Tozzi R, Cantalamessa L. Color Doppler sonography in Graves' disease: value in assessing activity of disease and predicting outcome.  AJR Am J Roentgenol. 1996;  166 203-207
• 22 Ramsden JD. Angiogenesis in the thyroid gland.  J Endocrinol. 2000;  166 475-480
• 23 Becker D, Bair HJ, Becker W, Gunter E, Lohner W, Lerch S, Hahn EG. Thyroid autonomy with color-coded image-directed Doppler sonography: internal hypervascularization for the recognition of autonomous adenomas.  J Clin Ultrasound. 1997;  25 63-69
• 24 Cerbone G, Spiezia S, Colao A, Di Sarno A, Assanti AP, Lucci R, Siciliani M, Lombardi G, Fenzi G. Power Doppler improves the diagnostic accuracy of color Doppler ultrasonography in cold thyroid nodules: follow-up results.  Horm Res. 1999;  52 19-24
• 25 Pacella CM, Guglielmi R, Fabbrini R, Bianchini A, Rinaldi R, Panunzi C, Pacella S, Crescenzi A, Papini E. Papillary carcinoma in small hypoechoic thyroid nodules: predictive value of echo color Doppler evaluation. Preliminary results.  J Exp Clin Cancer Res. 1998;  17 127-128
• 26 Turner HE, Harris AL, Melmed S, Wass JA. Angiogenesis in endocrine tumors.  Endocr Rev. 2003;  24 600-632
• 27 Sancak S, Hardt A, Ricken A, Lorenz S, Eszlinger M, Sen LS, Gulluoglu BM, Sever Z, Eren FT, Akalin NS, Paschke R. Increased Percentage of Microvessels but Decreased Density of Large Vessels in Papillary Carcinomas as Compared to Hot and Cold Thyroid Nodules.  Exp Clin Endocrinol Diabetes. 2009;  117 637-644
• 28 Wong NA, Willott J, Kendall MJ, Sheffield EA. Measurement of vascularity as a diagnostic and prognostic tool for well differentiated thyroid tumours: comparison of different methods of assessing vascularity.  J Clin Pathol. 1999;  52 593-597
• 29 Fukunari N, Nagahama M, Sugino K, Mimura T, Ito K, Ito K. Clinical evaluation of color Doppler imaging for the differential diagnosis of thyroid follicular lesions.  World J Surg. 2004;  28 1261-1265
• 30 Argalia G, De Bernardis S, Mariani D, Abbattista T, Taccaliti A, Ricciardelli L, Faragona S, Gusella PM, Giuseppetti GM. Ultrasonographic contrast agent: evaluation of time-intensity curves in the characterisation of solitary thyroid nodules.  Radiol Med. 2002;  103 407-413
• 31 Folkman J. Seminars in Medicine of the Beth Israel Hospital, Boston. Clinical applications of research on angiogenesis.  N Engl J Med. 1995;  333 1757-1763
• 32 Maeda T, Adachi E, Kajiyama K, Takenaka K, Honda H, Sugimachi K, Tsuneyoshi M. CD34 expression in endothelial cells of small hepatocellular carcinoma: its correlation with tumour progression and angiographic findings.  J Gastroenterol Hepatol. 1995;  10 650-654
• 33 Schor AM, Schor SL. Tumour angiogenesis.  J Pathol. 1983;  141 385-413
• 34 Weidner N, Semple JP, Welch WR, Folkman J. Tumor angiogenesis and metastasis – correlation in invasive breast carcinoma.  N Engl J Med. 1991;  324 1-8
• 35 Gasparini G, Harris AL. Clinical importance of the determination of tumor angiogenesis in breast carcinoma: much more than a new prognostic tool.  J Clin Oncol. 1995;  13 765-782
• 36 Fox SB. Quantitative angiogenesis in breast cancer.  Methods Mol Med. 2006;  120 161-187
• 37 Weidner N, Folkman J, Pozza F, Bevilacqua P, Allred EN, Moore DH, Meli S, Gasparini G. Tumor angiogenesis: a new significant and independent prognostic indicator in early-stage breast carcinoma.  J Natl Cancer Inst. 1992;  84 1875-1887
• 38 Cantu DL, Lopez-Graniel C, Frias MM, Chanona VG, Gomez C, De La Garza SJ. Significance of microvascular density (MVD) in cervical cancer recurrence.  Int J Gynecol Cancer. 2003;  13 856-862
• 39 Banner BF, Whitehouse R, Baker SP, Swanson RS. Tumor angiogenesis in stage II colorectal carcinoma: association with survival.  Am J Clin Pathol. 1998;  109 733-737
• 40 de la Torre NG, Buley I, Wass JA, Turner HE. Angiogenesis and lymphangiogenesis in thyroid proliferative lesions: relationship to type and tumour behaviour.  Endocr Relat Cancer. 2006;  13 931-944
• 41 Dhar DK, Kubota H, Kotoh T, Tabara H, Watanabe R, Tachibana M, Kohno H, Nagasue N. Tumor vascularity predicts recurrence in differentiated thyroid carcinoma.  Am J Surg. 1998;  176 442-447
• 42 Goldenberg JD, Portugal LG, Wenig BL, Ferrer K, Wu JC, Sabnani J. Well-differentiated thyroid carcinomas: p53 mutation status and microvessel density.  Head Neck. 1998;  20 152-158
• 43 Herrmann G, Schumm-Draeger PM, Muller C, Atai E, Wenzel B, Fabian T, Usadel KH, Hubner K. T lymphocytes, CD68-positive cells and vascularisation in thyroid carcinomas.  J Cancer Res Clin Oncol. 1994;  120 651-656
• 44 Turner HE, Harris AL, Melmed S, Wass JA. Angiogenesis in endocrine tumors.  Endocr Rev. 2003;  24 600-632
• 45 Fleischer AC, Wojcicki WE, Donnelly EF, Pickens DR, Thirsk G, Thurman GB, Hellerqvist CG. Quantified color Doppler sonography of tumor vascularity in an animal model.  J Ultrasound Med. 1999;  18 547-551
• 46 Lassau N, Paturel-Asselin C, Guinebretiere JM, Leclere J, Koscielny S, Roche A, Chouaib S, Peronneau P. New hemodynamic approach to angiogenesis: color and pulsed Doppler ultrasonography.  Invest Radiol. 1999;  34 194-198
• 47 Taylor KJ, Burns PN, Woodcock JP, Wells PN. Blood flow in deep abdominal and pelvic vessels: ultrasonic pulsed-Doppler analysis.  Radiology. 1985;  154 487-493

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