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Use of doppler ultrasound in the evaluation of breast carcinoma
Use of Doppler Ultrasound in the Evaluation of Breast Carcinoma Tejas S. Mehta, Sughra Raza, and Janet K. Baum Ultrasound is an imaging modality commonly used to evaluate breast lesions in hopes to distinguish benign from malignant solid masses. Angiogenesis, defined as the emergence of new vessels to further the growth of tumor, has stimulated interest in the potential uses of Doppler ultrasound in patients with breast cancer. This article describes different forms of Doppler ultrasound, including color Doppler (CD), power Doppler (PD), and spectral Doppler (SD), as well as 3-dimensional (3D) ultrasound and ultrasound contrast media. We review the role of Doppler ultrasound in distinguishing benign from malignant solid breast masses. We also discuss the role of ultrasound in predicting tumor grade, histology, node status, and lymphatic vascular invasion, and in monitoring breast cancer treatment. Copyright © 2000 by W.B. Saunders Company
LTHOUGH MAMMOGRAPHY is the only widely accepted imaging modality used to screen for early, otherwise occult, breast cancers, there continues to be a large number of lesions with indistinguishable or indeterminate mammographic features. In the United States, the work-up of these lesions result in many negative biopsies, with positive biopsy rates of 10% to 35%. 1-4 Currently, there is no widely accepted role of breast ultrasound as a screening method because of high false-positive and false-negative rates. 5,6 However, breast ultrasound is routinely used as an adjunct to mammography, to help predict more accurately if a lesion is benign or malignant. Stavros et al7 used grey-scale sonography to prospectively classify solid breast lesions as benign, indeterminate, or malignant, and calculated a negative predictive value (NPV) of 99.5%. These investigators used state-of-the-art equipment and strict diagnostic criteria. To our knowledge, other investigators have not been able to corroborate their results. Although grey-scale sonographic features of benign and malignant solid breast lesions have been described, 8-~3 a significant number of breast masses do not present with a typical sonographic appearance.9,14,15 The phenomenon of tumor angiogenesis is well known from studies of tumor biology.16 Angiogenesis is defined as the formation of new blood vessels through the sprouting of capillaries from preexisting microvessels, a7 Tumors as small as 3 mm rely on the formation of these vessels to further their growth. TM The formation of these abnormal vessels is associated with an increased risk of malignancy. ~9 Blood vessels of malignant tumors are characterized by an atypical course, with irregular stenosis, occlusion, wide variation of caliber,
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sinusoidal widening, and arteriovenous shunts on angiography. It is these concepts of angiogenesis that have prompted investigation of the use of Doppler ultrasound (spectral Doppler [SD], color Doppler [CD], and power Doppler [PD]) in differentiating benign from malignant solid breast masses, and in better characterizing the invasiveuess and extent of malignant breast cancers. SD, CD, AND PD ULTRASOUND CD (Fig 1A and 113) and SD (Fig 1C) ultrasound are based on the mean Doppler frequency shift, and, thus, are subject to aliasing and are angle dependent. If the gain settings are too high or the Doppler display threshold is too low, noise will overwhelm the image. 2°,zl An advantage of both of these methods is that they allow for assessment of velocity and direction of flow. 21 PD (Fig 1D) ultrasound is based on the amplitude of Doppler shift, with the c010r map related to the number of red blood cells producing the Doppler shift. 2°-22PD is essentially angle independent and is not subject to aliasing. 21,23-25The higher dynamic range of PD makes it more sensitive than CD and SD in detection of smaller blood vessels and low-velocity blood flow. 2°-22,26 The main disadvantages of PD are that it cannot assess velocity or direction of
From the Department of Radiology, Beth Israel Deaconess Medical Center, Boston, MA. Address reprint requests to Tejas S. Mehta, MD, Beth Israel Deaconess Medical Center, Department of Radiology, TCC 4th Floor, 330 Brookline Avenue, Boston, MA 02215. E-mail: tmehta @caregroup.harvard, edu Copyright © 2000 by W..B. Saunders Company 0887-2171/00/2104-0003510. 00/0 doi:10.1053/sult.2000.8923
Seminars in Ultrasound, CT, and MR/, Vot 21, No 4 (August), 2000: pp 297-307
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Fig 1. Breast cancer interrogated with various ultrasound methods to assess tumor vascularity. (A) Grey-scale image of a nonpalpable breast cancer. (B) CD scan, (C) SD tracing, (D) PD imaging,
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flow, and it is much more sensitive to tissue motion than CD and S D . 21 DISTINGUISHING BENIGN FROM MALIGNANT SOLID BREAST MASSES
In 1988, Schoenberger et a127 performed pulsed duplex Doppler sonography on 38 patients and reported that Doppler sonography could predict malignancy with sensitivity and specificity of 100%. In their study, all malignant cases showed Doppler signal and all benign lesions had no Doppler signal. Since that time, advances in technology and improvements in ultrasound equipment have allowed improved detection of blood flow with Doppler sonography in all solid masses, benign and malignant, thus, lowering sensitivity and specificity.
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More recent studies have shown detectable Doppler flow in 14% to 60% of benign breast lesions 22,2833 and 65% to 98% of malignant breast cancers.22,28-35 Investigators have questioned if patterns of vascularity could be used to help differentiate benign from malignant lesions. A study from our institution28 using PD ultrasound characterized vascularity patterns in benign and solid lesions as none, peripheral, central, and penetrating (Fig 2). We found that penetrating vessels were more likely present in malignant tumors. Other subsequent studies have shown similar results. 22,34,36 In our study, by using penetrating vessels to indicate malignancy, the sensitivity for PD ultrasound was 68%, specificity was 95%, positive predictive value
Fig 2. Patterns of tumor vascularity in breast cancers as shown by PD. (A) No detectable vessels. (B) Peripheral nonbranching vessels. (C) Central vessels. (D) Penetrating vessels, with irregular branching,
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(PPV) was 85%, and NPV was 88%. Grey-scale ultrasound alone had a calculated sensitivity of 92%, specificity of 59%, PPV of 48%, and NPV of 95%. The addition of PD findings to grey-scale ultrasound resulted in improved sensitivity and NPV both to 100% (Fig 3). 28 Other studies using C D 22'33'36'37 and PD 22 signals to diagnose malignancy have reported sensitivities of 64% to 94%, specificities of 75% to 88%, NPV of 63% to 84%, and accuracy of 63% to 88%. Studies looking at the number of detectable Doppler vessels show that cancers have a significantly higher number of vessels than benign breast lesions. 22,37-4° Many investigators have examined the Doppler vascularity of breast lesions in terms of resistive
Fig 3. Penetrating vessels may occasionally be the only strong indication of malignancy, (A) Grey-scale US shows a smoothly marginated hypoechoic mass with acoustic enhancement, typical features of benignity, (B) PD reveals prominent penetrating vessels, prompting biopsy that revealed invasive carcinoma,
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index (RI), pulsatility index (PI), and mean velocity (Vmean) and maximum velocity (Vmax), with conflicting results26,29,36,3947[RI = (Vmax - Vmin)/ Vmax; PI = (Vmax - Vmin)/Vmean]. Hollerweger et a146 studied 117 cancers and fibroadenomas, and found that by using a threshold of RI -> 0.80 to diagnose malignancy, the calculated sensitivity was 55%, specificity was 96%, PPV was 92%, and NPV was 66%. They also calculated that using a threshold of ->0.20 for differences in RI values within the same lesion to diagnose malignancy, the calculated sensitivity was 39%, specificity was 97%, PPV was 93%, and NPV was 66%. They found no threshold that could predict benignity with high specificity because both benign lesions and cancers had RI values of less than 0.80. The high variation of velocities within cancers is presumably caused by the tortuous vessels and arteriovenous shunts that are typical of malignant neovascularization.48,49 Peters-Engl et a145 used RI -> 0.70 to indicate malignancy, with sensitivity of 82%, specificity of 81%, PPV of 70%, and NPV of 89%. Other studies also found significantly higher RI values in malignant breast cancers compared with benign breast lesions, 26,36 however, as with prior studies, there was overlap. Studies examining the usefulness of PI in distinguishing benign from malignant lesions have not been promising. Some studies have found no difference in PI values of benign and malignant breast masses. 29,45 One study did find a significant difference in PI values of benign versus malignant tumors, but with much overlap, thus, limiting its usefulness. 26 The formation of arteriovenous shunts and thinwalled vessels lacking smooth muscle, as seen in malignant tumors, result in high-velocity pulsatile tumor flow. 3°,5°,51 This theory has led investigators to examine Vmax on Doppler ultrasound to distinguish benign from malignant breast lesions. 36,39,4°,44,45All of these studies found significantly higher Vmax values in malignant tumors compared with benign tumors. One study45 stated that this finding could be related to tumor size because in their study the malignant tumors were larger than the benign tumors. Another study 35 looked at Vmax in 74 malignant breast tumors to see if this value could be used to predict survival rates. They found that patients with Vmax > 0,25
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m/s had a 4.33-fold increased risk of death secondary to the underlying disease. The calculated 5-year survival rate in patients with Vmax ---0.25 rrds was 82.3%. This decreased dramatically to 36.6% in patients with Vmax > 0.25 m/s. 35 Few studies have examined Vmean values on Doppler ultrasound. One study found higher Vmean in malignant compared with benign lesions 39 and another found no difference. 44
CORRELATION OF DOPPLER SIGNAL WITH MICROVESSEL DENSITY Another method to assess angiogenesis on a microscopic level, using immunohistochemical methods, is the determination of microvessel density (MVD). MVD has been shown to predict tumor progression, relapse, and survival rates. 52-s9 However, studies have shown that blood flow in breast cancers as measured by ultrasound methods have no correlation with MVD. 3°,6°-62 This suggests that the vessels assessed by Doppler ultrasound belong in a different category than those measured with microvessel count, probably larger. 63 One study of 207 cancers showed no significant difference in mean MVD when comparing tumors with detectable Doppler vessels to those with no Doppler vessels. However, when MVD was more than 80 vessels per 250× field, tumors were significantly more likely to be vascular on Doppler ultrasound. 62 ASSOCIATION AMONG DOPPLER SIGNAL AND TUMOR SIZE, GRADE, AND HISTOLOGY Many studies have shown no correlation between Doppler detectable vascularity and tumor size. 62,64-65 Our study of 176 patients with cancer using PD showed a significant difference between tumor size and presence or absence of vessels, however, there was overlap. 66 Other studies have shown no significant correlation between Doppler vascularity and t u m o r grade. 29,62,66,67 However, 2 studies have noted that grade 3 tumors were more likely to be vascular o n PD 66 or quantitatively show more vessels o n C D 68 t h a n tumors of lower grades. Obviously, it is also not possible to make a histological diagnosis based on Doppler ultrasound findings. However, a few studies have noted that invasive lobular carcinomas tend to be less vascular on CD 67 and P D 28'66 compared with other histological types.
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ASSESSING NODAL INVOLVEMENT BY EVALUATING THE PRIMARY LESION Lymph node status is a major prognostic indicator in patients with breast cancer. Axillary lymph node dissection is responsible for much of the morbidity associated with breast surgery. 69-71Sentinel node excision is an alternative method of lymph node sampling that has been studied and has recently become more widely used. A multicenter study on sentinel node biopsy 72 showed that it can predict the presence or absence of axillary-node metastases. However, this study also reported variable success rates based on patient age, location of primary carcinoma, and surgeons' experience. Various Doppler ultrasound methods have been studied as a potential noninvasive method of assessing lymph node status. 29'30'62'64-66'68 We studied 126 patients with breast cancer that underwent lymph node dissection. 66 The association of PD vessels in the primary lesion and lymph node involvement resulted in a calculated sensitivity of 93%, specificity of 32%, PPV of 43%, and NPV of 90%. In other words, because many breast cancers show vessels on PD, the sensitivity was high and specificity was low. However, when no PD vessels were seen, 90% had no lymph node involvement, compared with when PD vessels were seen, 57% had lymph node involvement. These results were significant, even after controlling for tumor size. Lee et aP ° used CD to study a smaller number of malignant breast lesions (n = 32), and found a significant association between higher tumor flow and nodal metastases for T1 lesions (---2 cm) but not for larger tumors. They concluded that the presence of a CD signal in T1 lesions may be helpful in identifying those patients with small, apparently early, but aggressive tumors with poorer prognosis. Kubek et al, 6~ using CD technique, also showed results similar to ours. They defined a rim sign as a curvilinear or branching pattern at the periphery of a mass on CD sonography. Of 33 malignant tumors, lymph node metastases were present in 50% when a rim sign was present, and only 10% of the time when a rim sign was absent. Holcombe et al68 evaluated 28 breast cancers and found that when 3 or more vessels were seen on CD flow, the patients were more likely to have lymph node involvement. Kuijpers et al64 used a different Doppler technique, but also yielded similar results to our study. They used pulsed Doppler of primary breast cancers to predict lymph node involvement. A positive
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signal, defined as a Doppler shift frequency of more than 1 kHz using a 5-MHz insonating frequency, was predictive of lymph node involvement with a calculated sensitivity of 84%, specificity of 56%, PPV of 51%, and NPV of 86%. Stems et al62 evaluated 207 patients with invasive ductal carcinoma, and found that lymph node involvement was present in 27 of 51 lesions showing vessels (PPV 53%) and in 47 of 156 lesions showing no vessels (false-negative rate 30%) on Doppler ultrasound. Other studies have shown no correlation between CD-detected tumor vascularity and lymph node involvement. 29 ASSESSING NODAL INVOLVEMENT BY EVALUATING THE AXILLA
As stated previously, the presence of axillary lymph node metastases is a major prognostic indicator in patients with newly diagnosed breast cancer. A patient with a T1 lesion undergoing axillary node dissection has an 80% chance of having no nodal involvement. 7~,74 Although the chance of nodal metastases is higher in T2 lesions, 65% of patients in this group also have negative nodes. 74 Clinical examination of the axilla is not a very sensitive method for identifying axillary node involvement, with reported sensitivities ranging from 32% to 58%. 75-77 It is difficult to see normal lymph nodes with grey-scale ultrasound because of similar echotexture of the surrounding axillary tissue, especially if there is abundant fat. 78 Pathological lymph nodes are more readily detectable because they are rounded and more hypoechoic (Fig 4). 79 Grey-scale ultrasound of the axilla has been used to evaluate nodal involvement with varying sensitivities of 60% to 73 %.80,81 Investigators have also examined the axilla using CD Ultrasound. When limited to patients with cancer, CD ultrasound has reported sensitivities of 70% to 75% and specificities of 96% to 100% in predicting axillary metastases. 67,82 Some studies have found that many of the true-positive nodes that did not have CD vessels were seen in those patients with no CD vessels in the primary breast lesion. 82Yang and Betreweli 83performed CD examination of the axilla of 81 women with breast carcinoma and 106 asymptomatic women who presented for screening and had no significant breast or axillary pathology. They found CD flow in 84% of normal nodes and 88% of metastatic nodes
Fig 4. US appearance of an abnormal axillary lymph node (marked by calipers). It is rounded and enlarged, with compressed fatty hilum.
in the patients with breast cancer, and 87% of normal nodes in the asymptomatic, normal screening patients. Thus, the presence of CD flow was highly nonspecific when used as the sole criteria to diagnose malignancy. There is also no method to distinguish the Doppler flow detected in malignant nodes from that in inflammatory nodes. 84,85 ASSESSING FOR LYMPHATIC VASCULAR INVASION
Tumors may spread to the lymph nodes through either a hematogenous route or lymphatic drainage. The latter mode stimulated us to investigate if there is a correlation between PD vascularity and lymphatic vascular invasion (LVI). 66 Of 150 breast cancers, 111 (74%) showed PD vessels and 39 (26%) showed no PD vessels. LVI was present in 47 of 111 (42%) patients with PD vessels and 5 of 29 (13%) with no PD vessels in the primary breast cancer. These results were significant. The calculated sensitivity of PD in predicting LVI was 90%, with specificity of 35%, PPV of 42%, and NPV of 87%.66 To our knowledge, only 2 other studies have examined Doppler flow in relation to LVI. 29,67 Dixon et a167 studied 32 breast cancers, of which 25 (78%) had CD flow. They reported that 6 patients had LVI, and all 6 had positive CD flow in the primary breast lesion. Cosgrove et a129 studied 37 patients with available histology and found no correlation between CD vascularity in the primary breast cancer and LVI.
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MONITORING BREAST CANCER TREATMENT
Although adjuvant therapy has been shown to decrease the rate of recurrence in early cases of breast cancer (in which the disease is local without distant metastases), local and regional treatments alone also have been shown to be curative. 86 In advanced cases of breast cancer in which the disease had spread, systemic therapy (including chemotherapy, hormonal therapy, or both) is needed. Recently, some tumors have been treated with systemic therapy as a first-line treatment before local surgical treatment (neoadjuvant therapy). 87 Conventional methods, such as a clinical examination, mammography, and grey-scale ultrasound, for assessing tumor response to therapy, have been used with limitations. 8749 Treatment of hepatocellular carcinomas and hyperfunctioning thyroid and parathyroid nodules have been monitored using CD and PD ultrasound. 9° Kedar et al91 studied 34 patients with large or centrally located breast cancers treated with neoadjuvant therapy to see if CD ultrasound could be used to monitor and predict the response of breast cancer to therapy. The 34 patients underwent 126 treatment cycles. In 97 (77%) of the cycles, the changes in CD vascularity were concordant with changes in the size of the tumor. A reduction in vascularity was seen with response to therapy, and an increase in tumor size and no reduction or increase in vascularity was seen with lack of response or tumor progression. Changes seen on CD occurred at least 4 weeks before those seen at clinical examination in 40% of patients, and before those seen with grey-scale ultrasound in 38% of patients. 91 Another smaller study of 18 patients with breast cancer also showed promising results. Sixteen of the 18 patients had no detectable CD signal at the end of treatment with local parenteral repeated administration of antiblastic drugs. Of the 2 remaining patients, in whom the CD signal remained present, both had histopathologically confirmed residual tumor cells. 9° 3-DIMENSIONAL DOPPLER SONOGRAPHY
Recently, 3-dimensional (3D) Doppler ultrasound technology has been developed (Fig 5A and 5B). One study suggested that 3D PD ultrasound could improve detection rates of smaller vessels than that seen by 2-dimensional (2D) methods. 92 Carson et al93,94 performed 2 studies looking at benign and malignant breast masses with 3D CD imaging, comparing it with 2D images and video-
Fig 5. PD scanning of breast cancer with 3D reconstruction. (A) 2D PD scan of a tumor. (B) 3D rendering of the PD data of the same tumor, clearly showing a larger number of vessels and showing branching patterns,
tape. Both studies concluded that 3D imaging provided a stronger subjective appreciation of vascular morphology and allowed somewhat better ultrasound discrimination of malignant lesions than did 2D images or videotape, although the results were not significant. Note also that real-time 2D imaging of the breast lesions by the radiologist, routinely performed in our institution and many others, was not incorporated as a comparative arm
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in either study. Our anecdotal experience with 3D PD ultrasound is that it does not add additional clinically relevant, diagnostic information. ULTRASOUND CONTRAST MEDIA
Several contrast agents are being developed for use with ultrasound. 95-97These intravascular agents improve the detection of low-volume blood flow by increasing the signal-to-noise ratio. The use of contrast media in breast tumors yields a larger number of Doppler ultrasound signals. 98 Huber et a199 examined 47 patients, 31 with breast cancer and 16 with benign breast lesions. They found significant differences in degree, onset, and duration of Doppler enhancement between the 2 groups after contrast. Cancers had higher peak color pixel density, shorter time to enhancement, and longer duration of enhancement than benign lesions. These results, although promising, had high interindividual variability, thus, limiting its value for prospective diagnosis. Kedar et al37 studied 34 patients, 18 with breast cancer and 16 with benign breast lesions. They examined the lesions before and after contrast. With contrast, they improved their sensitivity from 88.9% to 100%, specificity from 87.5% to 100%, and accuracy from 88.2% to 100%. CONCLUSIONS
Although grey-scale ultrasound remains the basis of sonographic evaluation of breast masses, Doppler ultrasound is sometimes an important adjunct to grey-scale ultrasound. Because of improved technology, Doppler flow is seen in both benign and malignant lesions. However, there are characteristic patterns of vascularity that are more
commonly seen in malignant lesions, including penetrating vessels, as well as a greater number of vessels, which can assist in diagnosis. RI, PI, and Vmax have not been shown to be of diagnostic value. Some studies have shown correlation between Doppler signal and tumor size, although none have shown correlation with tumor histology or grade. Because Doppler signal is present in a large number of breast cancers, it is highly sensitive but not specific in identifying patients with lymph node involvement or LVI. More importantly, however, 1 study 66 has shown that the absence of Doppler vessels had a high NPV for lymph node metastases and LVI. Examination of the axilla with Doppler ultrasound is not helpful in predicting nodal disease, although evaluation should still be performed looking for grey-scale features of abnormal lymph nodes. Preliminary studies evaluating the role of Doppler ultrasound in monitoring breast cancer treatment are promising, although further, larger scale studies need to be performed. Doppler ultrasound may be suitable for monitoring the subset of patients that are treated solely with radiation therapy, in patients with inadequate axillary node dissections, or in patients whose tumors are not amenable to primary surgery. Currently, 3D Doppler sonography does not have a significant role in assessment of breast cancer. Ultrasound contrast media will likely be used more commonly in the future, although currently these studies are still at the experimental stage. However, the use of contrast media adds an invasive component to an otherwise noninvasive study.
REFERENCES
1. Tersegno MM: Mammography:positive predictive value and true positive biopsy rate (letter). AJR Am J Roentgenol 160:660-661, 1993 2. McManusV, Desautels JE, BenediktssonH, et al: Enhancement of true positive rates for nonpalpable carcinoma of the breast through mammographic selection. Surg Gynecol Obstet 175:212-218, 1992 3. Bassett LW, Liu TH, GiulianoAE, et al: The prevalence of carcinoma in palpable versus impalpable mammographically detected lesions. AJRAm J Roentgenol 157:21-24, 1991 4. MayerJE, Eberlein TJ, StomperPC, et al: Biopsyof occult breast lesions: analysis of 1261 abnormalities.JAMA263:23412343, 1990 5. Teh W, Wilson ARM: The role of ultrasound in breast cancer screening. A consensus statement by the European group for breast cancer screening. Eur J Cancer 34:449-450, 1998
6. Jackson VP, Reynolds HE, Hawes DR, et al: Sonography of the breast. Semin Ultrasound CT MR 17:460-475,1996 7. Stavros AT, Thickman D, Rapp CL, et al: Solid breast nodules: use of sonographyto distinguish between benign and malignant lesions. Radiology 196:123-134, 1995 8. Egan RL, Egan KL: Automated water-path full breast sonography:correlationwith histologyin 176 solid lesions. AJR Am J Roentgenol 143:499-507, 1984 9. Cole-Beuglet C, Soriano RZ, Kurtz AB, et al: Fibroadenoma of the breast: sonomammographycorrelatedwith pathology in 122 patients. AJR Am J Roentgenol 140:369-373, 1983 10. Cole-BeugletC, SorianoRZ, KurtzAB, et al: Ultrasound analysis of 104 primary breast carcinomas classified according to histopathologictype. Radiology 147:191-196, 1983 11. Fomage BD, Lorigan JG, Andry E: Fibroadenomaof the breast: sonographicappearance. Radiology 172:671-675, 1989
DOPPLER ULTRASOUND IN BREAST CARCINOMA
12. Leucht WJ, Rabe DR, Humbert K: Diagnostic value of different interpretative criteria in real-time sonography of the breast. Ultrasound Med Biol 14:59-73, 1988 13. Ueno E, Tohno E, Itoh K: Classification and diagnostic criteria in breast echography. Jpn J Med Ultrasonics 13:19-31, 1986 14. Heywang SH, Lipsit ER, Glassman LM, et al: Specificity of ultrasonography in the diagnosis of benign breast masses. J Ultrasound Med 3:453-461, 1984 15. Jackson VE Rothschild PA, Kreipke DL, et al: The spectrum of sonographic findings of fibroadenoma of the breast. Invest Radio121:34-40, 1986 16. Folkman J, Watson K, Ingber D: Induction of angiogenesis during the transition from hyperplasia to neoplasia. Nature 339:58-62, 1989 17. Battegay E: Angiogenesis: mechanistic insights, neovascular diseases, and therapeutic prospects. J Mol Med 73:333346, 1995 18. Folkman J: Tumor angiogenesis: therapeutic implications. N Engl J Med 285:1182-1186, 1971 19. Folkman J: How is blood vessel growth regulated in normal and neoplastic tissue? GHA Clowes Memorial Award Lecture. Cancer Res 46:467-473, 1986 20. Bude RO, Rubin JM, Adler RS: Power versus conventional color Doppler sonography: comparison in the depiction of normal intrarenal vasculature. Radiology 192:777-780, 1994 21. Rubin JM, Bude RO, Carson PL, et al: Power Doppler US: a potentially useful alternative to mean frequency-based color Doppler US. Radiology 190:853-856, 1994 22. Kook S, Park H, Lee Y, et al: Evaluation of solid breast lesions with power Doppler sonography. J Clin Ultrasound 27:231-237, 1999 23. Dymling SO, Persson HW, Hertz CH: Measurement of blood perfusion in tissue using Doppler ultrasound. Ultrasound Med Biol 17:433-444, 1991 24. Jaln SE Fan PH, Philpot EF, et al: Influence of various instrument settings on the flow information derived from the power mode. Ultrasound Med Biol 17:49-54, 1991 25. Rubin JM, Adler RS: Power Doppler expands standard color capacity. Diagn Imag (San Franc) 15:66, 1993 26. Hayashi N, Miyamoto Y, Nakata N, et al: Breast masses: color Doppler, power Doppler, and spectral analysis findings. J Clin Ultrasound 26:231-238, 1998 27. Schoenberger SG, Sutherland CM, Robinson AE: Breast neoplasms: duplex sonographic imaging as an adjunct in diagnosis. Radiology 168:665-668, 1988 28. Raza S, Bantu J: Solid breast lesions: evaluation with power Doppler US. Radiology 203:164-168, 1997 29. Cosgrove DO, Kedar RP, Bamber JC, et al: Breast diseases: color Doppler US in differential diagnosis. Radiology 189:99-104, 1993 30. Lee WJ, Chu JS, Huang CS, et al: Breast cancer vascularity: color Doppler sonography and histopathology study. Breast Cancer Res Treat 37:291-298, 1996 31. Lee WJ, Chu JS, Chang KJ, et al: Occult breast carcinomause of color Doppler in localization. Breast Cancer Res Treat 37:299-302, 1996 32. Britton PD, Coulden RA: The use of duplex Doppler ultrasound in the diagnosis of breast cancer. Clin Radiol 42:399-401, 1990
305
33. Lee SK, Lee T, Lee KR, et al: Evaluation of breast tumors with color Doppler imaging: a comparison with image-directed Doppler ultrasound. J Clin Ultrasound 23:367-373, 1995 34. Rizzatto G, Chersevani R, Abbona M, et al: Highresolution sonography of breast carcinoma. Eur J Radio124:1119, 1997 35. Peters-Engl CH, Fran W, Leodolter S, et al: Tumor flow in malignant breast tumors measured by Doppler ultrasound: an independent predictor of survival. Breast Cancer Res Treat 54:65-71, 1999 36. Blohmer JU, Oellinger H, Schmidt C, et al: Comparison of various imaging methods with particular evaluation of color Doppler sonography for planning surgery for breast tumors. Arch Gynecol Obstet 262:159-171, 1999 37. Kedar RE Cosgrove D, McCready VR, et al: Microbubble contrast agent for color Doppler US: effect on breast masses. Radiology 198:679-686, 1996 38. Adler DD, Carson PL, Rubin JM, et al: Doppler ultrasound color flow imaging in the study of breast cancer: preliminary findings. Ultrasound Med Biol 16:553-559, 1990 39. McNicholas MMJ, Mercer PM, Miller JC, et al: Color Doppler sonography in the evaluation of palpable breast masses. AJR Am J Roentgenol 161:745-771, 1993 40. Madjar H, Sanerbrei W, Prompeler HJ, et al: Color Doppler and duplex flow analysis for classification of breast lesions. Gyuecol Ouco164:392-403, 1997 41. Dock W: Duplex sonography of mammary tumors: a prospective study of 75 patients. J Ultrasound Med 2:79-82, 1993 42. Delorme S, Anton HW, Kuopp MV, et al: Breast tumors: assessment of vascularity by cotour Doppler. Eur Radiol 3:253257, 1993 43. Cosgrove DO, Bamber JC, Davey JB, et al: Color Doppler signals from breast tumors. Radiology 176:175-180, 1990 44. Kedar RP, Cosgrove DO, Bamber JC, et al: Automated quantification of color Doppler signals: a preliminary study in breast tumors. Radiology 197:39-43, 1995 45. Peters-Engl C, Medl M, Leodolter S: The use of colourcoded and spectral Doppler ultrasound in the differentiation of benign and malignant breast lesions. Br J Cancer 71:137-139, 1995 46. Hollerweger A, Rettenbacher T, Macheiner P, et al: New signs of breast cancer: high resistance flow and variations in resistive indices evaluation by color Doppler sonography. Ultrasound Med Bio123:851-856, 1997 47. Huber S, Delorme S, Knopp MV, et al: Breast tumors: computer-assisted quantitative assessment with color Doppler US. Radiology 192:797-801, 1994 48. Schor AM, Schor SL: Tumor angiogenesis. J Pathol 141:385-413, 1983 49. Strickland B: The value of arteriography in the diagnosis of bone tumours. Br J Radiol 32:705-713, 1959 50. Taylor KJW, Ramos 1, Carter D: Correlation of Doppler US tumor signals with neovascular morphology features. Radiology 166:57-62, 1988 51. Shubik P: Vascularization of tumors: a review. J Cancer Res Clin Oncol 103:211-216, 1982 52. Weidner N, Semple SP, Welch WR, et al: Tumor angiogen-
306
esis and metastasis---correlation in invasive breast carcinoma. N Engl J Med 324:1-8, 1991 53. Weidner N, Folkman J, Pozza F, et al: Tumor angiogenesis: a new significant and independent prognostic indicator in early-stage breast carcinoma. J Natl Cancer Inst 84:1875-1887, 1992 54. Bosari S, Lee AK, Delellis RA, et al: Microvessel quantitation and prognosis in invasive breast carcinoma. Hum Patho123:755-761, 1992 55. Gasparini G, Weidner N, Bevilacqua R et al: Tumor microvessel density, p53 expression, tumor size, and peritumoral lymphatic vessel invasion are relevant prognostic markers in node-negative breast carcinoma. J Clin Oncol 12:454-466, 1994 56. Fox SB, Leek RD, Smith K, et al: Tumor angiogenesis in node-negative breast carcinomas--relationship with epidermal growth factor, estrogen receptor and survival. Breast Cancer Res Treat 29:109-116, 1994 57. Bevilacqua P, Barbareschi M, Verderio R et al: Prognostic value of intratumoral microvessel density, a measure of tumor angiogenesis, in node-negative breast carcinoma--results of a multiparametric study. Breast Cancer Res Treat 36:205-217, 1995 58. Toi M, Inada K, Suzuki H, et al: Tumor angiogenesis in breast cancer: its importance as a prognostic indicator and the association with vascular endothelial growth factor expression. Breast Cancer Res Treat 36:193-204, 1995 59. Obermair A, Kurz C, Czerwenka K, et al: Microvessel density and vessel invasion in lymph-node negative breast cancer: effect on recurrence-free survival. Int J Cancer 62:126131, 1995 60. Buadu LD, Murakami J, Murayama S, et al: Colour Doppler sonography of breast masses: a multiparameter analysis. Clin Radiol 52:917-923, 1997 61. Peters-Engl C, Medl M, Mirau M, et al: Color-coded and spectral Doppler flow in breast carcinomas--relationship with the tumor microvasculature. Breast Cancer Res Treat 47:83-89, 1998 62. Stems EE, SenGupta S, Sannders F, et al: Vascularity demonstrated by Doppler ulla-asound and immunohistochemistry in invasive ductal carcinoma of the breast. Breast Cancer Res Treat 40:197-203, 1996 63. Lee W, Chu J, Houng S, et al: Breast cancer angiogenesis: a quantitative morphologic and Doppler imaging study. Ann Surg Oncol 2:246-251, 1995 64. Kuijpers TJA, Obedijn AIM, Kruyt RH, et al: Solid breast neoplasms: differential diagnosis with pulsed Doppler ultrasound. Ultrasound Med Bio120:517-520, 1994 65. Kubek KA, Chan L, Frazier T: Color Doppler flow as an indicator of nodal metastasis in solid breast masses. J Ultrasound Med 15:835-841, 1996 66. Mehta TS, Raza S: Power Doppler sonography of breast cancer: does vascularity correlate with node status or lymphatic vascular invasion? AJR Am J Roentgenol 173:303-307, 1999 67. Dixon JM, Walsh J, Patterson D, et al: Colour Doppler ultrasonography studies of benign and malignant breast lesions. Br J Surg 79:259-260, 1992 68. Holcombe C, Pugh N, Lyons K, et al: Blood flow in breast cancer and fibroadenoma estimated by colour Doppler ultrasonography. Br J Surg 82:787-788, 1995 69. Larson D, Weinstein M, Goldberg I, et al: Edema of the
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arm as a function of the extent of axillary surgery in patients with stage I-II carcinoma of the breast treated with primary radiotherapy. Int J Radiat Oncol Biol Phys 12:1575-1582, 1986 70. Maunsell E, Brisson J, Deschenes L: Arm problems and psychological distress after surgery for breast cancer. Can J Surg 36:315-320, 1993 71. Hladiuk M, Huchcroft S, Temple W, et al: Arm function after axillary dissection for breast cancer: a pilot study to provide parameter estimates. J Surg Oncol 50:47-52, 1992 72. Krag D, Weaver D, Ashikaga T, et al: The sentinel node in breast cancer. N Eng J Med 339:941-946, 1998 73. Silverstein MJ, Eugene DG, Waisman JR, et al: Axillary node dissection in Tla breast carcinoma. Cancer 73:664-667, 1994 74. Cady B: The need to re-examine axillary lymph node dissection in invasive breast carcinoma. Cancer 73:505-508, 1994 75. Pamilo M, Soiva M, Lavast E: Real-time ultrasound, axillary mammography, and clinical examination in the detection of axillary lymph node metastases in breast cancer patients. J Ultrasound Med 8:115-120, 1989 76. Bruneton JN, Caramella E, Hery M, et al: Axillary lymph node metastases in breast cancer: preoperative detection with US. Radiology 158:325-326, 1986 77. Vaidya JS, Vyas JJ, Thakur MH, et al: Role of ultrasonography to detect axillary node involvement in operable breast cancer. Eur J Surg Onco122:140-143, 1996 78. Marchal G, Oyen R, Verschakelen J, et al: Sonographic appearance of normal lymph nodes. J Ultrasound Med 4:417419, 1985 79. Yoshinaka H, Nisha M, Kajisa T, et al: Ultrasonic detection of lymph node metastases in the region around the celiac axis in esophageal and gastric cancer. J Clin Ultrasound 13:153-160, 1985 80. Buneton JN, Caramella E, Hery M, et al: Axillary lymph node metastases in breast cancer: preoperative detection with US. Radiology 158:325-326, 1986 81. Verbanck J, Vandewiele I, De Winter H, et al: Value of axillary ultrasonography and sonographically guided puncture of axillary nodes: a prospective study in 144 consecutive patients. J Clin Ultrasound 25:53-56, 1997 82. Walsh JS, Dixon JM, Chett U, et al: Colour Doppler studies of axillary node metastases in breast carcinoma. Clin Rad 49:189-191, 1994 83. Yang WT, Betreweli C: Colour Doppler flow in normal axillary lymph nodes. Br J Radio171:381-382, 1998 84. Swischuk LE, Desai PB, John SD: Exuberant blood flow in enlarged lymph nodes: findings on colour flow Doppler. Pediatr Radio122:419-421, 1992 85. Mountford RA, Atkinson P: Doppler ultrasound examination of pathologically enlarged lymph nodes. Br J Radiol 52:464-467, 1979 86. NIH concensus conference: Treatment of early-stage breast cancer. JAMA 265:391-395, 1991 87. Smith JE: Primary (neoadjuvant) medical therapy, in Powles TJ, Smith IE (eds): Medical Management of Breast Cancer. London, England, Martin Dunitz, 1991, pp 259-265 88. Hayward LJ, Carbone PP, Hewson JC: Assessment of response to therapy in advanced breast cancer. Br J Cancer 35:292-301, 1977 89. Moscovic EC, Mansi JL, King DM, et al: Mammography
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in the assessment of response to medical treatment of large primary breast cancer. Clin Radio147:339-344, 1993 90. Lagalla R, Caruso G, Finazzo M: Monitoring treatment response with color and power Doppler. Eur J Radio128(suppl): 149-156, 1998 91. Kedar RR Cosgrove DO, Smith IE, et al: Breast carcinoma: measurement of tumor response to primary medical therapy with color Doppler flow Imaging. Radiology 190:825830, 1994 92. Downey DB, Fenster A: Vascular imaging with a threedimensional power Doppler system. AJR Am J Roentgenol 165:665-668, 1995 93. Carson PL, Moskalik AR Govil A, et al: The 3D and 2D color flow display of breast masses. Ultrasound Med Biol 23:837-849, 1997 94. Carson PL, Fowlkes JB, Roubidoux MA, et al: 3-D color
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Doppler image quantification of breast masses. Ultrasound Med Bio124:945-952, 1998 95. Schlief R: Ultrasound contrast agents. Radiology 3:198207, 1991 96. Ophir J, Parker KJ: Contrast agents in diagnostic ultrasound. Ultrasound Med Biol 15:319-333, 1989 97. Goldberg BB, Liu J, Burns RN, et al: Galactose-based intravenous sonographie contrast agent: experimental studies. J Ultrasound Med 12:463-470, 1993 98. Huber S: Doppler ultrasound in the diagnosis of breast lesions. Anticancer Res 18:2147-2150, 1998 99. Huber S, Helbichg T, Kettenbach J, et al: Effects of a microbubble contrast agent on breast tumors: computer-assisted quantitative assessment with color Doppler US--early experience. Radiology 208:485-489, 1998
LTHOUGH MAMMOGRAPHY is the only widely accepted imaging modality used to screen for early, otherwise occult, breast cancers, there continues to be a large number of lesions with indistinguishable or indeterminate mammographic features. In the United States, the work-up of these lesions result in many negative biopsies, with positive biopsy rates of 10% to 35%. 1-4 Currently, there is no widely accepted role of breast ultrasound as a screening method because of high false-positive and false-negative rates. 5,6 However, breast ultrasound is routinely used as an adjunct to mammography, to help predict more accurately if a lesion is benign or malignant. Stavros et al7 used grey-scale sonography to prospectively classify solid breast lesions as benign, indeterminate, or malignant, and calculated a negative predictive value (NPV) of 99.5%. These investigators used state-of-the-art equipment and strict diagnostic criteria. To our knowledge, other investigators have not been able to corroborate their results. Although grey-scale sonographic features of benign and malignant solid breast lesions have been described, 8-~3 a significant number of breast masses do not present with a typical sonographic appearance.9,14,15 The phenomenon of tumor angiogenesis is well known from studies of tumor biology.16 Angiogenesis is defined as the formation of new blood vessels through the sprouting of capillaries from preexisting microvessels, a7 Tumors as small as 3 mm rely on the formation of these vessels to further their growth. TM The formation of these abnormal vessels is associated with an increased risk of malignancy. ~9 Blood vessels of malignant tumors are characterized by an atypical course, with irregular stenosis, occlusion, wide variation of caliber,
A
sinusoidal widening, and arteriovenous shunts on angiography. It is these concepts of angiogenesis that have prompted investigation of the use of Doppler ultrasound (spectral Doppler [SD], color Doppler [CD], and power Doppler [PD]) in differentiating benign from malignant solid breast masses, and in better characterizing the invasiveuess and extent of malignant breast cancers. SD, CD, AND PD ULTRASOUND CD (Fig 1A and 113) and SD (Fig 1C) ultrasound are based on the mean Doppler frequency shift, and, thus, are subject to aliasing and are angle dependent. If the gain settings are too high or the Doppler display threshold is too low, noise will overwhelm the image. 2°,zl An advantage of both of these methods is that they allow for assessment of velocity and direction of flow. 21 PD (Fig 1D) ultrasound is based on the amplitude of Doppler shift, with the c010r map related to the number of red blood cells producing the Doppler shift. 2°-22PD is essentially angle independent and is not subject to aliasing. 21,23-25The higher dynamic range of PD makes it more sensitive than CD and SD in detection of smaller blood vessels and low-velocity blood flow. 2°-22,26 The main disadvantages of PD are that it cannot assess velocity or direction of
From the Department of Radiology, Beth Israel Deaconess Medical Center, Boston, MA. Address reprint requests to Tejas S. Mehta, MD, Beth Israel Deaconess Medical Center, Department of Radiology, TCC 4th Floor, 330 Brookline Avenue, Boston, MA 02215. E-mail: tmehta @caregroup.harvard, edu Copyright © 2000 by W..B. Saunders Company 0887-2171/00/2104-0003510. 00/0 doi:10.1053/sult.2000.8923
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Fig 1. Breast cancer interrogated with various ultrasound methods to assess tumor vascularity. (A) Grey-scale image of a nonpalpable breast cancer. (B) CD scan, (C) SD tracing, (D) PD imaging,
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flow, and it is much more sensitive to tissue motion than CD and S D . 21 DISTINGUISHING BENIGN FROM MALIGNANT SOLID BREAST MASSES
In 1988, Schoenberger et a127 performed pulsed duplex Doppler sonography on 38 patients and reported that Doppler sonography could predict malignancy with sensitivity and specificity of 100%. In their study, all malignant cases showed Doppler signal and all benign lesions had no Doppler signal. Since that time, advances in technology and improvements in ultrasound equipment have allowed improved detection of blood flow with Doppler sonography in all solid masses, benign and malignant, thus, lowering sensitivity and specificity.
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More recent studies have shown detectable Doppler flow in 14% to 60% of benign breast lesions 22,2833 and 65% to 98% of malignant breast cancers.22,28-35 Investigators have questioned if patterns of vascularity could be used to help differentiate benign from malignant lesions. A study from our institution28 using PD ultrasound characterized vascularity patterns in benign and solid lesions as none, peripheral, central, and penetrating (Fig 2). We found that penetrating vessels were more likely present in malignant tumors. Other subsequent studies have shown similar results. 22,34,36 In our study, by using penetrating vessels to indicate malignancy, the sensitivity for PD ultrasound was 68%, specificity was 95%, positive predictive value
Fig 2. Patterns of tumor vascularity in breast cancers as shown by PD. (A) No detectable vessels. (B) Peripheral nonbranching vessels. (C) Central vessels. (D) Penetrating vessels, with irregular branching,
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(PPV) was 85%, and NPV was 88%. Grey-scale ultrasound alone had a calculated sensitivity of 92%, specificity of 59%, PPV of 48%, and NPV of 95%. The addition of PD findings to grey-scale ultrasound resulted in improved sensitivity and NPV both to 100% (Fig 3). 28 Other studies using C D 22'33'36'37 and PD 22 signals to diagnose malignancy have reported sensitivities of 64% to 94%, specificities of 75% to 88%, NPV of 63% to 84%, and accuracy of 63% to 88%. Studies looking at the number of detectable Doppler vessels show that cancers have a significantly higher number of vessels than benign breast lesions. 22,37-4° Many investigators have examined the Doppler vascularity of breast lesions in terms of resistive
Fig 3. Penetrating vessels may occasionally be the only strong indication of malignancy, (A) Grey-scale US shows a smoothly marginated hypoechoic mass with acoustic enhancement, typical features of benignity, (B) PD reveals prominent penetrating vessels, prompting biopsy that revealed invasive carcinoma,
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index (RI), pulsatility index (PI), and mean velocity (Vmean) and maximum velocity (Vmax), with conflicting results26,29,36,3947[RI = (Vmax - Vmin)/ Vmax; PI = (Vmax - Vmin)/Vmean]. Hollerweger et a146 studied 117 cancers and fibroadenomas, and found that by using a threshold of RI -> 0.80 to diagnose malignancy, the calculated sensitivity was 55%, specificity was 96%, PPV was 92%, and NPV was 66%. They also calculated that using a threshold of ->0.20 for differences in RI values within the same lesion to diagnose malignancy, the calculated sensitivity was 39%, specificity was 97%, PPV was 93%, and NPV was 66%. They found no threshold that could predict benignity with high specificity because both benign lesions and cancers had RI values of less than 0.80. The high variation of velocities within cancers is presumably caused by the tortuous vessels and arteriovenous shunts that are typical of malignant neovascularization.48,49 Peters-Engl et a145 used RI -> 0.70 to indicate malignancy, with sensitivity of 82%, specificity of 81%, PPV of 70%, and NPV of 89%. Other studies also found significantly higher RI values in malignant breast cancers compared with benign breast lesions, 26,36 however, as with prior studies, there was overlap. Studies examining the usefulness of PI in distinguishing benign from malignant lesions have not been promising. Some studies have found no difference in PI values of benign and malignant breast masses. 29,45 One study did find a significant difference in PI values of benign versus malignant tumors, but with much overlap, thus, limiting its usefulness. 26 The formation of arteriovenous shunts and thinwalled vessels lacking smooth muscle, as seen in malignant tumors, result in high-velocity pulsatile tumor flow. 3°,5°,51 This theory has led investigators to examine Vmax on Doppler ultrasound to distinguish benign from malignant breast lesions. 36,39,4°,44,45All of these studies found significantly higher Vmax values in malignant tumors compared with benign tumors. One study45 stated that this finding could be related to tumor size because in their study the malignant tumors were larger than the benign tumors. Another study 35 looked at Vmax in 74 malignant breast tumors to see if this value could be used to predict survival rates. They found that patients with Vmax > 0,25
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m/s had a 4.33-fold increased risk of death secondary to the underlying disease. The calculated 5-year survival rate in patients with Vmax ---0.25 rrds was 82.3%. This decreased dramatically to 36.6% in patients with Vmax > 0.25 m/s. 35 Few studies have examined Vmean values on Doppler ultrasound. One study found higher Vmean in malignant compared with benign lesions 39 and another found no difference. 44
CORRELATION OF DOPPLER SIGNAL WITH MICROVESSEL DENSITY Another method to assess angiogenesis on a microscopic level, using immunohistochemical methods, is the determination of microvessel density (MVD). MVD has been shown to predict tumor progression, relapse, and survival rates. 52-s9 However, studies have shown that blood flow in breast cancers as measured by ultrasound methods have no correlation with MVD. 3°,6°-62 This suggests that the vessels assessed by Doppler ultrasound belong in a different category than those measured with microvessel count, probably larger. 63 One study of 207 cancers showed no significant difference in mean MVD when comparing tumors with detectable Doppler vessels to those with no Doppler vessels. However, when MVD was more than 80 vessels per 250× field, tumors were significantly more likely to be vascular on Doppler ultrasound. 62 ASSOCIATION AMONG DOPPLER SIGNAL AND TUMOR SIZE, GRADE, AND HISTOLOGY Many studies have shown no correlation between Doppler detectable vascularity and tumor size. 62,64-65 Our study of 176 patients with cancer using PD showed a significant difference between tumor size and presence or absence of vessels, however, there was overlap. 66 Other studies have shown no significant correlation between Doppler vascularity and t u m o r grade. 29,62,66,67 However, 2 studies have noted that grade 3 tumors were more likely to be vascular o n PD 66 or quantitatively show more vessels o n C D 68 t h a n tumors of lower grades. Obviously, it is also not possible to make a histological diagnosis based on Doppler ultrasound findings. However, a few studies have noted that invasive lobular carcinomas tend to be less vascular on CD 67 and P D 28'66 compared with other histological types.
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ASSESSING NODAL INVOLVEMENT BY EVALUATING THE PRIMARY LESION Lymph node status is a major prognostic indicator in patients with breast cancer. Axillary lymph node dissection is responsible for much of the morbidity associated with breast surgery. 69-71Sentinel node excision is an alternative method of lymph node sampling that has been studied and has recently become more widely used. A multicenter study on sentinel node biopsy 72 showed that it can predict the presence or absence of axillary-node metastases. However, this study also reported variable success rates based on patient age, location of primary carcinoma, and surgeons' experience. Various Doppler ultrasound methods have been studied as a potential noninvasive method of assessing lymph node status. 29'30'62'64-66'68 We studied 126 patients with breast cancer that underwent lymph node dissection. 66 The association of PD vessels in the primary lesion and lymph node involvement resulted in a calculated sensitivity of 93%, specificity of 32%, PPV of 43%, and NPV of 90%. In other words, because many breast cancers show vessels on PD, the sensitivity was high and specificity was low. However, when no PD vessels were seen, 90% had no lymph node involvement, compared with when PD vessels were seen, 57% had lymph node involvement. These results were significant, even after controlling for tumor size. Lee et aP ° used CD to study a smaller number of malignant breast lesions (n = 32), and found a significant association between higher tumor flow and nodal metastases for T1 lesions (---2 cm) but not for larger tumors. They concluded that the presence of a CD signal in T1 lesions may be helpful in identifying those patients with small, apparently early, but aggressive tumors with poorer prognosis. Kubek et al, 6~ using CD technique, also showed results similar to ours. They defined a rim sign as a curvilinear or branching pattern at the periphery of a mass on CD sonography. Of 33 malignant tumors, lymph node metastases were present in 50% when a rim sign was present, and only 10% of the time when a rim sign was absent. Holcombe et al68 evaluated 28 breast cancers and found that when 3 or more vessels were seen on CD flow, the patients were more likely to have lymph node involvement. Kuijpers et al64 used a different Doppler technique, but also yielded similar results to our study. They used pulsed Doppler of primary breast cancers to predict lymph node involvement. A positive
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signal, defined as a Doppler shift frequency of more than 1 kHz using a 5-MHz insonating frequency, was predictive of lymph node involvement with a calculated sensitivity of 84%, specificity of 56%, PPV of 51%, and NPV of 86%. Stems et al62 evaluated 207 patients with invasive ductal carcinoma, and found that lymph node involvement was present in 27 of 51 lesions showing vessels (PPV 53%) and in 47 of 156 lesions showing no vessels (false-negative rate 30%) on Doppler ultrasound. Other studies have shown no correlation between CD-detected tumor vascularity and lymph node involvement. 29 ASSESSING NODAL INVOLVEMENT BY EVALUATING THE AXILLA
As stated previously, the presence of axillary lymph node metastases is a major prognostic indicator in patients with newly diagnosed breast cancer. A patient with a T1 lesion undergoing axillary node dissection has an 80% chance of having no nodal involvement. 7~,74 Although the chance of nodal metastases is higher in T2 lesions, 65% of patients in this group also have negative nodes. 74 Clinical examination of the axilla is not a very sensitive method for identifying axillary node involvement, with reported sensitivities ranging from 32% to 58%. 75-77 It is difficult to see normal lymph nodes with grey-scale ultrasound because of similar echotexture of the surrounding axillary tissue, especially if there is abundant fat. 78 Pathological lymph nodes are more readily detectable because they are rounded and more hypoechoic (Fig 4). 79 Grey-scale ultrasound of the axilla has been used to evaluate nodal involvement with varying sensitivities of 60% to 73 %.80,81 Investigators have also examined the axilla using CD Ultrasound. When limited to patients with cancer, CD ultrasound has reported sensitivities of 70% to 75% and specificities of 96% to 100% in predicting axillary metastases. 67,82 Some studies have found that many of the true-positive nodes that did not have CD vessels were seen in those patients with no CD vessels in the primary breast lesion. 82Yang and Betreweli 83performed CD examination of the axilla of 81 women with breast carcinoma and 106 asymptomatic women who presented for screening and had no significant breast or axillary pathology. They found CD flow in 84% of normal nodes and 88% of metastatic nodes
Fig 4. US appearance of an abnormal axillary lymph node (marked by calipers). It is rounded and enlarged, with compressed fatty hilum.
in the patients with breast cancer, and 87% of normal nodes in the asymptomatic, normal screening patients. Thus, the presence of CD flow was highly nonspecific when used as the sole criteria to diagnose malignancy. There is also no method to distinguish the Doppler flow detected in malignant nodes from that in inflammatory nodes. 84,85 ASSESSING FOR LYMPHATIC VASCULAR INVASION
Tumors may spread to the lymph nodes through either a hematogenous route or lymphatic drainage. The latter mode stimulated us to investigate if there is a correlation between PD vascularity and lymphatic vascular invasion (LVI). 66 Of 150 breast cancers, 111 (74%) showed PD vessels and 39 (26%) showed no PD vessels. LVI was present in 47 of 111 (42%) patients with PD vessels and 5 of 29 (13%) with no PD vessels in the primary breast cancer. These results were significant. The calculated sensitivity of PD in predicting LVI was 90%, with specificity of 35%, PPV of 42%, and NPV of 87%.66 To our knowledge, only 2 other studies have examined Doppler flow in relation to LVI. 29,67 Dixon et a167 studied 32 breast cancers, of which 25 (78%) had CD flow. They reported that 6 patients had LVI, and all 6 had positive CD flow in the primary breast lesion. Cosgrove et a129 studied 37 patients with available histology and found no correlation between CD vascularity in the primary breast cancer and LVI.
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MONITORING BREAST CANCER TREATMENT
Although adjuvant therapy has been shown to decrease the rate of recurrence in early cases of breast cancer (in which the disease is local without distant metastases), local and regional treatments alone also have been shown to be curative. 86 In advanced cases of breast cancer in which the disease had spread, systemic therapy (including chemotherapy, hormonal therapy, or both) is needed. Recently, some tumors have been treated with systemic therapy as a first-line treatment before local surgical treatment (neoadjuvant therapy). 87 Conventional methods, such as a clinical examination, mammography, and grey-scale ultrasound, for assessing tumor response to therapy, have been used with limitations. 8749 Treatment of hepatocellular carcinomas and hyperfunctioning thyroid and parathyroid nodules have been monitored using CD and PD ultrasound. 9° Kedar et al91 studied 34 patients with large or centrally located breast cancers treated with neoadjuvant therapy to see if CD ultrasound could be used to monitor and predict the response of breast cancer to therapy. The 34 patients underwent 126 treatment cycles. In 97 (77%) of the cycles, the changes in CD vascularity were concordant with changes in the size of the tumor. A reduction in vascularity was seen with response to therapy, and an increase in tumor size and no reduction or increase in vascularity was seen with lack of response or tumor progression. Changes seen on CD occurred at least 4 weeks before those seen at clinical examination in 40% of patients, and before those seen with grey-scale ultrasound in 38% of patients. 91 Another smaller study of 18 patients with breast cancer also showed promising results. Sixteen of the 18 patients had no detectable CD signal at the end of treatment with local parenteral repeated administration of antiblastic drugs. Of the 2 remaining patients, in whom the CD signal remained present, both had histopathologically confirmed residual tumor cells. 9° 3-DIMENSIONAL DOPPLER SONOGRAPHY
Recently, 3-dimensional (3D) Doppler ultrasound technology has been developed (Fig 5A and 5B). One study suggested that 3D PD ultrasound could improve detection rates of smaller vessels than that seen by 2-dimensional (2D) methods. 92 Carson et al93,94 performed 2 studies looking at benign and malignant breast masses with 3D CD imaging, comparing it with 2D images and video-
Fig 5. PD scanning of breast cancer with 3D reconstruction. (A) 2D PD scan of a tumor. (B) 3D rendering of the PD data of the same tumor, clearly showing a larger number of vessels and showing branching patterns,
tape. Both studies concluded that 3D imaging provided a stronger subjective appreciation of vascular morphology and allowed somewhat better ultrasound discrimination of malignant lesions than did 2D images or videotape, although the results were not significant. Note also that real-time 2D imaging of the breast lesions by the radiologist, routinely performed in our institution and many others, was not incorporated as a comparative arm
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in either study. Our anecdotal experience with 3D PD ultrasound is that it does not add additional clinically relevant, diagnostic information. ULTRASOUND CONTRAST MEDIA
Several contrast agents are being developed for use with ultrasound. 95-97These intravascular agents improve the detection of low-volume blood flow by increasing the signal-to-noise ratio. The use of contrast media in breast tumors yields a larger number of Doppler ultrasound signals. 98 Huber et a199 examined 47 patients, 31 with breast cancer and 16 with benign breast lesions. They found significant differences in degree, onset, and duration of Doppler enhancement between the 2 groups after contrast. Cancers had higher peak color pixel density, shorter time to enhancement, and longer duration of enhancement than benign lesions. These results, although promising, had high interindividual variability, thus, limiting its value for prospective diagnosis. Kedar et al37 studied 34 patients, 18 with breast cancer and 16 with benign breast lesions. They examined the lesions before and after contrast. With contrast, they improved their sensitivity from 88.9% to 100%, specificity from 87.5% to 100%, and accuracy from 88.2% to 100%. CONCLUSIONS
Although grey-scale ultrasound remains the basis of sonographic evaluation of breast masses, Doppler ultrasound is sometimes an important adjunct to grey-scale ultrasound. Because of improved technology, Doppler flow is seen in both benign and malignant lesions. However, there are characteristic patterns of vascularity that are more
commonly seen in malignant lesions, including penetrating vessels, as well as a greater number of vessels, which can assist in diagnosis. RI, PI, and Vmax have not been shown to be of diagnostic value. Some studies have shown correlation between Doppler signal and tumor size, although none have shown correlation with tumor histology or grade. Because Doppler signal is present in a large number of breast cancers, it is highly sensitive but not specific in identifying patients with lymph node involvement or LVI. More importantly, however, 1 study 66 has shown that the absence of Doppler vessels had a high NPV for lymph node metastases and LVI. Examination of the axilla with Doppler ultrasound is not helpful in predicting nodal disease, although evaluation should still be performed looking for grey-scale features of abnormal lymph nodes. Preliminary studies evaluating the role of Doppler ultrasound in monitoring breast cancer treatment are promising, although further, larger scale studies need to be performed. Doppler ultrasound may be suitable for monitoring the subset of patients that are treated solely with radiation therapy, in patients with inadequate axillary node dissections, or in patients whose tumors are not amenable to primary surgery. Currently, 3D Doppler sonography does not have a significant role in assessment of breast cancer. Ultrasound contrast media will likely be used more commonly in the future, although currently these studies are still at the experimental stage. However, the use of contrast media adds an invasive component to an otherwise noninvasive study.
REFERENCES
1. Tersegno MM: Mammography:positive predictive value and true positive biopsy rate (letter). AJR Am J Roentgenol 160:660-661, 1993 2. McManusV, Desautels JE, BenediktssonH, et al: Enhancement of true positive rates for nonpalpable carcinoma of the breast through mammographic selection. Surg Gynecol Obstet 175:212-218, 1992 3. Bassett LW, Liu TH, GiulianoAE, et al: The prevalence of carcinoma in palpable versus impalpable mammographically detected lesions. AJRAm J Roentgenol 157:21-24, 1991 4. MayerJE, Eberlein TJ, StomperPC, et al: Biopsyof occult breast lesions: analysis of 1261 abnormalities.JAMA263:23412343, 1990 5. Teh W, Wilson ARM: The role of ultrasound in breast cancer screening. A consensus statement by the European group for breast cancer screening. Eur J Cancer 34:449-450, 1998
6. Jackson VP, Reynolds HE, Hawes DR, et al: Sonography of the breast. Semin Ultrasound CT MR 17:460-475,1996 7. Stavros AT, Thickman D, Rapp CL, et al: Solid breast nodules: use of sonographyto distinguish between benign and malignant lesions. Radiology 196:123-134, 1995 8. Egan RL, Egan KL: Automated water-path full breast sonography:correlationwith histologyin 176 solid lesions. AJR Am J Roentgenol 143:499-507, 1984 9. Cole-Beuglet C, Soriano RZ, Kurtz AB, et al: Fibroadenoma of the breast: sonomammographycorrelatedwith pathology in 122 patients. AJR Am J Roentgenol 140:369-373, 1983 10. Cole-BeugletC, SorianoRZ, KurtzAB, et al: Ultrasound analysis of 104 primary breast carcinomas classified according to histopathologictype. Radiology 147:191-196, 1983 11. Fomage BD, Lorigan JG, Andry E: Fibroadenomaof the breast: sonographicappearance. Radiology 172:671-675, 1989
DOPPLER ULTRASOUND IN BREAST CARCINOMA
12. Leucht WJ, Rabe DR, Humbert K: Diagnostic value of different interpretative criteria in real-time sonography of the breast. Ultrasound Med Biol 14:59-73, 1988 13. Ueno E, Tohno E, Itoh K: Classification and diagnostic criteria in breast echography. Jpn J Med Ultrasonics 13:19-31, 1986 14. Heywang SH, Lipsit ER, Glassman LM, et al: Specificity of ultrasonography in the diagnosis of benign breast masses. J Ultrasound Med 3:453-461, 1984 15. Jackson VE Rothschild PA, Kreipke DL, et al: The spectrum of sonographic findings of fibroadenoma of the breast. Invest Radio121:34-40, 1986 16. Folkman J, Watson K, Ingber D: Induction of angiogenesis during the transition from hyperplasia to neoplasia. Nature 339:58-62, 1989 17. Battegay E: Angiogenesis: mechanistic insights, neovascular diseases, and therapeutic prospects. J Mol Med 73:333346, 1995 18. Folkman J: Tumor angiogenesis: therapeutic implications. N Engl J Med 285:1182-1186, 1971 19. Folkman J: How is blood vessel growth regulated in normal and neoplastic tissue? GHA Clowes Memorial Award Lecture. Cancer Res 46:467-473, 1986 20. Bude RO, Rubin JM, Adler RS: Power versus conventional color Doppler sonography: comparison in the depiction of normal intrarenal vasculature. Radiology 192:777-780, 1994 21. Rubin JM, Bude RO, Carson PL, et al: Power Doppler US: a potentially useful alternative to mean frequency-based color Doppler US. Radiology 190:853-856, 1994 22. Kook S, Park H, Lee Y, et al: Evaluation of solid breast lesions with power Doppler sonography. J Clin Ultrasound 27:231-237, 1999 23. Dymling SO, Persson HW, Hertz CH: Measurement of blood perfusion in tissue using Doppler ultrasound. Ultrasound Med Biol 17:433-444, 1991 24. Jaln SE Fan PH, Philpot EF, et al: Influence of various instrument settings on the flow information derived from the power mode. Ultrasound Med Biol 17:49-54, 1991 25. Rubin JM, Adler RS: Power Doppler expands standard color capacity. Diagn Imag (San Franc) 15:66, 1993 26. Hayashi N, Miyamoto Y, Nakata N, et al: Breast masses: color Doppler, power Doppler, and spectral analysis findings. J Clin Ultrasound 26:231-238, 1998 27. Schoenberger SG, Sutherland CM, Robinson AE: Breast neoplasms: duplex sonographic imaging as an adjunct in diagnosis. Radiology 168:665-668, 1988 28. Raza S, Bantu J: Solid breast lesions: evaluation with power Doppler US. Radiology 203:164-168, 1997 29. Cosgrove DO, Kedar RP, Bamber JC, et al: Breast diseases: color Doppler US in differential diagnosis. Radiology 189:99-104, 1993 30. Lee WJ, Chu JS, Huang CS, et al: Breast cancer vascularity: color Doppler sonography and histopathology study. Breast Cancer Res Treat 37:291-298, 1996 31. Lee WJ, Chu JS, Chang KJ, et al: Occult breast carcinomause of color Doppler in localization. Breast Cancer Res Treat 37:299-302, 1996 32. Britton PD, Coulden RA: The use of duplex Doppler ultrasound in the diagnosis of breast cancer. Clin Radiol 42:399-401, 1990
305
33. Lee SK, Lee T, Lee KR, et al: Evaluation of breast tumors with color Doppler imaging: a comparison with image-directed Doppler ultrasound. J Clin Ultrasound 23:367-373, 1995 34. Rizzatto G, Chersevani R, Abbona M, et al: Highresolution sonography of breast carcinoma. Eur J Radio124:1119, 1997 35. Peters-Engl CH, Fran W, Leodolter S, et al: Tumor flow in malignant breast tumors measured by Doppler ultrasound: an independent predictor of survival. Breast Cancer Res Treat 54:65-71, 1999 36. Blohmer JU, Oellinger H, Schmidt C, et al: Comparison of various imaging methods with particular evaluation of color Doppler sonography for planning surgery for breast tumors. Arch Gynecol Obstet 262:159-171, 1999 37. Kedar RE Cosgrove D, McCready VR, et al: Microbubble contrast agent for color Doppler US: effect on breast masses. Radiology 198:679-686, 1996 38. Adler DD, Carson PL, Rubin JM, et al: Doppler ultrasound color flow imaging in the study of breast cancer: preliminary findings. Ultrasound Med Biol 16:553-559, 1990 39. McNicholas MMJ, Mercer PM, Miller JC, et al: Color Doppler sonography in the evaluation of palpable breast masses. AJR Am J Roentgenol 161:745-771, 1993 40. Madjar H, Sanerbrei W, Prompeler HJ, et al: Color Doppler and duplex flow analysis for classification of breast lesions. Gyuecol Ouco164:392-403, 1997 41. Dock W: Duplex sonography of mammary tumors: a prospective study of 75 patients. J Ultrasound Med 2:79-82, 1993 42. Delorme S, Anton HW, Kuopp MV, et al: Breast tumors: assessment of vascularity by cotour Doppler. Eur Radiol 3:253257, 1993 43. Cosgrove DO, Bamber JC, Davey JB, et al: Color Doppler signals from breast tumors. Radiology 176:175-180, 1990 44. Kedar RP, Cosgrove DO, Bamber JC, et al: Automated quantification of color Doppler signals: a preliminary study in breast tumors. Radiology 197:39-43, 1995 45. Peters-Engl C, Medl M, Leodolter S: The use of colourcoded and spectral Doppler ultrasound in the differentiation of benign and malignant breast lesions. Br J Cancer 71:137-139, 1995 46. Hollerweger A, Rettenbacher T, Macheiner P, et al: New signs of breast cancer: high resistance flow and variations in resistive indices evaluation by color Doppler sonography. Ultrasound Med Bio123:851-856, 1997 47. Huber S, Delorme S, Knopp MV, et al: Breast tumors: computer-assisted quantitative assessment with color Doppler US. Radiology 192:797-801, 1994 48. Schor AM, Schor SL: Tumor angiogenesis. J Pathol 141:385-413, 1983 49. Strickland B: The value of arteriography in the diagnosis of bone tumours. Br J Radiol 32:705-713, 1959 50. Taylor KJW, Ramos 1, Carter D: Correlation of Doppler US tumor signals with neovascular morphology features. Radiology 166:57-62, 1988 51. Shubik P: Vascularization of tumors: a review. J Cancer Res Clin Oncol 103:211-216, 1982 52. Weidner N, Semple SP, Welch WR, et al: Tumor angiogen-
306
esis and metastasis---correlation in invasive breast carcinoma. N Engl J Med 324:1-8, 1991 53. Weidner N, Folkman J, Pozza F, et al: Tumor angiogenesis: a new significant and independent prognostic indicator in early-stage breast carcinoma. J Natl Cancer Inst 84:1875-1887, 1992 54. Bosari S, Lee AK, Delellis RA, et al: Microvessel quantitation and prognosis in invasive breast carcinoma. Hum Patho123:755-761, 1992 55. Gasparini G, Weidner N, Bevilacqua R et al: Tumor microvessel density, p53 expression, tumor size, and peritumoral lymphatic vessel invasion are relevant prognostic markers in node-negative breast carcinoma. J Clin Oncol 12:454-466, 1994 56. Fox SB, Leek RD, Smith K, et al: Tumor angiogenesis in node-negative breast carcinomas--relationship with epidermal growth factor, estrogen receptor and survival. Breast Cancer Res Treat 29:109-116, 1994 57. Bevilacqua P, Barbareschi M, Verderio R et al: Prognostic value of intratumoral microvessel density, a measure of tumor angiogenesis, in node-negative breast carcinoma--results of a multiparametric study. Breast Cancer Res Treat 36:205-217, 1995 58. Toi M, Inada K, Suzuki H, et al: Tumor angiogenesis in breast cancer: its importance as a prognostic indicator and the association with vascular endothelial growth factor expression. Breast Cancer Res Treat 36:193-204, 1995 59. Obermair A, Kurz C, Czerwenka K, et al: Microvessel density and vessel invasion in lymph-node negative breast cancer: effect on recurrence-free survival. Int J Cancer 62:126131, 1995 60. Buadu LD, Murakami J, Murayama S, et al: Colour Doppler sonography of breast masses: a multiparameter analysis. Clin Radiol 52:917-923, 1997 61. Peters-Engl C, Medl M, Mirau M, et al: Color-coded and spectral Doppler flow in breast carcinomas--relationship with the tumor microvasculature. Breast Cancer Res Treat 47:83-89, 1998 62. Stems EE, SenGupta S, Sannders F, et al: Vascularity demonstrated by Doppler ulla-asound and immunohistochemistry in invasive ductal carcinoma of the breast. Breast Cancer Res Treat 40:197-203, 1996 63. Lee W, Chu J, Houng S, et al: Breast cancer angiogenesis: a quantitative morphologic and Doppler imaging study. Ann Surg Oncol 2:246-251, 1995 64. Kuijpers TJA, Obedijn AIM, Kruyt RH, et al: Solid breast neoplasms: differential diagnosis with pulsed Doppler ultrasound. Ultrasound Med Bio120:517-520, 1994 65. Kubek KA, Chan L, Frazier T: Color Doppler flow as an indicator of nodal metastasis in solid breast masses. J Ultrasound Med 15:835-841, 1996 66. Mehta TS, Raza S: Power Doppler sonography of breast cancer: does vascularity correlate with node status or lymphatic vascular invasion? AJR Am J Roentgenol 173:303-307, 1999 67. Dixon JM, Walsh J, Patterson D, et al: Colour Doppler ultrasonography studies of benign and malignant breast lesions. Br J Surg 79:259-260, 1992 68. Holcombe C, Pugh N, Lyons K, et al: Blood flow in breast cancer and fibroadenoma estimated by colour Doppler ultrasonography. Br J Surg 82:787-788, 1995 69. Larson D, Weinstein M, Goldberg I, et al: Edema of the
MEHTA, RAZA, AND BAUM
arm as a function of the extent of axillary surgery in patients with stage I-II carcinoma of the breast treated with primary radiotherapy. Int J Radiat Oncol Biol Phys 12:1575-1582, 1986 70. Maunsell E, Brisson J, Deschenes L: Arm problems and psychological distress after surgery for breast cancer. Can J Surg 36:315-320, 1993 71. Hladiuk M, Huchcroft S, Temple W, et al: Arm function after axillary dissection for breast cancer: a pilot study to provide parameter estimates. J Surg Oncol 50:47-52, 1992 72. Krag D, Weaver D, Ashikaga T, et al: The sentinel node in breast cancer. N Eng J Med 339:941-946, 1998 73. Silverstein MJ, Eugene DG, Waisman JR, et al: Axillary node dissection in Tla breast carcinoma. Cancer 73:664-667, 1994 74. Cady B: The need to re-examine axillary lymph node dissection in invasive breast carcinoma. Cancer 73:505-508, 1994 75. Pamilo M, Soiva M, Lavast E: Real-time ultrasound, axillary mammography, and clinical examination in the detection of axillary lymph node metastases in breast cancer patients. J Ultrasound Med 8:115-120, 1989 76. Bruneton JN, Caramella E, Hery M, et al: Axillary lymph node metastases in breast cancer: preoperative detection with US. Radiology 158:325-326, 1986 77. Vaidya JS, Vyas JJ, Thakur MH, et al: Role of ultrasonography to detect axillary node involvement in operable breast cancer. Eur J Surg Onco122:140-143, 1996 78. Marchal G, Oyen R, Verschakelen J, et al: Sonographic appearance of normal lymph nodes. J Ultrasound Med 4:417419, 1985 79. Yoshinaka H, Nisha M, Kajisa T, et al: Ultrasonic detection of lymph node metastases in the region around the celiac axis in esophageal and gastric cancer. J Clin Ultrasound 13:153-160, 1985 80. Buneton JN, Caramella E, Hery M, et al: Axillary lymph node metastases in breast cancer: preoperative detection with US. Radiology 158:325-326, 1986 81. Verbanck J, Vandewiele I, De Winter H, et al: Value of axillary ultrasonography and sonographically guided puncture of axillary nodes: a prospective study in 144 consecutive patients. J Clin Ultrasound 25:53-56, 1997 82. Walsh JS, Dixon JM, Chett U, et al: Colour Doppler studies of axillary node metastases in breast carcinoma. Clin Rad 49:189-191, 1994 83. Yang WT, Betreweli C: Colour Doppler flow in normal axillary lymph nodes. Br J Radio171:381-382, 1998 84. Swischuk LE, Desai PB, John SD: Exuberant blood flow in enlarged lymph nodes: findings on colour flow Doppler. Pediatr Radio122:419-421, 1992 85. Mountford RA, Atkinson P: Doppler ultrasound examination of pathologically enlarged lymph nodes. Br J Radiol 52:464-467, 1979 86. NIH concensus conference: Treatment of early-stage breast cancer. JAMA 265:391-395, 1991 87. Smith JE: Primary (neoadjuvant) medical therapy, in Powles TJ, Smith IE (eds): Medical Management of Breast Cancer. London, England, Martin Dunitz, 1991, pp 259-265 88. Hayward LJ, Carbone PP, Hewson JC: Assessment of response to therapy in advanced breast cancer. Br J Cancer 35:292-301, 1977 89. Moscovic EC, Mansi JL, King DM, et al: Mammography
DOPPLER ULTRASOUND IN BREAST CARCINOMA
in the assessment of response to medical treatment of large primary breast cancer. Clin Radio147:339-344, 1993 90. Lagalla R, Caruso G, Finazzo M: Monitoring treatment response with color and power Doppler. Eur J Radio128(suppl): 149-156, 1998 91. Kedar RR Cosgrove DO, Smith IE, et al: Breast carcinoma: measurement of tumor response to primary medical therapy with color Doppler flow Imaging. Radiology 190:825830, 1994 92. Downey DB, Fenster A: Vascular imaging with a threedimensional power Doppler system. AJR Am J Roentgenol 165:665-668, 1995 93. Carson PL, Moskalik AR Govil A, et al: The 3D and 2D color flow display of breast masses. Ultrasound Med Biol 23:837-849, 1997 94. Carson PL, Fowlkes JB, Roubidoux MA, et al: 3-D color
307
Doppler image quantification of breast masses. Ultrasound Med Bio124:945-952, 1998 95. Schlief R: Ultrasound contrast agents. Radiology 3:198207, 1991 96. Ophir J, Parker KJ: Contrast agents in diagnostic ultrasound. Ultrasound Med Biol 15:319-333, 1989 97. Goldberg BB, Liu J, Burns RN, et al: Galactose-based intravenous sonographie contrast agent: experimental studies. J Ultrasound Med 12:463-470, 1993 98. Huber S: Doppler ultrasound in the diagnosis of breast lesions. Anticancer Res 18:2147-2150, 1998 99. Huber S, Helbichg T, Kettenbach J, et al: Effects of a microbubble contrast agent on breast tumors: computer-assisted quantitative assessment with color Doppler US--early experience. Radiology 208:485-489, 1998