part ii. medical imaging of ductal carcinoma in situ

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Part II. Medical Imaging of Ductal Carcinoma In Situ

~ J ~ efore screening mammography, the clinical presentation of ductal carcinoma in situ (DCIS) included a palpable mass, nipple discharge or the setting of Paget's disease. Furthermore, DCIS was

frequently extensively distributed throughout the breast and was therefore treated with mastectomy. Currently, DCIS is usually seen with abnormal microcalcifications on a screening mammogram and can more frequently be treated with a breast-conserving approach.

DCIS is a heterogeneous disease with varied radiographic appearances. Therefore, the breast radiologist has many roles related to DCIS---early detection, preoperative diagnosis with core biopsy, determination of the extent of disease, intraoperative and postoperative assessment of completeness of excision and, finally, early detection of recurrence. The National Surgical Adjuvant Breast Project (NSABP) B-17 trial, l a ran- domized clinical trial in which local excision alone was compared with local excision followed by radiotherapy, showed that after breast-conserving surgery without radiation, in 26.8% of patients, a local recurrence developed, recurred and half of the local recurrences were invasive cancer. The possibility that short-term recurrences are caused by the presence of residual disease after initial local excision has heightened emphasis on the need for accurate preoperative imaging to help guide the surgical decision-making process, as well as accurate intraoperative and postoperative imaging to ensure that the entire lesion has been removed.

Mammography Mammography is the most important imaging modality for the detec-

tion of DCIS, for assessment of the extent of disease, and to facilitate radiographic-guided biopsies to confirm the diagnosis of intraductal carcinoma. The mammographic appearance of DCIS is often varied, which reflects the biological heterogeneity of DCIS; however, the presence of a cluster of microcalcifications is the most common presentation. In a published report by Tabar et al 2 on 207 cases of DCIS, mammographic abnormalities were seen in 198 cases (95%). Mammographic findings included the presence of microcalcifications (76%), asymmetric density (10%), the presence of a dominant mass (8%), and abnormal galactograms in patients with nipple discharge (6%). 2

Curr Probl Cancer, May/June 2000 113

In several studies, researchers have attempted to correlate the mammographic appearance of microcalcifications with the pathologic classification of DCIS. 2-7 However, the lack of consensus on the histologic classification of DCIS makes it difficult to evaluate and compare these studies. The best mammographic-histologic correlation appears to be between the pattern of microcalcification and cytonuclear differentiation. 4 In poorly differentiated DCIS, the microcalcifications are frequently linear and branching (casting), or coarse granular, and often occur in areas of necrosis, whereas in well-differentiated DCIS, the presence of multiple clusters of fine granular (cotton ball) microcalcifications are characteristic. 2,5 Moderately differentiated DCIS is most commonly associated with a cluster of heterogeneous granular (crushed stone) calcifications, although this appearance can be associated with any histologic type. 2

The presence of comedo necrosis, another potential prognostic marker of DCIS, 1 has also been correlated with mammographic findings. 6 DCIS with necrosis is more likely to contain calcifications that are linear and branching with a ductal distribution. Mammographic images of DCIS without comedo necrosis are less likely to contain microcalcifications and are more likely either to be normal or to contain noncalcified mammographic abnormalities. When calcifications are present, they tend to be fine granular in appearance and are often visualized in association with benign disease. Although these studies have helped improve our understanding of the mammographic appearance of DCIS, the pathology often cannot be accurately predicted by imaging because of considerable heterogeneity of mammographic findings of DCIS. 6'7

Although it is now less commonly seen, patients with DCIS may still have nipple discharge. The mammographic findings are often normal, and therefore one should proceed to galactography in the workup of these patients. Galactography may show multiple small filling defects, which are characteristic of DCIS. In contrast to the findings with papillomas, the duct system is usually not dilated. Furthermore, DCIS may be multifocal or multicentric in distribution, particularly with the micropapillary histologic subtype. 8

Paget's Disease The imaging of patients with Paget's disease presents special problems.

In a review of 34 patients with clinical features of Paget's disease, 21 patients were found to have DCIS. 9 Seventeen patients in this series had normal mammograms. Mammographic findings visualized in association with Paget's disease of the nipple include retroareolar mass, calcifications, and nipple thickening. For patients with clinical findings of Paget's

114 Curr Probl Cancer, May/June 2000

disease with a normal mammogram, magnification views of the nipple and breast ultrasonograms should be obtained. A preliminary report on the role of magnetic resonance imaging (MRI) shows promise in the ability of MRI to show abnormalities within the nipple-areolar complex. 1°

Preoperative and Intraoperative Assessment of DCIS If patients with DCIS are to be considered for breast conservation, then

the extent of disease needs to be accurately determined preoperatively. Because the majority of intraductal carcinomas are not palpable, the extent of microcalcifications is usually the only guide for the surgeon. The relationship between the extent of pathologic disease and the mammographic calcifications has been studied with the use of whole organ processing techniques of mastectomy specimens. 3'5'11 It was found that with magnification mammography, the extent of DCIS is generally underestimated by an average of 1 to 2 cm. However, there is less discrepancy for poorly differentiated DCIS compared with intermediate or well-differentiated disease.

Suboptimal preoperative imaging may significantly impede adequate surgical excision of DCIS. Routine mammographic views alone are frequently not enough. The extent of microcalcifications needs to be determined with state-of-the-art microfocus magnification views in the cranial caudal and lateral projections. If the microcalcifications appear to be extensive, the entire breast should be magnified with a metallic marker on the nipple. This may require several views. It is often important to include the retroareolar area because the tumor may skip down the duct system to the nipple. Hol- land et al3 showed that in 43 (52%) of 82 cases of DCIS, the tumor was in the retroareolar area, especially if the size of the DCIS lesion was greater than 40 mm. Magnification views often show that the calcifications are more extensive than predicted from the routine views. The mammographic size is within 2 cm of the histologic size in 80% to 85% of the cases if state-of-the-art magnification mammography is used for preoperative assessment. 5

Accurate pre-operative localization is important for the surgeon. Mam- mography can be used to localize lesions preoperatively. DCIS lesions may be localized by wire insertion or dye injection. More than one wire insertion or dye injection may be required, particularly if the calcifications are extensive.

Specimen radiography should be performed with the use of a microfocus magnification technique to ensure that all calcifications are removed. The specimen is then serially sectioned and radiographed to guide the pathologist to the calcifications, although the area of concern may still be


missed. It is important to realize that occasionally the calcifications will be situated at the bottom of the tissue block. Thus superficial sections will miss the area of concern, which will only be shown with further radiographs of the paraffin block. Adequate excision requires communication between the surgeon, the radiologist, and the pathologist.

Postoperative Marnmography A postsurgical, preradiation therapy mammogram is mandatory for

those patients whose tumors had calcifications to document complete removal of the calcifications and hence adequacy of tumor excision, lz Currently, completeness of excision appears to correlate with out- come. 13,~4 However, more precise and consistent methods need to be developed to assist in the determination of adequate removal of DCIS. A baseline study is recommended at 6 months after radiotherapy. Serial mammography is needed to detect any adverse changes, but the frequency of mammographic follow-up is controversial, ls-17 Mammography of the affected side every 6 months for the first 3 years may be considered, particularly if adjuvant radiation was not administered. 13 It is important to carefully evaluate the tumor bed because most recurrences are located within a few centimeters of the initial site of excision.18 Calcifications are an important marker of new or recurrent breast carcinoma. ~9 Microcalci- fications accounted for 43% of mammographically detected recurrences in one study, z° After breast conservation therapy, it is important to mini- mize the misinterpretation of postprocedural change as tumor recurrence and to diagnose recurrence as early as possible. Achievement of these objectives will be facilitated by increased understanding of the time course of tumor recurrences and by improved knowledge of mammographic changes associated with surgery and radiation therapy of the breast.

Ultrasonography In addition to patients with nipple discharge and Paget's disease, false-

negative mammograms are seen for patients with palpable masses caused by DCIS. Therefore all patients with a palpable mass and a normal mammogram need to be assessed with a breast ultrasonogram, zl In the assessment of clinical abnormalities, one reason for combined false-negative mammography and ultrasonography is the presence of noncalcified DCIS. Nevertheless, the combination of newer high-resolution transduc- ers and increasing experience with breast ultrasonography is leading to increased sensitivity of ultrasonography in the detection of DCIS. Sono- graphically, DCIS may be seen as a bulky, hypoechoic vascular mass


with ductal extensions. In addition, microlobules may be prominent. Benign fibrocystic disease may have similar findings, but in contrast to DCIS, these changes are usually present in both breasts. Occasionally, distended ducts with small papillary nodules may be seen. Sonographic evaluation of a nonspecific lesion viewed by mammography may reveal DCIS associated with an intracystic lesion. Although mammography is considerably better for the detection of microcalcifications, these lesions can occasionally be visualized with state-of-the-art ultrasonographic equipment, particularly in the presence of dense breasts for which the diagnostic ability of mammography is significantly diminished.

Novel Imaging Modalities for DCIS Digital Mammography

Digital mammography is similar to conventional film/screen mammography because low-dose ionizing radiation is used, there is compression of the breast, and the positioning of the breast is the same as encountered in conventional film/screen mammography. Digital mammography has several advantages over conventional film/screen mammography. The image can be manipulated to improve visualization of difficult areas within the image. Areas of concern on the initial image can be improved and magnified if desired without repeating the image (ie, without additional ionizing radiation). The speed of acquisition of the images is decidedly improved. When digital mammography becomes widely used, telemammography will be a significant advantage. Double reading of mammograms has been shown to improve the accuracy of findings. 2 In a similar fashion, the use of computer-aided diagnosis will also improve accuracy. 23,24

Breast MRI with the use of intravenous injection of gadolinium-dieth- ylene-triamine-pentaacetic acid has received considerable attention as a potential means for the detection and diagnosis of breast cancer. 25 The use of contrast enhancement in conjunction with digital mammography could provide similar information about the presence and extent of disease. In general, breast tumors are enhanced more rapidly than other tissues in the breast, although many benign lesions also exhibit enhancement. In a pilot study based on digital subtraction angiography, Watt et a126 showed significant enhancement in breast tumors with the administration of iodinated contrast material. The relationship of angiogenesis to the development of breast cancer has been suggested by Doppler ultrasonographic studies and by the observation with computed tomography of increased concentration of iodinated contrast material in breast tumors after intravenous administration of the contrast material. 27-29


Low doses of contrast agents could be used to allow multiple images to be acquired so that the kinetics of enhancement could be tracked with digital mammography. Overall, this offers the potential for digital mammography to serve as a cost-effective and more readily available alternative to contrast-enhanced MRI.

MRI

MRI has recently been shown to be an effective method for the detection and staging of breast cancer. 3° There is accurate demonstration of tumor size, number, and extent of disease. MRI has been suggested as a diagnostic workup tool to reduce the number of unnecessary biopsies of benign disease. If suspicious mammographic abnormalities are evaluated with MRI before biopsy, one could consider follow-up rather than biopsy in cases in which no contrast enhancement was seen. In this way, the advantage of the high negative predictive value of MRI may be used to facilitate clinical decision making. 3~

There are numerous advantages of MRI. No ionizing radiation is used. There is reportedly high sensitivity for DCIS. 32 Little compression is used. Dense breast tissue presents no limitation to the accuracy of MRI, and there is accurate delineation of the extent of disease, including the ability to delineate multifocal disease. In patients who have had previous surgery, scar tissue can be more easily differentiated from recurrence of cancer with MRI.

As with all new modalities, there are some disadvantages with MRI. The cost of MRI is high, and MRI is not readily available. The examination takes considerably longer than conventional mammography and no standardized method of examination has yet been found. There is also limited experience with needle biopsies and surgical biopsy guidance.

MRI enhancement may be a reflection of tumor angiogenesis. Slower rates of enhancement tend to represent benign entities and rapid rates of enhancement tend to denote malignancy. The morphology of the enhancement can also be used to help differentiate benign disease and malignant disease. Benign enhancement tends to be in the form of round, sharply demarcated masses and malignant enhancement tends to be spic- ulated and linear and often has rim enhancement.

Breast MRI is a potentially powerful tool that can provide information that is complementary to conventional mammography in the workup of mammographically or clinically detected breast abnormalities. 33 The ability of MRI to aid in the assessment of the accuracy of extent of disease in DCIS is improving. 34 The efficacy of MRI as a screening modality in the detection of breast cancer is currently being studied in many centers.


Biopsy Techniques Image-guided biopsies have an important role in the diagnosis and man-

agement of DCIS. Image-guided biopsy has been shown to be a reliable, minimally invasive, cost-effective method to reduce the number of benign surgical biopsies for abnormalities detected with mammography. When the diagnosis of DCIS is established, definitive surgery can be planned. If the calcifications are extensive, core biopsies from one or more areas will confirm the diagnosis and this will lead directly to mastectomy. For lumpectomies, a preoperative core diagnosis of DCIS could reduce the need for re-excision for the obtainment of negative margins. 14,35 Surgeons may be unwilling to do large biopsies and risk cosmetic deformity until the diagnosis is confirmed. Without a preoperative diagnosis, a two-stage surgical procedure is often needed: one stage for diagnosis and one stage for definitive treatment. Libennan et a136 reported a reduction in surgical procedures of 42% when a preoperative core biopsy was obtained for suspicious calcifications. 36 In some cases, however, core biopsy was an unnecessary procedure. For a small DCIS, lesions, surgical excisional biopsy of the suspicious cluster would be definitive treatment.

Because of the number of insufficient specimens and the inability to differentiate invasive from in situ carcinoma, fine-needle aspiration biopsy is not used for the assessment of calcifications. Tissue is needed for histopathologic diagnosis. In the early 1990s, large core needle biopsy with the use of a tru-cut needle in a spring-loaded automated gun was introduced as a percutaneous method to obtain tissue for histology. Ini- tially there was controversy about whether this technique was suitable for the evaluation of calcifications to rule out DCIS. The multi-institutional study showed that false-negative core biopsy diagnosis was higher for calcifications compared with masses. 37 To avoid insufficient specimens and false-negative diagnoses, the procedure needed to be standardized in the following ways: stereotactic mammographic guidance, 14-gauge nee- dles with large (19-mm) sampling notches, 5 to 10 passes, and specimen radiographs of the cores to confirm the presence of representative calcifications.38; 39

It is important to recognize the limitations of large core needle biopsy in the diagnosis of DCIS that are attributable to sampling errors. A core biopsy diagnosis of atypical ductal hyperplasia is often inaccurate and subsequent excisional biopsy will detect both in situ and invasive carcinoma in 44% to 58% of cases . 4°'41 Both qualitative and quantitative criteria are used to make the diagnosis of DCIS, and sometimes the cores do not provide enough tissue to meet the quantitative criteria. Another sam- piing error is that 15% to 20% of cases initially diagnosed as DCIS with


large core needle biopsy will be invasive carcinoma when completely excised. 4°-42 These patients will often need a second surgical procedure, axillary dissection. Overdiagnosis of invasion can also occur because of epithelial displacement of tumor from the core biopsies. 42 Diaz et a143 found tumor displacement in 32% of core biopsies. Because the incidence and amount was inversely related to the interval between the core biopsy and the surgical excisional biopsy, Diaz et a143 postulated that the cells do not survive displacement and are not biologically relevant.

These limitations of the tru-cut needle in an automated biopsy gun have led to the development of a new percutaneous biopsy device, the vacuum- assisted biopsy. Although 14-gauge probes are available, more accurate results are obtained with 11-gauge probes. The device uses a vacuum to pull tissue into the probe and an inner cutter captures the tissue, which is withdrawn into a collection chamber. The device is rotated and more tissue is retrieved. With the 11-gauge probe, 94.4 mg of tissue is obtained per core compared with 17.7 mg with the 14-gauge, tru-cut needle-automated gun combination. 44 If all the calcifications are removed, a surgical clip can be inserted to localize the area if further biopsy is needed. Because the probe does not have to be reinserted or fired, tumor displacement is less likely than with the gun technique in which the needle is re-inserted and fired through the calcifications 5 to 10 times. 45

The most important advantage of the vacuum-assisted biopsy device is the reduction in sampling error because the biopsies are larger and the sampling is contiguous. In one study none of the 8 ADH lesions diagnosed with 14-gauge vacuum-assisted biopsy were determined to be carcinoma with surgical excisional biopsy. 41 Similarly, none of the 32 DCIS lesions had evidence of invasion at surgery. Subsequent studies, however, have shown that there are still inaccuracies with the vacuum-assisted biopsy diagnosis of atypical ductal hyperplasia and DCIS. In a study at John Hopkins University, 25% of cases initially diagnosed as atypical ductal hyperplasia with 11-gauge, vacuum-assisted biopsy had evidence of carcinoma when the lesions were excised. 46 In another study, microin- vasion was found in the lumpectomy in 15% of cases initially diagnosed as DCIS with 11-gauge, vacuum-assisted biopsy. 4v The number of sam- ples taken may account for the different results. In the study in which no underestimation occurred, 41 26 to 27 cores (14 gauge) were obtained, whereas in other studies there were fewer biopsies. The most important drawback of the vacuum-assisted biopsy is the cost of the probe, which is approximately 10 to 20 times that of a tru-cut needle. 48

Not all calcifications are suitable for sampling with large core biopsy. Single or multiple clusters of powdery, cotton ball calcifications are often


sclerosing adenosis with adjacent low nuclear grade, well differentiated DCIS that could easily be missed by the sampling error associated with core biopsy that targets the calcifications. Tabar et al, 2 in particular, recommended that these calcifications be assessed with excisional biopsy with preoperative localization.

A new device, Advanced Breast Biopsy Instrumentation (United States Surgical, Norwalk, Conn), has been introduced to percutaneously completely excise nonpalpable breast lesions. This device removes a cylinder of tissue 5 to 20 mm in diameter with the use of stereotactic mammographic guidance to target the lesion. Liberman 48 recently reviewed the results of several published series, and the rate of positive margins for invasive and noninvasive carcinoma ranged from 64% to 100%. This procedure is associated with more complications, more technical failures, and higher cost without meeting the goal of completely excising the lesion. Advanced Breast Biopsy Instrumentation appears to have no advantage over either directional vacuum-assisted biopsy or 14-gauge automated core needle biopsy.

Ultrasonographic guidance can also be used for biopsy of suspicious calcifications when stereotactic biopsy is not technically possible. Simi- larly, when routine galactography fails, ultrasonographic guidance may facilitate the injection of contrast material for the visualization of the presence of abnormal ducts. Furthermore, areas of invasive carcinoma, which are seen as hypoechoic areas on ultrasonograms, can be biopsied for more accurate staging. It should be emphasized that mammography is considerably better for the detection, characterization, and biopsy guidance of microcalcifications. The inability to consistently show microcalcifications is one reason ultrasonography cannot be used as a sole screening method for the detection of carcinoma.

Conclusion The challenge for breast imagers will be to accurately determine the

extent of DCIS to reduce the rate of recurrence after breast-conserving treatment for a disease that should be curable. Recurrences may be invasive and therefore potentially life threatening. On the basis of the extent of calcifications, the size of DCIS is underestimated with mammography, although this can be reduced with preoperative magnification views. Poorly differentiated DCIS is more likely to recur 1 but is also less likely to be underestimated by the extent of calcifications if adequately assessed preoperatively. Contrast-enhanced digital mammography may further improve the preoperative mapping of disease. Although contrast enhanced MRI does not detect all DCIS, it is expected that it will improve


the assessment of tumor extent in many cases. Ultrasonography will show some of the noncalcified DCIS that presents as a clinical mass, and galactography remains the procedure of choice for the assessment of the extent of DCIS that produces nipple discharge. Image-guided core biopsies provide preoperative confirmation of DCIS so that definitive surgery can be planned. Although it is more expensive, the new vacuum-assisted biopsy appears to be more accurate in the diagnosis of DCIS; however, underestimation of disease still occurs. Magnification radiographs of the intact and serially sectioned specimens are needed to ensure that all calcifications have been removed. This can be confirmed with a 1-month postoperative mammogram. After that, mammograms should be obtained at 6- to 12-month intervals for 3 years and then yearly so that recurrences may be detected at an early stage. The primary goal of imaging for DCIS is to accurately depict the extent of disease preoperatively to reduce the likeli- hood of recurrence.

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Charles Catzavelos, MD, is a pathologist who underwent his residency training at the University of Ottawa and Harvard Medical School. He sub- sequently completed a postdoctoral fellowship in the laboratory of Dr Jef- frey Sklar at the Brigham and Women's Hospital; this fellowship was followed by breast subspecialty training with Dr Jim Connolly at the Beth Israel Hospital. He is currently an assistant professor at the University of Toronto and a staff pathologist at Sunnybrook and Women's College Health Sciences Centre. His main research interest is in the molecular basis of breast cancer progression.


part ii. medical imaging of ductal carcinoma in situ

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