Complex Cystic Breast Masses: Diagnostic Approach and Imaging- Pathologic Correlation 1

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1 Note: This copy is for your personal, non-commercial use only. To order presentation-ready copies for distribution to your colleagues or clients, use the RadioGraphics Reprints form at the end of this article. APPLICATIONS OF CURRENT TECHNOLOGY Complex Cystic Breast Masses: Diagnostic Approach and Imaging- Pathologic Correlation 1 S53 CME FEATURE See accompanying test at /education /rg_cme.html LEARNING OBJECTIVES FOR TEST 2 After reading this article and taking the test, the reader will be able to: Recognize the imaging features of complex cystic breast masses. Describe current biopsy techniques used to diagnose complex cystic breast masses. Identify the common pathologic diagnoses of complex cysts in the breast. Devang J. Doshi, MD David E. March, MD Giovanna M. Crisi, MD, PhD Bret F. Coughlin, MD Complex cystic breast masses demonstrate both anechoic (cystic) and echogenic (solid) components at ultrasonography (US). US is used to identify and characterize such masses and to guide percutaneous biopsy. Numerous pathologic entities may produce complex cystic breast lesions or may be associated with them, and biopsy is usually indicated. Common benign findings include fibrocystic changes, intraductal or intracystic papilloma without atypia, and fibroadenoma. Common atypical findings include atypical ductal hyperplasia, atypical papilloma, atypical lobular hyperplasia, and lobular carcinoma in situ. Malignant findings include ductal carcinoma in situ, infiltrating ductal carcinoma, and infiltrating lobular carcinoma. If the biopsy approach is tailored to the individual patient and if the imaging features are closely correlated with findings at pathologic analysis, US-guided percutaneous biopsy may be used effectively to diagnose and to guide management of complex cystic masses. RSNA, 2007 TEACHING POINTS See last page Abbreviations: DCIS ductal carcinoma in situ, H-E hematoxylin-eosin RadioGraphics 2007; 27:S53 S64 Published online /rg.27si Content Codes: 1 From the Departments of Radiology (D.J.D., D.E.M., B.F.C.) and Pathology (G.M.C.), Baystate Medical Center The Western Campus of Tufts University School of Medicine, 759 Chestnut St, Springfield, MA Recipient of a Certificate of Merit award for an education exhibit at the 2006 RSNA Annual Meeting. Received February 21, 2007; revision requested April 2 and received April 23; accepted May 3. All authors have no financial relationships to disclose. Address correspondence to D.J.D. ( djdoshi12@yahoo.com). RSNA, 2007

2 S54 October 2007 RG f Volume 27 Special Issue Teaching Point Introduction Cystic breast lesions are commonly observed at ultrasonography (US) performed for the evaluation of palpable or mammographically detected breast masses. Complex cysts contain cystic and solid components and are associated with a variety of benign, atypical, and malignant pathologic diagnoses. Complex cystic breast masses have a substantial chance of being malignant; malignancy was reported in 23% (1) and 31% (2) of cases in two series. For that reason, percutaneous or surgical biopsy is usually indicated. Techniques that may be used for sampling of complex cystic breast masses include fine-needle aspiration, core-needle biopsy (with an automated spring-loaded or vacuum-assisted device), and surgical excision. This article reviews the imaging evaluation of complex cystic breast masses, various approaches to percutaneous biopsy, and common pathologic diagnoses. Imaging Evaluation Mammography Many patients with complex cystic masses have undergone recent mammography, which may help characterize the mass, depict associated microcalcifications (Fig 1), and show additional suspicious lesions (3). If a lesion appears fat-containing at mammography, it represents a benign entity such as an oil cyst or galactocele, and biopsy can be avoided. For lesions that are proved malignant at biopsy, mammography may provide important information about the extent of disease and thus may influence subsequent surgical management. Ultrasonography At US, breast cysts are categorized as simple, complicated, or complex (1,4,5). Appropriate categorization is important because the management of each type differs. Simple cysts are defined as anechoic, well-circumscribed, round or ovoid masses with an imperceptible wall and increased through-transmission of sound waves. When all the criteria of simple breast cysts are present, they are considered benign and do not require intervention. Painful cysts can be aspirated for symptom relief. Complicated cysts contain low-level internal echoes or intracystic debris that may layer and shift with changes in patient position. The homogeneous internal echoes within some complicated cysts may produce an appearance identical to that of a circumscribed solid mass. Complicated cysts do not contain thick walls, thick septa, or other discrete solid-appearing components. The risk of malignancy among complicated breast cysts is less than 2%; these cysts generally can be managed with short-interval follow-up imaging or aspiration. However, if a complicated cyst is symptomatic, new, or enlarging, needle aspiration is indicated (1,5,6). Complex breast cysts are defined as cysts with thick walls, thick septa, intracystic masses, or other discrete solid components (4). By using criteria adapted from Berg et al (1), we can categorize complex cystic breast masses into four classes on the basis of their US features: Type 1 masses have a thick outer wall, thick internal septa, or both; type 2 masses contain one or more intracystic masses; type 3 masses contain mixed cystic and solid components and are at least 50% cystic; and type 4 masses are predominantly (at least 50%) solid with eccentric cystic foci. Approach to Biopsy Decision making about the best approach to use for percutaneous biopsy of a complex cystic mass involves balancing the need to obtain sufficient material for an accurate diagnosis against the need to minimize the invasiveness of the procedure. The percutaneous biopsy of complex cystic masses may present a challenge, compared with the biopsy of other types of breast lesions, because of the presence of a cystic component that is typically disrupted during the biopsy procedure. In some cases, the decompression of the cystic component may make it more difficult to detect the remaining solid component at US and, therefore, more difficult to target and sample it. The techniques used for biopsy of complex cystic breast masses include fine-needle aspiration, core-needle biopsy, and surgical biopsy. Avoiding Unnecessary Intervention A thorough patient history and mammographic evaluation may obviate intervention. For example, a hematoma with a complex cystic appearance might form soon after a needle biopsy, surgi- Teaching Point

3 RG f Volume 27 Special Issue Doshi et al S55 Figure 1. Infiltrating ductal carcinoma and ductal carcinoma in situ (DCIS) in a 44-year-old woman. (a) Mediolateral oblique mammogram shows a large mass with adjacent linear calcifications (arrow) in the upper part of the right breast. (b) US image demonstrates a type 1 complex cystic mass with a thick wall and thick septum. The diagnosis was based on the results of a core-needle biopsy. Figure 2. Oil cyst after reduction mammoplasty in a 23-year-old woman with a palpable mass in the region of postoperative scarring in the left breast. (a) Doppler US image shows a type 3 complex cystic mass without internal flow. (b) Tangential spot magnification mammogram, obtained after placement of an external marker, shows a well-circumscribed fatdensity mass (arrows) with a characteristically benign appearance. Biopsy was not indicated. cal biopsy, or trauma. When a hematoma is suspected, a follow-up US examination (usually in 2 3 months) is recommended to reevaluate the finding and verify regression. Areas of fat necrosis due to surgery or trauma, as well as galactoceles, also may appear as complex cystic masses (Fig 2). Thus, biopsy may be averted in the appropriate clinical setting or if the mass has a characteristically benign mammographic appearance.

4 S56 October 2007 RG f Volume 27 Special Issue Figure 3. Complicated cyst in a 46-year-old woman. (a) US image shows dependent intracystic echoes. (b) US image from a repeat examination with the patient in the left decubitus position shows mobility of the intracystic material. The cyst resolved completely after fine-needle aspiration, which yielded nonbloody material, and core-needle biopsy was not indicated. Figures 4, 5. (4) Papillary apocrine hyperplasia with atypical ductal hyperplasia. Doppler US image shows a type 2 complex cystic mass with flow within the solid component (arrow). The mass was diagnosed at coreneedle biopsy, and the diagnosis was confirmed at surgical excision. (5) Papilloma in a 71-year-old woman. Power Doppler US image shows a type 2 complex cystic mass with flow within the solid components. The mass was diagnosed at core-needle biopsy. Palpable Lesions When a complex cystic mass is palpable, percutaneous biopsy with US guidance is preferable to guidance with palpation only. The potential pitfalls of aspiration or core biopsy performed only with palpation for guidance include (a) difficulty in accurately targeting the solid component, (b) fluid aspiration or extraluminal leakage rendering a mass impalpable during biopsy and making subsequent biopsy passes less accurate, and

5 RG f Volume 27 Special Issue Doshi et al S57 Figure 6. Fibrocystic changes in a 59-year-old woman with a palpable breast mass. (a) Initial US image shows a cyst with a slightly thick wall (type 1). Fine-needle aspiration yielded nonbloody fluid. (b) Follow-up US image shows a residual ill-defined hypoechoic mass demarcated by electronic calipers. Histologic analysis of a core-needle biopsy specimen obtained with a 14-gauge automated device indicated cystic apocrine metaplasia and dense fibrous stroma with reactive stromal changes, findings consistent with cyst wall. Teaching Point Teaching Point (c) resolution of palpability in conjunction with benign findings at cytologic and histologic analysis, which may be falsely reassuring and delay the diagnosis of a potential malignant lesion. Fine-Needle Aspiration Fine-needle aspiration may be performed initially if the presence of a true solid component within a complex cystic mass is in question on the basis of US findings; it may be unclear whether the intracystic echogenicity represents debris, pus, or a clot within a complicated cyst, or a mass within a complex cyst. The evaluation of mobility and flow is a useful strategy for distinguishing between a complex cyst and a complicated cyst. If the echogenic component is mobile with a position change, it represents debris, pus, or a clot (Fig 3). If the echogenic component is immobile, it may represent either a true intracystic mass or debris adherent to the cyst wall. The demonstration of flow within a solid-appearing region at Doppler imaging is indicative of a true intracystic mass (Figs 4, 5). If no flow is seen, it is impossible to differentiate a debris-containing mass from a hypovascular mass. When a complex cystic mass is aspirated and the aspirate appears purulent, it is submitted for microbiologic analysis and antibiotic sensitivity testing. A bloody aspirate is submitted for cytologic examination. A clip is placed internally at the aspiration site if the aspirate is submitted for cytologic examination and there is no residual mass or other adjacent imaging landmark (7). If a mass resolves after aspiration that yields nonbloody and nonpurulent fluid, the aspirate is discarded (8). If a complex cyst contains a true solid component, biopsy is indicated for histologic diagnosis. When fine-needle aspiration is performed and a solid mass remains visible at US, core-needle biopsy of the residual solid lesion may be performed immediately after the aspiration procedure (Figs 6, 7). Reliance solely on benign cytologic findings in the fine-needle aspirate is not advisable, because the residual mass may represent a malignancy even if the aspirated material does not contain malignant cells (9,10).

6 S58 October 2007 RG f Volume 27 Special Issue Figure 7. Infiltrating ductal carcinoma in a 33-year-old woman with a palpable breast mass. (a) US image demonstrates a thick-walled complex cystic mass (arrows). (b) US image shows the mass during fine-needle aspiration, which yielded bloody fluid. The mass did not resolve completely. (c, d) US images obtained during core-needle biopsy, before (c) and after (d) firing of a 14-gauge automated device, show sampling of the small residual solid component. (e, f) Photomicrographs (original magnification, 100 in e, 400 in f; hematoxylin-eosin [H-E] stain) of a specimen obtained at core-needle biopsy reveal grade 3 infiltrating ductal carcinoma. Teaching Point US-guided Core-Needle Biopsy Core-needle biopsy of a complex cyst may be performed without prior fine-needle aspiration if the lesion (a) contains a definite solid component observed at US or flow observed at color Doppler imaging, (b) demonstrates associated suspicious mammographic findings (clustered calcifications, suspicious shape or margins, or architectural distortion), or (c) contains a small solid-appearing component that would be difficult or impossible to target with a large-gauge needle after fluid aspiration.

7 RG f Volume 27 Special Issue Doshi et al S59 Figure 8. Intracystic papilloma. (a) US image shows a type 2 complex cystic mass. (b) US image obtained during a vacuum-assisted biopsy shows an 11-gauge needle probe (arrows) positioned deep to the mass. The diagnosis was established at vacuum-assisted biopsy. Figure 9. Intracystic papilloma in a 45-year-old woman. US image shows a type 2 complex cystic mass that contains a small intracystic papilloma suspended on a stalk. The mass was surgically excised. If a percutaneous biopsy had been performed, the solid part of the mass may have been difficult or impossible to target for biopsy after the fluid-filled portion was drained. In our practice, a core-needle biopsy is performed when a solid component is present. Either a 14-gauge spring-loaded device or an 11-gauge vacuum-assisted device is used. We found this approach accurate in a series of 31 patients with 32 complex cystic masses and with 1-year follow-up of benign lesions (2). A US-guided coreneedle biopsy performed with a 14-gauge springloaded device is a low-cost, well-tolerated approach for the biopsy of lesions with a solid component that is expected to remain clearly visible throughout the procedure. For biopsy of masses that are primarily cystic and have only a small solid component, we prefer to use an 11- gauge hand-held vacuum-assisted device (Fig 8). After the biopsy, if there is a concern that the residual mass might be difficult to localize for subsequent surgical excision on the basis of pathologic findings, a clip is deployed at the biopsy site. Clip deployment devices for use with springloaded and vacuum-assisted needle biopsy devices are widely available. Furthermore, several types of clips are visible both at US and at mammography, and their visibility may facilitate wire localization when either modality is used for guidance. Specimen radiography is performed if the lesion is associated with calcifications. Surgical excision of a complex cystic mass is recommended instead of core-needle biopsy if adequate sampling with core-needle biopsy would be technically difficult because of the size or location of the solid components (Fig 9).

8 S60 October 2007 RG f Volume 27 Special Issue Figure 10. Fibrocystic changes in a 45- year-old woman with a nonpalpable mass poorly depicted at mammography. (a) US image shows a type 1 complex cystic mass with thick septa. (b, c) Photomicrographs (original magnification, 40; H-E stain) of specimens from core-needle biopsy show apocrine metaplasia (b) and apocrine metaplasia with cyst formation (c). Figure 11. Papilloma without atypia in a 62-year-old woman. (a) Craniocaudal mammogram shows a well-circumscribed mass (arrow) in the medial part of the breast. (b) Doppler US image demonstrates a type 3 complex cystic mass. (c) Photomicrograph (original magnification, 100; H-E stain) of a specimen from a core-needle biopsy shows intraductal papilloma without atypia, with apocrine metaplasia and microcalcifications.

9 RG f Volume 27 Special Issue Doshi et al S61 Figure 12. Lobular carcinoma in situ associated with multiple papillomas in a 45-year-old woman with mammographic findings of a mass and calcifications. (a) US image shows a type 2 complex cystic mass. (b) Radiograph of a specimen obtained at core-needle biopsy with an 11- gauge vacuum-assisted device shows calcifications. (c) Photomicrograph (original magnification, 100; H-E stain) of a core-needle biopsy specimen demonstrates an infarcted papilloma with calcifications. (d) Photomicrograph (original magnification, 40 [background], 400 [inset]; H-E stain) of the subsequent excisional biopsy specimen shows incidental lobular carcinoma in situ. Pathologic Findings Complex cystic breast masses may be due to a wide range of pathologic entities, including benign, atypical (high-risk), and malignant lesions. Benign Lesions Common benign diagnoses of complex cystic breast masses include fibrocystic changes, intraductal or intracystic papilloma without atypia, and fibroadenoma (1). Fibrocystic changes include adenosis, sclerosing adenosis, apocrine metaplasia, cyst formation with or without rupture, and ductal ectasia. Fibrocystic changes are nonproliferative changes with three predominant morphologic features: cyst formation, fibrosis, and adenosis (Fig 10) (11,12). These findings are not associated with an increased risk for breast cancer (13 15). Intraductal or intracystic papilloma without atypia is composed of multiple branching fibrovascular cores lined by two layers of epithelial and myoepithelial cells (Figs 11, 12) (11,12). This diagnosis is associated with a slightly increased (by one and a half to two times) risk for breast cancer (13 15) when multiple lesions are present. Fibroadenoma, a fibroepithelial tumor, is composed of glandular and stromal tissue. The stroma encloses glandular spaces lined by myoepithelial and epithelial cells. The stroma may be fibrous, hyalinized, or myxoid (Fig 13) (11,12). The diagnosis of fibroadenoma is not associated with an increased risk for breast cancer (13 15).

10 S62 October 2007 RG f Volume 27 Special Issue Figure 13. Fibroadenoma in a 48-year-old woman. (a) Craniocaudal mammogram shows an oval mass (arrow) in the lateral part of the breast. (b) US image demonstrates a type 1 complex cystic mass. (c) Photomicrograph (original magnification, 40; H-E stain) of a specimen from core-needle biopsy reveals fibroadenoma. Atypical and High-Risk Lesions Common atypical pathologic findings in complex cystic breast masses include atypical ductal hyperplasia and atypical papilloma. Lobular neoplasia (atypical lobular hyperplasia or lobular carcinoma in situ) also may be associated with complex cystic breast masses. Atypical ductal hyperplasia bears a histologic resemblance to low-grade DCIS but is more limited in its extent. The lesion is characterized by a partially monomorphic cell population, regular cell placement, and microlumen formation (11,12). It is associated with a moderately increased (four- to fivefold) risk for breast cancer (13 15). Atypical papilloma demonstrates areas of atypical ductal hyperplasia within an intraductal or intracystic papilloma or papillary lesion (11, 12). This lesion also is associated with a moderately increased (four- to fivefold) risk for breast cancer (13 16). Lobular neoplasia is usually found incidentally at biopsy and produces no characteristic mammographic features (17). Atypical lobular hyperplasia is characterized by a proliferation of monomorphic lobular-type cells similar to those in lobular carcinoma in situ, except that they do not fill or distend more than 50% of acini within the lobule (11,12). Atypical lobular hyperplasia is associated with a moderately increased (four- to fivefold) risk for breast cancer (13 15,18). Lobular carcinoma in situ, which usually is also an incidental pathologic finding, consists of a loosely cohesive population of neoplastic cells with scant cytoplasm and small round to larger nuclei; the neoplastic cells fill and expand the lobules and terminal ducts (11,19). Lobular carcinoma in situ is associated with a markedly increased (eight- to 10-fold) risk for breast cancer (13,14,18). Malignant Lesions The most common malignancies among complex cystic masses include DCIS and infiltrating ductal carcinoma. Infiltrating lobular carcinoma also may have a complex cystic appearance. Berg et al (1) reported two findings of infiltrating lobular carcinoma (one a mixed lesion with infiltrating ductal carcinoma and DCIS) among 18 carcinomas (11%) in their patient series; both were type 4 complex cystic lesions.

11 RG f Volume 27 Special Issue Doshi et al S63 Figure 14. DCIS in a 64-year-old woman. (a) Mammogram shows an oval mass that corresponds to a palpable abnormality. (b) US image depicts a type 3 complex cystic mass. (c) Photomicrograph (original magnification, 100; H-E stain) of a specimen from core-needle biopsy reveals lowgrade cribriform DCIS. DCIS consists of a proliferation of monomorphic neoplastic epithelial cells that fill the ductal lumina. Different types of DCIS are recognized on the basis of their architectural pattern and nuclear characteristics. The myoepithelial cell layer remains intact (Fig 14) (11,20). DCIS is associated with a markedly increased (eight- to 10-fold) risk for infiltrating ductal carcinoma (13,14). Infiltrating ductal carcinoma is characterized by glandular or solid clusters of malignant tumor cells with infiltrating margins. The appearance of the lesion is highly variable and depends on the degree of cellularity, stromal reaction, necrosis, and inflammatory cell infiltration (Fig 7) (11,21). Infiltrating lobular carcinoma is characterized by loosely cohesive tumor cells that infiltrate the fibrous stroma as single cells, form threadlike strands, or do both. The tumors are classified as classic or pleomorphic on the basis of the nuclear characteristics of the neoplastic cells (22). Imaging-Pathologic Correlation As with percutaneous biopsies of all breast lesions, the pathologic findings from biopsies of complex cystic masses should be correlated with the imaging features to determine whether they are concordant. An understanding of the common histologic findings that produce a complex cystic appearance at US is important in this process. To establish concordance, the specific imaging features of concern (such as a thick-walled cyst or an intracystic mass) should be explainable on the basis of the pathologic findings. The pathologist should be provided with a detailed description of the imaging findings, including differential diagnoses, to enable an optimal comparison of the pathologic findings with the imaging features of the lesion. Pathologic findings that appear to be discordant with imaging findings should be discussed with the pathologist. Pathologic, imaging, and clinical correlation is essential to ensure that the targeted lesion was adequately sampled; in cases of discordance, a repeat core-needle biopsy or surgical biopsy should be considered. Among the common pathologic findings of complex cystic masses, it is widely agreed that atypical ductal hyperplasia and atypical papilloma are indications for surgical excision. The management of lobular neoplasia and of papillary lesions without atypia is more controversial and has been discussed elsewhere (7,23,24). Six-month follow-up imaging of patients with benign concordant pathologic findings is recommended to reevaluate the lesion and minimize the potential consequences of a falsenegative biopsy result (25).

12 S64 October 2007 RG f Volume 27 Special Issue Conclusions Complex cystic breast masses are suspicious US findings that usually warrant biopsy. US is the modality of choice for characterizing and guiding biopsy of these lesions. Common benign causes of complex cystic masses include fibrocystic changes, intraductal or intracystic papilloma without atypia, and fibroadenoma. Atypical findings include atypical ductal hyperplasia, lobular neoplasia, and atypical papilloma. Malignant findings include DCIS, infiltrating ductal carcinoma, and infiltrating lobular carcinoma. USguided percutaneous biopsy is an effective method for diagnosing and guiding the management of complex cystic masses. References 1. Berg WA, Campassi CI, Ioffe OB. Cystic lesions of the breast: sonographic-pathologic correlation. Radiology 2003;227(1): Doshi DJ, March DE, Coughlin BF, Crisi GM. Accuracy of ultrasound-guided percutaneous biopsy of complex cystic breast masses [abstr]. In: Radiological Society of North America scientific assembly and annual meeting program. Oak Brook, Ill: Radiological Society of North America, 2006; American College of Radiology. ACR practice guidelines for the performance of diagnostic mammography. In: ACR guidelines and technical standards. Reston, Va: American College of Radiology, American College of Radiology. ACR BI-RADSultrasound. In: ACR breast imaging reporting and data system, breast imaging atlas. Reston, Va: American College of Radiology, Mendelson EB, Berg WA, Merritt CR. Toward a standardized breast ultrasound lexicon, BI-RADS: ultrasound. Semin Roentgenol 2001;36(3): Venta LA, Kim JP, Pelloski CE, Morrow M. Management of complex breast cysts. AJR Am J Roentgenol 1999;173(5): Berg WA. Image-guided breast biopsy and management of high-risk lesions. Radiol Clin North Am 2004;42(5): Smith DN, Kaelin CM, Korbin CD, Ko W, Meyer JE, Carter GR. Impalpable breast cysts: utility of cytologic examination of fluid obtained with radiologically guided aspiration. Radiology 1997;204(1): Pisano ED, Fajardo LL, Caudry DJ, et al. Fineneedle aspiration of nonpalpable breast lesions in a multicenter clinical trial: results from the Radiologic Diagnostic Oncology Group V. Radiology 2001;219(3): Giard RW, Hermans J. The value of aspiration cytologic examination of the breast: a statistical review of the medical literature. Cancer 1992; 69(8): Schnitt SJ, Connolly JL. Pathology of benign breast disorders. In: Harris JR, Lippman ME, Morrow M, Osborne CK, eds. Diseases of the breast. 3rd ed. Philadelphia, Pa: Lippincott, Williams & Wilkins, 2004; Tavassoli FA. Intraepithelial neoplasia: risk factors for subsequent development of invasive carcinoma. In: Tavassoli FA. Pathology of the breast. 2nd ed. Hong Kong: Appleton & Lange, 1999; Dupont WD, Page DL. Risk factors for breast cancer in women with proliferative breast disease. N Engl J Med 1985;312(3): Fitzgibbons PL, Henson DE, Hutter RV. Benign breast changes and the risk for subsequent breast cancer: an update of the 1985 Consensus Statement. Arch Pathol Lab Med 1998;122(12): Shaaban AM, Sloane JP, West CR, et al. Histopathologic types of benign breast lesions and the risk of breast cancer: case-control study. Am J Surg Pathol 2002;26(4): Page DL, Salhany KE, Jensen RA, Dupont WD. Subsequent breast carcinoma risk after biopsy with atypia in a breast papilloma. Cancer 1996; 78(2): Sonnenfeld MR, Frenna TH, Weidner N, Meyer JE. Lobular carcinoma in situ: mammographicpathologic correlation of results of needle-directed biopsy. Radiology 1991;181(2): Crisi GM, Manavilli S, Cronin E, Ricci A Jr. Invasive mammary carcinoma after immediate and short-term follow-up for lobular neoplasia on core biopsy. Am J Surg Pathol 2003;27(3): Fulford LG, Reis-Filho JS, Lakhani SR. Lobular carcinoma in situ: biology and pathology. In: Harris JR, Lippman ME, Morrow M, Osborne CK, eds. Diseases of the breast. 3rd ed. Philadelphia, Pa: Lippincott, Williams & Wilkins, 2004; Morrow M, Harris JR. Ductal carcinoma in situ and microinvasive carcinoma. In: Harris JR, Lippman ME, Morrow M, Osborne CK, eds. Diseases of the breast. 3rd ed. Philadelphia, Pa: Lippincott, Williams & Wilkins, 2004; Schnitt SJ, Guidi AJ. Pathology of invasive breast cancer. In: Harris JR, Lippman ME, Morrow M, Osborne CK, eds. Diseases of the breast. 3rd ed. Philadelphia, Pa: Lippincott, Williams & Wilkins, 2004; Rosen PP. Invasive lobular carcinoma. In: Rosen PP. Rosen s breast pathology. 2nd ed. Philadelphia, Pa: Lippincott Williams & Wilkins, 2001; Jacobs TW, Connolly JL, Schnitt SJ. Nonmalignant lesions in breast core needle biopsies: to excise or not to excise? Am J Surg Pathol 2002; 26(9): Reynolds HE. Core needle biopsy of challenging breast lesions: a comprehensive literature review. 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13 RG Volume 27 Special Issue October 2007 Doshi et al Complex Cystic Breast Masses: Diagnostic Approach and Imaging-Pathologic Correlation Devang J. Doshi, MD, et al RadioGraphics 2007; 27:S53 S64 Published online /rg.27si Content Codes: Page S54 Complex cystic breast masses have a substantial chance of being malignant; malignancy was reported in 23% and 31% of cases in two series. For that reason, percutaneous or surgical biopsy is usually indicated. Page S54 Complex breast cysts are defined as cysts with thick walls, thick septa, intracystic masses, or other discrete solid components. Page S57 Fine-needle aspiration may be performed initially if the presence of a true solid component within a complex cystic mass is in question on the basis of US findings; it may be unclear whether the intracystic echogenicity represents debris, pus, or a clot within a complicated cyst, or a mass within a complex cyst. Page S57 The evaluation of mobility and flow is a useful strategy for distinguishing between a complex cyst and a complicated cyst. Page S58 Core-needle biopsy of a complex cyst may be performed without prior fine-needle aspiration if the lesion (a) contains a definite solid component observed at US or flow observed at color Doppler imaging, (b) demonstrates associated suspicious mammographic findings (clustered calcifications, suspicious shape or margins, or architectural distortion), or (c) contains a small solid-appearing component that would be difficult or impossible to target with a large-gauge needle after fluid aspiration.

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15 RadioGraphics 2007 Black and White Reprint Prices Domestic (USA only) # of Pages $213 $228 $260 $278 $295 $ $338 $373 $420 $453 $495 $ $450 $500 $575 $635 $693 $ $555 $623 $728 $805 $888 $ $673 $753 $883 $990 $1,085 $1, $785 $880 $1,040 $1,165 $1,285 $1, $895 $1,010 $1,208 $1,350 $1,498 $1, $1,008 $1,143 $1,363 $1,525 $1,698 $1,865 Covers $95 $118 $218 $320 $428 $530 International (includes Canada and Mexico) # of Pages $263 $275 $330 $385 $430 $ $415 $443 $555 $650 $753 $ $563 $608 $773 $930 $1,070 $1, $698 $760 $988 $1,185 $1,388 $1, $848 $925 $1,203 $1,463 $1,705 $1, $985 $1,080 $1,420 $1,725 $2,025 $2, $1,135 $1,248 $1,640 $1,990 $2,350 $2, $1,273 $1,403 $1,863 $2,265 $2,673 $3,075 Covers $148 $168 $308 $463 $615 $768 Minimum order is 50 copies. For orders larger than 500 copies, please consult Cadmus Reprints at Reprint Cover Cover prices are listed above. The cover will include the publication title, article title, and author name in black. Shipping Shipping costs are included in the reprint prices. Domestic orders are shipped via UPS Ground service. Foreign orders are shipped via a proof of delivery air service. Multiple Shipments Orders can be shipped to more than one location. Please be aware that it will cost $32 for each additional location. Delivery Your order will be shipped within 2 weeks of the journal print date. Allow extra time for delivery. Color Reprint Prices Domestic (USA only) # of Pages $218 $233 $343 $460 $579 $ $343 $388 $584 $825 $1,069 $1, $471 $503 $828 $1,196 $1,563 $1, $601 $633 $1,073 $1,562 $2,058 $2, $738 $767 $1,319 $1,940 $2,550 $3, $872 $899 $1,564 $2,308 $3,045 $3, $1,004 $1,035 $1,820 $2,678 $3,545 $4, $1,140 $1,173 $2,063 $3,048 $4,040 $5,028 Covers $95 $118 $218 $320 $428 $530 International (includes Canada and Mexico)) # of Pages $268 $280 $412 $568 $715 $ $419 $457 $720 $1,022 $1,328 $1, $583 $610 $1,025 $1,492 $1,941 $2, $742 $770 $1,333 $1,943 $2,556 $3, $913 $941 $1,641 $2,412 $3,169 $3, $1,072 $1,100 $1,946 $2,867 $3,785 $4, $1,246 $1,274 $2,254 $3,318 $4,398 $5, $1,405 $1,433 $2,561 $3,788 $5,014 $6,237 Covers $148 $168 $308 $463 $615 $768 Tax Due Residents of Virginia, Maryland, Pennsylvania, and the District of Columbia are required to add the appropriate sales tax to each reprint order. For orders shipped to Canada, please add 7% Canadian GST unless exemption is claimed. Ordering Reprint order forms and purchase order or prepayment is required to process your order. Please reference journal name and reprint number or manuscript number on any correspondence. You may use the reverse side of this form as a proforma invoice. Please return your order form and prepayment to: Cadmus Reprints P.O. Box Charlotte, NC Note: Do not send express packages to this location, PO Box. FEIN #: Please direct all inquiries to: Rose A. Baynard (toll free number) (direct number) (FAX number) baynardr@cadmus.com ( ) Reprint Order Forms and purchase order or prepayments must be received 72 hours after receipt of form. Page 2 of 2