Lisa A. Newman
Presentation
A 45-year-old African American female undergoes routine screening mammogram and is found to have scattered indeterminate microcalcifications bilaterally. One cluster in the lower left breast at the 6 o’clock position is particularly suspicious because it appears prominent and has a more branching pattern when compared to the patient’s prior mammograms, which have been performed annually since age 40 years. She is referred to a surgeon for discussion of biopsy options. This patient’s past medical history is noncontributory, but she does have a sister who was diagnosed with breast cancer at 40 years of age. Her clinical breast exam is negative for any skin abnormalities; there are no dominant or discrete palpable masses; there is no nipple discharge; and there is no suspicious adenopathy in either the axillary or supraclavicular nodal basins.
Differential Diagnosis
Mammographically detected microcalcifications can represent benign breast findings (fibrocystic hyperplasia, vascular calcifications, cystic hyperplasia, etc.), or they can represent a breast malignancy. Patients are routinely recommended to avoid use of talc-based deodorants or topical preparations, as these can create calcification artifact. Patients with history of prior breast surgery or radiation can also develop calcifications that are of a benign, inflammatory nature (fat necrosis). An experienced breast imaging team is necessary to distinguish the high-risk and frankly malignant patterns that require biopsy from the clearly benign patterns that can be monitored noninvasively.
Workup
Additional diagnostic mammographic views (compression and magnification images) will generally be necessary for the further evaluation of microcalcifi-cations (Figure 1). Calcifications that follow a linear and branching pattern, or that are associated with a spiculated density, will be considered more suspicious of a malignant etiology. Calcifications that layer out (e.g., “teacup” pattern) suggest benign cystic hyperplasia. Targeted breast ultrasound is indicated if there is any question of a coexisting mass density. Breast magnetic resonance imaging (MRI) will not be useful at this juncture because a normal MRI will not negate any mammographic indications for proceeding to biopsy. Any management decisions must be correlated with the clinical breast exam—a suspicious finding on breast exam (e.g., palpable breast mass or bloody nipple discharge) would be an indication to proceed with biopsy in order to obtain histopathologic information regarding the nature of the finding, regardless of whether or not the lesion has an imaging correlate.
FIGURE 1 • A,B: Patient mammogram, revealing microcalcifications in left breast.
This patient’s additional imaging confirmed a dominant cluster of microcalcifications in the lower hemisphere of the left breast, and biopsy was recommended. Diagnostic biopsy options for nonpalpable, mammographically or sonographically detected breast abnormalities include image-guided fine needle aspiration (FNA), image-guided core needle biopsy, or wire localization surgical biopsy (Table 1). A diagnostic surgical biopsy is the most definitive procedure because it yields the largest pathology specimen, and may result in complete extraction of the image-detected abnormality, but as a surgical volume-extracting procedure, it can result in cosmetic deformity and is less efficient compared to needle biopsy procedures. Image-guided needle biopsy procedures are generally preferred as the initial diagnostic maneuver, as they are less invasive and less costly. Core needle biopsy tends to have an improved diagnostic yield compared to FNA; falsenegative/sampling error rates are usually <10% for core needle biopsies (especially if vacuum assisted) but can be as high as 30% with FNA biopsy. The FNA provides a cytologic sample only and therefore cannot distinguish in situ cancer from invasive cancer. Furthermore, while the spun-down cells from a cancerous FNA biopsy can be used for immunohistochemical evaluation of molecular markers (estrogen receptor, progesterone receptor and HER2/neu), it would not be known whether these markers were expressed on the invasive or the in situ component of the cancer.
TABLE 1. Key Technical Steps and Potential Pitfalls in Breast Biopsy Options for Nonpalpable, Screen-detected Abnormalities
Mammography can be used to guide a percutaneous needle biopsy (the stereotactic approach) or ultrasound may be used. Patient and image factors dictate the selection of image guidance. Microcalcifications usually require mammographic, stereotactic biopsy. While upright equipment is available, most stereotactic biopsies are performed on a specially designed table and require prone positioning of the patient. The affected breast is fitted through an aperture facing the floor, and the ipsilateral arm must be raised above the head during the entire procedure. The biopsy needle is directed toward the target within the breast using stereotactic guidance, and a range of 5 to 12 core specimens are typically extracted under local anesthesia. Because of the positioning and table design prerequisites, some cases will not be amenable to the stereotactic biopsy approach: lesions that are adjacent to the pectoralis muscle, lesions that are too superficial or within the nipple, small breasts that compress to a thickness that is exceeded by the core needle trajectory, patients who cannot tolerate prone positioning for prolonged periods (half-hour or longer), and patients who exceed the weight limit of the biopsy table. Solid mass lesions that are sonographically visible can be biopsied with ultrasound guidance. A radiopaque marker should be left in place at the biopsy site to document the site that was sampled. In the event that a subsequent surgical procedure is needed (and the imaged target is no longer visible on postbiopsy films), the clip would serve as the target for a wire localization resection. The core biopsy specimens should be imaged to insure adequate sampling of the target, especially in cases of microcalcifications. Specific needle biopsy pathology results that mandate a follow-up surgical resection include the following: failed procedures, where the target is not adequately sampled; benign pathologic findings that are radiographically interpreted as being discordant with the target images; and “high-risk” pathology, such as lobular carcinoma in situ (LCIS), atypical lobular hyperplasia, and atypical ductal hyperplasia. These high-risk lesions are associated with an approximately 15% to 20% frequency of coexisting cancer (ductal carcinoma in situ and/or invasive cancer) when a follow-up diagnostic surgical wire localization biopsy is performed.
In this patient, the cluster of microcalcifications was not amenable to the percutaneous needle biopsy because of small breast size, and the patient therefore underwent a wire localization surgical biopsy. It is mandatory that a specimen mammogram be obtained for this type of procedure as well, and unfortunately in this case there were no calcifications visible in the excised breast specimen. Pathology evaluation nonetheless revealed a diagnosis of LCIS (Figure 2).
FIGURE 2 • Biopsy slide revealing LCIS.
Diagnosis and Treatment
The specimen mammography in this case documented a failed wire localization procedure. When this occurs, the surgeon can attempt to “blindly” resect or sample some breast fragments in the biopsy field, but once the wire has been extracted with the initial tissue specimen, it is extremely difficult to obtain an appropriate secondary specimen. Another option is to close the wound and await pathology results, and if these are negative for cancer, then the patient should undergo repeat mammography within the next few weeks (as chosen by the surgeon and patient in this particular case). A decision regarding any additional biopsy attempts would be made based upon the appearance of the follow-up mammogram.
In this patient, the surgical specimen revealed high-risk pathology in the form of LCIS. LCIS is identified in fewer than 5% of otherwise benign breast biopsies and is most commonly detected among women in their forties. It may be found coincidentally with other breast pathology in up to 25% of breast surgical cases. The magnitude of the increased future breast cancer risk for LCIS is approximately 1% per year, and this risk may be higher in women with a positive family history of breast cancer in addition to the LCIS. LCIS is perceived as a microscopic pattern of breast tissue that is present diffusely and bilaterally, but usually without any clinical or radiographic correlate; it therefore tends to be detected as an incidental finding in women undergoing biopsy for some other reason. The future breast cancer risk is expressed equally in terms of laterality, and of those patients who do develop subsequent breast cancer, two-thirds will be diagnosed with ductal histopathology as opposed to invasive lobular cancer. LCIS is therefore a marker of increased risk and not an actual precursor lesion. When LCIS is detected incidentally at the time of lumpectomy for breast cancer, the margins do not need to be free of the LCIS histology.
Because LCIS is a marker of risk for either breast, the management options must address the bilateral breast tissue. These management options include close surveillance/observation alone, chemoprevention with either tamoxifen (appropriate for premenopausal as well as postmenopausal women) or raloxifene (only approved for use in postmenopausal women), or bilateral prophylactic mastectomy. The surveillance options generally include annual or biannual clinical breast exam and annual mammography, and annual breast MRI may be considered as well. Chemoprevention can halve the future breast cancer risk and is usually prescribed for 5 years. Raloxifene may be used in selected postmenopausal women for longer periods if it is indicated in the control of osteoporosis. Premenopausal women must be advised to avoid pregnancy while taking tamoxifen. Both of these selective estrogen receptor modulators are associated with vasomotor symptoms (night sweats, hot flashes), thromboembolic phenomena, and uterine problems. Risk of uterine cancer is relatively greater in postmenopausal women taking tamoxifen. Patients opting for bilateral prophylactic mastectomy should meet with a plastic surgeon to assess their reconstruction options (immediate reconstruction vs. delayed; tissue expander/implant reconstruction versus autologous tissue reconstruction). Axillary staging surgery is not necessary for LCIS patients choosing prophylactic mastectomy.
Atypical hyperplasia (ductal or lobular) represents another high-risk pathology. Future risk of breast cancer is approximately four to five times that of the general female population with benign “usual” fibrocystic hyperplasia, and most of this risk is expressed within the initial 5 to 10 years after diagnosis. In contrast to the LCIS-associated breast cancer risk, atypia is more similar to a true cancer precursor lesion—subsequent breast cancers usually occur at the site where the atypia was identified (especially in cases of atypical ductal hyperplasia).
The patient in the scenario presented in this chapter underwent follow-up mammography imaging 3 months later that was unchanged, and the patient was offered the option of continued observation at that point because of the subtle/indeterminate appearance of her microcalcifications. She opted to undergo bilateral prophylactic with immediate reconstruction. Her final pathology revealed diffuse and bilateral LCIS (as expected) as well as extensive severe atypical ductal hyperplasia. Microcalcifications were identified in areas of atypical hyperplasia and also in areas of benign/usual hyperplasia.
Discussion Points/Special Considerations
Screening Mammography: This patient initiated annual screening mammography at age 40, despite ongoing controversy regarding whether surveillance mammography should begin prior to age 50 years. The American Cancer Society, the American College of Radiology, and the American College of Surgeons continue to advocate in favor of screening mammography beginning at age 40 years. Additional factors in this particular patient that support screening during the fifth decade of life include her positive family history, with breast cancer diagnosed at a young age in a second-degree relative, and her racial–ethnic identity. Lifetime incidence rates for breast cancer are lower for African American women compared to White American women, despite paradoxically higher mortality rates, and African American women have a younger age distribution. For American women younger than 45 years of age, breast cancer incidence rates are higher for African American compared to White American women.
Breast Cancer Risk Assessment: Individualized breast cancer risk is frequently estimated by use of the Gail model, a statistical tool that assesses likelihood of a woman being diagnosed with breast cancer over the following 5 years, and over her lifetime. Conventional thresholds for identifying “high-risk” women are based upon 5-year risk estimate that exceed 1.7%, or lifetime risk estimate >20% to 25%. The Gail model calculates risk probabilities by accounting for first-degree family history of breast cancer; reproductive history (age at menarche, age at first live birth); breast biopsy history (number of prior biopsies and whether or not any prior biopsy revealed atypical hyperplasia). The Gail model may underestimate risk in women with hereditary predisposition, since it does not account for the extended family history or the paternal family history. The Gail model is not indicated for risk assessment in women with a personal history of breast cancer or a documented history of LCIS, as both of these features are associated with an established future new primary breast cancer risk that approximates 1% per year.
TAKE HOME POINTS
· Annual screening mammography in women with a normal breast exam should be initiated at age 40.
· The initial, preferred biopsy approach for a mammographically detected abnormality is via image-guided percutaneous core needle biopsy.
· High-risk pathology detected on needle biopsy specimens (LCIS, atypical hyperplasia) indicates the need for follow-up diagnostic surgical wire localization biopsy. This procedure will reveal coexisting cancer in approximately 15% of cases.
· LCIS is associated with an approximately 1% risk per year of subsequent breast cancer, affecting each breast equally and diffusely. Management options include surveillance (annual clinical breast exam, annual mammography, and possible annual breast MRI); chemoprevention; and bilateral prophylactic mastectomy.
· Atypical ductal hyperplasia is associated with an approximately four- to fivefold increased relative risk of breast cancer, with most of this risk expressed within the first 5 years after diagnosis, and mainly affecting the site where the atypia was detected. Management options include surveillance (as described above) and/or chemoprevention.
SUGGESTED READINGS
Kilbride K, Newman LA. Lobular carcinoma in situ. In: Harris JR, Lippman ME, Morrow M, et al., eds. Diseases of the Breast. 4th ed. Philadelphia, PA: Lippincott, Williams, and Wilkins, 2010.
Newman LA. Surgical management of high risk breast lesions. Probl Gen Surg. 2003;20:99–112.
Saslow D, Boetes C, Burke W, et al. American Cancer Society Guidelines for breast screening with MRI as an adjunct to mammography. CA Cancer J Clin. 2007;57:75–89.
Smith RA, Cokkinides V, Brooks D, et al. Cancer screening in the United States, 2011: a review of current American Cancer Society guidelines and issues in cancer screening. CA Cancer J Clin. 2011;61:8–30.