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Original Research |
il Günhan-Bilgen1enur Oktay1 Both authors: Department of Radiology, Ege University Hospital, Bornova, Izmir, Turkey 35100-TR.
Received January 20, 2006;
accepted after revision May 30, 2006.
Address correspondence to I. Günhan-Bilgen
(isilbilgen{at}hotmail.com).
Abstract
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MATERIALS AND METHODS. A retrospective review of mammograms of 402 patients who were treated with conservative surgery and radiation therapy between 1987 and 2005 revealed 68 cases of new calcifications (in 66 patients) with follow-up (n = 55) or biopsy (n = 13) results. Analysis included the time between completion of radiation therapy and the appearance of calcifications; location of calcifications relative to the site of the original lesion; the morphology and distribution of calcifications; and changes in number, density, morphology, and rate of change of calcifications.
RESULTS. The median rate of development after lumpectomy was 24 months (range, 6-84 months) for benign and 52 months (range, 20-90 months) for malignant calcifications. In 63 cases (93%), the new calcifications developed in the same quadrant as the primary tumor. None of the calcifications initially interpreted as BI-RADS category 2 (n = 40/68; 59%) and category 3 (n = 19/68; 28%) represented recurrent disease. Nine (13%) of 68 calcifications were initially classified as BI-RADS category 4 or 5; six (67%) of the nine were malignant and three (33%) were benign at biopsy.
CONCLUSION. Newly occurring calcifications in the treated breast are usually benign, and they can be managed conservatively in many cases by using morphology and pattern of distribution as a guide.
Keywords: breast • breast conservation therapy • breast neoplasms • calcifications • mammography
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The purpose of this study was to determine whether the mammographic features (morphology and distribution) of new microcalcifications, the time of their appearance, and the rate of evolution of benign and malignant calcifications that develop in women treated with lumpectomy and radiation therapy can allow differentiation of benign changes from recurrent neoplasm.
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Breast conservation therapy included breast-conserving surgery with axillary lymph node staging followed by radiation therapy with or without systemic therapy. Axillary lymph node staging was made either by lymph node dissection or by sentinel lymph node mapping at the discretion of the surgeon. Residual microcalcifications were excluded before radiation therapy by performing spot compression magnification mammography to show that all preoperatively visible microcalcifications had indeed been removed.
Follow-up mammograms of the treated breast were obtained at 6-month intervals for the first 2 years and annually for the contralateral breast. After the initial 2-year follow-up period, annual bilateral mammograms were obtained. In each patient, questionnaires, physical examination records, mammograms (at the time of diagnosis and of follow-ups), prints of sonograms and records, and histopathologic results were recorded and archived in the mammography unit. The initial and follow-up mammographic findings and histopathologic results were retrospectively analyzed. The research ethics committee of our university did not require its approval or informed consent from patients for this retrospective study. Radiation therapy doses were not readily obtainable in our patient population; therefore, those doses were not correlated with the development of calcifications at the lumpectomy bed.
Mammography in two standard planes of imaging (craniocaudal [CC] and mediolateral oblique [MLO]) was performed with two dedicated mammography units (Senographe 600T Senix HF, GE Healthcare; or Mammomat 3000, Siemens Medical Solutions). During the follow-up period after radiation therapy, spot compression magnification views were obtained at the discretion of the interpreting mammographer—that is, they were available for all cases considered probably benign or suspicious but were not always obtained for cases considered obviously benign. If microcalcifications were considered to be probably benign (BI-RADS category 3), 6-month follow-up mammography was performed with a single-view routine mammogram (CC or MLO) combined with the magnification view.
Retrospective mammographic review was performed as follows: All mammograms of the 402 patients who underwent breast conservation therapy were reviewed by one radiologist. Then mammograms that were considered probably benign or suspicious on the initial interpretation were reviewed in consensus by two radiologists who were experienced in breast imaging. In both of the retrospective mammographic reviews, the radiologists were blinded to knowledge of whether each case did or did not have recurrent cancer.
In our study group, the following mammographic features were analyzed: the presence or absence of new calcifications that developed after surgery and radiation therapy; the time interval between completion of radiation therapy and the appearance of calcifications; the location of calcifications relative to the site of the original lesion; the morphology and distribution of the calcifications; any change in number, density, morphology, and the rate of change in calcifications; and the presence or absence of mammographically depicted calcifications in the primary tumor. Calcifications were classified according to the BI-RADS classification [12]. Using BI-RADS terminology, morphology of calcifications was classified as coarse, dystrophic; linear; punctate; or pleomorphic. Distribution of microcalcifications was classified as clustered (grouped), linear, segmental, or regional. Calcifications were given a mammographic decision of benign (BI-RADS category 2), probably benign (BI-RADS category 3), indeterminate and requiring biopsy (BI-RADS category 4), or malignant in appearance (BI-RADS category 5). The site of recurrence was recorded with respect to the original tumor and specified as at the surgical site, within the original quadrant, or elsewhere in the treated breast. Records were also reviewed for the pathologic features of the initial tumor and the final outcome of the newly developed calcifications.
In 13 patients, the microcalcifications were preoperatively located by the mammographically guided needle-wire localization system and were surgically excised.
Finally, the mammographic findings were correlated with the histopathologic results obtained from surgical pathology reports.
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Sixty-three (93%) of the 68 newly developed calcifications were in the same quadrant as the primary tumor, and 6% (4/63) of these calcifications represented recurrence. In one patient, the primary tumor, which manifested with segmental pleomorphic calcifications in the upper outer quadrant, was diagnosed as comedo-type ductal carcinoma in situ (DCIS). After 90 months of disease-free imaging results, pleomorphic calcifications in the lower quadrant developed, and histopathologic examination disclosed infiltrating ductal carcinoma with an extensive intraductal component. In another patient, 20 months after breast conservation therapy for an upper outer quadrant mass (infiltrating ductal carcinoma), microcalcifications that developed in the upper inner quadrant were excised and diagnosed as microinvasive ductal carcinoma. In the other three patients who developed new calcifications in different quadrants from the original tumor, the calcifications were typically of the coarse, dystrophic type (BI-RADS category 2).
Forty (59%) of 68 cases of calcifications clearly showed coarse, dystrophic morphology and were initially interpreted as BI-RADS category 2. All of these patients were disease-free at a mean follow-up of 60 months (range, 24-108 months).
Nineteen (28%) of 68 cases of calcifications were initially interpreted as BI-RADS category 3. Morphologic characteristics and the pattern of distribution of these calcifications are summarized in Table 1. Twelve (63%) of 19 calcifications were downgraded to BI-RADS category 2 at a mean follow-up of 18 months (range, 6-30 months) on the basis of stability (n = 3) or increasingly coarse morphology (n = 9) (Fig. 1A, 1B). In one patient, the microcalcifications resolved in 18 months. In another patient, the microcalcifications increased in number in 12 months, but on magnification view they showed dystrophic morphology with radiolucent centers, and the patient was disease-free at her 5-year follow-up.
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Five of 19 cases of calcifications were upgraded to BI-RADS category 4. In one patient with increasing pleomorphism at the 6-month follow-up, biopsy disclosed atypical ductal hyperplasia. In two patients, the microcalcifications increased in number by the 6-month follow-up, thus mandating biopsy, in which the specimen revealed fat necrosis (Fig. 2). In two patients, the microcalcifications, which were initially very faint, increased in density (became prominent without a change in number or shape) by the 12- and 6-month follow-ups. In the first, fibrocystic changes and dystrophic calcifications were diagnosed at biopsy. In the second, biopsy was recommended but could not be performed because of severe cardiovascular problems; the patient was disease-free at her 2-year follow-up.
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Nine (13%) of 68 cases of calcifications were initially interpreted as BI-RADS category 4 or 5, all with suspicious morphology and distribution detailed in Table 1. Histopathologic examination of these nine patients showed two fat necroses (Fig. 3), one sclerosing adenosis and dystrophic calcifications, three DCIS (Fig. 4), two ductal carcinomas with microinvasion, and one infiltrating ductal carcinoma with an extensive intraductal component. The six cases with tumor recurrence are detailed in Table 2.
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On the basis of morphology, no cases with coarse, dystrophic calcifications represented disease recurrence. All calcifications representing local tumor recurrence showed pleomorphism and clustered linear or regional distribution on initial presentation (n =6). Four (40%) of 10 cases (one of the four developed pleomorphism at follow-up) with pleomorphic microcalcifications represented benign disease (two fat necrosis, one sclerosing adenosis, one atypical ductal hyperplasia) at biopsy.
The primary tumors were DCIS in nine, infiltrating ductal carcinoma in 30, infiltrating lobular carcinoma in 14, medullary carcinoma in nine, microinvasive papillary carcinoma in one, glycogen-rich carcinoma in one, and tubular carcinoma in two patients. None of the primary tumors had an extensive intraductal component. The primary tumors of the six recurrences in this study were DCIS (n = 4) and infiltrating ductal carcinoma (n = 2). Seventeen (26%) of the 66 patients had calcifications associated with their original tumor (six DCIS, 11 infiltrating ductal carcinoma). Of these 17 patients, five (29%) developed a recurrence manifested with microcalcifications. Five (83%) of the six patients with newly developed histopathologically proven malignant microcalcifications had calcifications associated with their primary tumor (five isolated microcalcifications and one mass associated with a few microcalcifications).
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It is common for new calcifications to occur at the site of the tumor excision in patients treated with breast conservation therapy. Mendelson [14] reported new calcifications in 28% of 110 patients treated by breast conservation therapy. In our series, this rate was 16% in 402 patients. New microcalcifications in a breast previously treated for carcinoma may be thought to represent recurrent or new breast carcinoma, but these calcifications are frequently benign [15, 16]. In women in whom suspicious microcalcifications develop after treatment with breast conservation therapy and radiation therapy, benign disease has been reported to be 42%, 50%, and 85%, in series of 19, 45, and 51 patients, by Solin et al. [10], Stomper et al. [5], and Giess et al. [7], respectively. In our study, the rate of benign calcifications was higher (91%) than in most studies in the literature, probably because the criteria for inclusion in the study were different in our study compared with previous studies. That is, in two previous studies [5, 10], posttreatment mammograms were studied in only those patients who underwent biopsy of an irradiated breast for suspected local recurrence. In our study, similar to that of Giess et al. [7], all patients who developed new calcifications at the lumpectomy site and who had follow-up or biopsy results were included.
Calcifications are the most important marker of new or recurrent breast carcinoma. In the series by Stomper et al. [5], 43% of the mammographically detected recurrences were manifested by microcalcifications. The positive predictive value for local tumor recurrence of new microcalcifications without an associated mass in the conservatively treated breast ranges from 33% to 100% in various studies [1, 5, 7-11, 17]. In our study, the positive predictive value was 46% (6/13). This finding is in contrast to the positive biopsy rate for microcalcifications in the nonirradiated breast, which has been reported to be 14-46% in multiple series [18-22].
In evaluating calcifications at the lumpectomy site, radiologists should apply the same morphologic and distributional features used preoperatively to rate the probability of malignancy [16]. Morphology of new microcalcifications has been referred to in several studies, although without strict classification of morphologic criteria. More coarse, classically benign calcifications frequently are seen in irradiated breasts [15]. These may be linear or round calcifications and are readily differentiated from those fine, irregular calcifications that suggest new or recurrent tumor [6, 23, 24]. Just as formation of these coarse calcifications may be related to irradiation, fine, dystrophic calcifications may also result from therapy [6]. When their pattern is compared with the pattern of calcifications seen in women who had recurrent tumor, irregular linear or branching microcalcifications appear to herald recurrence, whereas punctate calcifications are associated with dystrophic change [15].
In the study by Dershaw et al. [13], the patterns of calcifications associated with tumor recurrence were more than 10 calcifications (77%), linear (68%), pleomorphic (77%), clustered (73%), and segmental (18%). In their study, recurrences were usually (77%) highly suspicious (BI-RADS category 5) with pleomorphism, irregularity, and small size. The punctate and coarse forms, when not associated with more worrisome patterns of calcification, were not found in association with recurrent tumor, and patients with this pattern were spared further biopsy [13]. In a study by Orel et al. [11], mammograms were considered suspicious for recurrence if there were new, nondystrophic calcifications, with 76% of positive mammograms in patients with recurrence showing new calcifications. In the study by Solin et al. [10], 12 of 16 recurrences showed calcifications meeting accepted criteria for biopsy.
In our study, 66 of 402 patients (with a total of 68 cases of new calcifications) developed calcifications. Of those, 13 patients (19%) had malignant or indeterminate calcifications and underwent biopsy. Six biopsies (46%) of microcalcifications were positive for malignancy. All of our recurrences showed pleomorphic (100%) morphology with either clustered (66%), linear (17%), or regional (17%) distribution. No cases of calcifications with benign (BI-RADS category 2) or probably benign (BI-RADS category 3) morphology represented recurrent disease.
The time elapsed between the completion of therapy for the original tumor and the appearance of new findings on mammography may also be helpful in differentiating benign from recurrent malignant tumors. This issue has been addressed by several authors, with Dershaw et al. [15] and Giess et al. [7] reporting benign calcifications developing earlier and Rebner et al. [1] reporting them developing later than malignant calcifications. Most studies assign a low probability of malignancy to calcifications that occur soon (6-18 months) after the surgery and radiation therapy [25]. In our results, the median time of development of benign calcifications was earlier than that of malignant ones. Although the time course may not always be reliable, it serves as a reasonable guide to interpret alterations in the mammographic appearance, with early changes often being benign [16]. Our results also support the recommendation by Giess et al. [7] that short-interval mammographic follow-up of BI-RADS category 3 calcifications is useful because most calcifications considered probably benign evolve to more suspicious or benign morphology at short-interval mammographic follow-up.
The development of fat necrosis or postirradiation dystrophic calcifications invariably occurs at the site of the original tumor; when these events occur elsewhere in the breast, they are more suggestive of malignant tumor [3, 10]. However, in our study, during their follow-up period three patients developed typically coarse, dystrophic type calcifications in different breast quadrants from the original tumor. Because most recurrences are at the primary site, adequate imaging of this area of the breast is important. If radiopaque marking clips were not already placed by the surgeon in the tumor bed at the time of the excisional biopsy, the location of the primary tumor site is aided by placement of a wire marker over the biopsy scar during the initial posttreatment mammogram and by correlation with prebiopsy films that show the primary tumor [5].
Magnification views can be helpful and are recommended selectively in patients in whom new mammographic findings have developed [25]. Our study supports the concept that the greatest impact of magnification mammography is on better determination of the extent of distribution and better definition of equivocal findings originally seen on conventional views [26, 27].
Dershaw et al. [13] believe that it is inappropriate to perform a biopsy in a woman with a pattern of calcifications that would be considered benign in other women, even when the calcifications are new. In addition, when indeterminate calcifications (BI-RADS category 4) form in these women, they suggest further evaluation with techniques other than surgical biopsy, such as core biopsy or MRI, because of the low incidence of the association of these types of calcifications with recurrence. Although preoperative core biopsy of the calcifications would be the preferred recommendation, in our study group all suspicious microcalcifications underwent surgery without core biopsy because a vacuum-assisted stereotactic biopsy system was not available.
The histopathology report of the primary tumor is important because the expectation of recurrence is higher after excision of invasive carcinoma with extensive intraductal carcinoma or with large areas of comedocarcinoma [16, 28]. In our study group, none of the primary tumors had an extensive intraductal component. However, the presence or absence of microcalcifications in the original tumor influenced our interpretation of new microcalcifications after treatment. Although Philpotts et al. [29] reported a similar mammographic appearance for primary and locally recurrent tumor in most cases, Giess et al. [30] found that this similarity varied with histopathology. Solin et al. [10] also found no correlation between microcalcifications in the original tumor and the cause of new calcifications at the lumpectomy bed. In our study, 83% (5/6) of the recurrences had calcifications associated with the primary tumor.
In conclusion, newly occurring calcifications in the treated breast are usually benign, and they can be managed conservatively in many cases by using morphology and distribution pattern as a guide. Although benign calcifications usually develop sooner than malignant calcifications, the time of onset cannot reliably be used as a guide because of the overlapping times of development of malignant and benign calcifications. Accuracy of interpretation is furthered by familiarity with the clinical background and careful review of sequential studies and magnification radiography of the lumpectomy site and other areas in which calcifications are suspected. It is particularly important to avoid biopsy of BI-RADS category 3 type microcalcifications in the irradiated breast because that may compromise the cosmetic result of breast conservation therapy.
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