512828
research-article2013
SJS103310.1177/1457496913512828P. Merkkola-von Schantz, T. Jahkola, A. Carpelan, L. Krogerus, K. Hukkinen, S. KauhanenBreast reduction and histopathology
Original Article
Scandinavian Journal of Surgery 103: 209–214, 2013
Adverse Histopathology and Imaging Findings in Reduction Mammaplasty Day-Surgery Patients P. Merkkola-von Schantz1, T. Jahkola1, A. Carpelan2,3, L. Krogerus4, K. Hukkinen5, S. Kauhanen1 1
Department of Plastic Surgery, Helsinki University Central Hospital, Helsinki, Finland Division of Digestive Surgery and Urology, Turku University Hospital, Turku, Finland 3 Department of Surgery, University of Turku, Turku, Finland 4 Department of Pathology, Helsinki University Central Hospital, Helsinki, Finland 5 Department of Radiology, Helsinki University Central Hospital, Helsinki, Finland 2
Abstract
Background and Aims: Reduction mammaplasty is a popular procedure in plastic surgery. Occasionally, occult invasive breast carcinoma or findings demonstrating increased risk of breast cancer occur in reduction mammaplasty specimens. The incidences have been studied elsewhere, but in Finland, the data on this subject are lacking. Our aim was to analyze the incidence of occult invasive and in situ carcinoma and benign breast disease causing increased risk of breast cancer in reduction mammaplasty specimens. We also analyzed preoperative mammograms and ultrasound images and compared findings with reduction mammaplasty specimens. Material and Methods: We performed a retrospective study of 100 women who underwent reduction mammaplasty during 1 January 2007 to 30 April 2009 in Jorvi Hospital day-surgery unit. Demographic data, findings in preoperative imaging, pathology reports, postoperative follow-up, and retrospective reanalysis of preoperative imaging were recorded. Results: Histological abnormality occurred in 14.6% of the patients. In situ carcinoma was diagnosed in 4.5% of the patients, and findings demonstrating increased risk of breast cancer were diagnosed in 13.5% of the patients. More than one lesion demonstrating increased risk of breast cancer was diagnosed in 4.5% of the patients. No invasive carcinoma occurred. Preoperative mammogram was performed for the majority (94.0%) of the patients. Conclusions: We detected a considerable amount of findings in reduction mammaplasty specimens with prognostic value with regard to future breast cancer risk. We recommend
Correspondence: Päivi Merkkola-von Schantz, M.D. Department of Plastic Surgery Töölö Hospital Helsinki University Central Hospital P.O. Box 266 Helsinki 00029 HUS Finland Email: [email protected]
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histological analysis for reduction mammaplasty specimens and focus attention on systematically performed preoperative imaging. Key words: Reduction mammaplasty, breast cancer, occult cancer, benign breast disease, breast cancer risk, preoperative imaging, histopathology
Introduction Reduction mammaplasty is a frequently performed procedure in plastic surgery. In 2011, 1597 Finnish women underwent reduction mammaplasties in public health-care hospitals (1). Indications for reduction mammaplasty are macromastia causing severe head and neck pain, congenital asymmetry, and contralateral breast symmetrization during or after breast cancer surgery. Breast cancer is the most frequent cancer among women, the lifetime risk in Finland being one in eight women. Thus, it is unsurprising that occult carcinomas are revealed in reduction mammaplasty specimens. The incidence of occult breast carcinoma in reduction mammaplasty specimens has been studied in several countries (2–13). The incidence ranges from 0.05% to 4.0%. The highest incidences are from institutional studies (2, 3), and the lowest are from large population-based studies (4, 5). A literature review by Hassan and Pacifico (6), however, demonstrated variations in study methodologies, inclusion of in situ carcinomas, and what is defined as a relevant breast pathology finding. This discrepancy makes studies difficult to compare. Benign breast disease is typically subdivided into nonproliferative lesions, proliferative lesions without atypia, and atypical hyperplasias (14, 15). Nevertheless, several studies indicate that women with benign breast disease, such as proliferative and atypical lesions, are at higher risk of breast cancer (2, 14–20). In Finland, in general, women undergo regular mammograms due to a comprehensive national breast cancer screening protocol. Mammogram is performed every 2 years for the age group 50–69 years (1). Thus, a low incidence of premalignant and malignant findings in reduction mammaplasty specimens would be expected. This has, however, not been studied to date. This study aims to analyze the incidence of occult invasive carcinomas, in situ carcinomas, and benign breast disease findings with increased risk of breast cancer in reduction mammaplasty specimens. In addition, radiological findings in preoperative mammograms and ultrasound images are studied. When radiological findings occur, we will also describe the measures taken. Material and Methods A total of 101 patients underwent surgery for symptomatic macromastia in Jorvi Hospital day-surgery unit during 1 January 2007 to 30 April 2009. One patient was excluded because of the history of breast carcinoma, giving the total amount of 100 patients. The average age of the patients was 43.9 years (range = 16–64 years).
The retrospective patient material was retrieved from patient records. Descriptive statistics were reported as the mean value and range between minimum and maximum. Demographic data, findings in preoperative mammograms and ultrasound images, pathology reports, postoperative follow-up, and retrospective radiologic reviewing of images were recorded. We categorized abnormal histological findings in reduction mammaplasty specimens based on a consensus statement outlined by the Cancer Committee of the College of American Pathologists in 1985 and incorporated the 1998 consensus statement update (19). Experienced pathologists performed histological evaluation of reduction mammaplasty specimens. After formaline fixation, weighing and examination of specimens were carried out. Reduction mammaplasty specimens were cut into 1-cm slices that were palpated for masses and for areas of increased density. Approximately six to eight blocks were taken from macroscopically suspicious areas and evaluated histologically. Results Radiology
In our study material, a preoperative mammogram was performed in 94.0% of the patients, an ultrasound was performed in 79.0% of the patients, and both imaging methods in 78.0% of the patients (Table 1). Only ultrasound was carried out for one (1.0%) patient. In 5% of the patients, neither of the imaging methods was completed or the information about imaging could not be confirmed. The average age of the patients who did not have preoperative mammogram, ultrasound, or neither of the imaging was 36.2 years (range = 16–64 years), 48.1 years (range = 16–64 years), and 38.2 years (range = 16–64 years), respectively. In two (2.0%) patients, abnormal preoperative imaging led to further examinations. Fine needle biopsy was performed for one of them and core needle biopsy for the other. The results showed no cell atypia and mastopathia chronica, respectively. The average age of the patients who required further workup was 50.5 years. Specimen for Pathology
Reduction mammaplasty specimens from both breasts weighed between 400 and 3119 g (mean = 1168 g). Pathology reports on the reduction mammaplasty specimens were normal or benign in 76 (85.4%) of the patients. The most common diagnosis was mastopathia chronica reported in 44 (49.4%) of the patients. Specimens were not sent for pathologic examination
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Breast reduction and histopathology Table 1 Preoperative imaging.
Table 3 Adverse findings related to patient ages.
Imaging method
Number of patients
%
Age group
≤40
41–50
51–60
≥61
Mammography Ultrasound Mammography and ultrasound No imaging
94 79 78 5
94 79 78 5
Number of patients Number of adverse findings %
32 0 0
27 2 7.4
23 9 39.1
7 2 28.6
Table 2 Patient-related abnormal histological findings. Finding
Number of patients
%
DCIS LCIS Intraductal papilloma ADH ALH Sclerosing adenosis
1 3 3 10 1 1
1.1 3.4 3.4 11.2 1.1 1.1
DCIS: ductal carcinoma in situ; LCIS: lobular carcinoma in situ; ADH: atypical ductal hyperplasia; ALH: atypical lobular hyperplasia. aIn four patients, more than one lesion demonstrating increased risk of cancer was diagnosed.
in 11 (11.0%) of the patients, and the mean age of these patients was 35.6 years (range = 22–59 years). The frequency of histological abnormality was calculated on a patient basis (how many women were affected) and, in addition, among the samples available (89 patients with two samples each giving a total of 178 samples). Histologically Abnormal Findings
In reduction mammaplasty specimens, histologic abnormality occurred in 13 (14.6%) of the patients (Table 2.). The median age of these patients was 55.2 years (range = 45–63 years). In situ carcinoma was diagnosed in four (4.5%) of the patients: ductal carcinoma in situ (DCIS) in one (1.1%) and lobular carcinoma in situ (LCIS) in three (3.4%) of the patients. Breast lesions demonstrating increased risk of breast cancer were diagnosed in 12 (13.5%) of the patients. Atypical ductal hyperplasia (ADH) was diagnosed in 10 (11.2%), atypical lobular hyperplasia (ALH) in one (1.1%), intraductal papilloma in three (3.4%), and sclerosing adenosis in one (1.1%) of the patients. When calculating the frequency of histologic abnormalities among samples available, we found 22 single adverse findings amounting 12.4%. Four (4.5%) patients presented with more than one simultaneous lesion demonstrating increased risk of breast cancer. Three (3.4%) patients had findings in both breasts. Histologically abnormal findings for different age groups are presented in Table 3. The weight of the reduction mammaplasty specimen of the patients with carcinoma in situ findings varied between 230 to 754 g for the right breast and between 291 and 635 g for the left breast. The average age of the patients with carcinoma in situ findings was 52.0 years (range = 45–62 years). In this patient material, reoperation
due to abnormal histological finding was not recommended in any case. Due to increased risk of future carcinoma, however, regular clinical and radiological follow-up was recommended. Retrospective analysis of Preoperative Imaging
Preoperative mammograms of the 13 patients with histologically abnormal findings were retrospectively searched for and seven were retrieved and reanalyzed by an experienced radiologist. Micro-calcifications existed in one of the preoperative mammograms analogous to intraductal papilloma diagnosed histologically (Fig. 1). Preoperative mammograms were negative in six (46.0%) of these patients. Carcinoma in Situ Findings and Radiology
Among patients having neither of the imaging methods completed, histological abnormality occurred in one patient. Pathological evaluation showed both DCIS and ADH in the same breast. All patients diagnosed with LCIS findings showed normal preoperative mammograms. Preoperative ultrasound was completed in only one patient with carcinoma in situ findings, and it appeared normal. Patient with DCIS finding completed neither of the imaging methods. Discussion Our results show that a substantial amount of abnormal histological findings occur in reduction mammaplasty specimens. In the present institutional study, the total incidence of occult in situ carcinoma was 4.5%, whereas no invasive carcinoma occurred. Our results are within the higher end of the range reported in previous studies (2–13), which in part may be explained due to inclusion of in situ carcinomas in our study. In some studies, for example, LCIS results are not included in the cancer findings (6). There has been a debate concerning the role of LCIS as a precursor for breast cancer. Epidemiologic and molecular studies, however, have demonstrated that LCIS is a precursor for invasive cancer and a lesion demonstrating increased risk for ipsi- and contralateral breast cancer (15, 20–22). Benign breast disease is an important predictor of the future risk of cancer development, and the incidence of benign breast lesions was one focus of our study (2, 14–20). According to the categories of the College of American Pathologists, nonproliferative breast lesions do not cause increased risk of breast carcinoma, whereas proliferative breast lesions cause
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Fig. 1. Micro-calcifications analogous to intraductal papilloma diagnosed in reduction mammaplasty specimen.
slightly increased risk (1.5–2.0 times), ADH and ALH cause moderately increased risk (4.0–5.0 times), and DCIS and LCIS markedly increased risk (8.0–10.0 times) of breast carcinoma (19). Altogether, we found histological abnormality in 13 (14.6%) of the patients including the above-mentioned carcinoma in situ findings. Based on the categories of the College of American Pathologists (19), our results show that four (4.5%) of the patients have markedly increased risk (8.0–10.0 times) of breast carcinoma, 11 (12.4%) of the patients have moderately increased risk (4.0–5.0 times), and 4 (4.5%) of the patients have slightly increased risk (1.5–2.0 times) of breast carcinoma. In four patients, more than one lesion demonstrating increased risk of carcinoma occurred at the same time. Other studies have discovered similar risk ratios. Clark et al. (2) categorized reduction mammaplasty tissue samples based on an above-mentioned consensus statement (19) and demonstrated that most of the reduction mammaplasty specimens have abnormal breast tissue. They showed that 13.3% of patients had slightly increased risk and 6.2% of patients had moderately increased risk of breast cancer. In their research, Dupont and Page (14) discovered that women with atypical hyperplasia had 5.3 times the risk of cancer and women with proliferative lesions without atypia had 1.9 times the risk of cancer compared to women with nonproliferative lesions. Hartmann et al. (18) also demonstrated in a follow-up study for a median of 15 years that women with benign breast disease diagnosed by open surgical biopsy had increased risk of breast cancer. They concluded that atypical hyperplasia had a relative risk of 4.24, proliferative disease
without atypia had a relative risk of 1.88, and nonproliferative lesions had a relative risk of 1.27 of breast cancer. According to our results, it seems that despite a thorough breast cancer screening protocol in Finland, a considerable number of abnormal findings occur in reduction mammaplasty specimens. This may be due to the fact that several patients undergoing reduction mammaplasties are of young age, and thus not yet included in the screening protocol. Another explanation could be that histological evaluation of reduction mammaplasty specimens reveals atypia on a cellular level that is not detectable in mammograms. After diagnosing abnormal histological findings in reduction mammaplasty specimens, follow-up is essential due to the known risk of developing invasive breast cancer. In our patient population the risk affected patient follow-up, and clinical and radiological examinations were recommended every two years. Page et al. (15) carried out a follow-up study, where women with ADH or ALH diagnosed in breast biopsy specimens, were followed for approximately 17.5 years. ADH and ALH were diagnosed in 3.6% of the breast biopsy specimens. Overall 12% of women with ADH and 13% of women with ALH developed invasive breast carcinoma and the interval between biopsy and diagnosis of invasive cancer was 8.2 years and 11.9 years, respectively. In some countries, women may opt for chemoprevention to diminish their breast cancer risk. In Finland, chemoprevention has not been recommended for patients with premalignant lesions. Coopey et al. (23) studied the benefit of chemoprevention in women with a diagnosis of atypical breast lesions including ADH, ALH, LCIS, and severe ADH. They reported estimated 10-year cancer risks of 17.3% with ADH, 20.7% with ALH, 23.7% with LCIS, and 26.0% with severe ADH. They concluded that 56.4% of patients with atypical lesions did not have chemoprevention and 11.1% of them developed invasive breast cancer or DCIS at an average follow-up of 68 months. They stated that the risk of breast cancer can be reduced an estimated 50% at 5 years and 65% at 10 years with chemoprevention. In the study by Clark et al. (2), 9.5% of the patients with atypical hyperplasia started selective estrogen modulator therapy with tamoxifen. Based on these studies, in some countries, reduction mammaplasty specimen may lead women to evaluation for chemoprevention of breast cancer. In Finland, preoperative mammogram and breast ultrasound are usually required regardless of patient’s age, but some variations exist among surgeons. The radiologic examinations have to be completed within six months before surgery. Standard use of preoperative imaging is still controversial in the literature. Mammography is variously recommended from the age of 30 years (24), from the age of 40 years (3, 10, 25), or for patients over the age of 50 years (26). Colwell et al. (10) examined the incidence of breast cancer in reduction mammaplasties, and in their study, all patients had preoperative mammograms with negative results. Hage and Karim (25) carried out a study to estimate the occurrence of breast cancer among reduction mammaplasty patients and to evaluate the strategies used by plastic surgeons to detect such
Breast reduction and histopathology
cancer in the Netherlands. They found out that only 3% of the responders routinely required a preoperative mammogram of every patient and 31% never did. Only one responder routinely required preoperative ultrasound and 75% of the responders never did. They advocated that mammography should be performed in all reduction mammaplasty patients aged 40 years or older. Campbell et al. (27) studied the benefit of mammography before reduction mammaplasty. Mammography was completed less than one year before the initial consultation for the operation or between the initial consultation and the surgery. They found out that 16% of the patients had abnormal preoperative mammograms with false positive findings. They also compared findings in breast reduction specimens with mammography findings. Interestingly, incidental discovery of atypical hyperplasia or LCIS lesions was not significantly associated with abnormal preoperative mammographic results. Blansfield et al. (24) retrospectively reviewed reduction mammaplasty patients, of which 10% had proliferative changes. The majority (95%) of proliferative changes were found in patients over 30 years, with a highest portion of patients between ages 30 and 39 years. Preoperative mammogram was performed for 41% of the patients. Based on their study, they recommend routine preoperative mammogram for all patients older than 30 years. Studies have, however, showed that sensitivity of mammography is lower among young women and in dense breasts (28). In addition, Kuhl et al. (29) showed that when comparing mammography and magnetic resonance imaging (MRI) for diagnosing DCIS, 56% of the cases were diagnosed by mammography versus 92% diagnosed by MRI. Almost all the patients in our study had conducted preoperative mammogram, and 78.0% of the patients had conducted both mammogram and ultrasound. Only a small minority had no preoperative imaging. When comparing ages between these groups, our results show that the patients who did not undergo preoperative mammogram and neither mammogram nor ultrasound were younger than the average age of our study population. One reason for this may be that younger patients are treated as low cancer risk patients, and therefore imaging is not performed. There were, however, older patients without imaging as well. In one of them, a notification about performed imaging existed in the patient records, but no data could be retrieved from the hospital database. This focuses attention on the importance of routines in the process of preoperative evaluation of the patients. Furthermore, in our study, the number of patients who needed further examinations due to an abnormal preoperative imaging was low. This differed from the results made by Campbell et al. (27). Our study showed that the majority of patients with abnormal histological findings underwent preoperative mammogram. Retrospective review of radiologic imaging showed findings in only one patient analogous with the histologic finding. The fact that almost half of the preoperative imaging could not be retrieved later from the database may be due to a large number of patients who conduct imaging in the private sector. Patients bring the pictures to the hospital
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at the time of the surgery, but the pictures are not stored in the hospital database. Again, attention is focused on creating standardized preoperative assessment. Histopathologic assessment of reduction mammaplasty specimens is a routine procedure in Helsinki, but variations to this practice exist on a national level. Cook and Fuller (7) demonstrated that microscopic examination of macroscopically normal breast tissue might reveal important pathological findings. They showed that 2.1% of patients who had no macroscopic abnormality within breast tissue had significant pathologic diagnosis. Ambaye et al. (3) used systematic sampling of additional tissue sections to evaluate whether increased sampling would identify more significant pathologic findings. They demonstrated that 12.4% of patients had significant pathological findings (ADH, ALH, LCIS, DCIS, and invasive carcinoma) and 4% of patients had carcinoma findings in reduction mammaplasty specimens. Interestingly, increased tissue sampling was associated with a greater frequency of significant pathologic findings only in patients 40 years and older. We identified abnormal findings in 14.6% of the patients. These patients were over 45 years old, suggesting that in this study material, the significant results were found in older patients. An interesting point of view in Ambaye et al.’s (3) study is that the majority of patients with significant pathologic findings had negative preoperative mammograms within one year preceding surgery, and most of the patients had screening within 6 months. In addition, none of the pathologic findings were detected on preoperative mammogram. They recommended high-risk screening algorithms with close clinical and imaging follow-up for all patients with significant pathologic findings. In our study, histological evaluation of reduction mammaplasty specimens had not been performed in 11 patients. Their average age was markedly lesser than the mean age of the study population. This might be due to surgeons regarding them as low-cancer-risk patients. Still, the oldest patient of this group was 59 years old. The reason for these over-40-year-old patients not to have histology done remains obscure. Due to the substantial amount of abnormal findings in our study, we strongly recommend that pathologists evaluate reduction mammaplasty specimens. This is supported by Degnim et al. (30) who showed that most reduction mammaplasty samples (87.6%) had some histologic abnormality, and proliferative disease with or without atypical hyperplasia was present in 17.0% of reduction mammaplasty tissues. Reduction mammaplasty lowers the subsequent risk of breast cancer (5). Boice et al. (5) showed 28% reduction in breast cancer risk after reduction mammaplasty, and the decreased risk was most evident in women 50 years and older. In women operated before the age of 40 years, the risk was lowered in the long run. Benign breast disease and carcinoma in situ findings are important predictors of the future breast cancer risk (2, 14–20). Although reduction mammaplasty diminishes the risk of cancer, a notable amount of breast tissue is still left after surgery. Therefore, in our opinion, histological evaluation of the reduction mam-
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maplasty specimens is crucial, and based on the pathological diagnosis, analysis of the future breast cancer risk should be made. To the best of our knowledge, this seems to be the first report of incidences of invasive, and in situ carcinoma, and benign breast disease demonstrating increased risk of breast cancer in reduction mammaplasty specimens in Finland. In conclusion, reduction mammaplasty specimens may reveal a substantial amount of important pathological findings that have prognostic value for the patient and can affect the clinical follow-up. Therefore, in our opinion, reduction mammaplasty specimens should be sent for histopathological evaluation. More frequent clinical and radiologic follow-ups, which differed from normal national breast cancer screening protocol, were recommended for patients with abnormal findings. Emphasis should be made on a routine protocol for preoperative diagnostics, and difficult cases should be evaluated by a multidisciplinary team. Acknowledgements We thank Professor Erkki Tukiainen for providing general support for the study.
Declaration of Conflicting Interests None declared.
Funding This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
References 1. National Institute for Health and Welfare. THL Home Page. http://www.thl.fi 2. Clark CJ, Whang S, Paige KT: Incidence of precancerous lesions in breast reduction tissue: A pathologic review of 562 consecutive patients. Plast Reconstr Surg 2009;124:1033–1039. 3. Ambaye AB, MacLennan SE, Goodwin AJ et al: Carcinoma and atypical hyperplasia in reduction mammaplasty: Increased sampling leads to increased detection. A prospective study. Plast Reconstr Surg 2009;124:1386–1392. 4. Tang CL, Brown MH, Levine R et al: Breast cancer found at the time of breast reduction. Plast Reconstr Surg 1999; 103:1682–1686. 5. Boice JD, Jr, Persson I, Brinton LA: Breast cancer following breast reduction surgery in Sweden. Plast Reconstr Surg 2000;106:755–762. 6. Hassan FE, Pacifico MD: Should we be analyzing breast reduction specimens? A systematic analysis of over 1,000 consecutive cases. Aesthetic Plast Surg 2012;36:1105–1113. 7. Cook IS, Fuller CE: Does histopathological examination of breast reduction specimens affect patient management and clinical follow up? J Clin Pathol 2004;57:286–289. 8. Jansen DA, Murphy M, Kind GM et al: Breast cancer in reduction mammoplasty: Case reports and a survey of plastic surgeons. Plast Reconstr Surg 1998;101:361–364. 9. Ishag MT, Bashinsky DY, Beliaeva IV et al: Pathologic findings in reduction mammaplasty specimens. Am J Clin Pathol 2003;120:377–380.
10. Colwell AS, Kukreja J, Breuing KH et al: Occult breast carcinoma in reduction mammaplasty specimens: 14-year experience. Plast Reconstr Surg 2004;113:1984–1988. 11. Kakagia D, Fragia K, Grekou A et al: Reduction mammaplasty specimens and occult breast carcinomas. Eur J Surg Oncol 2005;31:19–21. 12. Slezak S, Bluebond-Langner R: Occult carcinoma in 866 reduction mammaplasties: Preserving the choice of lumpectomy. Plast Reconstr Surg 2011;127:525–530. 13. Freedman BC, Smith SM, Estabrook A et al: Incidence of occult carcinoma and high-risk lesions in mammaplasty specimens. Int J Breast Cancer 2012;2012:145630. 14. Dupont WD, Page DL: Risk factors for breast cancer in women with proliferative breast disease. N Engl J Med 1985;312:146–151. 15. Page DL, Dupont WD, Rogers LW et al: Atypical hyperplastic lesions of the female breast. A long-term follow-up study. Cancer 1985;55:2698–2708. 16. Carter CL, Corle DK, Micozzi MS et al: A prospective study of the development of breast cancer in 16,692 women with benign breast disease. Am J Epidemiol 1988;128:467–477. 17. Dupont WD, Parl FF, Hartmann WH et al: Breast cancer risk associated with proliferative breast disease and atypical hyperplasia. Cancer 1993;71:1258–1265. 18. Hartmann LC, Sellers TA, Frost MH et al: Benign breast disease and the risk of breast cancer. N Engl J Med 2005;353:229–237. 19. Fitzgibbons PL, Henson DE, Hutter RV: Benign breast changes and the risk for subsequent breast cancer: An update of the 1985 consensus statement. Cancer Committee of the College of American Pathologists. Arch Pathol Lab Med 1998;122:1053–1055. 20. Page DL, Schuyler PA, Dupont WD et al: Atypical lobular hyperplasia as a unilateral predictor of breast cancer risk: A retrospective cohort study. Lancet 2003;361:125–129. 21. Lakhani SR, Audretsch W, Cleton-Jensen AM et al: EUSOMA. The management of lobular carcinoma in situ (LCIS). Is LCIS the same as ductal carcinoma in situ (DCIS)? Eur J Cancer 2006;42:2205–2211. 22. Sinn HP, Elsawaf Z, Helmchen B et al: Early breast cancer precursor lesions. Lessons learned from molecular and clinical studies. Breast Care 2010;5:218–226. 23. Coopey SB, Mazzola E, Buckley JM et al: The role of chemoprevention in modifying the risk of breast cancer in women with atypical breast lesions. Breast Cancer Res Treat 2012;136:627–633. 24. Blansfield JA, Kukora JS, Goldhahn RT Jr et al: Suspicious findings in reduction mammaplasty specimens: Review of 182 consecutive patients. Ann Plast Surg 2004;52:126–130. 25. Hage JJ, Karim RB: Risk of breast cancer among reduction mammaplasty patients and the strategies used by plastic surgeons to detect such cancer. Plast Reconstr Surg 2006;117:727–735. 26. Van der Torre PM, Butzelaar RM: Breast cancer and reduction mammoplasty: The role of routine pre-operative mammography. Eur J Surg Oncol 1997;23:341–342. 27. Campbell MJ, Clark CJ, Paige KT: The role of preoperative mammography in women considering reduction mammoplasty: A single institution review of 207 patients. Am J Surg 2010;199:636–640. 28. Saarenmaa I, Salminen T, Geiger U et al: The effect of age and density of the breast on the sensitivity of breast cancer diagnostic by mammography and ultrasonography. Breast Cancer Res Treat 2001;67:117–123. 29. Kuhl CK, Schrading S, Bieling HB et al: MRI for diagnosis of pure ductal carcinoma in situ: A prospective observational study. Lancet 2007;370:485–492. 30. Degnim AC, Visscher DW, Hoskin TL et al: Histologic findings in normal breast tissues: Comparison to reduction mammaplasty and benign breast disease tissues. Breast Cancer Res Treat 2012;133:169–177.
Received: May 26, 2013 Accepted: October 17, 2013
research-article2013
SJS103310.1177/1457496913512828P. Merkkola-von Schantz, T. Jahkola, A. Carpelan, L. Krogerus, K. Hukkinen, S. KauhanenBreast reduction and histopathology
Original Article
Scandinavian Journal of Surgery 103: 209–214, 2013
Adverse Histopathology and Imaging Findings in Reduction Mammaplasty Day-Surgery Patients P. Merkkola-von Schantz1, T. Jahkola1, A. Carpelan2,3, L. Krogerus4, K. Hukkinen5, S. Kauhanen1 1
Department of Plastic Surgery, Helsinki University Central Hospital, Helsinki, Finland Division of Digestive Surgery and Urology, Turku University Hospital, Turku, Finland 3 Department of Surgery, University of Turku, Turku, Finland 4 Department of Pathology, Helsinki University Central Hospital, Helsinki, Finland 5 Department of Radiology, Helsinki University Central Hospital, Helsinki, Finland 2
Abstract
Background and Aims: Reduction mammaplasty is a popular procedure in plastic surgery. Occasionally, occult invasive breast carcinoma or findings demonstrating increased risk of breast cancer occur in reduction mammaplasty specimens. The incidences have been studied elsewhere, but in Finland, the data on this subject are lacking. Our aim was to analyze the incidence of occult invasive and in situ carcinoma and benign breast disease causing increased risk of breast cancer in reduction mammaplasty specimens. We also analyzed preoperative mammograms and ultrasound images and compared findings with reduction mammaplasty specimens. Material and Methods: We performed a retrospective study of 100 women who underwent reduction mammaplasty during 1 January 2007 to 30 April 2009 in Jorvi Hospital day-surgery unit. Demographic data, findings in preoperative imaging, pathology reports, postoperative follow-up, and retrospective reanalysis of preoperative imaging were recorded. Results: Histological abnormality occurred in 14.6% of the patients. In situ carcinoma was diagnosed in 4.5% of the patients, and findings demonstrating increased risk of breast cancer were diagnosed in 13.5% of the patients. More than one lesion demonstrating increased risk of breast cancer was diagnosed in 4.5% of the patients. No invasive carcinoma occurred. Preoperative mammogram was performed for the majority (94.0%) of the patients. Conclusions: We detected a considerable amount of findings in reduction mammaplasty specimens with prognostic value with regard to future breast cancer risk. We recommend
Correspondence: Päivi Merkkola-von Schantz, M.D. Department of Plastic Surgery Töölö Hospital Helsinki University Central Hospital P.O. Box 266 Helsinki 00029 HUS Finland Email: [email protected]
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histological analysis for reduction mammaplasty specimens and focus attention on systematically performed preoperative imaging. Key words: Reduction mammaplasty, breast cancer, occult cancer, benign breast disease, breast cancer risk, preoperative imaging, histopathology
Introduction Reduction mammaplasty is a frequently performed procedure in plastic surgery. In 2011, 1597 Finnish women underwent reduction mammaplasties in public health-care hospitals (1). Indications for reduction mammaplasty are macromastia causing severe head and neck pain, congenital asymmetry, and contralateral breast symmetrization during or after breast cancer surgery. Breast cancer is the most frequent cancer among women, the lifetime risk in Finland being one in eight women. Thus, it is unsurprising that occult carcinomas are revealed in reduction mammaplasty specimens. The incidence of occult breast carcinoma in reduction mammaplasty specimens has been studied in several countries (2–13). The incidence ranges from 0.05% to 4.0%. The highest incidences are from institutional studies (2, 3), and the lowest are from large population-based studies (4, 5). A literature review by Hassan and Pacifico (6), however, demonstrated variations in study methodologies, inclusion of in situ carcinomas, and what is defined as a relevant breast pathology finding. This discrepancy makes studies difficult to compare. Benign breast disease is typically subdivided into nonproliferative lesions, proliferative lesions without atypia, and atypical hyperplasias (14, 15). Nevertheless, several studies indicate that women with benign breast disease, such as proliferative and atypical lesions, are at higher risk of breast cancer (2, 14–20). In Finland, in general, women undergo regular mammograms due to a comprehensive national breast cancer screening protocol. Mammogram is performed every 2 years for the age group 50–69 years (1). Thus, a low incidence of premalignant and malignant findings in reduction mammaplasty specimens would be expected. This has, however, not been studied to date. This study aims to analyze the incidence of occult invasive carcinomas, in situ carcinomas, and benign breast disease findings with increased risk of breast cancer in reduction mammaplasty specimens. In addition, radiological findings in preoperative mammograms and ultrasound images are studied. When radiological findings occur, we will also describe the measures taken. Material and Methods A total of 101 patients underwent surgery for symptomatic macromastia in Jorvi Hospital day-surgery unit during 1 January 2007 to 30 April 2009. One patient was excluded because of the history of breast carcinoma, giving the total amount of 100 patients. The average age of the patients was 43.9 years (range = 16–64 years).
The retrospective patient material was retrieved from patient records. Descriptive statistics were reported as the mean value and range between minimum and maximum. Demographic data, findings in preoperative mammograms and ultrasound images, pathology reports, postoperative follow-up, and retrospective radiologic reviewing of images were recorded. We categorized abnormal histological findings in reduction mammaplasty specimens based on a consensus statement outlined by the Cancer Committee of the College of American Pathologists in 1985 and incorporated the 1998 consensus statement update (19). Experienced pathologists performed histological evaluation of reduction mammaplasty specimens. After formaline fixation, weighing and examination of specimens were carried out. Reduction mammaplasty specimens were cut into 1-cm slices that were palpated for masses and for areas of increased density. Approximately six to eight blocks were taken from macroscopically suspicious areas and evaluated histologically. Results Radiology
In our study material, a preoperative mammogram was performed in 94.0% of the patients, an ultrasound was performed in 79.0% of the patients, and both imaging methods in 78.0% of the patients (Table 1). Only ultrasound was carried out for one (1.0%) patient. In 5% of the patients, neither of the imaging methods was completed or the information about imaging could not be confirmed. The average age of the patients who did not have preoperative mammogram, ultrasound, or neither of the imaging was 36.2 years (range = 16–64 years), 48.1 years (range = 16–64 years), and 38.2 years (range = 16–64 years), respectively. In two (2.0%) patients, abnormal preoperative imaging led to further examinations. Fine needle biopsy was performed for one of them and core needle biopsy for the other. The results showed no cell atypia and mastopathia chronica, respectively. The average age of the patients who required further workup was 50.5 years. Specimen for Pathology
Reduction mammaplasty specimens from both breasts weighed between 400 and 3119 g (mean = 1168 g). Pathology reports on the reduction mammaplasty specimens were normal or benign in 76 (85.4%) of the patients. The most common diagnosis was mastopathia chronica reported in 44 (49.4%) of the patients. Specimens were not sent for pathologic examination
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Breast reduction and histopathology Table 1 Preoperative imaging.
Table 3 Adverse findings related to patient ages.
Imaging method
Number of patients
%
Age group
≤40
41–50
51–60
≥61
Mammography Ultrasound Mammography and ultrasound No imaging
94 79 78 5
94 79 78 5
Number of patients Number of adverse findings %
32 0 0
27 2 7.4
23 9 39.1
7 2 28.6
Table 2 Patient-related abnormal histological findings. Finding
Number of patients
%
DCIS LCIS Intraductal papilloma ADH ALH Sclerosing adenosis
1 3 3 10 1 1
1.1 3.4 3.4 11.2 1.1 1.1
DCIS: ductal carcinoma in situ; LCIS: lobular carcinoma in situ; ADH: atypical ductal hyperplasia; ALH: atypical lobular hyperplasia. aIn four patients, more than one lesion demonstrating increased risk of cancer was diagnosed.
in 11 (11.0%) of the patients, and the mean age of these patients was 35.6 years (range = 22–59 years). The frequency of histological abnormality was calculated on a patient basis (how many women were affected) and, in addition, among the samples available (89 patients with two samples each giving a total of 178 samples). Histologically Abnormal Findings
In reduction mammaplasty specimens, histologic abnormality occurred in 13 (14.6%) of the patients (Table 2.). The median age of these patients was 55.2 years (range = 45–63 years). In situ carcinoma was diagnosed in four (4.5%) of the patients: ductal carcinoma in situ (DCIS) in one (1.1%) and lobular carcinoma in situ (LCIS) in three (3.4%) of the patients. Breast lesions demonstrating increased risk of breast cancer were diagnosed in 12 (13.5%) of the patients. Atypical ductal hyperplasia (ADH) was diagnosed in 10 (11.2%), atypical lobular hyperplasia (ALH) in one (1.1%), intraductal papilloma in three (3.4%), and sclerosing adenosis in one (1.1%) of the patients. When calculating the frequency of histologic abnormalities among samples available, we found 22 single adverse findings amounting 12.4%. Four (4.5%) patients presented with more than one simultaneous lesion demonstrating increased risk of breast cancer. Three (3.4%) patients had findings in both breasts. Histologically abnormal findings for different age groups are presented in Table 3. The weight of the reduction mammaplasty specimen of the patients with carcinoma in situ findings varied between 230 to 754 g for the right breast and between 291 and 635 g for the left breast. The average age of the patients with carcinoma in situ findings was 52.0 years (range = 45–62 years). In this patient material, reoperation
due to abnormal histological finding was not recommended in any case. Due to increased risk of future carcinoma, however, regular clinical and radiological follow-up was recommended. Retrospective analysis of Preoperative Imaging
Preoperative mammograms of the 13 patients with histologically abnormal findings were retrospectively searched for and seven were retrieved and reanalyzed by an experienced radiologist. Micro-calcifications existed in one of the preoperative mammograms analogous to intraductal papilloma diagnosed histologically (Fig. 1). Preoperative mammograms were negative in six (46.0%) of these patients. Carcinoma in Situ Findings and Radiology
Among patients having neither of the imaging methods completed, histological abnormality occurred in one patient. Pathological evaluation showed both DCIS and ADH in the same breast. All patients diagnosed with LCIS findings showed normal preoperative mammograms. Preoperative ultrasound was completed in only one patient with carcinoma in situ findings, and it appeared normal. Patient with DCIS finding completed neither of the imaging methods. Discussion Our results show that a substantial amount of abnormal histological findings occur in reduction mammaplasty specimens. In the present institutional study, the total incidence of occult in situ carcinoma was 4.5%, whereas no invasive carcinoma occurred. Our results are within the higher end of the range reported in previous studies (2–13), which in part may be explained due to inclusion of in situ carcinomas in our study. In some studies, for example, LCIS results are not included in the cancer findings (6). There has been a debate concerning the role of LCIS as a precursor for breast cancer. Epidemiologic and molecular studies, however, have demonstrated that LCIS is a precursor for invasive cancer and a lesion demonstrating increased risk for ipsi- and contralateral breast cancer (15, 20–22). Benign breast disease is an important predictor of the future risk of cancer development, and the incidence of benign breast lesions was one focus of our study (2, 14–20). According to the categories of the College of American Pathologists, nonproliferative breast lesions do not cause increased risk of breast carcinoma, whereas proliferative breast lesions cause
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Fig. 1. Micro-calcifications analogous to intraductal papilloma diagnosed in reduction mammaplasty specimen.
slightly increased risk (1.5–2.0 times), ADH and ALH cause moderately increased risk (4.0–5.0 times), and DCIS and LCIS markedly increased risk (8.0–10.0 times) of breast carcinoma (19). Altogether, we found histological abnormality in 13 (14.6%) of the patients including the above-mentioned carcinoma in situ findings. Based on the categories of the College of American Pathologists (19), our results show that four (4.5%) of the patients have markedly increased risk (8.0–10.0 times) of breast carcinoma, 11 (12.4%) of the patients have moderately increased risk (4.0–5.0 times), and 4 (4.5%) of the patients have slightly increased risk (1.5–2.0 times) of breast carcinoma. In four patients, more than one lesion demonstrating increased risk of carcinoma occurred at the same time. Other studies have discovered similar risk ratios. Clark et al. (2) categorized reduction mammaplasty tissue samples based on an above-mentioned consensus statement (19) and demonstrated that most of the reduction mammaplasty specimens have abnormal breast tissue. They showed that 13.3% of patients had slightly increased risk and 6.2% of patients had moderately increased risk of breast cancer. In their research, Dupont and Page (14) discovered that women with atypical hyperplasia had 5.3 times the risk of cancer and women with proliferative lesions without atypia had 1.9 times the risk of cancer compared to women with nonproliferative lesions. Hartmann et al. (18) also demonstrated in a follow-up study for a median of 15 years that women with benign breast disease diagnosed by open surgical biopsy had increased risk of breast cancer. They concluded that atypical hyperplasia had a relative risk of 4.24, proliferative disease
without atypia had a relative risk of 1.88, and nonproliferative lesions had a relative risk of 1.27 of breast cancer. According to our results, it seems that despite a thorough breast cancer screening protocol in Finland, a considerable number of abnormal findings occur in reduction mammaplasty specimens. This may be due to the fact that several patients undergoing reduction mammaplasties are of young age, and thus not yet included in the screening protocol. Another explanation could be that histological evaluation of reduction mammaplasty specimens reveals atypia on a cellular level that is not detectable in mammograms. After diagnosing abnormal histological findings in reduction mammaplasty specimens, follow-up is essential due to the known risk of developing invasive breast cancer. In our patient population the risk affected patient follow-up, and clinical and radiological examinations were recommended every two years. Page et al. (15) carried out a follow-up study, where women with ADH or ALH diagnosed in breast biopsy specimens, were followed for approximately 17.5 years. ADH and ALH were diagnosed in 3.6% of the breast biopsy specimens. Overall 12% of women with ADH and 13% of women with ALH developed invasive breast carcinoma and the interval between biopsy and diagnosis of invasive cancer was 8.2 years and 11.9 years, respectively. In some countries, women may opt for chemoprevention to diminish their breast cancer risk. In Finland, chemoprevention has not been recommended for patients with premalignant lesions. Coopey et al. (23) studied the benefit of chemoprevention in women with a diagnosis of atypical breast lesions including ADH, ALH, LCIS, and severe ADH. They reported estimated 10-year cancer risks of 17.3% with ADH, 20.7% with ALH, 23.7% with LCIS, and 26.0% with severe ADH. They concluded that 56.4% of patients with atypical lesions did not have chemoprevention and 11.1% of them developed invasive breast cancer or DCIS at an average follow-up of 68 months. They stated that the risk of breast cancer can be reduced an estimated 50% at 5 years and 65% at 10 years with chemoprevention. In the study by Clark et al. (2), 9.5% of the patients with atypical hyperplasia started selective estrogen modulator therapy with tamoxifen. Based on these studies, in some countries, reduction mammaplasty specimen may lead women to evaluation for chemoprevention of breast cancer. In Finland, preoperative mammogram and breast ultrasound are usually required regardless of patient’s age, but some variations exist among surgeons. The radiologic examinations have to be completed within six months before surgery. Standard use of preoperative imaging is still controversial in the literature. Mammography is variously recommended from the age of 30 years (24), from the age of 40 years (3, 10, 25), or for patients over the age of 50 years (26). Colwell et al. (10) examined the incidence of breast cancer in reduction mammaplasties, and in their study, all patients had preoperative mammograms with negative results. Hage and Karim (25) carried out a study to estimate the occurrence of breast cancer among reduction mammaplasty patients and to evaluate the strategies used by plastic surgeons to detect such
Breast reduction and histopathology
cancer in the Netherlands. They found out that only 3% of the responders routinely required a preoperative mammogram of every patient and 31% never did. Only one responder routinely required preoperative ultrasound and 75% of the responders never did. They advocated that mammography should be performed in all reduction mammaplasty patients aged 40 years or older. Campbell et al. (27) studied the benefit of mammography before reduction mammaplasty. Mammography was completed less than one year before the initial consultation for the operation or between the initial consultation and the surgery. They found out that 16% of the patients had abnormal preoperative mammograms with false positive findings. They also compared findings in breast reduction specimens with mammography findings. Interestingly, incidental discovery of atypical hyperplasia or LCIS lesions was not significantly associated with abnormal preoperative mammographic results. Blansfield et al. (24) retrospectively reviewed reduction mammaplasty patients, of which 10% had proliferative changes. The majority (95%) of proliferative changes were found in patients over 30 years, with a highest portion of patients between ages 30 and 39 years. Preoperative mammogram was performed for 41% of the patients. Based on their study, they recommend routine preoperative mammogram for all patients older than 30 years. Studies have, however, showed that sensitivity of mammography is lower among young women and in dense breasts (28). In addition, Kuhl et al. (29) showed that when comparing mammography and magnetic resonance imaging (MRI) for diagnosing DCIS, 56% of the cases were diagnosed by mammography versus 92% diagnosed by MRI. Almost all the patients in our study had conducted preoperative mammogram, and 78.0% of the patients had conducted both mammogram and ultrasound. Only a small minority had no preoperative imaging. When comparing ages between these groups, our results show that the patients who did not undergo preoperative mammogram and neither mammogram nor ultrasound were younger than the average age of our study population. One reason for this may be that younger patients are treated as low cancer risk patients, and therefore imaging is not performed. There were, however, older patients without imaging as well. In one of them, a notification about performed imaging existed in the patient records, but no data could be retrieved from the hospital database. This focuses attention on the importance of routines in the process of preoperative evaluation of the patients. Furthermore, in our study, the number of patients who needed further examinations due to an abnormal preoperative imaging was low. This differed from the results made by Campbell et al. (27). Our study showed that the majority of patients with abnormal histological findings underwent preoperative mammogram. Retrospective review of radiologic imaging showed findings in only one patient analogous with the histologic finding. The fact that almost half of the preoperative imaging could not be retrieved later from the database may be due to a large number of patients who conduct imaging in the private sector. Patients bring the pictures to the hospital
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at the time of the surgery, but the pictures are not stored in the hospital database. Again, attention is focused on creating standardized preoperative assessment. Histopathologic assessment of reduction mammaplasty specimens is a routine procedure in Helsinki, but variations to this practice exist on a national level. Cook and Fuller (7) demonstrated that microscopic examination of macroscopically normal breast tissue might reveal important pathological findings. They showed that 2.1% of patients who had no macroscopic abnormality within breast tissue had significant pathologic diagnosis. Ambaye et al. (3) used systematic sampling of additional tissue sections to evaluate whether increased sampling would identify more significant pathologic findings. They demonstrated that 12.4% of patients had significant pathological findings (ADH, ALH, LCIS, DCIS, and invasive carcinoma) and 4% of patients had carcinoma findings in reduction mammaplasty specimens. Interestingly, increased tissue sampling was associated with a greater frequency of significant pathologic findings only in patients 40 years and older. We identified abnormal findings in 14.6% of the patients. These patients were over 45 years old, suggesting that in this study material, the significant results were found in older patients. An interesting point of view in Ambaye et al.’s (3) study is that the majority of patients with significant pathologic findings had negative preoperative mammograms within one year preceding surgery, and most of the patients had screening within 6 months. In addition, none of the pathologic findings were detected on preoperative mammogram. They recommended high-risk screening algorithms with close clinical and imaging follow-up for all patients with significant pathologic findings. In our study, histological evaluation of reduction mammaplasty specimens had not been performed in 11 patients. Their average age was markedly lesser than the mean age of the study population. This might be due to surgeons regarding them as low-cancer-risk patients. Still, the oldest patient of this group was 59 years old. The reason for these over-40-year-old patients not to have histology done remains obscure. Due to the substantial amount of abnormal findings in our study, we strongly recommend that pathologists evaluate reduction mammaplasty specimens. This is supported by Degnim et al. (30) who showed that most reduction mammaplasty samples (87.6%) had some histologic abnormality, and proliferative disease with or without atypical hyperplasia was present in 17.0% of reduction mammaplasty tissues. Reduction mammaplasty lowers the subsequent risk of breast cancer (5). Boice et al. (5) showed 28% reduction in breast cancer risk after reduction mammaplasty, and the decreased risk was most evident in women 50 years and older. In women operated before the age of 40 years, the risk was lowered in the long run. Benign breast disease and carcinoma in situ findings are important predictors of the future breast cancer risk (2, 14–20). Although reduction mammaplasty diminishes the risk of cancer, a notable amount of breast tissue is still left after surgery. Therefore, in our opinion, histological evaluation of the reduction mam-
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maplasty specimens is crucial, and based on the pathological diagnosis, analysis of the future breast cancer risk should be made. To the best of our knowledge, this seems to be the first report of incidences of invasive, and in situ carcinoma, and benign breast disease demonstrating increased risk of breast cancer in reduction mammaplasty specimens in Finland. In conclusion, reduction mammaplasty specimens may reveal a substantial amount of important pathological findings that have prognostic value for the patient and can affect the clinical follow-up. Therefore, in our opinion, reduction mammaplasty specimens should be sent for histopathological evaluation. More frequent clinical and radiologic follow-ups, which differed from normal national breast cancer screening protocol, were recommended for patients with abnormal findings. Emphasis should be made on a routine protocol for preoperative diagnostics, and difficult cases should be evaluated by a multidisciplinary team. Acknowledgements We thank Professor Erkki Tukiainen for providing general support for the study.
Declaration of Conflicting Interests None declared.
Funding This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
References 1. National Institute for Health and Welfare. THL Home Page. http://www.thl.fi 2. Clark CJ, Whang S, Paige KT: Incidence of precancerous lesions in breast reduction tissue: A pathologic review of 562 consecutive patients. Plast Reconstr Surg 2009;124:1033–1039. 3. Ambaye AB, MacLennan SE, Goodwin AJ et al: Carcinoma and atypical hyperplasia in reduction mammaplasty: Increased sampling leads to increased detection. A prospective study. Plast Reconstr Surg 2009;124:1386–1392. 4. Tang CL, Brown MH, Levine R et al: Breast cancer found at the time of breast reduction. Plast Reconstr Surg 1999; 103:1682–1686. 5. Boice JD, Jr, Persson I, Brinton LA: Breast cancer following breast reduction surgery in Sweden. Plast Reconstr Surg 2000;106:755–762. 6. Hassan FE, Pacifico MD: Should we be analyzing breast reduction specimens? A systematic analysis of over 1,000 consecutive cases. Aesthetic Plast Surg 2012;36:1105–1113. 7. Cook IS, Fuller CE: Does histopathological examination of breast reduction specimens affect patient management and clinical follow up? J Clin Pathol 2004;57:286–289. 8. Jansen DA, Murphy M, Kind GM et al: Breast cancer in reduction mammoplasty: Case reports and a survey of plastic surgeons. Plast Reconstr Surg 1998;101:361–364. 9. Ishag MT, Bashinsky DY, Beliaeva IV et al: Pathologic findings in reduction mammaplasty specimens. Am J Clin Pathol 2003;120:377–380.
10. Colwell AS, Kukreja J, Breuing KH et al: Occult breast carcinoma in reduction mammaplasty specimens: 14-year experience. Plast Reconstr Surg 2004;113:1984–1988. 11. Kakagia D, Fragia K, Grekou A et al: Reduction mammaplasty specimens and occult breast carcinomas. Eur J Surg Oncol 2005;31:19–21. 12. Slezak S, Bluebond-Langner R: Occult carcinoma in 866 reduction mammaplasties: Preserving the choice of lumpectomy. Plast Reconstr Surg 2011;127:525–530. 13. Freedman BC, Smith SM, Estabrook A et al: Incidence of occult carcinoma and high-risk lesions in mammaplasty specimens. Int J Breast Cancer 2012;2012:145630. 14. Dupont WD, Page DL: Risk factors for breast cancer in women with proliferative breast disease. N Engl J Med 1985;312:146–151. 15. Page DL, Dupont WD, Rogers LW et al: Atypical hyperplastic lesions of the female breast. A long-term follow-up study. Cancer 1985;55:2698–2708. 16. Carter CL, Corle DK, Micozzi MS et al: A prospective study of the development of breast cancer in 16,692 women with benign breast disease. Am J Epidemiol 1988;128:467–477. 17. Dupont WD, Parl FF, Hartmann WH et al: Breast cancer risk associated with proliferative breast disease and atypical hyperplasia. Cancer 1993;71:1258–1265. 18. Hartmann LC, Sellers TA, Frost MH et al: Benign breast disease and the risk of breast cancer. N Engl J Med 2005;353:229–237. 19. Fitzgibbons PL, Henson DE, Hutter RV: Benign breast changes and the risk for subsequent breast cancer: An update of the 1985 consensus statement. Cancer Committee of the College of American Pathologists. Arch Pathol Lab Med 1998;122:1053–1055. 20. Page DL, Schuyler PA, Dupont WD et al: Atypical lobular hyperplasia as a unilateral predictor of breast cancer risk: A retrospective cohort study. Lancet 2003;361:125–129. 21. Lakhani SR, Audretsch W, Cleton-Jensen AM et al: EUSOMA. The management of lobular carcinoma in situ (LCIS). Is LCIS the same as ductal carcinoma in situ (DCIS)? Eur J Cancer 2006;42:2205–2211. 22. Sinn HP, Elsawaf Z, Helmchen B et al: Early breast cancer precursor lesions. Lessons learned from molecular and clinical studies. Breast Care 2010;5:218–226. 23. Coopey SB, Mazzola E, Buckley JM et al: The role of chemoprevention in modifying the risk of breast cancer in women with atypical breast lesions. Breast Cancer Res Treat 2012;136:627–633. 24. Blansfield JA, Kukora JS, Goldhahn RT Jr et al: Suspicious findings in reduction mammaplasty specimens: Review of 182 consecutive patients. Ann Plast Surg 2004;52:126–130. 25. Hage JJ, Karim RB: Risk of breast cancer among reduction mammaplasty patients and the strategies used by plastic surgeons to detect such cancer. Plast Reconstr Surg 2006;117:727–735. 26. Van der Torre PM, Butzelaar RM: Breast cancer and reduction mammoplasty: The role of routine pre-operative mammography. Eur J Surg Oncol 1997;23:341–342. 27. Campbell MJ, Clark CJ, Paige KT: The role of preoperative mammography in women considering reduction mammoplasty: A single institution review of 207 patients. Am J Surg 2010;199:636–640. 28. Saarenmaa I, Salminen T, Geiger U et al: The effect of age and density of the breast on the sensitivity of breast cancer diagnostic by mammography and ultrasonography. Breast Cancer Res Treat 2001;67:117–123. 29. Kuhl CK, Schrading S, Bieling HB et al: MRI for diagnosis of pure ductal carcinoma in situ: A prospective observational study. Lancet 2007;370:485–492. 30. Degnim AC, Visscher DW, Hoskin TL et al: Histologic findings in normal breast tissues: Comparison to reduction mammaplasty and benign breast disease tissues. Breast Cancer Res Treat 2012;133:169–177.
Received: May 26, 2013 Accepted: October 17, 2013
