Multicentric mammary carcinoma

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Breast Carcinoma in Women Age 25 Years or Less e read the article by Kothari et al.1 with interest. In this study, 9 of 13 patients with invasive breast carcinoma (69%) experienced disease recurrence and died. Such a high mortality rate indicates the need for the careful selection of both local and adjuvant systemic therapy to maximize the possibility of cure in this very young age group. In the study by Kothari et al.,1 no patients underwent mammography, and only one patient had undergone an ultrasound. Furthermore, two patients had a family history of breast carcinoma, including disease occurring in first-degree relatives. In nearly all patients, the only preoperative diagnostic method used was palpation. However, in the event of a palpable breast mass, we use imaging modalities for several purposes: 1) to define better the nature of the mass, 2) to detect unexpected ipsilateral or contralateral tumors, and 3) to identify a nonpalpable extensive intraductal component to reduce the possibility of recurrence after breastconservation therapy.2 In women age ⬍30 years, ultrasonography is the preferred initial imaging modality for the evaluation of a palpable mass. If ultrasonography identifies a suspicious abnormality, mammography should be performed to identify possible multifocal lesions or an intraductal component of an invasive tumor.2 Preoperative ultrasonography especially improves planning the conservative management of breast carcinoma.3 Moreover, contrast-enhanced magnetic resonance imaging may reveal unsuspected multifocal, multicentric, or contralateral breast carcinoma and result in changes in therapy.4 We cannot understand why Kothari et al. did not use preoperative imaging modalities.

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REFERENCES 1. 2. 3.

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Kothari AS, Beechey-Newman N, D’Arrigo C, et al. Breast carcinoma in women age 25 years or less. Cancer. 2002;94:606 – 614. Bassett LW. Imaging of breast masses. Radiol Clin North Am. 2000;38:669 – 691. Ernst R, Weber A, Bauer KH, Friemann J, Zumtobel V. Significance of sonography of the breast for surgical treatment of breast cancer Zentralbl Chir. 1990;115:963–975. Fischer U, Kopka L, Grabbe E. Breast carcinoma: effect of preoperative contrast-enhanced MR imaging on the therapeutic approach. Eur J Radiol. 1997; 24:11–19.

Selda Tez, M.D. Department of Radiology Fatih University School of Medicine Ankara, Turkey Cenap Dener, M.D. Department of Surgery Fatih University School of Medicine Ankara, Turkey DOI 10.1002/cncr.11112 © 2002 American Cancer Society

Correspondence

Author Reply

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he letter from Tez and Dener nicely summarizes the current radiologic evaluation of young women with a possible mass in the breast. High-frequency ultrasound (12–16 megahertz) is the mainstay of diagnosis and most likely would be offered to the majority of women age ⬍ 25 years who had any clinically detectable discreet mass or area of focal thickening. All 13 patients with invasive breast carcinoma in our study had 1 or other of these palpable abnormalities and at the current time would undergo this type of examination. The value of ultrasound in the large number of women in this age group with no palpable masses on clinical examination but who themselves are convinced that there is a change in their breasts is a debatable one. Conversely, mammography has been shown to be ineffective as a diagnostic modality in very young women.1 In the U.K., there is a tendency to have a slightly higher age minimum of 35 years for routine mammography. However, we agree with Tez and Dener that once the diagnosis has been made, mammography, even in patients as young as 20 –25 years, is a valuable tool with which to exclude the extensive microcalcification associated with ductal carcinoma in situ. The role of magnetic resonance imaging (MRI) in very young women still is being explored. The potentially low specificity of the technique is the main problem, and in this respect it is vital to perform the scan in the week after the cessation of menstrual bleeding. Even then, studies have demonstrated that benign fibroadenomas in younger women share more of the features that are characteristic of malignancy than fibroadenomas occurring in older women.2 The sensitivity and positive predictive value of breast MRI with respect to the differentiation between benign and malignant lesions also may decrease in young women (age ⬍ 40 years vs. ages 40 –50 years).3 It currently is difficult to state how useful breast MRI would be in the group of patients age ⱕ 25 years. The point of our article was to learn more regarding breast carcinoma occurring in very young women (age ⱕ 25 years). In the U.K., these cases are extremely rare, and are reported to occur with a frequency of just 1.2 per 100,000 women. Even in what to our knowledge is one of the largest breast units in the U.K., very few cases have been diagnosed in this age group and we had to include patients from as far back as 1970. We deliberately excluded our very recent cases so that each patient would have meaningful follow-up data and, as a result, our cases spanned a 25-year period from 1970 to 1995. The inevitable problem with this type of historic study is that both diagnostic procedures and treatment are heterogeneous within the

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group and often are very different from current practice. The two imaging modalities that currently would have been used in these patients were either unavailable or far less sophisticated when our patients originally were seen. In theU.K. ultrasound became a routine investigation for breast problems only in the early 1990s and even then was far less sensitive than it currently is because of the low frequency of ultrasound employed. Breast MRI is a relatively new imaging modality and was first performed only in 1993. Our patients appear to be dangerously underinvestigated by current standards but it is important to remember that breast radiology has come a long way in 32 years.

REFERENCES 1.

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Brand IR, Sapherson DA, Brown TS. Breast imaging in women under 35 with symptomatic breast disease. Br J Radiol. 1993;66:394 –397. Hochman MG, Orel SG, Powell CM, Schnall MD, Reynolds CA, White LN. Fibroadenomas: MR imaging appearances with radiologic-histopathologic correlation. Radiology 1997; 204:123–129. Kuhl CK, Klaschik S, Mielcarek P, Gieseke J, Wardelmann E, Schild HH. Do T2-weighted pulse sequences help with the differential diagnosis of enhancing lesions in dynamic breast MRI? J Magn Reson Imaging 1999;9:187–196.

Nicholas Beechey-Newman, M.S. Ashutosh S. Kothari, M.S. Hedley Atkins Breast Unit Department of Academic Oncology Guy’s Hospital London, United Kingdom DOI 10.1002/cncr.11088

Multicentric Mammary Carcinoma Evidence of Monoclonal Proliferation e read with interest the article by Middleton et al.1 in which, by comparing histologic and immunohistochemical features, the authors attempted to evaluate whether multiple, ipsilateral breast tumors arise through intramammary spreading of a single clonal proliferation or are independent primaries arising in the same breast. Based on the phenotypic similarities they found in most cases, the authors suggested that synchronous breast tumors arise through spreading of a single primary breast carcinoma. However, they acknowledge that “future molecular genetic analysis of these multifocal separate tumors ultimately will aid in ascertaining their pathogenesis and biology.” However, such data, acquired both by cytogenetic and molecular genetic means, have already been reported and are already available in the scientific litera-

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CANCER February 1, 2003 / Volume 97 / Number 3

ture. Our group has studied the evolutionary relationship among multiple ipsilateral breast carcinomas by cytogenetic analysis of 37 tumorous lesions from 17 patients.2– 4 At least two macroscopically distinct carcinoma foci were karyotypically abnormal in each of 12 patients, making them informative with regard to the clonal relationship among the breast tumors. Nine of these cases (75%) had an evolutionarily related, cytogenetically abnormal clone in the different tumor lesions from the same breast. This is strong evidence that the dominant mechanism for the origin of multiple ipsilateral breast tumors is intramammary spreading from a single primary neoplasm. In the remaining three informative patients, however, no one clonal chromosome aberration was common to the foci. The disparate nature of the observed karyotypic changes in each focus indicates that the synchronous lesions arose by pathogenetically independent processes within the same breast in these three cases, although we cannot completely disregard the possibility that the karyotypically unique foci could have been related by a shared submicroscopic mutation. The study of the pathogenetic relationship among multiple tumorous breast lesions has also made good use of molecular genetic techniques. Based on an analysis of restriction fragment length polymorphisms of the X-linked phosphoglycerokinase gene and on the random inactivation by methylation early in embryogenesis of one X chromosome in females, Noguchi et al.5 showed that the same X chromosome was inactivated in all foci from each of three patients with unilateral breast carcinoma, indicating that the foci were clonally related. Conversely, Tsuda et al.6 compared the pattern of loss of heterozygosity from 16q among multiple synchronous breast tumors and concluded that in some cases the disparate tumors were clonally related, whereas in other they were independent. The data now available make it possible to use the terms multicentric and multifocal breast carcinoma in a more biologically precise manner. We suggest that the term multicentric breast carcinoma be used only about multiple, clonally independent breast carcinomas, whereas the term multifocal breast carcinoma be reserved for cases where multiple breast tumors have arisen through intramammary dissemination of a single carcinomatous process. The title chosen by Middleton et al,1 would be misleading by this classification, as it links multicentricity with monoclonal proliferation. Because the majority of malignant breast tumors are ductal carcinomas of no special type, the tumor histology in most instances cannot discriminate between multifocal and multicentric carcinomas. Other parameters, such as the location of the foci in different quadrants of the breast or the presence of a carcinoma in situ (CIS) component in

each lesion, have been considered indicators of multicentricity.7 It is nevertheless becoming clear that these morphologic features are insufficient to distinguish between the two pathogenetically different entities. Some cases with carcinoma foci located far apart (6 cm) were nevertheless classified unequivocally as multifocal carcinomas because the same rare karyotypic changes were found in both lesions.4 On the other hand, our cytogenetic findings do not support the equally common notion that the presence of CIS in each lesion is evidence of multicentricity,7 since four of the cases classified as multifocal by the karyotypic data had a CIS component in both foci.4 The data presented by Middleton et al.1 concur with our earlier suggestion, since 72% of their series had CIS in both lesions in spite of the fact that the authors consider them to be biologically related (multicentric in their terminology, multifocal in ours). To explain these findings, Middleton et al.1 proposed that neoplastic cells can spread along the ducts and eventually develop into two invasive carcinoma foci, even in separate quadrants of the breast. This interpretation is supported by the earlier findings of Ohtake et al.,8 who performed a detailed study using stereomicroscopic techniques to generate three-dimensional graphic reconstructions of the mammary ductal systems in 20 patients with breast carcinoma. Intraductal tumor extension was found in 80% of the cases, all of which had continuous and segmental involvement, and in some cases also involving adjacent duct systems. In conclusion, we consider that both multifocality (often) and multicentricity (rarely) exists in breast carcinogenesis and that they call for nomenclature standardization. Morphologic criteria, including the distance between foci and the presence or absence of CIS in each lesion, are inadequate to discriminate between these two biologic entities, something that is better done using the genetic changes of the tumor lesions as clonality markers.

REFERENCES 1.

2.

3.

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Middleton LP, Vlastos G, Mirza NQ, Singletary SE, Sahin AA. Multicentric mammary carcinoma. Evidence of monoclonal proliferation. Cancer. 2002;94:1910-1916. Teixeira MR, Pandis N, Bardi G, et al. Cytogenetic analysis of multifocal breast carcinomas: detection of karyotypically unrelated clones as well as clonal similarities between tumour foci. Br J Cancer. 1994;70:922-927. Pandis N, Teixeira MR, Gerdes AM, et al. Chromosome abnormalities in bilateral breast carcinomas. Cytogenetic evaluation of the clonal origin of multiple primary tumors. Cancer. 1995;76:250-258. Teixeira MR, Pandis N, Bardi G, et al. Discrimination between multicentric and multifocal breast carcinoma by cytogenetic investigation of macroscopically distinct ipsilateral lesions. Genes Chromosomes Cancer. 1997;18:170-174.

Correspondence 5.

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7. 8.

Noguchi S, Aihara T, Koyama H, Motomura K, Inaji H, Imaoka S. Discrimination between multicentric and multifocal carcinomas of the breast through clonal analysis. Cancer. 1994;74:872-877. Tsuda H, Hirohashi S. Identification of multiple breast cancers of multicentric origin by histological observations and distribution of allele loss on chromosome 16q. Cancer Res. 1995;55:3395-3398. Dawson PJ. What is new in our understanding of multifocal breast cancer. Pathol Res Pract. 1993;189:111-116. Ohtake T, Abe R, Kimijima I, et al. Intraductal extension of primary invasive breast carcinoma treated by breast-conservative surgery: computer graph three-dimensional reconstruction of the mammary duct-lobular system. Cancer. 1995;76:32-45.

Manuel R. Teixeira, M.D. Department of Genetics Portuguese Oncology Institute Porto, Portugal Department of Cancer Genetics The Norwegian Radium Hospital Oslo, Norway Nikos Pandis, Ph.D. Department of Genetics Saint Savas Hospital Athens, Greece Sverre Heim, M.D. Department of Cancer Genetics The Norwegian Radium Hospital Oslo, Norway DOI 10.1002/cncr.11109

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e thank the authors for their interest in our manuscript1 and appreciate the opportunity to respond. We correlated morphologic features and immunohistochemical expression in a cohort of patients with T1 and T2 multicentric breast carcinomas to investigate whether these tumors represent intramammary spread of a single clone of tumor cells with similar antigenic expression or multiple independent primary tumors with different phenotypes. Our question was more than an academic exercise, as we re-evaluated the current practice in our institution of performing immunohistochemical analysis on patients’ individual, separate invasive tumors. We found near identical immunohistochemical results in the early multicentric carcinomas we studied, with the prognostic and predictive breast biomarkers supporting the mechanism of clonal growth and/or intramammary spread of a single carcinoma. Contrary to Teixeira et al.’s supposition that we are not aware that molecular and genetic analysis has

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been performed in attempts to further evaluate the pathogenesis and biology of multicentric breast carcinomas, students of this conundrum are faced with a body of disparate molecular literature that supports both clonally derived synchronous tumors and independent primaries. In fact, in their own words, the authors conclude that existing data is limited.2 The suggestion by the authors to use the clinical terminology multicentric only when clonality has been established is not clinically applicable. Various treatment decisions are made daily in patients with multifocal and multicentric breast cancer that could not wait until molecular confirmation of clonality. We agree with Teixeira et al. that the majority of malignant breast tumors are invasive ductal carcinomas, not otherwise specified, and that is why, in addition to tumor classification, we evaluated traditional histologic parameters, including nuclear grade, presence of in situ carcinoma, lymphovascular invasion, and the tumor’s immunohistochemical profile, in attempts to classify whether the tumors in our cohort represented intramammary spread of a clone of tumor cells or multiple independent primaries with different phenotypic expression. These aforementioned morphologic criteria are currently readily available to the practicing pathologist. Our conclusion remains that further study is necessary, and that is why we are in the process of studying our group of multicentric breast carcinomas using available molecular techniques in the quest to understand the genesis of multifocal and multicentric breast neoplasia.

REFERENCES 1.

2.

Middleton LP, Vlastos G, Mirza NQ, Singletary SE, Sahin AA. Multicentric mammary carcinoma: evidence of monoclonal proliferation. Cancer. 2002;94:1910-1916. Teixeira MR, Pandis N, Bardi G, et al. Cytogenetic analysis of multifocal breast carcinomas: detection of karyotypically unrelated clones as well as clonal similarities between tumour foci. Br J Cancer. 1994;70:922-927.

Lavinia P. Middleton, M.D. Department of Pathology The University of Texas M. D. Anderson Cancer Center Houston, Texas S. Eva Singletary, M.D. Department of Surgery The University of Texas M. D. Anderson Cancer Center Houston, Texas Aysegul A. Sahin, M.D. Department of Pathology The University of Texas M. D. Anderson Cancer Center Houston, Texas DOI 10.1002/cncr.11089