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ORIGINAL ARTICLE Journal of Breast Cancer J Breast Cancer 2009 March; 12(1): 47-53 DOI: 1048/jbc.2009.12.1.47 수질성유방암의임상병리학적특성과예후 오재원 1 ㆍ박세호 1 ㆍ김주희 1 ㆍ구자승 2 ㆍ허호 1 ㆍ양우익 2,3 ㆍ박병우 1,3 ㆍ이경식 1 1 연세대학교의과대학외과학교실 2 병리학교실 3 BK21 project Clinical Analysis of Medullary Carcinoma of the Breast Jae-Won Oh 1, Seho Park 1, Joo-Hee Kim 1, Ja-Seung Koo 2, Ho Hur 1, Woo-Ick Yang 2,3, Byeong-Woo Park 1,3, Kyong-Sik Lee 1 Departments of 1 Surgery and 2 Pathology, 3 Brain Korea 21 Project, Yonsei University College of Medicine, Seoul, Korea Purpose: Medullary carcinoma of the breast is a variant of breast cancer characterized by the histologic appearance of poorly differentiated cells surrounded by a prominent lymphoid stroma. Medullary carcinoma has been reported to carry a prognosis better than other invasive breast carcinomas, but it is frequently overdiagnosed due to the difficulty in diagnosis. The aim of this study was to assess the clinical manifestations and outcome of medullary carcinoma of the breast. Methods: We reviewed the data of 91 patients diagnosed with medullary carcinoma and 3,743 patients with invasive ductal carcinoma, not otherwise specified (NOS) from January 1980 to December 2005 at Yonsei University Severance Hospital. The clinicopathologic features, disease free survival (DFS) and overall survival (OS) for patients with medullary carcinoma were compared with those of the NOS patients. Results: With reviewing the pathologic slides, 69 (75.8%) patients had findings compatible with typical medullary carcinoma (TMC) and the remaining 22 (24.2%) patients were reclassified as atypical medullary carcinoma (AMC). Early stage cancer was more frequent at medullary carcinoma and lymph node positive cancer was less frequent at medullary carcinoma. The expression of ER/PR was positive in either the TMC (18.9%/16.2%) and AMC (15.0%/2%) as compared to the NOS (63.2%/57.2%), and the difference was significant (p<01). In contrast, the HER-2/neu expression rate was significantly higher in the TMC (47.4%) and AMC (45.5%) than in the NOS (28.3%, p=01). The 10- year disease free survival and 10-year overall survival of the atypical medullary carcinoma patients (67.8%, 77.8%) were in fact similar to the NOS carcinoma patients (68.3%, 74.7%). There was significant difference in 10-year disease free survival and 10-year overall survival between the TMC (77.8%, 86.0%) and NOS carcinoma (68.3%, 74.7%) patients (p=02, p=06). Conclusion: The clinical outcome of typical medullary carcinoma is favorable in spite of its aggressive pathologic features and it differs from atypical medullary carcinoma. For precise prediction of prognosis of medullary cancer, we should apply strict criteria for the diagnosis of subtype with medullary features. Key Words: Invasive ductal carcinoma, Medullary carcinoma of the breast 중심단어 : 침윤성유관암, 수질성유방암 서 수질성유방암은합포체양상으로자라고, 단핵세포침윤등의특 책임저자 : 박병우 120-752 서울시서대문구신촌동 134, 연세대학교의과대학외과 Tel: 02-2228-2100, Fax: 02-313-8289 E-mail: bwpark@yumc.yonsei.ac.kr 접수일 : 2008년 6월 16 일게재승인일 : 2008년 11월 13일 * 본논문은 2006년춘계한국유방암학회에서구연되었음. * 본연구는 Brain Korea 21 project의지원및ㄜ동아제약, ㄜ노바티스, ㄜ아스트라제네카, ㄜ릴리의지원으로이루어졌음. 론 징적인조직학적특징을갖는유방암의하나이다. 1945년 Moore 와 Foote는간질에림프구침윤이있으며경계가매우좋은유방암으로기술하였고, 발생률은전체유방암의 1-7% 정도로보고되고있다.(1-3) 수질성유방암은일반적으로양호한예후인자로알려진호르몬수용체의발현이적고, 높은핵등급과조직학적등급을갖는것으로알려져있지만예후에있어서는다른침윤성유방암에비해양호한것으로알려져있다.(4-6) 하지만 Fisher 등 (7) 과 Ellis 등 (8) 은수질성유방암이다른침윤성유방암에비해예후에있어크게유리하지않다고하였으며이러한차이는수질 47

48 Jae-Won Oh, et al. 성유방암의진단기준의차이에기인한것으로생각된다. 따라서예후의정확한예측을위해수질암에대한엄격한진단기준의중요성이강조되게되었다.(9,10) 유방암의조직학적진단은재현성이높고예후에있어서동일한결과를나타낼수있어야하지만초기수질성유방암의진단에있어연구자에따라차이가있었으며, Fisher 등 (11) 과 Ridolfi 등 (3) 의진단기준을사용했을때검사자간진단의재현성이일치하지않는문제점이있어,(12) 보다단순화된진단기준들이제시되기도하였지만,(9,10,13) 현재까지도예후를가장잘대변하는것으로알려진 1977년 Ridolfi 등 (3) 에의해제안된진단기준이널리사용되고있다. 저자들은과거수질성유방암으로진단된환자의병리조직슬라이드를 Ridolfi 등 (3) 의진단기준에의거하여전형적수질성유방암과, 비전형적수질성유방암으로구분하여각각의임상병리학적특성과예후를침윤성유관암 (Not Otherwise Specified, NOS) 과비교하였다. 방법 1. 대상환자 1980년 1월에서 2005년 12월까지연세대학교의과대학세브란스병원에서유방암으로수술받은환자는 4,601명이었으며이들을침윤성유관암 (NOS, 3743), 수질성유방암과기타 ( 남성유방암, 비침윤성유방암, 특수형유방암등 ) 로분류하여기타를제외하고연구를시행하였다. 대상환자중수질성유방암으로진단받은환자는총 91 명이었으며전체의 2.4% 에해당하였다. 전형적수질성유방암과비전형적수질성유방암의분류는 Ridolfi 등 (3) 의진단기준 (Table 1) 에근거하였다. 평균추적관찰기간은 73 개월이었으며의무기록을토대로진단당시나이, 종괴의크기, TNM 병기, 액와림프절전이, 수술방법, 호르몬수용체발현유무, HER2/neu 발현, 수술후보조치료방법및생존율에대해후향적으로연구를시행하였으며병기 IV 인침윤성유관암 36 명은생존율분석에서제외하였다. 2. 면역조직화학적염색의판정호르몬수용체발현유무의판정은면역조직화학적염색상 1-10% 염색정도를보이는등급 2 이상을양성으로정하였으며, Ligand-binding assay가시행되었던 1994년이전의결과는 3 fmol/mg protein 이상일경우를양성으로정하였다. HER2/ neu 의양성판정은면역조직화학적염색에의한염색정도의점수가 3+ 인경우만을양성으로정하였다. 3. 통계학적분석분석처리는 SPSS (version 12.0) 를사용하였으며, t-test와 chi-square test를이용하여유의성을분석하였고, 생존율의분석은 Kaplan-Meier curve을이용하였고 log-rank method를이용하여유의확률을비교하였다. p-value가 5 미만일경우통계학적의미가있는것으로정의하였다. 결과 1. 병리학적재검수질성유방암으로진단되었던환자의조직슬라이드를 Ridolfi 등 (3) 의진단기준 (Table 1) 에기준하여재검하였고전형적수질성유방암은총 91 예중 69 명 (75.8%) 이었으며, 비전형적수질성유방암은 22 예 (24.2%) 였다. 합포체형성이 75% 미만인핵분화도가나쁜저분화성침윤성유관암을수질성유방암으로진단한예는없었다. 2. 임상및병리학적특성전형적수질성유방암, 비전형적수질성유방암, 침윤성유관암세군간의연령은침윤성유관암군에서 47.6세로가장높았지만통계학적으로유의한차이는없었다. 종양의크기와, 수술방법에있어서도세군간에차이가없었다. 유방암에서림프절전이의빈도는전형적수질성유방암에서 21.7%, 비전형적수질성유방암에서 31.8%, 침윤성유관암에서 48.1% 로유의한차이가있었다 (p< Table 1. Histologic criteria for classification of medullary carcinoma of the breast* Typical medullary carcinoma Predominent syncytial growth pattern (>75% of tumor area) Completely circumscribed with pushing margins Moderate to marked mononuclear infiltrate in supporting and surrounding stroma Grade 2 or 3 nuclei No intraductal component No microglandular differentiation Atypical medullary carcinoma Predominent syncytial growth pattern (>75% of tumor area) Infiltrative margins Spare or only peripheral mononuclear infiltrate Grade 1 nuclei Presence of intraductal component Presence microglandular features *adapted from Ridolfi et al.(3)

Clinical Analysis of Medullary Breast Carcinoma 49 01). TNM 병기는수질성유방암에서 1기 2기조기유방암이침윤성유관암에비해많았다 (p=02). 에스트로겐수용체와프로게스테론수용체의경우전형적수질성유방암에서 18.9% 와 16.2% 였으며, 비전형적수질성유방암에서 15.0%, 2% 의양성률을보였고, 침윤성유관암에서 63.2%, 57.2% 로나타나수질성유방암과침윤성유관암사이에의미있는차이가있었다 (p<01). HER2/neu 발현은전형적수질성유방암과비전형적수질성유방암에서 47.4%, 45.5% 로침윤성유관암에서의 28.3% 에비해 Table 2. Clinicopathologic characteristics TMC (%) AMC (%) IDC (%) p-value Number of patients 69 22 3,743 Mean age (range) 46.7 (25-76) 46.9 (30-73) 47.6 (20-93) 0.395 Age (yr) <35 16 (23.2) 4 (18.2) 774 (20.7) 41 35 53 (76.8) 18 (81.8) 2,968 (79.3) Tumor size T1 30 (43.5) 4 (18.2) 1,551 (41.4) 26 T2 35 (50.7) 17 (77.3) 1,900 (5) T3 4 (5.8) 1 (4.5) 207 (5.5) T4 84 (2.3) TNM stage I 24 (34.8) 2 (9.1) 1,071 (28.7) 02 II 41 (59.4) 18 (81.8) 1,738 (46.5) III 4 (5.8) 2 (9.1) 892 (23.8) IV 36 () Node status Negative 54 (78.3) 15 (68.2) 1,937 (51.9) <01 Positive 15 (21.7) 7 (31.8) 1,798 (48.1) Surgery BCS 16 (23.2) 4 (18.2) 774 (20.7) 41 RM 53 (76.8) 18 (81.8) 2,968 (79.3) ER receptor Negative 30 (81.1) 17 (85.0) 1,067 (36.8) <01 Positive 7 (18.9) 3 (15.0) 1,833 (63.2) PR receptor Negative 31 (83.8) 16 (8) 1,212 (42.8) <01 Positive 6 (16.2) 4 (2) 1,622 (57.2) HER2 Negative 10 (52.6) 6 (54.5) 1,387 (71.7) 01 Positive 9 (47.4) 5 (45.5) 547 (28.3) CTx Not done 33 (5) 3 (14.3) 996 (27.6) <01 Done 32 (49.2) 18 (85.7) 2,618 (72.4) HRTx Not done 54 (84.4) 16 (76.2) 1,642 (46.7) <01 Done 10 (15.6) 5 (23.8) 1,874 (53.3) RTx Not done 44 (68.8) 16 (8) 2,199 (62.7) 39 Done 20 (31.2) 4 (2) 1,306 (37.3) TMC=typical medullary carcinoma; AMC=atypical medullary carcinoma; IDC=invasive ductal carcinoma; ER=estrogen; PR=progesterone; CTx=chemotherapy; HRTx=hormonal therapy; RTx=radiation therapy. 높게나타났다 (p=01). 수술후호르몬치료는호르몬수용체양성이상대적으로많았던침윤성유관암에서많이시행되었으며, 항암치료도침윤성유관암군에서좀더많이시행된것으로조사되었다 (p<01, Table 2). 3. 생존율분석 1) 무병생존율 5 년, 10 년무병생존율은전형적수질성유방암이 85.4%, 77.8% 를보였으며비전형적수질성유방암은 75.3%, 67.8% 를침윤성유관암은 77.6%, 68.3% 의생존율을각각보여전형적수질성유방암과침윤성유관암사이에는생존율의차이가있었지만 (p= 02), 비전형적수질성유방암과침윤성유관암과는의미있는차이가없었다 (p=0.117, Figure 1). p=019 Figure 1. Comparison of disease-free survival curve between medullary subtype and infiltrating ductal carcinoma. TMC=typical medullary carcinoma; AMC=atypical medullary carcinoma; IDC=invasive ductal carcinoma. p=059 Figure 2. Comparison of overall survival curve between medullary subtype and infiltrating ductal carcinoma. TMC=typical medullary carcinoma; AMC=atypical medullary carcinoma; IDC=invasive ductal carcinoma.

50 Jae-Won Oh, et al. Table 3. Prognostic significance of clinicopathologic variables of TMC Variable DFS p-value Age (<35 vs. 35 ) 08 0.543 Tumor size ( 2 cm vs. >2 cm) 89 65 Nodal status (+/-) 42 45 ER (+/-) 0.587 0.597 PR (+/-) 0.511 0.588 Chemotherapy (Not done/done) 0.762 92 Hormonal therapy (Not done/done) 79 0.368 Radiation therapy (Not done/done) 0.516 95 TMC=typical medullary carcinoma; DFS=disease free survival; OS= overall survival; ER=estrogen receptor; PR=progesterone receptor. OS 2) 전체생존율 5 년, 10 년누적생존율은전형적수질성유방암이 90.7%, 86.0% 를보였으며비전형적수질성유방암은 84.9%, 77.8% 를침윤성유관암은 80.5%, 74.7% 의생존율을각각보여전형적수질성유방암과침윤성유관암사이에는생존율의차이를관찰할수있었으나 (p=06), 비전형적수질성유방암과침윤성유관암사이에는차이가없었다 (p=0.314, Figure 2). 3) 병기별생존율의비교 TNM 병기 1기와 3기의경우는생존율에있어통계학적차이를보이지않았지만병기 2기에서는전형적수질성유방암과침윤성유관암사이에의미있는무병생존율과전체생존율의차이를 TNM stage=i TNM stage=ii TNM stage=iii p=0.3874 0 1 3 p=312 p=191 A Figure 3. Disease free survival curve according to TNM stage. TMC=typical medullary carcinoma; AMC=atypical medullary carcinoma; IDC=invasive ductal carcinoma. B C TNM stage=i TNM stage=ii TNM stage=iii p=417 p=418 p=0.5850 A B C Figure 4. Overall survival curve according to TNM stage. TMC=typical medullary carcinoma; AMC=atypical medullary carcinoma; IDC=invasive ductal carcinoma.

Clinical Analysis of Medullary Breast Carcinoma 51 확인할수있었다 (p=31, p=42, Figure 3, 4). 4. 전형적수질성유방암의예후인자분석전형적수질성유방암의생존에영향을미치는요인에대한단변량분석시환자의나이, 종양의크기, 호르몬수용체발현유무, 수술후보조요법의종류와유무는통계학적유의성을확인할수없었으나림프절침범여부는무병생존율과전체생존율에영향을미치는요인으로나타났다 (p=42, p=45, Table 3). 고찰 1977년 Ridolfi 등 (3) 이수질성유방암의여섯가지엄격한진단기준을제시한이후진단의어려움으로병리학자간혹은동일한병리학자내에서도진단의재현성이떨어진다는문제점이제시되었고, 그로인해단순화되고재현성이높은진단기준이계속보고되었다.(9,10,13,14) 그러나단순화된진단기준들은수질암의과잉진단과이로인해일반적인침윤성유방암에가까운비전형적수질성유방암과, 비수질성유방암을수질성유방암으로진단하여부적절한치료와예후의예측에있어문제점을만들게되었다.(14,15) 1997년 Jensen 등 (5) 은진단기준에따른수질성유방암의재분류와그에따른예후를비교하여어떤진단기준이예후를가장잘반영하는가에대한연구를시행하였다. Ridolfi 등 (3) 의진단기준보다단순화된 Pedersen 등 (12) 의진단기준이나, 더엄격한 Tavassoli(6) 의진단기준모두예후의차이를잘나타내지못함을확인하였고, Ridolfi 등 (3) 의진단기준에의한분류가전형적수질성유방암의예후를가장잘반영한다고주장하였다. 본연구도 Ridolfi 등 (3) 의진단기준에따라수질성유방암을분류하여진행하였으며, 전형적수질성유방암의예후를잘반영하는결과를보였다. 유방암의임상병리학적특성중침윤성유방암에서적용할수있는예후인자들이수질성유방암에서는혼동을야기시킬수있는데변형 Bloom-Richardson의점수계산법에의한핵등급이나, 호르몬수용체발현, HER2/neu 발현등은다른침윤성유방암과는반대되는결과를나타낸다. 수질성유방암의임상양상을살펴보면다른침윤성암종에비해젊은나이에발병한다는보고와,(10, 14) 비슷한연령때에발병한다는보고들도있으나,(4,16,17) 본연구결과는수질성유방암과다른침윤성암종사이에서발병연령의차이는없었다. 유방암의예후인자로가장중요한액와림프절전이빈도는수질성유방암에서상대적으로낮아대부분의연구에서전이양성률을낮게보고하고있다.(10,14,18) 저자들의결과도전형적수질성유방암에서액와림프절전이가 21.7% 로다른침 윤성암의 48.1% 에비해낮은것으로조사되었다. 호르몬수용체양성률은수질성유방암에서다른침윤성암종에비해낮은것으로보고되고있다. Jensen 등 (19) 은수질성유방암의형태를갖는 60 명의대상중 13 명의전형적수질성유방암환자에서모두호르몬수용체가발현되지않았다고보고하였고, Ponsky 등 (4) 도수질성유방암에서에스트로겐수용체양성률을 25%, 프로게스테론수용체양성률을 10% 로보고하였다. 본연구의결과에서전형적수질성유방암과비전형적수질성유방암의에스트로겐수용체양성률 (18.9%, 15.0%) 과프로게스테론수용체양성률 (16.2%, 2%) 이다른침윤성암종 (63.2%, 57.2%) 에비해낮은것을확인할수있었다 (p<01, Table 2). HER2/neu 유전자의증폭의경우, Xu 등 (20) 은비전형적수질성유방암에서 46% 의발현율을보고하였다. 저자들도전형적수질성유방암과비전형적수질성유방암에서 HER2/neu 발현이각각 47.4%, 45.5% 로다른침윤성유관암의 28.3% 에비해높게측정되었지만조사대상의수가적어결과를단정하기는어렵다. Jacquemier 등 (21) 은수질성유방암의이해와진단을향상시키기위한방법으로 tissue microarray (TMA) 를이용하여여러표지자를알아보았으며 P-cardherin, MIB1, ERBB2, p53과의연관성을언급하였다. 저자들도유방암의성장과진행에관여하는보다많은예후인자에대한조사가필요할것으로생각된다. 이와같이수질성유방암은낮은호르몬수용체발현과높은 HER2/neu 발현등의분화가나쁜병리학적특성을보이면서액와림프절전이가적은생물학적특성을보인다. 전형적수질성유방암의예후에있어 Fourquet 등 (17) 은 83% 의환자가재발없이 6년간생존하였다고보고하였고, Ridolfi 등 (3) 도수술적치료후단핵구침윤정도에따라 84-91% 가 10 년생존율을보였으며, Krutz 등 (22) 과 Wargotz 등 (14) 은각각 90% 와 94% 의 5년생존율을보였다고보고하였다. 하지만비전형적수질성유방암의예후는다른침윤성유방암과크게다르지않아 Rapin 등 (10) 은 10 년무병생존율을각각 53%, 51% 로보고하였다. 본연구결과역시 10 년무병생존율과전체생존율이전형적수질성유방암 (77.8%, 86.0%), 비전형적수질성유방암 (67.8%, 77.8%) 에서각각조사되어침윤성유관암 (68.3%, 74.7%) 과의비교에서전형적수질성유방암의예후는침윤성유관암보다양호한것으로조사되었으며, 비전형적수질성유방암과침윤성유관암사이의예후에있어서는차이가없었다. 저자들은수질성유방암과침윤성유관암의병기별생존율을비교분석하였으며 TNM 병기 1기에서는생존율의의미있는차이를발견하지못하였으며, 병기 3의경우도생존율의차이를확인할수없었는데유효분석대상의수가적어결과를단정하기어렵다. 병기 2의경우는무병생존율과전체생존율에있어모두전형적수질성유방암이침윤성유관암에비해예후가좋은것으로나타났으며, 무병생존

52 Jae-Won Oh, et al. 율에있어서는전형적수질 / 성유방암과비전형적수질성유방암사이에도전형적수질성유방암이양호한예후를보이는것으로나타났다 (p=37). 전형적수질성유방암의생존에영향을주는요인에대한분석으로 Reinfuss 등 (18) 은 52 명의전형적수질성유방암환자에대한조사에서 17 명이액와림프절전이양성이었으며 10 년무병생존율과관련된인자는단지액와림프절전이유무라고주장하였고, Kim 등 (23) 도수질성유방암에서림프절전이가있거나 35 세이하의젊은연령인경우재발이증가함을확인하였다. 저자들도단변량분석을통한전형적수질성유방암의생존에영향을주는인자가림프절전이여부임을확인하였지만, 발병연령은생존율에영향을미치는요인으로확인되지않았다. 그외 HER2/neu 에대한분석은추가적인환자예와대상기간을다시정하여분석하는것이필요할것으로사료된다. 결론전형적수질성유방암은병리학적특성상높은핵등급과조직학적등급, 호르몬수용체발현율의감소등좋지않은예후인자가많음에도불구하고다른침윤성유관암종에비해좋은예후를나타내지만, 비전형적수질성유방암은다른침윤성유관암종과비슷한예후를나타내는것으로조사되었다. 따라서수질성유방암의진단은전형적수질성유방암인지비전형적수질성유방암인지아형의분류에따른정확한진단이필요하며이에따라추가적치료방향을설정하는것이치료성적의향상에도움이될것으로생각된다. 참고문헌 1. Moore OS, Foote FW Jr. The relatively favorable prognosis of medullary carcinoma of the breast. Cancer 1949;2:635-42. 2. Dardick I, Yazdi HM, Brosko C, Rippstein P, Hickey NM. A quantitative comparison of light and electron microscopic diagnoses in specimens obtained by fine-needle aspiration biopsy. Ultrastruct Pathol 1991;15:105-29. 3. Ridolfi RL, Rosen PP, Port A, Kinne D, Mike V. Medullary carcinoma of the breast: a clinicopathologic study with 10 year followup. Cancer 1977;40:1365-85. 4. Ponsky JL, Gliga L, Reynolds S. Medullary carcinoma of the breast: an association with negative hormonal receptors. J Surg Oncol 1984; 25:76-8. 5. Jensen ML, Kiaer H, Andersen J, Jensen V, Melsen F. Prognostic comparison of three classifications for medullary carcinomas of the breast. Histopathology 1997;30:523-32. 6. Tavassoli FA. Infiltrating carcinomas, common and familiar special types: medullary carcinoma. In: Schnitt ST, editor. Pathology the breast. Norwalk: Appleton & Lange; 1992. p.333-9. 7. Fisher ER, Kenny JP, Sass R, Dimitrov NV, Siderits RH, Fisher B. Medullary cancer of the breast revisited. Breast Cancer Res Treat 1990;16:215-29. 8. Ellis IO, Galea M, Broughton N, Locker A, Blamey RW, Elston CW. Pathological prognostic factors in breast cancer. II. Histological type. Relationship with survival in a large study with long-term follow-up. Histopathology 1992;20:479-89. 9. Pedersen L, Zedeler K, Holck S, Schiodt T, Mouridsen HT. Medullary carcinoma of the breast, proposal for a new simplified histopathological definition. Based on prognostic observations and observations on inter- and intraobserver variability of 11 histopathological characteristics in 131 breast carcinomas with medullary features. Br J Cancer 1991;63:591-5. 10. Rapin V, Contesso G, Mouriesse H, Bertin F, Lacombe MJ, Piekarski JD, et al. Medullary breast carcinoma. A reevaluation of 95 cases of breast cancer with inflammatory stroma. Cancer 1988;61:2503-10. 11. Fisher ER, Gregorio RM, Fisher B, Redmond C, Vellios F, Sommers SC. The pathology of invasive breast cancer. A syllabus derived from findings of the National Surgical Adjuvant Breast Project (protocol no. 4). Cancer 1975;36:1-85. 12. Pedersen L, Holck S, Schiodt T, Zedeler K, Mouridsen HT. Interand intraobserver variability in the histopathological diagnosis of medullary carcinoma of the breast, and its prognostic implications. Breast Cancer Res Treat 1989;14:91-9. 13. Pedersen L, Holck S, Schiodt T, Zedeler K, Mouridsen HT. Medullary carcinoma of the breast, prognostic importance of characteristic histopathological features evaluated in a multivariate Cox analysis. Eur J Cancer 1994;30A:1792-7. 14. Wargotz ES, Silverberg SG. Medullary carcinoma of the breast: a clinicopathologic study with appraisal of current diagnostic criteria. Hum Pathol 1988;19:1340-6. 15. Rubens JR, Lewandrowski KB, Kopans DB, Koerner FC, Hall DA, McCarthy KA. Medullary carcinoma of the breast. Overdiagnosis of a prognostically favorable neoplasm. Arch Surg 1990;125:601-4. 16. Black CL, Morris DM, Goldman LI, McDonald JC. The significance of lymph node involvement in patients with medullary carcinoma of the breast. Surg Gynecol Obstet 1983;157:497-9.

Clinical Analysis of Medullary Breast Carcinoma 53 17. Fourquet A, Vilcoq JR, Zafrani B, Schlienger P, Jullien D, Campana F. Medullary breast carcinoma: the role of radiotherapy as primary treatment. Radiother Oncol 1987;10:1-6. 18. Reinfuss M, Stelmach A, Mitus J, Rys J, Duda K. Typical medullary carcinoma of the breast: a clinical and pathological analysis of 52 cases. J Surg Oncol 1995;60:89-94. 19. Jensen ML, Kiaer H, Melsen F. Medullary breast carcinoma vs. poorly differentiated ductal carcinoma: an immunohistochemical study with keratin 19 and oestrogen receptor staining. Histopathology 1996;29: 241-5. 20. Xu R, Feiner H, Li P, Yee H, Inghirami G, Delgado Y, et al. Differential amplification and overexpression of HER-2/neu, p53, MIB1, and estrogen receptor/progesterone receptor among medullary carcinoma, atypical medullary carcinoma, and high-grade invasive ductal carcinoma of breast. Arch Pathol Lab Med 2003;127:1458-64. 21. Jacquemier J, Padovani L, Rabayrol L, Lakhani SR, Penault-Llorca F, Denoux Y, et al. Typical medullary breast carcinomas have a basal/ myoepithelial phenotype. J Pathol 2005;207:260-8. 22. Kurtz JM, Jacquemier J, Torhorst J, Spitalier JM, Amalric R, Hunig R, et al. Conservation therapy for breast cancers other than infiltrating ductal carcinoma. Cancer 1989;63:1630-5. 23. Kim SW, Kang HJ, Noh DY, Youn YK, Oh SK, Choe KJ. Comparison of the prognostic factors between medullary cancer and infiltrating ductal carcinoma in the breast. J Korean Surg Soc 2000;59:182-90.