ORIGINAL ARTICLE J Breast Dis 2014 December; 2(2): JBD Journal of Breast Disease 유방전절제술후즉시유방재건술을시행받은유방암

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1 ORIGINAL ARTICLE J Breast Dis 2014 December; 2(2): JBD Journal of Breast Disease 유방전절제술후즉시유방재건술을시행받은유방암환자의치료성적 남상근, 박세호, 이동원 1, 송승용 1, 박형석, 김승일, 박병우, 유대현 1 연세대학교의과대학외과학교실, 1 성형외과학교실 Clinical Outcome of Breast Reconstruction after Mastectomy for Breast Cancer Sanggeun Nam, Seho Park, Dong Won Lee 1, Seung Yong Song 1, Hyung Seok Park, Seung Il Kim, Byeong-Woo Park, Dae Hyun Lew 1 Departments of Surgery and 1 Plastic and Reconstructive Surgery, Yonsei University College of Medicine, Seoul, Korea Purpose: This study aimed to investigate clinical outcomes of breast cancer patients who underwent mastectomy with or without immediate breast. Methods: Of 1,847 patients undergoing total mastectomy, 371 (20.1%) underwent immediate between January 2005 and December Clinicopathological characteristics and survival were compared by performing univariate and multivariate analysis. Results: The proportion of had been gradually increasing since Reconstruction group showed younger age at diagnosis and lower cancer stages. Adjuvant chemotherapy and radiation therapy were more frequently administered in the mastectomy alone group. During a median follow-up period of 57 months, locoregional relapse-free survival (LRRFS) was similar regardless of type of surgery. However the group showed a more favorable overall survival (OS). Multivariate analysis for LRRFS revealed no statistical significance but the OS was higher in the group. In the mastectomy alone group, two-thirds died of breast cancer, while all patients in the group died of breast cancer. Stage-matched breast cancer specific survival was similar between both groups. Conclusion: breast is oncologically safe after mastectomy for breast cancer. Considering the quality of life, the patient should be preoperatively counseled by a multidisciplinary team regarding possible immediate. Key Words: Breast neoplasms, Mastectomy, Reconstructive surgical procedures, Survival 서론 유방재건술은유방암치료를위해유방절제술을받은환자에게 원래의유방형태로복원해주기위한수술이다. 우리나라여성에서 유방암발병률은점차증가하고있을뿐만아니라 [1], 한국유방암학 회의보고에의하면유방암발생연령이 30 대가 12.7%, 40 대가 37.1% 로젊은환자에서많이발생하고있다. 이와함께유방검진의증가 와진단기술의발달로유방암의조기발견이늘어나고있으며, 삶의 질향상을위하여유방절제술후동시또는지연유방재건술에대 Correspondence: Seho Park Department of Surgery, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul , Korea Tel: , Fax: , PSH1025@yuhs.ac Received: July 18, 2014 Accepted: October 6, 2014 한수요도증가하고있다 [2]. 유방재건술은유방절제술후신체이미지손상에대한상실감을줄여주고환자의삶의질을향상시켜주는장점이있다 [3]. 유방재건술은시술시기에따라크게종양제거수술과함께동시에유방을복원하는즉시재건술과유방절제술후보조적치료를완료한후시행하는지연재건술두가지로나뉜다. 현재까지시행되고있는대표적인유방재건술의방법은크게두가지로조직확장기와보형물을이용하는것과환자자신의근육, 지방그리고피부를포함한자가조직을이용하는피판술이있다. 유방절제술후유방재건술은보편화되고있지만재건수술이가능한환자를선택하는것과재건수술시기나방법을결정하는것에대한일관된지침은미흡한상태이다. 즉시재건술에대한종양학적인안정성은여러연구들에의해밝혀지고있다 [4-8]. Knottenbelt 등 2014 Korean Breast Cancer Society. All rights reserved. eissn This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

2 유방전절제술후즉시유방재건술을시행받은유방암환자의치료성적 45 [4] 은즉시재건술후국소재발률과생존율에차이가없으며국소재발의진단을늦추지않고보조항암요법치료결과에도영향을미치지않는다고보고하였으며, Bezuhly 등 [6] 은즉시재건술후유방암특이생존율이젊은환자에있어서증가한다고보고하였다. 하지만이러한보고들에도불구하고즉시재건술에대한종양학적인안정성은근거수준이낮으며 [9,10], 국내의연구역시부족한실정이다. 이에본연구자들은국내단일기관에서유방전절제술을시행한군과유방전절제술후즉시재건술을받은군간의임상병리학적특성과치료성적을후향적으로비교하여즉시유방재건술의종양학적안정성을평가하고자하였다. 방법 2005년 1월부터 2011년 12월까지연세대학교의과대학세브란스병원에서원발성유방암으로진단받고유방전절제술을시행받은환자를대상으로후향적연구를진행하였다. 유방보존술을받은환자, 수술전항암약물치료를받은환자, 전이성유방암이나악성엽상종양등의비상피기원유방암환자그리고지연재건술을받은환자를제외한총 1,847명의환자를대상으로하였다. 본연구는세브란스병원연구심의위원회 (Institutional Review Board) 의승인하에진행하였다 ( 승인번호 : ). 세브란스병원유방암전문클리닉등록자료와환자의의무기록검토를통하여환자의나이, 종양의크기, 액와림프절전이여부, 유방암병기, 조직학적형태와등급, 호르몬수용체발현유무, 성장인자수용체유형 2 (HER2) 과발현유무, 재발이나사망자료를조사하였다. 미국임상종양학회 / 미국병리학회 (American Society Clinical Oncology/College of American Pathologists) 권고안에따라면역조직화학염색법을이용하여종양의핵내염색이 1% 이상인경우호르몬수용체양성으로정의하였다 [11]. HER2의경우면역조직화학염색에의한점수가 3+ 이거나, 2+ 인경우는형광동소교잡반응 (fluorescence in situ hybridization) 검사상유전자증폭이확인된경우를양성으로정하였다. 생존율은무국소영역재발생존율 (locoregional relapse-free survival) 과전체생존율 (overall survival) 을비교하였다. 국소영역재발은동측피부나흉벽에암이다시발생한경우또는동측액와부, 쇄골상하림프절이나내유림프절에암이재발한경우로정의하였다. 수술일로부터사망원인에상관없이사망유무가확인되거나마지막추적관찰된날까지를전체생존기간으로정의하였다. 유방전절제술을시행한군과유방전절제술후즉시유방재건술을받은군간의임상병리학적특성이나보조치료방법의비교는 교차분석을이용하였다. 유방재건술유무에따른유방암환자의 국소영역재발률과생존율의차이는 Kaplan-Meier 분석후 logrank 검정으로유의성을평가하였으며, 콕스비례위험모형 (Cox proportional hazard model) 을이용하여독립적인설명변수를알아 보았다. 통계분석은 SPSS version 20.0 (IBM Corp., Armonk, USA) 프 로그램을이용하였으며, p 값이 0.05 미만인경우통계학적으로유의 하다고판정하였다. 환자의임상병리학적특징 결과 대상환자 1,847 명의평균나이는 51.3 ± 1 세였으며, 중앙추적 관찰기간은 57 개월 ( 범위, 개월 ) 이었다. 전체환자중유방전 절제술후즉시유방재건술을시행받은환자는 371 명 (20.1%) 이었 다. 유방재건방법으로조직확장기과보형물을이용한환자는 163 명 (43.9%) 이었으며, 자신의근육, 지방그리고피부를포함한자가조 직을이용하는피판수술을받은환자는 208 명 (56.1%) 이었다. 수술 연도에따라즉시유방재건술의비율은 2009 년도부터점차증가 추세를보이고있으며, 2011 년도에는약 1/3 의환자에서동시재건 술이시행되었다 (Figure 1). 환자의나이, 종양의크기, 액와림프절상태, 암병기, 조직학적형 태와등급, 에스트로겐및프로게스테론수용체, HER2 발현상태 등은 Table 1 과같다. 유방전절제술만을시행받은환자와비교하여 즉시유방재건술을시행받은경우 40 세이하의젊은환자가약 40% 로더많았으며, 종양과액와림프절의병기가낮아약 70% 의환 자는암병기 0 1 기였다. 에스트로겐수용체발현이나 HER2 상태 Proportion (%) Year Figure 1. Proportion of immediate according to operation year.

3 46 남상근외 Table 1. Clinicopathologic characteristics and adjuvant therapies of patients undergoing mastectomy with or without immediate Characteristic Mastectomy alone (n= 1,476) No. (%) (n= 371) No. (%) p-value Age (yr)* 53.3± ± 8.1 < (11.5) 147 (39.6) < > 40 1,306 (88.5) 224 (60.4) Tumor stage Tis 230 (15.6) 102 (27.5) < T1 724 (49.1) 193 (52.0) T2 492 (33.3) 74 (19.9) T (2.0) 2 () Node stage N0 1,000 (67.8) 297 (80.1) < N1 353 (23.9) 58 (15.6) N2 78 (5.3) 12 (3.2) N3 45 (3.0) 4 (1.1) TNM Stage (15.5) 102 (27.5) < (35.1) 152 (4) (40.2) 101 (27.2) (9.1) 16 (4.3) Histologic type Ductal 1,292 (87.5) 328 (88.4) Lobular 56 (3.8) 18 (4.9) Special 128 (8.7) 25 (6.7) Histologic grade (n= 1,366) I/II 844 (74.2) 169 (73.8) 92 III 293 (25.8) 60 (26.2) ER (n= 1,825) Negative 414 (28.3) 93 (25.7) Positive 1,049 (71.7) 269 (74.3) PR (n= 1,825) Negative 546 (37.3) 113 (31.2) Positive 917 (62.7) 249 (68.8) HER2 (n= 1,824) Negative 962 (65.8) 220 (6) Equivocal 169 (11.6) 52 (14.4) Positive 332 (22.7) 89 (24.7) Radiation therapy Not done 1,253 (84.9) 339 (91.4) Done 223 (15.1) 32 (8.6) Chemotherapy Not done 631 (42.8) 198 (53.4) < Done 845 (57.2) 173 (46.6) Hormonal therapy Not done 413 (28.0) 103 (27.8) 33 Done 1,063 (72.0) 268 (72.2) Targeted therapy Not done 1,385 (93.8) 344 (92.7) Done 91 (6.2) 27 (7.3) TNM = tumor, node, metastasis; ER = estrogen receptor; PR = progesterone receptor; HER2= human epidermal growth factor receptor 2. *Mean± SD. 는두군간에차이가없었으나, 폐경후여성의빈도가높은유방전 절제술만을시행받은환자군의경우프로게스테론수용체의양성 발현빈도는즉시유방재건술을시행받은환자군보다낮았다. 수술후보조요법 (adjuvant therapy) 으로는방사선치료, 항암약물 치료, 항호르몬치료, 표적치료가시행되었으며, 진행된암병기환자 의비율이높은유방전절제술만을받은군에서방사선치료와항 암약물치료를받은환자가통계학적으로유의하게많은것으로나 타났다 (Table 1). 수술방법에따른생존율분석 추적기간동안국소영역재발은대상환자 1,847 명중 48 예 (2.6%) 에서발생하였다. 유방전절제술시행군에서 42 예 (2.8%), 즉시재건 술환자에서 6 예 (1.6%) 확인되었다. Kaplan-Meier 방법을이용한생 존율비교에서즉시유방재건술의시행여부에상관없이무국소영 역재발생존율은통계학적으로유의한차이가없었다 (Figure 2A). 유방전절제술을시행받은군의 5 년무국소영역재발생존율은 p = Mastectomoy alone p < Mastectomoy alone Figure 2. Survival of patients undergoing mastectomy with or without immediate. (A) was similar regardless of type of surgery. (B) was favorable in the group. A B

4 유방전절제술후즉시유방재건술을시행받은유방암환자의치료성적 47 Table 2. Cox proportional hazards model for survival Variable LRRFS HR 95% CI p-value HR 95% CI p-value Age ( 40 yr) Tumor stage (T2-4) Node stage (positive) < ER (negative) HER2 (positive) Surgery (immediate ) Radiation therapy (done) Chemotherapy (done) Hormonal therapy (done) < Targeted therapy (done) LRRFS = locoregional relapse-free survival; OS = overall survival; HR = hazard ratio; CI = confidence interval; ER = estrogen receptor; HER2 = human epidermal growth factor receptor 2. OS 96.7% 였으며, 즉시재건술을시행받은군의 5년무국소영역재발생존율은 98.1% 였다. 하지만전체생존율분석에서는통계적으로유의하게유방전절제술만시행받은환자군의예후가불량하였다 (Figure 2B). 유방전절제술을시행받은군의 5년전체생존율은 92.7% 였으며, 즉시재건술을시행받은군의 5년전체생존율은 98.8% 였다 (p < 0.001). 즉시유방재건술을받은환자만을대상으로보형물을이용한재건술과자가조직을이용한재건술사이의무국소영역재발생존율이나전체생존율은유방재건술의방법에따라통계적인차이는발견되지않았다. 는유방전절제술만받은군의생존이불량한경향성을보였으나통계적인유의성은없었다 (Figure 4B, C). 추적기간동안총 103명 (5.6%) 의환자가사망하였으며, 사망원인이확인되지않은 7명을제외하고, 유방재건술을받은환자중 4명이사망하였으며, 재건술에의한합병증과관련된사망은없었고모두유방암으로사망하였다. 유방전절제술만받은환자중사망원인이확인된 92명중 34명 (37.0%) 은유방암이외의원인으로사망하였으며, 58명 (63.0%) 은유방암으로사망하였다. 암병기를일치시킨후유방암특이생존율을확인하였을때, 유방재건술의유무에상관없이유방암특이생존율은통계적으로차이가없었다. 생존율의다변량분석과사망원인다른임상병리학적특성과수술후보조치료요법을보정한다변량분석에서도즉시유방재건술여부에따라무국소영역재발생존율은통계학적인유의성을보이지않았다. 종양의크기와림프절전이유무가국소영역재발과관련된독립적인예후인자였다 (Table 2). 하지만전체생존율을다변량분석한결과즉시유방재건술을시행받은경우위험비가 (95% 신뢰구간, ) 로통계적으로유의하게생존율이양호하였다 (Table 2). 종양의크기가큰경우나액와림프절전이가있는경우는불량한전체생존율을보이는예후인자였으며, 항암약물치료와항호르몬치료를시행한경우는양호한전체생존율의독립적인예후인자였다. 암병기를일치시켜무국소영역재발생존율을비교하였을때암병기 0 1기, 2기와 3기각각에서유방재건술의여부에상관없이통계적으로차이가없었다 (Figure 3). 암병기를일치시킨전체생존율분석에서는암병기 0 1기인경우즉시유방재건술을받은군이통계적으로양호한생존을보였다 (Figure 4A). 암병기 2기와 3기에서 고찰 유방암은세계전체여성암의 23% 를차지하며여성암중최다발생률을보인다. 우리나라에서는갑상선암에이어두번째로흔한암으로점차발생이증가하고있다 [1]. 유방암에대한여성들의관심과유방검진의증가에따라초기유방암으로진단되는환자들과젊은유방암환자들의발생빈도가점차증가하는추세이며, 이와더불어삶의질향상을위해유방재건술을받는경우도해마다증가하고있다 [2]. 한국유방암학회의보고에의하면 [12], 2000년보다 2011년에는유방재건수술이 7배이상증가했으며본연구에서도 2009년부터점차증가하는추세를보이고있다 (Figure 1). 유방재건술은보형물을이용한재건방법과자가조직을이용한방법으로나뉘어진다. 보형물을이용한유방재건술은수술이간단하고, 추가적인흉터가생기지않으며, 비용이저렴하고, 회복기간이빠르다는장점이있으나, 이물질에대한거부감, 감염, 피막구축등의합병증, 보형물의내구성및수명등의단점이있다 [13]. 자가조

5 48 남상근외 p = p = A A p = 77 p = B B p = p = C C Figure 3. Stage-matched locoregional relapse-free survival curve. (A) Stage 0 1. (B) Stage 2. (C) Stage 3. Figure 4. Stage-matched overall survival curve. (A) Stage 0 1. (B) Stage 2. (C) Stage 3. 직을이용한재건시에는이와같은합병증은없거나드물지만, 피판의괴사, 긴수술시간및회복기간그리고공유부에생기는후유증의문제가있다 [14]. 양자간에는차이가있지만즉시유방재건술은유방절제술후신체의손상에대한두려움과정신적인고통을 피할수있으며유방절제술과유방재건술을동시에실시함으로써수술의횟수도줄일수있는장점이있다. 유방암절제술후유방재건술이점차보편화되고있지만재건수술이가능한환자를선택하는것과재건수술시기나방법을결

6 유방전절제술후즉시유방재건술을시행받은유방암환자의치료성적 49 정하는것에대한일관된지침은미흡한상태이다. 유방재건술후국소영역재발의발견과치료에방해를받지않을까하는염려, 국소영역재발의증가, 수술후보조치료계획에영향을주지않을까하는걱정, 그리고이에따르는생존율에미치는영향을고려해야한다는의견들도있다 [9,10,15]. 또한 Isern 등 [16] 은지연재건술을받은환자들에서국소영역재발률이 2.08배높다고보고하기도하였다. 이와는달리 Knottenbelt 등 [4] 은즉시재건술후 5년무병생존율 (disease-free survival) 93% 로생존율에차이가없으며국소재발의진단을늦추지않고보조항암요법치료결과에도영향을미치지않는다고보고하였으며, Bezuhly 등 [6] 은즉시재건술후유방암특이생존율이재건술을받지않은군에비해증가한다고보고하였으며 ( 위험비, 4; 95% 신뢰구간, 8 0), 특히 50세미만의환자에있어서증가한다고보고하였다 ( 위험비, 0.47; 95% 신뢰구간, ). 본연구에서도즉시유방재건술을받은환자에서국소영역재발률은유방절제술만을받은환자와차이가없었다. 하지만전체생존율을단변량분석하였을때즉시유방재건수술을시행받은환자군의생존율이더높았다. 이는본연구가후향적분석으로조사하였기때문에환자군의선택편향과연관된것으로사료된다. 대상환자들의임상병리학적특성을비교하였을때즉시유방재건술을받은환자에서평균진단시연령이낮고암병기가낮았다. 즉시유방재건술을받은환자중 40대이하는 39.6% 로유방절제술만을받은군의 11.5% 에비해높았으며, TNM 병기에서도암병기 0 1은즉시유방재건술을받은환자에서 68.5% 로유방전절제술만받은군의 5% 에비해높은비율을차지하고있었다. 원발종양이큰경우와액와임파선전이가있는경우국소재발이나원격전이의확률이높음은잘알려져있으며이러한차이가생존율에영향을미칠수있을것으로생각된다. 본연구의대상환자군의임상병리학적특성이달랐으므로선택편향을보정하기위하여다변량분석을시행한결과수술방법에따라무국소영역재발생존율은통계적유의성이없었다. 하지만유방절제술만시행한군의전체생존율은즉시재건술을시행한경우보다더불량하였다. 이는상대적으로고령의환자가유방절제술만시행한군에더많았으며, 사망원인조사에서유방절제술만시행한군의사망환자중 1/3은유방암이외의원인으로사망한것으로보아유방암재발이외의원인이연관된것으로생각된다. 이를확인하기위해병기를일치시킨후유방암특이생존율을분석한결과두군간에통계적유의성은확인할수없었다. 이러한결과는즉시유방재건술의종양학적안정성을보여주는결과라할수있으며이는다른연구결과와동일하다 [4-8]. 본연구의제한점은먼저중앙추적관찰기간이 57개월로생존 율을평가하기에는짧은기간이라는것이다. 추적기간중사망은 5.6% 에서만발생하였으므로생존율의해석에주의가필요하다. 향후추적관찰기간이늘어난다면결과가달라질가능성이있으므로장기간추적관찰연구가필요할것으로사료된다. 또한재건술후보조치료의지연여부와예후와의상관성에논란이있었으나본연구에서는보조치료의방법에따른시작시기, 종류나횟수등에관해분석이되지않아추가연구가필요할것으로생각된다. 본연구에서는유방암으로유방절제수술과동시에재건수술을받은환자와재건술을시행하지않은환자의임상적결과비교를통해두군간에국소재발률이나치료성적에차이가없음을확인하였다. 유방암환자의유방절제술후즉시재건술은적절한복원방법과술기의적용으로비교적안전하게시행될수있다. 유방암환자의안전한종양치료와완전한일상생활이나사회생활의복귀를위해서수술전즉시재건술에대한외과와성형외과뿐만아니라종양내과, 방사선종양학과등유방암다학제진료팀에의한상담과치료계획수립은유방암환자들의삶의질향상에기여할것으로생각된다. REFERENCES 1. Park SK, Kang D, Kim Y, Yoo KY. Epidemiologic characteristics of the breast cancer in Korea. J Korean Med Assoc 2009;52: Enewold LR, McGlynn KA, Zahm SH, Poudrier J, Anderson WF, Shriver CD, et al. Breast after mastectomy among Department of Defense beneficiaries by race. Cancer 2014;120: Guyomard V, Leinster S, Wilkinson M. Systematic review of studies of patients satisfaction with breast after mastectomy. Breast 2007;16: Knottenbelt A, Spauwen PH, Wobbes T. The oncological implications of immediate breast. Eur J Surg Oncol 2004;30: Sandelin K, Wickman M, Billgren AM. Oncological outcome after immediate breast for invasive breast cancer: a longterm study. Breast 2004;13: Bezuhly M, Temple C, Sigurdson LJ, Davis RB, Flowerdew G, Cook EF Jr. postmastectomy is associated with improved breast cancer-specific survival: evidence and new challenges from the Surveillance, Epidemiology, and End Results database. Cancer 2009;115:

7 50 남상근외 7. Le GM, O Malley CD, Glaser SL, Lynch CF, Stanford JL, Keegan TH, et al. Breast implants following mastectomy in women with early-stage breast cancer: prevalence and impact on survival. Breast Cancer Res 2005;7:R Baker JL, Mailey B, Tokin CA, Blair SL, Wallace AM. Postmastectomy is associated with improved survival in patients with invasive breast cancer: a single-institution study. Am Surg 2013; 79: Alderman AK, Hawley ST, Waljee J, Mujahid M, Morrow M, Katz SJ. Understanding the impact of breast on the surgical decision-making process for breast cancer. Cancer 2008;112: Alderman AK, Hawley ST, Waljee J, Morrow M, Katz SJ. Correlates of referral practices of general surgeons to plastic surgeons for mastectomy. Cancer 2007;109: Rakha EA, Starczynski J, Lee AH, Ellis IO. The updated ASCO/ CAP guideline recommendations for HER2 testing in the management of invasive breast cancer: a critical review of their implications for routine practice. Histopathology 2014;64: Kim Z, Min SY, Yoon CS, Lee HJ, Lee JS, Youn HJ, et al. The basic facts of korean breast cancer in 2011: results of a nationwide survey and breast cancer registry database. J Breast Cancer 2014;17: Cordeiro PG, McCarthy CM. A single surgeon s 12-year experience with tissue expander/implant breast : part II. An analysis of long-term complications, aesthetic outcomes, and patient satisfaction. Plast Reconstr Surg 2006;118: Kim EK, Eom JS, Ahn SH, Son BH, Lee TJ. Evolution of the pedicled TRAM flap: a prospective study of 500 consecutive cases by a single surgeon in Asian patients. Ann Plast Surg 2009;63: Lewis RS, Kontos M. Autologous tissue immediate breast : desired but oncologically safe? Int J Clin Pract 2009;63: Isern AE, Manjer J, Malina J, Loman N, Mårtensson T, Bofin A, et al. Risk of recurrence following delayed large flap after mastectomy for breast cancer. Br J Surg 2011;98:

Jkbcs016(92-97).hwp

Jkbcs016(92-97).hwp Expression of bcl-2 and Apoptosis and Its Relationship to Clinicopathological Prognostic Factors in Breast Cancer - A Study with Long Term Follow-up correlated with the survival rate.(journal of Korean