<30312DC1BEBCB328C8B2C0CEC5C32DC0AFC1F6C8C D E696E6464>

Transcription

1 REVIEW Korean J Obstet Gynecol 2011;54(2):67-78 doi: /KJOG pissn eissn THE PROPER APPROACHES FOR BREAST DISEASE Jihoon Yu, MD, Intaek Hwang, MD Department of Obstetrics and Gynecology, Eulji University College of Medicine, Daejeon, Korea The gynecologists are the primary care physician to women and the breast is an organ of reproduction and reproductive hormones are the most important factors for breast cancer. Therefore it seems logical to accept the position that diseases of the breast are the responsibility of the gynecologists. The breast examination is a part of the through gynecologic examination and the knowledge of the contemporary treatment of breast diseases is an essential components of the current practice of gynecology. In addition to history and physical examination, the gynecologist should be prepared to understand certain diagnostic studies. It seems a logical step that breast cancer patients will be treated by a multidisciplinary team, in which the gynecologist will also take part. Keywords: Gynecologists, Reproductive factors, Breast diseases 유방암의병인론중생식요인은가장중요한요인으로서, 유방질환의이해를포함하여질환의치료와이과정에서발생할수있는문제들은산부인과영역에서좀더구체적으로접근할수있다. 유방질환의선별검사를포함하여병변의진단과추적검사, 치료와더불어직면할수있는문제를고찰하고자한다. 유관의종단부는종말관 (terminal duct or ductule) 이라부르고, 소엽 (lobule) 과함께유방의기능적단위인종말관소엽단위 (terminal duct lobular unit, TDLU) 를이루며대부분의병리가이곳에서발생한다 (Fig. 1). 유방초음파에서는피하지방의에코정도를기준으로병변의에코가지방보다높으면고에코, 지방과같으면등에코, 지방보다낮으면저에코라한다. 따라서시간게인보상을조절하고검사해야한다 [1]. 정상유방의초음파해부학은다음과같다 (Fig. 2). 유방통은여성의 60-70% 에서인생에한번은겪는매우흔한증상이지만아직정확한원인과적절한치료방법은정립되지않았다. 유방의통증은생리주기와연관하여주기적인유방통과비주기적인유방통으로구분한다. 1) 주기적유방통주기적유방통 (cyclic breast pain) 이전체통증의 ⅔를차지하며, 생리때통증이가장심하고, 생리후좋아지는과정을보인다. 대부분양측성이며상외측에주로호발한다. 치료에앞서유방암과감별하고이러한통증이유방암때문은아님을이해시키는것이중요하다. 환자의약 85% 에서특별한치료가필요없으며유방의움직임을줄이기위해견고한브래지어를착용하거나온열요법또는 acetaminophen이나 aspirin 등의진통제도사용할수있다. 커피, 쵸콜릿, 차등카페인을줄이는식이요법은약 2-3개월간시행하여야효과를볼수있고, 지방질을줄이는식이도약 6개월간시행하여야유방의통증을줄일수있다 [2]. 식이요법이나진통제에효과가없는경우타목시펜을하루 10 mg을투여하여약 80% 이상에서효과가있다고보고되고있지만 [3], 용량이증가할수록안면홍조, 질분비물의증가, 우울증, 오심등부작용을보이며여러독성검사를종합해보면타목시펜은유방암치료시에만사용하는것을권한다 [4]. Received: Accepted: Corresponding author: Intaek Hwang, MD Department of Obstetrics and Gynecology, Eulji University Hospital, 1306 Dunsan-dong, Seo-gu, Daejeon , Korea Tel: Fax: ithwang@eulji.ac.kr This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. Copyright Korean Society of Obstetrics and Gynecology 67

2 KJOG Vol. 54, No. 2, 2011 Fig. 1. Terminal duct lobular unit. Skin and subcutaneous fat Mammary layer Retromammary fat layer Cooper s ligament Superficial layer of superficial fascia Deep layer of superficial fascia Pectoralis muscle Skin and subcutaneous fat Mammary layer Retromammary fat layer Fig. 3. Investigation of nipple discharge. *Suspicious means discharge that is blood stained or contains moderate or large amounts of blood on testing, is associated with a mass, or is a new development in women older than age 50 and is not thick or cheesy (From Dixon MJ, Bundred NJ. Diagnosis and management of benign breast diseases. In: Harris JR, Lippman ME, Morrow M, et al, editors. Diseases of the breast. 2nd edition. Philadelphia: Lippincott Williams and Wilkins; p. 48, with permission) [66]. Pectoralis muscle Collecting duct Lactiferous sinus Rib and Pleura Fig. 2. Sonographic fi nding of normal breast anatomy. 2) 비주기적유방통비주기적인유방통 (non cyclic breast pain) 은생리주기와무관하게발생하고지속적또는간헐적으로나타나며일측통증으로, 유방의안쪽부분이나유두아래와같이국소적인형태를띤다. 30대여성에서호발하고약 50% 의환자에서자연적으로없어지는과정을보이며주기적인유방통보다는짧은자연사 (natural history) 를보인다. 이런비주기적인통증은약물요법에잘반응하지않고병리적연관성이주기적인통증의경우보다높게나타난다. 3) 유방암과유방통유방암환자가유방통만을주요증상으로호소하는경우는약 5% 이하이며, 유방암과관련된유방통은대부분일측유방에국한되고지속적이며심하다는특징을보인다. 유방통을보이는환자는주로폐경전여성이고폐경후의유방통은악성질환일가능성이상대적으로증가한다. 또한 35세이상의환자가최근 1년간유방촬영술없이새로운유방통을호소하면영상학적검사를시행하고유방암의증거가발견되지않았더라도 1-2개월후추적관찰을하도록권장하고있다 [5]. 1) 유두분비물의평가자발적인지, 짜야만분비되는지, 일측성또는양측성인지, 분비물의색깔, 하나의유관에서분비되는지아니면여러유관에서다발성으로분비되는지확인해야한다. 종양과관계된유두분비는자발적, 일측성, 혈성으로나오는경우이며종괴가만져지면서분비물이함께나오는경우는반드시병리적원인을정확히밝혀야한다 (Fig. 3). 2) 비산욕기에양쪽유방에서유즙성분비물이지속적으로나오는경우이를유즙과다 (galactorrhea) 라부르는데특히시야장애, 무월경, 불임등의소견이같이나타나면뇌하수체선종을생각할수있다. 이런경우혈중프로락틴을측정하고지속적으로이수치가증가하면뇌단층촬영이나자기공명영상을통하여종양의유무를확인한다. 하지만갑상선기능저하증이나약물 ( 항고혈압제, 경구피임약, 진정제, 제산제 [H 2 blocker], phenothiazine계약물등 ) 이나유두자극등으로도혈중프로락틴이증가할수있음을기억해야한다. 통증이없이만져지는종괴는유방암의가장흔한증상이다. 유방종괴를진단할때환자의연령과폐경상태에따라차이는있겠지만, 먼저이종괴가낭종인지고형인지를구분하는것이중요하다. 유두분비는종괴, 통증과더불어흔한유방증상으로대부분은양성질환이지만증상을보이는여성들은유방암의공포를갖고있다. 유두분비만을보이는여성이유방암으로밝혀지는경우는약 1% 로보고되고있다 [6]. 1) 유방낭종의처치낭종은 30대부터폐경까지아주흔히발견되는병변이고생리주기에따라그크기가변할수있다 [7]. 진단을위해초음파와바늘흡인 (needle aspiration) 을시행할수있는데흡인은이자체가영상학적으로흔적 (artifact) 을남길수있기때문에흡인전유방영상촬영을권한다. 낭성종괴는흡인후에완전히사라져야하며, 만약사라지지않는다면다른 68

3 Jihoon Yu, et al. The proper approaches for breast disease 생검방법으로확인해야한다. 낭종의내용물은혈성액체가아니어야하며, 혈성액체가있다면세포학적검사와초음파검사를통하여절제생검하는것이좋다. 흡인시행약 4-6주후에재진찰하여재발되었는지, 잔류낭종이있는지확인하여재발하거나잔류성분이있다면외과적절제를한다 [8]. 2) 고형종괴의진단 (1) 40세이하의종괴 40세이하의젊은여성의유방종괴는거의대부분양성질환으로섬유선종, 섬유낭종성변화, 섬유화등으로인하여발생한다. 폐경전여성에서는정상적으로유방조직이생리주기에따라변하거나단단해서진찰결과비정상소견으로나타나는경우가흔하다. 특히 35세미만환자들은초음파검사를동시에실시하는것이좋다. 양성유방종괴의치료에는외과적절제와, 비수술적인 3중검사 (triple test) 후경과를관찰하는방법이있는데삼중검사란유방진찰, 유방영상촬영, 침생검을말하며고형종괴의평가에서삼중검사가표준검사이다. (2) 40세이상의종괴연령이증가함에따라임상적으로악성유방질환의빈도가높아지는데, 40세이상의여성에서비낭종성종괴 (noncystic mass) 는임상적인소견과관계없이악성가능성을고려해야하고 [9], 유방내종괴가확실하게있는데유방촬영술상정상소견을보인다고유방암이없다고단정지을수없다. 보고에따르면약 9-22% 에서촉지성종괴가있음에도불구하고유방촬영술상병변이보이지않은예가있다 [9]. 유방영상을촬영한후 40세이상의여성의분명한유방종괴는조직학적검사를시행한다 (Fig. 4). 3) 유방의병리학 (1) 양성병변조직검사후양성으로밝혀진병변은이후에암으로진행할상대위험도에따라다음과같이분류한다 (Table 1) [10]. (2) 악성병변유방의악성병변은상피내암과침윤암으로나누어생각할수있으며이중관상피내암과일반형침윤성관상피암이내부분을차지한다. : 상피내암 (15-30%) Ductal carcinoma in situ (DCIS) (80%) Lobular carcinoma in situ (LCIS) (20%) : 침윤암 (70-85%) Invasive carcinoma, No special type (Invasive ductal carcinoma, NST) Invasive lobular carcinoma Medullary carcinoma Mucinous (colloid) carcinoma Tubular carcinoma Invasive papillary carcinoma Metaplastic carcinoma 우리나라에서는국가암조기검진프로그램의일환으로 1) 30세이상의여성 : 매월자가검진, 2) 35-40세의여성 : 2년에한번의사에의한유방임상진찰, 3) 40세이상의여성 : 2년마다유방촬영술과유방임상진 Table 1. Classifi cation of benign breast diseases by the relative risk (RR) for malignancy Fig. 4. Diagnostic algorithm for patients with palpable breast masses (From Klein S. Am Fam Physician 2005;71:1731-8, with permission the American Academy of Family Physicians) [67]. Benign breast diseases Risk for malignancy (1) Non proliferative changes (fi brocystic change) Risk (-) Duct ectasia Cyst Apocrine change Adenosis Mild hyperplasia Fibroadenoma without complex feature (2) Proliferative disease without atypia Mild risk (RR= ) Moderate or fl orid hyperplasia Papilloma Complex sclerosing lesion (radial scar) Fibroadenoma with complex features (3) Proliferative disease with atypia Moderate risk (RR= ) Atypical ductal hyperplasia (ADH) Atypical lobular hyperplasia (ALH) 69

4 KJOG Vol. 54, No. 2, 2011 찰을함께할것을권고하고있다. 1) 문진유방환자의문진시첫번째로자세한과거력을얻어야한다. 문진시확인해야할정보는표와같다 (Table 2). 2) 시진앉거나서있는자세에서유방의크기, 대칭성, 피부와유두의함몰 (retraction), 종괴등을관찰하고, 양팔을머리위로올리거나허리를펴고두팔을내려검사를시행한다. 아지므로전체유방을자세히관찰할수있다. 두손을모두이용하고가운데손가락의두마디정도를사용하여환자가통증을느끼지않을정도의압력으로시행하는데, 순서를갖고골고루촉진하는것이중요하다. 환자는본인이만져지는종괴를쉽게찾을수있으나의사가이를찾지못하는경우도있다. 이런경우에는환자와같이병변을만져보는것도좋은방법이며이상이있는부위는위치, 범위, 경도와이동성을기록하고월경주기에따라다시검사해도도움이될수있다. 액와림프절이만져지는지검사를해야하는데, 앉은상태에서팔을이완시키고손끝을모아서위쪽부터아래쪽으로만져본다. 1 cm 이하의부드럽고양측성이며, 움직이는경우에는악성가능성이적다. 3) 촉진앉거나서있는자세에서시행하고누운상태에서시행한다. 앉은자세는상부유방이얇아져서유방암이가장많이발생하는상부외측의진찰이용이할수있다. 누운자세는유방이흉벽에골고루퍼져두께가얇 Table 2. Check list before breast examination All women Age at menarche Marital history and age at marriage Number of pregnancy Number of delivery and miscarriage Age at fi rst delivery Breast feeding and duration Family history of breast cancer (Relation, age at onset, bilaterality) History of breast operation (name of a disease) History of breast trauma Premenopausal women Last menstruation period Duration and regularity of menses History of oral contraceptives Postmenopausal women Age at menopause History of hormone replacement therapy 1) 유방촬영술유방촬영술 (mammography) 은유방암의조기진단에있어선별검사로유일하게그효과를인증받은검사방법이다. 임상검사와유방촬영술로검진의가능성을조사하였던유방암발견프로그램 (Breast Cancer Detection Demonstration Program, BCDDP: 1977) 에서유방암의 88% 가유방촬영술에서발견되었으며유방촬영술에서만발견되는유방암이 42% 였고특히임파선전이가없는 1 cm 이하의조기유방암의경우 50% 이상의병변이유방촬영술에서만발견이되었으며임상검사에서만발견되는암도 9% 정도있었다. 즉, 유방암의검진을위해서유방촬영술은매우중요하며임상검사와유방촬영술은서로대치될수없는보완적인검사이다. 하지만유방촬영술의유방암의병변에대한민감도는 63-98% 이나, 치밀유방인경우는약 45-70% 로떨어지며, 치밀유방에서유방암발병률이비치밀유방에서의유방암에비해약 2.2-5배라는사실에서유방촬영술의제한점을생각해볼수있다 [11]. 치밀유방이많고상대적으로유방암의호발연령이젊은우리나라에서더욱유의해야할사항이라하겠다. 2) 유방초음파상대적으로젊은여성에서유방암발생률이높고치밀유방여성이많은우리나라에서는유방초음파가유방검진에있어서보조적인역할을할수있다. 초음파의유용성에관한연구들은평균정도의위험성을갖 Table 3. Investigations of breast sonography Investigator/yr No. No. biopsy (%) No. malig. (%) Prevalence (%) Gorden, et al/ , (2.2) 44/279 (16) 44/12,706 (0.35) Buchberger, et al/2000 8, (4.5) 32/362 (8.8) 32/8103 (0.39) (5.0) 8/43 (19) 8/867 (0.9) Kaplan/2001 1, (5.5) 6/99 (6.6) 6/1,862 (0.3) Kolb/ , (2.6) 37/358 (10) 37/13,547 (0.27) Crystal, et al/2003 1, (2.5) 7/38 (18) 7/1,517 (0.46) Leconte, et al/2003 4, /4,236 (0.38) Overall 42,838 1,182 (3.1) 134/1,171 (11.4) 150/42,838 (0.35) 70

5 Jihoon Yu, et al. The proper approaches for breast disease 는치밀유방을가진여성에서이루어졌는데, 42,838명의환자를대상으로한 6개그룹의초음파검사에서 150건 (0.35%) 의부가적인유방암이 126명의환자에서초음파검사에서만관찰되었다 (Table 3). 이러한유방초음파는유방의밀도가높을수록유용성이높아 126명의환자중 114명 (90.5%) 에서비균질성치밀유방이나매우치밀한유방 (pattern 3 or 4) 을보였고유방암의위험도가높은환자군에서초음파로암을발견할확률이 2-3배높았다. 또한초음파에서만발견된유방암환자의약 50% 에서가족력이나이전에비정형상피형성증등이있었다. 2003년 Berg [12] 가발표한 ACRIN6666 연구결과에의하면고위험군여성에서의유방촬영술과함께유방초음파검진을함으로써조기유방암의발견율을높일수있다고하였다. 하지만이러한유방초음파검사가선별검사로이용되기에는미흡한몇가지사항이있는데, 검사자에대한의존도가높고무작위추출표본검사로서의초음파검사로아주작은크기의유방암을발견할수있다던지유방암으로인한사망률을줄인다는통계학적근거가아직확립되지않았다. 또한진단과정에서위양성을피할수없어환자에게불안감을조성할수있고, 추가검사와조직검사를위해시간과비용이필요하며조직검사가양성으로나오는경우가많아초음파검사를선별검사에이용하는것은앞으로많은비교분석이필요하다 [13,14]. 1) 세침흡인생검 (Fine needle aspiration biopsy, FNAB) 19-20게이지를이용하여흡인을하고검체가맑은액체나치즈같은성분이면단순낭종, 유낭종 (galactocele) 으로진단할수있고반드시세포검사를보낼필요는없다. 하지만흡인후병변이없어지지않거나혈성분비물이면중심생검 (core biopsy) 를시행한다. 민감도는 62-89% 으로재생검을시행하는경우가종종발생한다. 서구에서는연령에따라지속적으로증가하지만우리나라에서는 50 세를기점으로 40-49세에서가장많은발생을보이다가이후감소하는경향을보이고, 사망률은발생률과비슷하게 50세근처에서가장높고이후감소한다 [15-17]. 생리주기중유방조직의유사분열정도는에스트로젠과프로제스테론의농도가낮은난포기에는매우천천히일어나고그농도가높은황체기에는매우활발히일어난다. 유방세포는이런호르몬에의하여증식-분화를하는데, 호르몬에대한노출시간이길면이러한증식과분화를하는횟수가많아지고이런과정속에서암세포의발현기회가늘어난다 [18]. 이것은규칙적인배란주기가유방암의위험을증가시킨다는것을말해준다 [19]. 1) 이른초경 11세이전의이른초경은유방암의위험인자로여겨지고 15세이후의늦은초경은유방암의위험이감소하는것으로알려져있으며 [20], 초경이 1년늦어질경우나중에유방암의위험이 5% 씩감소한다는보고가있다 [21]. 2) 늦은폐경평균폐경연령보다 1년씩폐경이늦어진다면유방암위험이 3% 씩증가한다는연구결과가있다 [22]. 2) 중심생검 (Core needle biopsy) 14-18게이지를이용하며, 유방병변에관해서는 14게이지가선호된다. 4-5조각의조직을얻는것이좋으며민감도는 92-98%, 특이도는 % 로보고되고있다. 이는 Breast Imaging-Reporting and Data system (BI-RADs) category 4, 5병변생검시시행한다. 3) 흡인조직검사 (Vacuum assited biopsy) 주로 8, 11게이지가사용되며한번의바늘삽입으로많은양의검체를얻어정확한진단이가능하다. 즉다른검사방법에비해병리학적과소평가률 (underestimation rate) 이적다. 하지만대부분의유방병변은중심생검으로진단이가능하여모든병변에대해흡인조직검사를시행할필요는없다. 적응증은유방촬영술에서보인석회화가초음파에서보이는경우, 병리학적과소평가가예측이되는경우, 중심생검에서양성으로진단되었지만영상소견과의불일치를보이는경우, 추적검사상병변이자랄가능성이있다고판단되는경우시행할수있고, 단순낭종은적응증이되지않는다. 3) 미산부 4) 늦은연령의첫만삭임신늦은연령의산모에서이른연령의산모보다에스트로젠농도가좀더높게측정되는것을보면알수있는데 [23], 이른연령에서의만삭임신은유방상피조직의적절한분화가이루어지고늦은연령에서의만삭임신은유방상피의부적절한분화가일어날수있다 [24]. 1) 비만비만은종종무배란주기를보이는데이는에스트로젠단독이나에스트로젠과프로제스테론의누적효과가발생하여호르몬에대한과다노출이생길수있다 [25]. 폐경후마른여성에비하여비만여성에서의에스트로젠고농도또한유방암의위험인자로작용한다 [26]. 71

6 KJOG Vol. 54, No. 2, ) 음주알코올대사 (alcohol metabolism) 와관계된효소는간 (liver), 유방을포함하여다른조직에도존재한다. 알코올은대사되어아세트알데하이드 (acetaldehyde) 로되는데, 이것이에스트로젠의대사와반응에있어미묘한변화를가져오고산소라디칼을형성하여 DNA손상을유도하게된다 [27]. 한국인의가족성유방암의약 21%, 젊은연령의유방암의약 11%, 산발성유방암의약 2.6% 에서 BReast CAncer (BRCA) 돌연변이가발견되었으며, 한국인의이러한유전자돌연변이빈도는서구와큰차이가없다 [28]. 일차관계 (the first relatives) 의가족에서는약 7.9배정도, 일차와이차를포괄하는가족관계 (first and second degree) 에서는약 2배 ( 범위, ) 정도로유방암의위험을증가시키는것으로알려져있다 [29,30]. 1) 예방인자와유발인자모유수유 [31], 운동 [31], 과일, 야채섭취 [32] 등은유방암을예방하는것으로알려져있으며흡연은유방암을유발하는것으로알려져있다. 2) 폐경기여성에서호르몬요법 (Relative risk, RR= 1.0) [33] 3) 포화지방, 육류섭취, 전리방사선 (Ionizing radiation) 1) 유방암위험을증가시키는요인 - 출생시과체중 (RR:1.15), 늦은연령의산모 (RR:1.13), 부계연령 (RR:1.12) : 임신시높은농도의성장인자 (growth factor) 에노출이되거나 insulin-like growth factor 2 (IGF2) 유전자의 imprinting의소실, 그리고 cancer stem-cell의형성은유방암의발생에관여하고 [35], 출생시과체중을보이는경우산모에서높은농도의성장인자가관찰되며 [36], 늦은연령의산모는젊은연령의산모보다에스트로젠농도가더높게측정된다. 부계연령 (paternal age) 이높은경우그자녀에서상염색체우성질환의발생이좀더높은것으로알려져있고, spermatozoa에서의염색체이상이높은비율로관찰된다 [37,38]. 2) 유방암위험과관계없는요인 - 임신기간 (RR:0.95) : 과거짧은임신기간과조산으로태어난여성이나중에유방암의위 험이증가한다는연구와 [39], 감소한다는연구가있었는데 [40] 이는임신기간과자궁내에스트로젠, 성장인자의노출은비례한다는이론을뒷받침해주고있으나최근연구에서는관계가없는것으로알려져있다. 3) 유방암의위험을감소시키는요인 - 자간증, 자간전증 (RR:0.48), 쌍태임신 (RR:0.95) : 자간증또는전가간증그리고쌍태임신을보이는산모는체표면적이증가하고임신연령이높아유방암의위험인자라고생각이되었으나실제연구에서는그렇지않았다 [39]. 하지만이연구의실험군과대조군의수가적어앞으로많은연구가필요하리라생각이된다. 여성호르몬은유방암의병인론을설명할수있는중요한인자이며유방암의위험인자가운데생식인자 (reproductive and hormonal factors) 는가장중요한요인으로알려져있어, 산부인과영역에서유방암의원인과치료에대한접근이필요하다. 과거연구들에서는경구피임약이유방암의위험을다소증가시키는것으로보고되었다. 하지만이상대위험도가낮거나미미하여경구피임약의잇점과유방암의위험인자로서의의미를반드시생각해야하는데 [41], 최근에보고되는연구들에서는임상적으로경구피임약이유방암의중요한위험인자가아니라고하였고유방암의가족력이나 BRCA1 나 BRCA2 유전자돌연변이를보이는고위험군에서의경구피임약복용도유방암의위험을증가시키지않는다고하였다 [42]. 2002년 Women s Health Initiative (WHI) 연구에의하면폐경후여성에서 5.2년이상의복합호르몬요법 (estrogen+progesterone, E+P) 은침윤성유방암의위험을약 26% 증가시킨다고하였고 [43], 다른연구에서도이러한호르몬요법에따른유방암의상대위험도를밝힌바있다 (Table 4). 하지만이러한호르몬요법이서구에서는유방암의가능한위험요인이나한국에서는위험성이확실하지않은상태이므로앞으로더많은연구가필요하리라생각된다 [43]. 또한자궁이없는경우, 대체요법으로에스트론단독투여가유용하며이경우유방암과는상관관계가없는것으로알려져 E+P 요법은유방암증가와상관관계가있는듯하다. 그리고아직연구는불충분하나프로게스테론의종류를잘선택함으로써유방암발생을줄일가능성도있으나현재아직도논쟁의대상이다. 72

7 Jihoon Yu, et al. The proper approaches for breast disease Table 4. Million Women Study Collaborators (from Beral V, et al. Lancet 2003;362:419-27, with permission Elsevier) [68] Relative risk of breast cancer relating to HRT use HRT use at baseline Cases/population Relative risk (95% FCI) * Never users 2894/392, ( ) Current users 3202/285, ( ) Last use <5 yr previously 579/81, ( ) Last use 5-9 yr previously 207/29, ( ) Last use >10 yr previously 79/12, ( ) χ 2 for heterogeneity between users = 161.5, P< HRT use at baseline Cases/population Relative risk (95% FCI) * All never users 2894/392, ( ) All past users 1044/150, ( ) Current users of : Oestrogen only 991/115, ( ) Oestrogen/progestogen 1934/142, ( ) Tibolone 184/18, ( ) Other/unknown types 93/ ( ) FCI, fl oated CI. * Relative to never users, stratifi ed by age, time since menopause, parity and age at fi rst birth, family history of breast cancer, body mass index, region, and deprivation index. 1) 병리학적특성임신중유방암을진단받은경우는그리흔하지않지만 (in the region of 1 in 1000 pregnancies) 진단당시높은종양등급과임파절전이를보인다 [44]. 약 60-80% 의환자에서에스트로젠수용체 (estrogen receptor, ER) 음성을보이며 28-58% 에서 Her2-Neu (HER2) 양성을보인다 [45]. 2) 진단과치료 (1) 정상임신중에유방조직에서는비정형세포양상 (atypical cytological features) 이흔히관찰되기때문에진단을위한조직검사로중심생검 (core biopsy) 이추천된다. (2) 영상학적검사로유방촬영술과초음파그리고자기공명영상이이용되고있다. 유방촬영술의전리방사선으로인한태아의영향에관해서는방사선피폭누적량과임신주수에따른이해가필요하다. 흉부 X-ray 와유방촬영술시노출되는전리방사선의양은약 10 mgy 이하임을감안하고, 착상과기관형성이시작되는초기임신시에는전리방사선의누적피폭량이 mgy 이상일때태아사 (fetal loss) 와기형을초래할수있다고하며, 기관형성이완료되는임신후반기에는약 1,000 mgy정도까지는이런태아합병증의발생이드물다고하므로유 Table 5. Potential adverse effects cytotoxic agent on the foetus First trimester Second and third trimesters Spontaneous abortion Intrauterine growth retardation Congenital malformations Impaired neurological development Cardiac toxicity Premature labour Infertility Carcinogenesis 방병변의진단에이용이되는유방촬영술로인한태아합병증은그빈도가미미하거나거의없다고할수있다 [46]. (3) 임신중유방암의수술에있어서는임신중산모의생리학적변화를인지하고있어야한다. 예를들면, 심박출량의증가, 산소소모의증가, 신장혈류의증가등을고려해야하며, 전신마취등으로인한태아의감시도중요한사항이다. (4) 방사선치료는많은양의전리방사선에노출이되기때문에대부분임신이종료된후로미루는경우가흔하고대부분수술후항암치료를시행하는데임신주수에따른항암치료의합병증은표와같다 (Table 5) [45]. 3) 유방암치료후임신유방암치료후임신이되면높은농도의에스트로젠에노출이되어재발의위험이높아질수있다. 또한 BRCA1 그리고 BRCA2 유전자의 73

8 KJOG Vol. 54, No. 2, 2011 돌연변이를갖는보인자에서는임신자체가유방암의위험인자로작용한다 [47]. 하지만실제유방암치료후임신이환자의생존율에명확하게나쁜영향을끼친다는보고는없다 [48]. 그리고최근연구에서도유방암치료후임신이된환자들의예후도비임신환자와크게다를바가없는것을알수있다 [49]. 유방암치료가이루어지고얼마후에임신을계획하느냐하는것에대하여, 대부분의유방암의재발이치료후 2년이내에발생하는것으로알려져있기때문에임상의들은약 2-3년후에임신을계획하도록하고있으며, 타목시펜 (tamoxifen) 의사용기간에관하여논의가필요하다 [49,50]. 1) 타목시펜치료시작전필요한부인과적검사는자세한병력청취 ( 나이, 이전항암치료종류, 이전호르몬치료, 체표면적 (kg/ m2 ), 초경연령, 폐경연령, 산과력, 모유수유등 ) 와골반의이하학적검사, 자궁경부세포진검사, 자궁초음파검사를통한자궁내막두께의측정등이있다. 적수술, 항암제치료후재발과원격전이를방지하기위한약제로에스트로젠수용체혹은프로게스테론수용체가양성인유방암환자에게투여하면약 40% 이상의재발및전이율감소의효과가있다고알려져있다 [51]. 현재추천되는보조적타목시펜치료는 5년동안하루 20 mg 복용이표준요법으로되어있다 [52]. (2) 폐경후타목시펜요법폐경후보조호르몬치료는타목시펜이표준치료로알려져왔으나, 몇개의 aromatase inhibitor (AI) 의대규모무작위 3상임상연구결과 [53-57] 가발표되면서 AI 요법이대두가되었다. Anastrozole, letrozole 등의 3세대 AI와타목시펜의비교연구에의하면, 이들약제는타목시펜보다무병생존기간을연장시키고일부에서는전체생존기간도연장할수있는것으로나타나 1차약제로쓰여지고있다 [52]. 또한부작용면에서도근골격계의질환빈도는증가하지만타목시펜에서나타나는작열감, 질분비물증가, 질출혈, 자궁내막암등의빈도는줄어드는것으로알려져있다 (Table 6). 하지만이러한 AI의선택과사용기간에대해서는앞으로더많은연구가필요한단계이다. 2) 수술후타목시펜요법 (1) 폐경전타목시펜요법폐경전여성에서의호르몬치료는타목시펜과난소기능억제제로크게나누어볼수있다. 타목시펜은안면홍조, 질분비물증가등의흔한부작용과자궁내막암, 혈전등의부작용이있으나그빈도가낮아근치 3) 타목시펜은진행된유방암환자에서이에따른부인과적선별검사및추적검사의필요성이대두되었는데, 이는타목시펜이유방조직의에스트로젠수용체에는 antagonist로작용하나자궁을포함한다른조직에서는 agonist로작용하기에부인과적접근이필요하다 [58]. 무증상을보이는폐경기유방암환자의타목시펜치료전자궁내막에 Table 6. Summary of randomized trials of adjuvant aromatase inhibitors Trial ATAC BIG I-98 IES ABCGS Trial 8 ITA MA-17 Sample size 9,366 total 5,216 HR+ 8,000 total 5,055 HR+ 4,742 total 3,853 HR+ 3,700 total All HR+ 448 total All HR+ 5,170 total All HR+ All LN+ Follow-up (month) Study design 68 5 yr Tam 5 yr Anastrozole 26 5 yr Tam 5 yr Letrozole Letrozole Tam Tam Letrozole yr Tam Tam 2-3 yr Tam Exemestane 30 2 yr Tam Tam 2 yr Tam Anastrozole yr Tam Tam 2-3 yr Tam Anastrozole 30 5 yr Tam 5 yr Letrozole 5 yr Tam Placebo Primary end point HR (95% CI) for primary end point DFS 0.87 ( ) DFS 0.81 ( ) DFS 0.68 ( ) EFS 0.68 ( ) PFS 0.43 ( ) EFS 0.58 ( ) ATAC, Arimidex, Tamoxifen, Alone or in Combination; BIG, Breast International Group; IES, Intergroup Exemestane Study; ABCSG, Austrian Breast and Colorectal Cancer Study Group; ITA, Italian Tamoxifen Anastrozole; MA, Multinational multiclinical randomized study of Aromatase inhibitor; HR+, hormone receptor-positive; LN+, lymph node-positive; Tam, tamoxifen; DFS, disease-free survival; EFS, event-free survival; PFS, progression-free survival. 74

9 Jihoon Yu, et al. The proper approaches for breast disease Table 7. Histopathologic findings in adnexal masses in women with breast cancer Ovarian histologic finding No. of patient (n=54) 대한초음파검사상자궁내막의두께가 5 mm 이상인경우비정상소견으로간주하고이에대한조직학적검사가필요하다. 이런경우비정상병리소견을보이는경우는 18.6% 정도이며용종 (polyp) 이가장흔한병변이다 [59]. 타목시펜사용중자궁내막이두께가 5 mm를넘는다면비정상병리소견의비율이증가하고특히질출혈등의증세가보인다면반드시자궁내막에대한조직학적확진이필요하다 [60]. 타목시펜사용에따른자궁병변의빈도는그용량과기간에비례한다고알려져있다. 1994년발표된대규모임상연구인 National Surgical Adjuvant Breast and Bowel Project (NSABBP) 의결과를보면수술후 5년미만의타목시펜사용환자에서의자궁내막암의빈도는 0.12% 였고, 5년이상사용한경우는 0.63% 로증가되는것으로나타났다 [61]. 유방암치료후타목시펜을복용하는환자에대하여 NSABBP에서는최소한 1년마다부인과검사를받을것을권고하고있다. No. of masses (n=72) Benign Simple cyst 8 9 Serous cystadenoma 7 8 Endometrioma 6 7 Mucinous cystadenoma 4 4 Teratoma 4 4 Fibroma 2 3 fi broid 1 1 Hydrosalpinx 1 1 Hemorrhagic cyst 1 1 Mesosalpinx cyst 1 1 Follicular cyst 1 1 Primary ovarian carcinoma 7 11 Serous ovarian carcinoma 5 8 Mixed serous and endometrioid carcinoma 1 2 Breast metastasis 7 * 14 Lobular carcinoma 3 * 6 Ductal carcinoma 4 8 *Two patients had breast metastases with a coexistent benign ovarian mass; one had a serous cyst, and one had a hemorrhagic cyst. One patient had breast metastases with a coexistent fi brothecoma. 1) 유방암환자에서부속기에종괴가보이는경우에원발종양과속발성종양의빈도가모두 2배이상증가한다 [62]. 이는 BRCA유전자변이를보이는집단에서더욱흔하고난소암의위험도증가한다. 2) 난소에전이된암중유방암이원발암인경우는 % 로관찰 Table 8. Comparison of ovarian histopathologic finding and stage of breast cancer at US * Stage of breast cancer at time of US 되고 [63,64], 유방암환자에서보이는부속기종괴의조직학적형태에관한연구가있었는데, 이중난소에발생한악성종양중원발암과유방암으로부터속발된악성종양의발생빈도는비슷하였다 (Table 7) [65]. 또한이연구에서유방암병기에따른난소종괴의조직학적소견은표와같다 (Table 8). 3) 과거에유방암의병기가진행이될수록전이성난소암의진단시기는짧아진다고하였고유방암발병후약 개월후에전이성난소암이진단된다고하였다 [63]. 최근유방암은여성암발생에서수위를차지하고앞으로도증가될것으로생각된다. 유방암발병원인중가장중요한요인은바로생식요인이며유방질환의치료는여러분야에걸친종합적인진료가필요하다. 따라서여성의생식기관에대하여가장잘이해하고있는산부인과의사가유방질환을이해하고치료에동참하며이에따르는여러가지문제들을해결하는것은합당하다할수있으며전문적인치료의일환이되리라생각한다. References Benign (n = 38) Primary ovarian cancer (n = 6) Breast metastases (n = 7) 0 8 (21) 0 0 Ⅰ 11 (29) 4 (66) 0 Ⅱ 13 (34) 1 (17) 0 Ⅲ 1 (3) 1 (17) 0 Ⅳ 5 (13) 0 7 (100) Unknown Numbers in parentheses are percentages, with the denominator being the number of patients with known breast cancer stage. The P-value for ovarian histopathologic fi nding and the stage of breast cancer at the time of US was<0.01. *Based on 51 patients with known breast cancer stage. Based on 51 patients with known breast cancer stage, ovarian histopathologic fi nding (benign and ovarian cancer breast metastases), and stage of breast cancer (0, Ⅰ, Ⅱ, Ⅲ, Ⅳ). 1. Venta LA, Dudiak CM, Salomon CG, Flisak ME. Sonographic evaluation of the breast. Radiographics 1994;14: Boyd NF, McGuire V, Shannon P, Cousins M, Kriukov V, Mahoney L, et al. Effect of a low-fat high-carbohydrate diet on symptoms of cyclical mastopathy. Lancet 1988;2:

10 KJOG Vol. 54, No. 2, Fentiman IS, Caleffi M, Brame K, Chaudary MA, Hayward JL. Double-blind controlled trial of tamoxifen therapy for mastalgia. Lancet 1986;1: Gateley CA, Mansel RE. Management of cyclical breast pain. Br J Hosp Med 1990;43: Conry C. Evaluation of a breast complaint: is it cancer? Am Fam Physician 1994;49:445-50, Chaudary MA, Millis RR, Davies GC, Hayward JL. The diagnostic value of testing for occult blood. Ann Surg 1982;196: Pruthi S. Detection and evaluation of a palpable breast mass. Mayo Clin Proc 2001;76: Lucas JH, Cone DL. Breast cyst aspiration. Am Fam Physician 2003;68: Morrow M. The evaluation of common breast problems. Am Fam Physician 2000;61:2371-8, Is fi brocystic disease of the breast precancerous? Arch Pathol Lab Med 1986;110: Berg WA, Gutierrez L, NessAiver MS, Carter WB, Bhargavan M, Lewis RS, et al. Diagnostic accuracy of mammography, clinical examination, US, and MR imaging in preoperative assessment of breast cancer. Radiology 2004;233: Berg WA. Rationale for a trial of screening breast ultrasound: American College of Radiology Imaging Network (ACRIN) AJR Am J Roentgenol 2003;180: Gordon PB. Ultrasound for breast cancer screening and staging. Radiol Clin North Am 2002;40: Gordon PB, Goldenberg SL. Malignant breast masses detected only by ultrasound. A retrospective review. Cancer 1995;76: Yoo KY, Kim Y, Park SK, Kang D. Lifestyle, genetic susceptibility and future trends of breast cancer in Korea. Asian Pac J Cancer Prev 2006;7: Yoo KY, Kang D, Park SK, Kim SU, Kim SU, Shin A, et al. Epidemiology of breast cancer in Korea: occurrence, high-tisk groups, and prevention. J Korean Med Sci 2002;17: Yoo KY, Shin HR, Park SK, Yoon HC, Shin AS, Kang DH, et al. Is breast cancer incidence rate further increasing in Korea? Korean J Epidemiol 2001;23: Potten CS, Watson RJ, Williams GT, Tickle S, Roberts SA, Harris M, et al. The effect of age and menstrual cycle upon proliferative activity of the normal human breast. Br J Cancer 1988;58: Henderson BE, Ross RK, Judd HL, Krailo MD, Pike MC. Do regular ovulatory cycles increase breast cancer risk? Cancer 1985;56: Kelsey JL, Bernstein L. Epidemiology and prevention of breast cancer. Annu Rev Public Health 1996;17: Hunter DJ, Spiegelman D, Adami HO, van den Brandt PA, Folsom AR, Goldbohm RA, et al. Non-dietary factors as risk factors for breast cancer, and as effect modifi ers of the association of fat intake and risk of breast cancer. Cancer Causes Control 1997;8: Breast cancer and hormone replacement therapy: collaborative reanalysis of data from 51 epidemiological studies of 52,705 women with breast cancer and 108,411 women without breast cancer. Collaborative Group on Hormonal Factors in Breast Cancer. Lancet 1997;350: Petridou E, Panagiotopoulou K, Katsouyanni K, Spanos E, Trichopoulos D. Tobacco smoking, pregnancy estrogens, and birth weight. Epidemiology 1990;1: de Waard F, Trichopoulos D. A unifying concept of the aetiology of breast cancer. Int J Cancer 1988;41: Henderson BE, Ross R, Bernstein L. Estrogens as a cause of human cancer: the Richard and Hinda Rosenthal Foundation award lecture. Cancer Res 1988;48: Ota DM, Jones LA, Jackson GL, Jackson PM, Kemp K, Bauman D. Obesity, non-protein-bound estradiol levels, and distribution of estradiol in the sera of breast cancer patients. Cancer 1986;57: Koch OR, Pani G, Borrello S, Colavitti R, Cravero A, Farre S, et al. Oxidative stress and antioxidant defenses in ethanolinduced cell injury. Mol Aspects Med 2004;25: Son BH, Ahn SH, Lee MH, Park SK, Kim SW; Korean Breast Cancer Society. Hereditary breast cancer in Korea: a review of the literature. J Breast Cancer 2008;11: Park SK, Yoo KY, Kang DH, Ahn SH, Noh DY, Choe KJ. The estimation of breast cancer disease-probability by difference of individual susceptibility. Cancer Res Treat 2003;35: Kim EK, Kim KS, Park SK, Ahn SH, Lee MH, Kim SW, et al. The Korean Hereditary Breast Cancer (KOHBRA) Study: Protocol Review. J Breast Cancer 2007;10: Lee SY, Kim MT, Kim SW, Song MS, Yoon SJ. Effect of lifetime lactation on breast cancer risk: a Korean women s cohort study. Int J Cancer 2003;105: Do MH, Lee SS, Jung PJ, Lee MH. Intake of fruits, vegetables, and soy foods in relation to breast cancer risk in Korean women: a case-control study. Nutr Cancer 2007;57: Hong SA, Kim K, Nam SJ, Kong G, Kim MK. A case-control study on the dietary intake of mushrooms and breast cancer 76

11 Jihoon Yu, et al. The proper approaches for breast disease risk among Korean women. Int J Cancer 2008;122: Xue F, Michels KB. Intrauterine factors and risk of breast cancer: a systematic review and meta-analysis of current evidence. Lancet Oncol 2007;8: Schernhammer ES. In-utero exposures and breast cancer risk: joint effect of estrogens and insulin-like growth factor? Cancer Causes Control 2002;13: Michels KB, Xue F. Role of birthweight in the etiology of breast cancer. Int J Cancer 2006;119: Jung A, Schuppe HC, Schill WB. Are children of older fathers at risk for genetic disorders? Andrologia 2003;35: Glaser RL, Jabs EW. Dear old dad. Sci Aging Knowledge Environ 2004;2004:re Ekbom A, Hsieh CC, Lipworth L, Adami HQ, Trichopoulos D. Intrauterine environment and breast cancer risk in women: a population-based study. J Natl Cancer Inst 1997;89: Hubinette A, Lichtenstein P, Ekbom A, Cnattingius S. Birth characteristics and breast cancer risk: a study among likesexed twins. Int J Cancer 2001;91: Casey PM, Cerhan JR, Pruthi S. Oral contraceptive use and risk of breast cancer. Mayo Clin Proc 2008;83: Brohet RM, Goldgar DE, Easton DF, Antoniou AC, Andrieu N, Chang-Claude J, et al. Oral contraceptives and breast cancer risk in the international BRCA1/2 carrier cohort study: a report from EMBRACE, GENEPSO, GEO-HEBON, and the IBCCS Collaborating Group. J Clin Oncol 2007;25: Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C, Stefanick ML, et al. Risks and benefi ts of estrogen plus progestin in healthy postmenopausal women: principal results From the Women s Health Initiative randomized controlled trial. JAMA 2002;288: Middleton LP, Amin M, Gwyn K, Theriault R, Sahin A. Breast carcinoma in pregnant women: assessment of clinicopathologic and immunohistochemical features. Cancer 2003;98: Ring AE, Smith IE, Ellis PA. Breast cancer and pregnancy. Ann Oncol 2005;16: Sharp C, Shrimpton JA, Bury RF. Diagnostic medical exposures: advice on exposure to ionizing radiation during pregnancy. Oxon (England): National Radiological Protection Board; Jernstrom HC, Johannsson OT, Loman N, Borg A, Olsson H. Reproductive factors in hereditary breast cancer. Breast Cancer Res Treat 1999;58: Kroman N, Jensen MB, Melbye M, Wohlfahrt J, Mouridsen HT. Should women be advised against pregnancy after breastcancer treatment? Lancet 1997;350: Ives A, Saunders C, Bulsara M, Semmens J. Pregnancy after breast cancer: population based study. BMJ 2007;334: Oktay K, Buyuk E, Libertella N, Akar M, Rosenwaks Z. Fertility preservation in breast cancer patients: a prospective controlled comparison of ovarian stimulation with tamoxifen and letrozole for embryo cryopreservation. J Clin Oncol 2005;23: Neven P, De Muylder X, Van Belle Y. Tamoxifen-induced endometrial polyp. N Engl J Med 1997;336: Polychemotherapy for early breast cancer: an overview of the randomised trials. Early Breast Cancer Trialists Collaborative Group. Lancet. 1998;352: Howell A, Cuzick J, Baum M, Buzdar A, Dowsett M, Forbes JF, et al. Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial after completion of 5 years adjuvant treatment for breast cancer. Lancet 2005;365: Jakesz R, Jonat W, Gnant M, Mittlboeck M, Greil R, Tausch C, et al. Switching of postmenopausal women with endocrineresponsive early breast cancer to anastrozole after 2 years adjuvant tamoxifen: combined results of ABCSG trial 8 and ARNO 95 trial. Lancet 2005;366: Coombes RC, Hall E, Gibson LJ, Paridaens R, Jassem J, Delozier T, et al. A randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer. N Engl J Med 2004;350: Goss PE, Ingle JN, Martino S, Robert NJ, Muss HB, Piccart MJ, et al. A randomized trial of letrozole in postmenopausal women after fi ve years of tamoxifen therapy for early-stage breast cancer. N Engl J Med 2003;349: Baum M, Budzar AU, Cuzick J, Forbes J, Houghton JH, Klijn JG, et al. Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early breast cancer: first results of the ATAC randomised trial. Lancet 2002;359: Kangas L. Agonistic and antagonistic effects of antiestrogens in different target organs. Acta Oncol 1992;31: Garuti G, Cellani F, Centinaio G, Sita G, Nalli G, Luerti M. Baseline endometrial assessment before tamoxifen for breast cancer in asymptomatic menopausal women. Gynecol Oncol 2005;98: Vosse M, Renard F, Coibion M, Neven P, Nogaret JM, Hertens D. Endometrial disorders in 406 breast cancer patients on tamoxifen: the case for less intensive monitoring. Eur J Obstet 77

12 KJOG Vol. 54, No. 2, 2011 Gynecol Reprod Biol 2002;101: Fisher B, Costantino JP, Redmond CK, Fisher ER, Wickerham DL, Cronin WM. Endometrial cancer in tamoxifen-treated breast cancer patients: fi ndings from the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-14. J Natl Cancer Inst 1994;86: Lingeman CH. Etiology of cancer of the human ovary: a review. J Natl Cancer Inst 1974;53: Demopoulos RI, Touger L, Dubin N. Secondary ovarian carcinoma: a clinical and pathological evaluation. Int J Gynecol Pathol 1987;6: Moore RG, Chung M, Granai CO, Gajewski W, Steinhoff MM. Incidence of metastasis to the ovaries from nongenital tract primary tumors. Gynecol Oncol 2004;93: Hann LE, Lui DM, Shi W, Bach AM, Selland DL, Castiel M. Adnexal masses in women with breast cancer: US findings with clinical and histopathologic correlation. Radiology 2000;216: Dixon MJ, Bundred NJ. Diagnosis and management of benign breast diseases. In: Harris JR, Lippman ME, Morrow M, Osborne CK, editors. Diseases of the breast. 2nd ed. Philadelphia (PA): Lippincott Williams and Wilkins; p Klein S. Evaluation of palpable breast masses. Am Fam Physician 2005;71: Beral V; Million Women Study Collaborators. Breast cancer and hormone-replacement therapy in the Million Women Study. Lancet 2003;362: 유방질환에대한적절한접근방법 을지대학교의과대학산부인과학교실유지훈, 황인택 부인과의사는여성의일차진료를하며, 유방은여성생식기관이고생식호르몬은유방암의가장중요한위험요인이다. 따라서부인과의사가유방질환을진료함은타당하다고할수있다. 유방진찰은부인과검사의하나이고유방질환의치료에대한지식은최근부인과진료의필수요소로, 부인과의사는유방질환의과거력과이하학적검사에더불어진단에대한이해가있어야한다. 유방암환자가여러전문가의치료를받게되고여기에부인과의사가포함되는것은당연한과정이될것이다. 중심단어 : 산부인과의사, 생식요인, 유방질환 78