종설 대한세포병리학회지 ISSN 1017-0391 유방세침흡인세포검사의진단적함정 : 위양성과위음성 인제대학교의과대학병리과 박경미 Diagnostic Pitfalls in Breast Fine Needle Aspiration Cytology: False Positive and False Negative Kyeongmee Park, M.D. Department of pathology, Inje university Sanggye Paik hospital, Seoul, Korea 논문접수 : 2007 년 7월 24일 게재승인 : 2007 년 7월 25일 책임저자 : 박 경 미 주 소 : (139-797) 서울특별시노원구상계 7동 761-1 인제대학교의과대학상계백병원병리과 전 화 : 02-950-1263 팩 스 : 02-951-6964 E-mail address : kmpark@sanggyepaik.ac.kr Fine needle aspiration cytology (FNAC) has become a highly preferred, minimally invasive diagnostic tool of choice in the diagnosis of a palpable breast mass owing to its sensitivity, specificity, cost-effectiveness, and expediency. Although breast needle biopsies have been widely employed recently due to the increased detection rate of nonpalpable early lesions, the importance of the use of FNAC cannot be underestimated. It comprises part of the diagnostic triad for the breast along with a physical examination and mammography, which together contribute to an increasing diagnostic accuracy. The differential diagnosis of a benign and malignant lesion is of the utmost importance in the diagnosis of breast lesions, and therefore the understanding of the possible diagnostic pitfalls is of great importance. (Korean J Cytopathol 2007;8(2):112-118) Key Words : Breast, Fine needle aspiration cytology 서 론 본 론 유방질환의세침흡인세포검사는높은민감도와특이도, 접근성의편리함, 경제성및안정성등으로진단적기여가크다. 1-4 최근방사선학적진단의발전과자가검진에대한인식도의증가로인하여비촉지성조기병변이증가함에따라유방의조직생검이늘어나는추세이지만세침흡인세포검사의중요성은지속적으로강조되고있다. 세침흡인세포검사는이학적검사, 유방촬영술 (mammography) 과함께유방의진단적 3요소라알려져있고세가지방법이병행할때진단적정확도가높다. 5-11 유방질환의진단중악성과양성병변의감별이가장우선이며따라서감별진단에있어실수하기쉬운함정을파악하는것이중요하다. 유방의세침흡인세포검사의적절성유방의세포소견을진단하기에앞서흡인된세포의양과도말표본상태의적절성을정확하게판단하는일이중요하다. 각세포를자세히관찰하기전저배율에서세포들의전반적형태를파악하여도말된세포군집이 3차원또는 2차원구조를이루었는지살펴보고세포군집내에섬유혈관성중심을갖는유두상구조가관찰되는지등의전반적인상을파악한다. 흡인된세포들이군집을이루었는지낱개로흩어져있는지관찰하는것도중요하다. 세포의핵모양과세포질뿐만아니라아포크린화생과같은 2차적변화의동반유무도관찰한다. 유방의세침흡인세포검사 112 대한세포병리학회지제18권제2호 / 2007
의중요한소견중의하나가근상피세포의존재유무이다. 세포군집내에서상피세포와근상피세포의두종류가관찰되는경우양성으로간주할수있는좋은근거가된다. 배경에기질조직이나낭성변화를의심할만한액체성물질이나조직구를관찰하는것도도움이된다. 악성진단의근거악성으로진단할수있는근거로제시된네가지소견으로첫째, 흡인된세포의밀도가매우높은경우둘째, 세포의응집력이감소한경우셋째, 세포학적비정형성넷째, 비정형적세포들이개개로산재되어있는소견이다. 12,13 만약위의네가지중세가지소견만관찰되는경우에는암종이의심된다고판독하며두가지소견만관찰된다면세포학적비정형성을동반한상피증식성병변으로판독하는데만약세포학적비정형성이확실히관찰되면세가지소견을충족시키지못하더라도세포학적비정형성을동반한상피증식성병변으로판독한다. 만약세포밀도의증가만관찰된다면세포학적비정형성을동반하지않은상피증식성병변으로판독한다. 상기네가지소견이전혀없는경우에는세포소견만을기술하여보고한다. 감별진단 1. 섬유낭성변화종괴가촉지되어병원을방문하는경우중가장흔한병변으로진단되는섬유낭성변화에서는세침흡인시고무를찌르는것처럼느껴지며병변내에서바늘이잘움직여지지않을뿐만아니라실제로얻어지는세포의양이적으므로검체채취실패의경우와감별해야한다. 2. 섬유선종섬유선종은저배율에서세포의군집이유두상구조와비슷하게보이는경우가있는데이때유두상종양과감별이필요하다. 14 세포의군집이 3차원으로겹쳐보이며군집의가장자리가뾰족하고군집의중심에섬유혈관성구조를가지면유두상구조로판독한다 (Fig. 1). 그러나군집을이루는세포들이얇게한층으로되어있으며군집의가장자리가둥글고부드럽게이어지는사슴뿔모양을나타내면유두상구조로판단하지않고섬유선종으로판독한다 (Fig. 2). 이때점액성간질조직과함께배경에다수의나핵이산 재된다면섬유선종으로진단한다. 15 섬유점액성간질조직은섬유선종에서관찰할수있는세포학적소견이지만엽상종양에서도이러한소견을관찰할수있다 (Fig. 3). 3. 엽상종양임상적으로종괴의성장속도가빠르며밖으로돌출되는현상을보이면섬유선종보다는엽상종양으로진단하는것이좋다. 엽상종양으로진단하는데있어유사분열의정도에따라양성에서악성까지등급을나눈다. 즉, 간질조직내에서유사분열이흔히관찰되면악성의가능성이높다. 4. 신경초종신경초종에서도저배율에서세포군집의양상이섬유선종의간질조직과유사하게보일수있는데확대하여관찰해보면방추형세포들의핵은길고구불구불한모양을가지며책상배열의고밀도부위와세포의밀도가떨어지는부위로나누어져있다 (Fig. 4). 5. 점액성병변점액을생성하는병변에는양성병변부터암종까지다양하다. 이들의감별은주요상피세포군집에근상피세포가동반되는지의여부가가장중요하다. 상피세포와근상피세포로구성되어있는군집이질서정연한형태를취하고있으면점액류유사종양 (mucocele-like tumor) 으로진단할수있지만 (Fig. 5) 상피세포로만구성되어있고세포가여러겹으로중첩되며핵의과염색상이나다형성을보이고주변에풍부한혈관이흡인되는경우암종으로진단할수있다 (Fig. 6). 6. 유방의소엽암종유방의소엽암종은종양세포가비교적균일한크기와모양을가지는경우가흔하기때문에악성림프종과의감별이어려운경우가많다. 그러나소엽암종의경우에는일렬로이어지는군집을관찰할수있고 (Fig. 7) 악성림프종에서는개개로산재해있는소견이특징적이다 (Fig. 8). 유방세침흡인세포검사의위음성문헌보고에의하면유방세침흡인세포검사의위음성률은 2 18% 까지다양하게보고되어있는데그원인은크게 The Korean Journal of Cytopathology Vol 18 No 2 / 2007 113
박경미 : 유방 세침흡인 세포검사의 진단적 함정 Fig. 1. Papillary clusters. Three-dimensional projections have fibrovascular core. (Papanicolaou). Fig. 4. Schwannoma. Spindle cells of hypercellular area reveal nuclear palisading. (Papanicolaou). Fig. 2. Fibroadenoma. Cell clusters reveal staghorn configuration and many naked nuclei in the background. (Papanicolaou). Fig. 5. Mucocele-like tumor. Monotonous epithelial and myoepithelial cells are noted in mucoid background. (Papanicolaou). Fig. 3. Stromal tissue. Clusters composed of spindle cells and fibromyxoid stroma from a fibroadenoma (left). Clusters show high cellularity of spindle cells from a phyllodes tumor (right). (Papanicolaou). Fig. 6. Mucinous carcinoma. Hyperchromatic and pleomorphic cell clusters are present in mucinous background. (Papanicolaou). 114 대한세포병리학회지 제18권 제2호 / 2007
Fig. 7. Lobular carcinoma. Small, monomorphic cells and loosely cohesive small groups are noted. (Papanicolaou). Fig. 8. Non-Hodgkin's lymphoma. Monotonous neoplastic cells are individually scattered with no organoid arrangement. (Papanicolaou). 검체습득의실수 16-18 와판독의실수 19 두가지로나누어볼수있다. 검체습득의실수에대한예를들면다음과같다. 종괴의크기가매우작거나다발성병변인경우세침흡인검사가정확한부위에서이루어지지않을수있다. 낭성병변을동반한질환인경우에낭성물질만흡인되어중요한병변을간과하게된다면오진을초래할수있다. 이와같이낭성물질이흡인되는경우에는가능한한액체를모두흡인한후다시한번촉지하여남아있는고형성병변의유무를확인하여다시흡인하는것이중요하다. 심한섬유화나경화성변화를동반한경우에도세포를충분히얻지못할수있으며유방의크기가커서바늘이병변에도달하지못하는경우에도검체습득의실수가초래된다. 판독의실수에대한예를들면소엽암종처럼핵모양이작고균일한경우, 양성으로잘못인식할수있다. 세침흡인이괴사부위에서시행되는경우악성의진단이이루어지지못할수있다. 이와같은이유때문에충분한세포학적경험이강조되고있고 20 실제로숙련된세포병리전문의에의하여세침흡인검사와판독이이루어지는경우민감도, 특이도, 양성예측률및음성예측률이높다고보고된바있다. 18,21-25 위음성에비해위양성의확률은매우적게보고되어있다. 세포가건조되면크기가커지고핵의염색질이제대로보존되지않아과염색상처럼보이기때문에세포를얻은직후신속한도말과고정을하는것이중요하다. 세포학적오진을피하기위해서는가장흔한병변들의세포학적소견을잘습득하고유사한세포소견을갖는다른병변들을이해하는것이중요하다. 유방세침흡인세포검사의위양성 1. 섬유선종과관상암종양성종괴가악성으로진단되는경우중가장흔한예가섬유선종으로알려져있다. 26-30 섬유선종의위양성결과의원인은세포의고밀도, 핵의비정형성, 상피세포군집의가장자리의세포가개개로떨어져있는소견때문이다. 그러나핵의배열이한층으로균일하게질서를이루고있고배경에괴사의소견이동반되어있지않으며양성간질조직의군집과같은소견이동반되면섬유선종으로진단한다. 저배율상섬유선종에서와같이작고균일한세포로구성된도말표본을나타내는악성종양이있는데대표적으로관상암종이이에속한다. 14 그러나고배율로자세히관찰하면구성하고있는상피세포가한종류로되어있고근상피세포의존재가없음을확인할수있다 (Fig. 9). 2. 유두상종양유방종괴의감별진단중어려운경우의하나가유두상종양에서악성과양성을감별하는일이다. 실제로세포소견만으로악성과양성을단정지을수없다는의견이압도적이며조직검사가절대적으로중요한종양이기도하다. 31 그러나악성도를의심할수있는세포학적소견으로몇가지를예로든다면핵의과염색상과중첩및개개로흩어지는경향을들수있다. 31 배경에종양세포의나핵이풍부하게관찰되며낱개로흩어져있는원주상세포도악성으로의심하는중요한소견이다 (Fig. 10). 26,32 특이하게유두상암종의경우에는양성인경우에비해세포의모양이균일 The Korean Journal of Cytopathology Vol 18 No 2 / 2007 115
Fig. 9. Tubular carcinoma. Monotonous neoplastic cells consist of epithelial cells only with lumen formation. (Papanicolaou). Fig. 10. Papillary carcinoma. Papillary clusters with abundant isolated columnar cells are noted. (Papanicolaou). 하다. 종양세포가아포크린화생을동반한경우에는양성병변의가능성이더높다. 14,26,31 양성유두종이출혈성괴사를동반하는경우도있으므로괴사의소견만으로악성을진단할수없으며 26,33 그외에핵내봉입체, 미세석회화등이감별진단에도움이되지않는다. 14 3. 선증선증 (adenosis) 은악성으로오진되기쉬운양성병변의하나인데그이유는세침흡인시다량의상피세포가흡인되기때문이다. 그러나고배율로관찰해보면상피세포와함께근상피세포가흡인되는것을볼수있으며군집을이루는세포들이질서정연하게일정한간격을유지하며한층을만들고있다 (Fig. 11). Fig. 11. Adenosis. Monolayered clusters show orderly arrangement of epithelial and myoepithelial cells. (Papanicolaou). 4. 관확장세침흡인시괴사와유사한무형태의물질이흡인되는경우가있는데관확장 (duct ectasia) 이이에속한다. 이와같은물질은진정한괴사물질이아닌확장된관구조에축적된물질이다. 이때관찰되는상피세포는근상피세포와함께질서정연한세포군집을이루고있다 (Fig. 12). 5. 지방괴사지방괴사의경우에괴사물질이흡인될수있지만주변에염증세포와다핵거대세포를동반한다 (Fig. 13). 활성화된조직구나상피세포가뚜렷한핵소체를가지고있어악성으로오인하기쉽지만핵의염색상이정상이다. 6. 임신과관련된병변임신이나수유중인경우정상에비해핵의크기가증가하고핵소체가관찰되며염색상이진해서악성과의감별이매우어렵다. 무엇보다환자의병력이중요하지만세포학적으로암종에비해세포의모양과크기가일정하며핵막이부드럽고염색상이고르게분포되어있으며핵소체가뚜렷하지만하나씩고르게있다 (Fig. 14). 이에반해암종의경우에는핵의다형성과핵막이불규칙하고염색상의분포가일정하지않으며핵소체의크기와개수가불규칙하다. 116 대한세포병리학회지제 18 권제 2 호 / 2007
Fig. 12. Duct ectasia. Benign clusters of epithelial and myoepithelial cells with amorphous degenerating material are noted. (Papanicolaou). Fig. 14. Lactation adenoma. Slightly enlarged monotonous nuclei have dark but uniform chromatin and nucleoli. (Papanicolaou). Fig. 13. Fat necrosis. Activated epithelial cells and macrophages are present in inflammatory background. (Papanicolaou). 결 론 이상과같이유방병변의세포학적진단은난이도가매우높고함정이많기때문에많은시간의훈련이필요하며결국경험이풍부한세포병리전문의가시행하고판독하는것이바람직하다. 그리고임상소견과방사선소견이병행될때진단정확도가높다. 참고문헌 1. Ariga R, Bloom K, Reddy VB, et al. Fine-needle aspiration of clinically suspicious palpable breast masses with histopathologic correlation. Am J Surg 2002;184:410-3. 2. Smith TJ, Safali H, Foster EA, Reinhold RB. Accuracy and cost effectiveness of fine needle aspiration biopsy. Am J Surg 1985;149:540-5. 3. Lannin DR, Silverman JF, Pories WJ, Walker C. Cost effectiveness of fine needle aspiration biopsy of the breast. Ann Surg 1986;203:474-80. 4. Wanebo H, Feldman PS, Wilhelm MC, Covell JL, Binns RL. Fine needle aspiration cytology in Lieu of open biopsy in management of primary breast cancer. Ann Surg 1984;199:569-79. 5. Kaufman Z, Shpitz B, Shapiro M, Rona R, Lew S, Dinbar A. Triple approach in the diagnosis of dominant breast masses: combined physical examination, mammography, and fine-needle aspiration. J Surg Oncol 1994;56:254-7. 6. Negri S, Bonetti F, Capitanio A, Bonzanini M. Preoperative diagnostic accuracy of fine-needle aspiration in the management of breast lesions: comparison of specificity and sensitivity with clinical examination, mammography, echography, and thermography in 249 patients. Diagn Cytopathol 1994;11:4-8. 7. Hermansen C, Poulsen HS, Jensen J, et al. Diagnostic reliability of combined physical examination, mammography, and fine-needle picture("triple test") in breast tumors: a prospective study. Cancer 1987;60:1866-71. 8. Boquoi E, Kreuzer G. Aspiration biopsy cytology, mammography and clinical exploration: a modern set up in diagnosis of the breast[abstract]. Acta Cytol 1981;25:45. 9. Thomas JM, Fitzharris BM, Redding WH, et al. Clinical examination, xeromammography, and fine-needle aspiration cytology in diagnosis of breast tumors. BMJ 1978;2:1139-41. 10. Choi YD, Choi YH, Lee JH, Na. JH, Juhng SW, Choi C. Analysis of fine needle aspiration cytology of the breast: a review of 1,297 cases and correlation with histologic diag- The Korean Journal of Cytopathology Vol 18 No 2 / 2007 117
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