대한세포병리학회지제 17 권제 1 호 The Korean Journal of Cytopathology 17 (1) : 32-37 2006 ISSN 1017-0391 난소의원발투명세포암종의세포소견 성균관대학교삼성제일병원병리과 박지영 김혜선 최종순 = Abstract = Cytologic Findings of Clear Cell Carcinoma of Ovary Ji Young Park, M.D., Hye Sun Kim, M.D., and Jong Sun Choi, M.D. Department of Pathology, Samsung Cheil Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea The objective of this study was to evaluate the cytomorphologic features of histologically confirmed clear cell carcinoma of the ovary and to evaluate the applicability of scrape or fine-needle aspiration cytology in making an intraoperative diagnosis. We reviewed scrape or fine-needle aspiration cytology findings in tissues taken from 6 patients with clear cell carcinoma of the ovary. The cytologic diagnosis was based primarily on findings in alcohol-fixed, hematoxylin-eosin (H-E) stained smears. The formation of material resembling a basement membrane was a characteristic finding in these smears. This extracellular hyaline material was stained light pink with H-E and was frequently found within tumor cell clusters as well as in the background material. Multinucleated giant cells were found occasionally. Each tumor cell had an abundant, clear, or granular cytoplasm with a distinct cellular membrane. Scrape cytology is a simple and rapid supportive method and could be helpful in diagnosing clear cell carcinoma of the ovary, especially when marked artifacts appear in the frozen section. Key words: Cytology, Ovary, Adenocarcinoma, Clear cell 논문접수 : 2006년 2월 23일게재승인 : 2006년 3월 7일 책임저자 : 최 종 순 주 소 : (100-380) 서울시중구묵정동 1-19, 삼성제일병원병리과 전 화 : 02-2000-7662 팩 스 : 02-2000-7779 E-mail address : jscmd.choi@cgh.co.kr
박지영외 : 난소의원발투명세포암종 33 서론 난소의투명세포암종 (clear cell adenocarcinoma) 은악성상피암종의 4~5% 를차지하며, 투명세포와유리모양바탕질이특징이다. 투명세포암종은난소의다른상피세포암종에비해화학약물치료에반응을잘하지않으며, 예후가좋지않은것으로알려져있다. 1,2 투명세포암종의임상소견이나병리소견에대한연구보고는많이있으나, 3-6 세포소견에대한보고는그리많지않다. 3,4,6-8 본연구에서저자들은, 난소에발생한투명세포암종을긁거나, 세침흡인하여얻은세포진을종합하여세포학적특징을알아보고자하였다. 또이러한세포소견을동결절편진단에이용해보고자하였다. 재료및방법 2003년 1월부터 2005년 5월까지삼성제일병원병리과에수술중진단을위해의뢰된난소종양중에서조직학적으로원발투명세포암종으로확진된 6예를대상으로찰과표본 (scraping) 과세침흡인세포검사를하였다. 찰과표본은동결절편검사를위한조직을얻은후육안적으로종양의대표적인부분의표면을긁어얻은, 직경 1~2mm의세포덩이를두장의슬라이드를이용하여도말하였다. 도말한슬라이드중한장또는두장을 90% 알코올에 5분간고정하여동결절편조직과함께헤마톡실린-에오진염색을시행하였다. 역시같은방법으로얻은슬라이드들중한두장은 밤새알코올에고정하여다음날 Papanicolaou (Pap) 염색을하였고, 그중한예 (case 6) 는공기중에말린후 May-Grunwald- Giemsa (MGG) 염색을추가하였다. 절제한조직의세침흡인은 24게이지굵기의바늘로흡인하여얻은세포조직을슬라이드에도말한후, 알코올에고정하여각각헤마톡실린-에오진염색과 Pap 염색을하였다. 모든예에서절제한조직을 10% 포르말린에고정하고, 탈수와함수과정을거친다음, 파라핀에포매후박절하여조직진단을위한슬라이드를제작하였다. 결과 환자의나이는평균 45.5세 ( 범위 33~57세 ) 로한쪽난소에병변이있는경우가 5예, 양쪽을침범한예가 1예있었다. 한예에서자궁내막증을동반하였다 (Table 1). 세포진의도말양상은 6예모두세포충실도가높았으며소견이비슷하다 (Table 2). 찰과표본과세침흡인표본의세포진은방법에따른차이가없이서로유사하였다. 세포들은주로낱개로흩어져있거나작은유두모양을이루기도하였으나대부분의경우는서로겹쳐진덩어리모양이나판모양으로배열하고있었다. 헤마톡실린-에오진염색한세포진을저배율에서관찰했을때모든예에서쉽게발견할수있었던것은연한분홍색을띠는유리질물질이었다. 이것들은대개잎이떨어진나뭇가지모양이거나타원형혹은판모양으로불규칙하게흩어져있었다. 좀더자세히들여다 Table 1. Clinicopathologic features of clear cell carcinomas of ovary Case No. Age (yrs) Cytologic specimen Tumor location Size (cm) Endometriosis Other Peritoneal washing cytology 1 52 Scrape Left ovary 15.5 11 5.5 No Metastasis to omentum & peritoneum 2 33 Scrape Left ovary 10.5 9 8 No Metastasis to paraaortic LN 3 52 Scrape and FNAC 4 44 Scrape and FNAC Right & left ovary 7.5 6 1(Rt) 11 10 4(Lt) PFMC NFMC Yes PFMC Right ovary 11 8 7.5 No Peritoneal endometriosis NFMC 5 57 Scrape Right ovary 20 13 2 No Metastasis to PFMC omentum 6 35 Scrape and FNAC Left ovary 15 15 8 No Hypercalcemia NFMC FNAC: fine needle aspiration cytology. PFMC: positive for malignant cells. NFMC: negative for malignant cells. LN: lymph node
34 대한세포병리학회지 / 제 17 권 / 제 1 호 / 2006 Table 2. Cytologic features in clear cell carcinoma of ovary (n=6) Cytologic Features No. of cases Cellularity Low 0 Moderate 3 High 3 Smear background Hyaline materials 6 Apototic cells 3 Necrosis 2 Calcification 1 Arrangement of tumor cells Papillary clusters 6 Single cells 5 Flat sheets 2 Tumor cells Bare nuclei 5 Cytoplasmic eosinophilic inclusion 5 Cytoplasmic vacuole 5 Intranuclear inclusion 4 Phagocytosis of lymphocytes 4 Raspberry body 4 Fig. 1. Scrape cytology findings. The smear shows a cohesive sheet of tumor cells with eosinophilic hyaline basement membrane like materials. (H-E) Fig. 2. Raspberry body. Typical cell cluster with hyaline stromal core is present. (H-E) 였다. 종양의조직소견에따라세포의종류가구별되었는데, 각각핵이중앙에위치하고풍부한세포질을가진세포, 비교적크기가작고진한분홍색의호산성세포질에의해변두리로핵이밀려있는세포, 고도의핵비정형을보이는세포, 세포덩이에서핵이밖으로밀려성냥알모양을보이는징세포 (hobnail cells) 등이었다 (Fig. 3). 세포질은호산성의아주고운입자를가지기도하였으나, 대부분작은공포를가지고있었다. 대부분 (5예) 에서세포질내호산성의둥근유리질봉입체를흔히보였다 (Fig. 4). 상대적으로세포질의양이많아서핵-세포질간비율은높지않았다. 종양세포의핵은둥글거나다각형으로중앙에뚜렷한핵소체가한개혹은서너개까지보였다. 핵중앙을차지하는투명한핵봉입체가모든예에서흔히보였다. 3예에서종양세포외에대식세포로생각되는다핵거대세포가흔히보였고 (Fig. 5), 세포고사 (apoptosis) 를보이는세포들이보였다. 보면이런물질들이세포사이사이에기저막처럼보이기도하였다 (Fig. 1). 유리양물질은 MGG염색에서는진한자주색이거나푸른보랏빛을띠고, Pap 염색에서는푸른녹색으로보였다. 암세포가둥근유리양물질을둘러싼구조로서투명세포암종의세포진에서특징적소견으로기술되었던 raspberry body 4,5,9 는 4예에서관찰하였는데, 비교적드물게존재하였다 (Fig. 2). 세포는세포질이비교적풍부하였고세포간의경계가명확하였으나일부세포간합포체를이루기도하 고찰 난소의투명세포암종은악성상피종양으로비교적특징적인조직소견을보이지만, 다양한조직양상으로나타나고, 얼음결정등으로인해동결진단을할때어려움이있다. 난소종양의수술중조직진단은수술의범위나림프절박리등을결정하는데필수적이다. 수술중난소종양을진단하는데에동결절편의유용성이나한계등은이미많은연구가되었으며, 10,11
박지영외 : 난소의원발투명세포암종 35 A B Fig. 3. High power view of scrape cytology. (A) Tumor cells show distinct cellular membrane, clear or abundant cytoplasm with centrally located nuclei. (Giemsa) (B) Tumor cells have granular or dense eosinophilic cytoplasm with peripherally displaced nuclei in hobnail appearance. Nuclear pleomorphism is also present. (H-E) Fig. 4. High power view of scrape cytology. There are hyaline globules in cytoplasm and intercellular spaces (arrows). (H-E) Fig. 5. High power view of scrape cytology. A multinucleated giant cell with abundant cytoplasm is present. (Papanicolaou) 최근에는세포진을이용한연구가다수보고되었다. 8,12-14 본연구에이용한 6예의경우도동결절편진단시 2예만투명세포암종이라고진단한반면나머지 4 예는감별진단에포함되었다. 기저막과유사한호산성유리양물질은세포진진단에서투명세포암종을진단할때중요한열쇠가된다. 1997년에 Ito 등 9 이중앙에둥근유리양물질을중심으로종양세포들이둘러싸고있는특징적인둥근구조를난소의투명세포암종이있는환자의복수에서처음기술하면서 raspberry body 라명명하였다. 이런구조들은간질에따로떨어진조각으로존재하기도 한다. 이런물질들은주로 Diff-Quik 염색이나 Giemsa 염색에서잘보이는것으로기술되나 3-5,7,9 헤마톡실린- 에오진염색표본에관한보고는드물다. 8 본연구에서는간질의유리양물질이모든증례에서흔히보였으나, 이들은불규칙적으로간질에존재하거나세포사이사이에존재하였고, 특징적인 raspberry body 를완전히갖춘것은흔하지않았다. 또한이들은헤마톡실린에오진염색에서밝은분홍색을띠는물질로잘구별되었다. 세포진으로투명세포암종과감별해야할질환으로난황낭종양, 장액낭샘암종이있다.
36 대한세포병리학회지 / 제 17 권 / 제 1 호 / 2006 난황낭종양은대부분어린연령에서발생하고, 조직에서특징적인 Schiller-Duval body를찾는다면쉽게진단할수있으나, 때때로동결절편진단을할때투명세포암종과감별하기어려운경우가있다. 난황낭종양의세침흡인세포진은상당량의점액물질이배경에불규칙하게분포한다. 종양세포는유두형태혹은느슨한세포덩이로존재하고, 낱개세포는드물게보인다. 또한세포질내분홍색의균질한봉입체가보인다. 3,15,16 투명세포암종에비해세포충실도가떨어지고, 낱개세포가비교적드물며, 핵의비정형이더심하고, 핵세포질의비율이더높다. 세포사이경계가불명하고, 세포질은얇지만거의없거나있어도풍부하지않다. 장액낭샘암종은유두형태로흔히존재하고, 고등도의핵비정형을보이며, 투명세포암종에서볼수있는유리양물질을보이지않는다. 결론 본연구에서투명세포암종의세포소견은흔히유두모양배열을하고있으며, 배경및버팀질에가지모양혹은둥근유리양물질을자주볼수있고, 세포사이경계가명확하며, 세포질이풍부하고얇았다. 조직진단은버팀질의유리양물질과투명한세포질등의특징적소견을발견하면어렵지않게진단할수있으나, 다양한배열과모양을보이므로진단의어려움이있다. 특히, 동결절편시조직을얼린후박절하기까지시간이지체되거나, 동결박절기내부의온도가지나치게낮은경우, 인위적인세포질내공포나봉입체가생길수있다. 또점액세포암종일때에도세포질내점액으로인해투명한세포질을보일수도있으며, 투명세포암종도일부반지모양세포가있을수있고점액성세포질로나타난다. 특히낭변화가거의없는충실한고형투명세포암종일경우세포질이투명하더라도그것이특징적소견인지, 인위적소견인지쉽게판단하기가어렵고, 다른상피세포암종과의감별도쉽지않다. 바탕질의유리양물질은세포진과동결절편모두에서쉽게보인다. 수술중세포검사단독으로진단을할수는없으나, 구성세포의모양과, 염색질의분포등을잘볼수있는장점이있다. 동결절편의인공산물변화로세포의자세한모양을관찰하기어려운경우, 세포검사를시행하면, Diff-Quik 염색을따 로하지않아도동결절편용헤마톡실린에오진염색에서진단적가치가있는분홍색의유리양물질이잘보이고, 투명세포암종의비교적특징적인세포소견으로진단에도움을받을수있다. 참고문헌 1. Montag AG, Jenison EL, Griffiths CT, Welch WR, Lavin PT, Knapp RC. Ovarian clear cell carcinoma. A clinicopathologic analysis of 44 cases. Int J Gynecol Pathol 1989;8:85-96. 2. Cha SH, Park H, Seong SJ, et al. Clinicopathologic characteristics and survival rate of primary clear cell carcinoma of the ovary. Korean J Gynecol Oncol 2003;14: 140-50. 3. Kuwashima Y, Uehara T, Kurosumi M, et al. Cytological distinction between clear cell carcinoma and yolk sac tumor of the ovary. Eur J Gynaecol Oncol 1996;17:345-50. 4. Atahan S, Ekinci C, Icli F, Erdogan N. Cytology of clear cell carcinoma of the female genital tract in fine needle aspirates and ascites. Acta Cytol 2000;44:1005-9. 5. Jimenez Heffernan JA, Vicandi B, Gonzalez Peramato P, et al. Cytologic features of clear cell carcinoma of the female genital tract. Diagnostic value of the "raspberry body" in nonexfoliative cytologic specimens. Acta Cytol 2004;48: 47-51. 6. Khunamornpong S, Thorner PS, Suprasert P, Siriaunkgul S. Clear cell adenocarcinoma of the female genital tract: presence of hyaline stroma and tigroid background in various types of cytologic specimens. Diagn Cytopathol 2005;32: 336-40. 7. Hirokawa M, Shimizu M, Nakamura E, et al. Basement membrane material and tigroid background in a fine needle aspirate of clear cell adenocarcinoma of the cervix. A case report. Acta Cytol 2000;44:251-4. 8. Khunamornpong S, Siriaunkgul S. Scrape cytology of the ovaries: potential role in intraoperative consultation of ovarian lesions. Diagn Cytopathol 2003;28:250-7. 9. Ito H, Hirasawa T, Yasuda M, Osamura RY, Tsutsumi Y. Excessive formation of basement membrane substance in clear cell carcinoma of the ovary: diagnostic value of the "raspberry body" in ascites cytology. Diagn Cytopathol 1997;16:500-4. 10. Michael CW, Lawrence WD, Bedrossian CW. Intraoperative consultation in ovarian lesions: a comparison between cytology and frozen section. Diagn Cytopathol 1996;15: 387-94. 11. Pinto PB, Andrade LA, Derchain SF. Accuracy of
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