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1 REVIEW ARTICLE J Korean Thyroid Assoc Vol. 4, No. 2, November 2011 저분화암및미분화암치료의난제 아주대학교의과대학외과학교실 이정훈, 소의영 Therapeutic Difficulties in Poorly Differentiated and Undifferentiated Thyroid Cancer Jeonghun Lee, MD and Euy oung Soh, MD, PhD Department of Surgery, School of Medicine, Ajou University, Suwon, Korea Poorly differentiated thyroid cancer (PDTC) and anaplastic thyroid cancer (ATC) have poor prognosis and rare incidence compared to well differentiate thyroid cancer. Since the original description of PDTC in 1983, PDTC was introduced as a separate entity in the WHO Classification of Endocrine Tumors. PDTC was defined as a thyroid cancer with thyroglobulinproducing nonfollicular nonpapillary growth pattern and highgrade features, having an intermediate behavior between well differentiated thyroid cancer (WDTC) and ATC. But the criteria of PDTC are still controversial and heterogeneously applied in the diagnostic practice. Also the modalities of treatment, such as the extent of thyroid surgery, the use of radioiodine therapy and external radiation therapy are still controversial. ATC is rapidly progressing human carcinoma with a median survival of 4 to 12 months after diagnosis. Although the complete resection combined with external radiation therapy was reported to be effective recently and multimodality treatment has been recommended, current treatment of ATC has not been adequate for controlling the diseases. Therefore there are new attempts for treatment, such as chemotherapy with paclitaxel, clinical trials of combretastatin 4 phosphate and CS7107 and multitargeted therapy of bevacizumab with doxorubicin, sorafenib, sunitinib etc. PDTC and ATC are an unexplored field like this, therefore, the studies for molecular pathology and therapeutic approach are necessary for improving survival and quality of life of patients. Key Words: Poorly differentiated thyroid cancer, Anaplastic thyroid cancer 저분화갑상선암 저분화갑상선암 (poorly differentiated thyroid cancer, PDTC) 은 1983년에 Sakamoto 등 1) 과 1984년에 Carcangiu 등 2) 에의해서처음으로보고되었다. Carcangiu 등 2) 은 PDTC는분화갑상선암이지만 84% 의재발률과 40% 이상의원격전이를가지는나쁜예후를가지는암으로치료초기에공격적인치료가필요하다고하였다. 이후에이에대한많은연구들이진행되었으며, 37) 년 WHO에서는 PDTC를고분화암 (well differentiated thyroid cancer, WDTC) 과미분화갑상선암 (anaplastic thyroid cancer, ATC) 의중간에해당하는임상적, 병리학적특성을지니는구별된갑상선암의한종류 (entity) 로분류하였고, 비유두 (nonpapillary) 또는비여포 (nonfollicular) 성장양상을보이며, 높은유사분열지수 (mitotic index) 와괴사를가지는것으로정의하였다. 그러나몇명의저자들은성장양상에따라특정암의아형을구별하는것에이견을제시하였고, PDTC의공격적인양상은진단당시의진행된병기상태나 highgrade feature와연관이있다고하였다. 3,4) 그리고정의에있어서도 Sakamoto 등 1) 은 solid, trabecular 또는 scirrhous growth pattern을가진것으로정의하였고, 다른저자들은갑상선유두암의침습적인아형 (variant) 논문접수일 : 2011 년 4 월 18 일 / 심사 ( 수정 ) 일 : 2011 년 9 월 16 일 / 심사완료일 : 2011 년 9 월 19 일교신저자 : 소의영, 경기도수원시영통구원천동산 5, , 아주대학교의과대학외과학교실 Tel: , Fax: , sohey@ajou.ac.kr 87

2 이정훈, 소의영 들인 columnar cell, tall cell, diffuse sclerosing과 solid variant를포함시키기도하였다. 57) 이러한 PDTC에대한논란에대해, 2006년유럽, 미국및아시아병리학자들이모여통일된진단기준을위하여 Turin에서 consensus conference가열렸으며, 이모임에서 PDTC 를 solid variant of papillary carcinoma와 well differentiated follicular carcinoma with a predominantly solid/ trabecular growth pattern을가진것들과구별하기위해서알고리즘을제안하였다. Turin proposal에서는 PDTC 를 STI pattern (solid/trabecular/insular growth pattern) 을가지고, 유두암의특징적인핵이없으며, 마지막으로 convoluted nuclei나괴사나유사분열 (mitoses) 을보이는경우로정의하였다. 8) 그러나이제안에서도 STI pattern과유두암의특징적인핵의분포가어느정도일때진단할수있는지에대한구체적인언급이없어이에대한더많은연구들이필요하다. 임상양상 PDTC는전체갑상선암중에서약 10% 을차지하 고, 9) 평균연령이 49세이상의고령이며, 평균종양의크기는 4.7 cm 이상, 림프절전이는대부분 40% 이상, 원격전이는대부분 50% 이상이었다 (Table 1). 5년생존율은 65 85% 였으며, 1,1012) 예후인자로는연령, 종양의크기, 림프절전이유무, 원격전이유무, 괴사유무, 유사분열의정도등이보고되었다 (Table 2). 1,10,1316) 그러나종양의크기, 림프절전이유무, 방사성요오드치료유무등은아직논란의여지가있다. 치료 PDTC는매우드문질환으로표준화된치료는없다. 그러나 PDTC 치료의기본은수술이다. 수술의범위에대해서는논란의여지가있을수있으나, Carcangiu 등 2) 은갑상선전절제술시재발률이낮으므로갑상선전절제술을시행해야한다고제안하였으며, 재발및생존의위험인자들의빈도가분화갑상선암에비해서높으므로술후 thyroglobulin을이용한추적관찰을위해서갑상선전절제술이필요하다고주장하였다. 9,17) 림프절의절제범위에대해서는림프절전이가대부분 40 Table 1. Clinical features of poorly differentiated thyroid carcinoma Author ear Number of patents Mean age F/M Mean size LN metastasis (%) Distant metastasis (%) Carcangiu et al. 2) Papotti et al. 14) Ashfaq et al. 70) Sasaki et al. 71) van den Brekel et al. 13) Asakawa et al. 72) Albareda et al. 73) Machens et al. 74) Pellegriti et al. 75) LunaOrtiz et al. 12) Chao et al. 76) Lai et al. 15) /17 20/11 16/10 32/12 16/11 5/1 6/0 12/2 12/1 4/4 56/ Table 2. Poor prognostic factors in poorly differentiated thyroid carcinoma Author ear Age Sex Tumor size Type of operation LN mets Distant mets RAI EBRT Necrosis Mitosis Sakamoto et al. 1) van den Brekel et al. 13) Volante et al. 10) Papotti et al. 14) Lai et al. 15) Jung et al. 16) Older Older Larger Larger (0.06) 4 cm Positive Positive NP NP >3/10 HPF >3/10 HPF EBRT: external radiation therapy, HPF: high power field, LN: lymph node, mets: metastasis, NP: not performed, : no significant factor, RAI: radioactive iodine therapy Vol. 4, No. 2,

3 저분화암및미분화암치료의난제 80% 로보고되므로중앙림프절절제술을시행하고가능한변형광범위경부림프절곽청술을고려해야할것이다. 9) PDTC는 75 85% 의방사성요오드섭취율을가지고있고, 9,18) 림프절과원격전이빈도가높으므로방사성요오드치료를하는것을고려해야할것이다. 9,13,16,17) 그러나방사성요오드치료가예후에미치는영향에관하여는상반된보고들이있고, 아직방사성요오드치료에대한전향적인연구자료들이없으므로논란의여지가있다. 9) 외부방사선치료 (external radiation therapy, EBRT) 의 PDTC에서의치료효과에대한연구는없으나, Chow 등 19) 은 1300명의유두상갑상선암환자를대상으로조사한연구에서수술시육안적인잔존암이있거나, 절제면의잔존암 (positive resection margin), 병리학적 T4 (pt4), 병리학적 N1b (pn1b), 또는전이된림프절의크기가 2 cm 이상인경우에국소재발률이낮다고보고하였다. 그러므로 DTC에비해서침습적인양상을보이는 PDTC에서도육안적잔존암, 미세한갑상선외침윤 (minimal extrathyroid extension), 림프절의피막외침윤, 광범위한림프절전이를가진경우에선택적으로 EBRT을고려할수있을것이다. 20) 미분화갑상선암 임상양상 ATC는갑상선암중에가장치명적이고, 중앙생존기간은 3 6개월이며, 1, 5년생존율은 17%, 8% 로보고되었다. 21,22) 갑상선암중에서단지 2 5% 만을차지하고, 23) 우리나라에서유병률은 1970년대이전에는 2% 정도였으나, 2000년도이후에는 0.3% 정도의낮은비율로감소하는추세를보이고있다. 24) 여성이약 60 70% 를차지하고, 대부분진단시평균연령이 67 71세이다. 23,25) 진단시에 98% 에서국소침윤소견을보이고, 46% 에서원격전이를보이며, 추적관찰중에 68% 에서원격전이가발견된다. 23) ATC는이렇듯진단당시이미진행된상태로발견되기때문에완전치유절제가어려울뿐아니라, 고령으로인해전신상태가불량하고, 적은증례로인해아직정립된치료방법이없다. 2628) ATC의양호한예후인자들로는아직논란의여지가있으나, 60세이하의연령, 여성, 양호한활동도 (performance status), 느린종양성장속도 (>3 month), 갑상선내병변, 5 6 cm 이하의크기, 국소증상 (acute local symptoms) 이없는경우, 다발성갑상선종이동반된경우, 완전절제, 외부방사선치료, 수술과외부방사선치료를시행한다각적치료등이보고되었다. 2527,29,30) 그러므로젊은층의비교적작은크기의종괴를가지면서원격전이가없는경우에는수술, 방사선요법및화학요법등의다각적치료를적용함으로써생존율을향상시킬수있을것이다 (Table 3). 25,3137) 치료 ATC의치료의기본은수술과외부방사선치료를포함한다각적치료이다. 1970년전에는 ATC의치료시수술의효과가미미하여일부환자에서만시행되었으나이후완전절제시생존율을향상시킬수있고, 감량수술 (debulking operation) 만으로도환자의질식위험을감소시켜삶의질을향상시킨다는결과들이보고된이후더많이시행되고있다. 37) 그러나완전절제가생존율에미치는효과에대해서는아직논란의여지가 Table 3. Prognostic factors in anaplastic thyroid carcinoma Author ear No. of patients Age Gender Tumor size Complete resection Radiation Chemotherapy Multimodality Venkatesh et al. 29) Junor et al. 35) Tan et al. 27) Kobayashi et al. 36) Lo et al. 77) Sugitani et al. 42) Haigh et al. 34) McIver et al. 23) Kim et al. 78) Besic et al. 79) Kebebew et al. 25) Kim et al. 80) : no significant factor, : yes (significant factor) 89 J Korean Thyroid Assoc

4 이정훈, 소의영 있다. Venkatesh 등 29) 과 Chang 등 38) 은생존율을증가시키지못한다고하였으나, Haigh 등 34) 은완전절제시에감량수술이나수술을받지않은군에비해서예후가좋다고하였다. 또한수술시절제범위에대해서도논란이있으며, Tan 등 27) 과 Nel 등 39) 은술후합병증을최소화하기위해서갑상선전절제술과상부종격동림프절을포함한광범위경부곽청술의시행으로완전절제가가능하다면적극적으로수술을하도록권유하였다. 34,4042) 그리고예방적기관지절개술은더딘상처치유로술후외부방사선치료를지연시키므로절박폐쇄시에만시행할것을권고하였다. 40) ATC 치료로써 EBRT가각광을받은것은 1973년 Wallgren과 Norin 43) 이항암제치료와함께시행시좋은결과를가지고올수있다는보고때문이었으며, 이후에도지속적인발전을해왔다. 1980년에는 Simpson 44) 이다분할조사법 (hyperfractionation radiation therapy [100 cgy qid]) 을갑상선암에서처음으로보고하였으며, Kim과 Leeper 45) 는이러한다분할조사법과함께 doxorubicin을 radiosensitizing chemoagent로사용하여효과적으로국소재발률을낮추었다고보고하였다. 다분할조사법은 ATC와같은 3 12일의 doubling time을가지는종양에서는외부방사선치료를하루에두번이상하여방사선치료간격을감소시키면빠르게분화하는세포들이정상세포보다더많이죽게되고만성적인저산소상태의종양세포들은또한정상세포에비해서방사선에의한손상으로부터회복하는속도가느려종양의크기가효과적으로감소하게된다. 4648) 그리고새로운방법들로 three dimensional conformal radiotherapy, intensitymodulated radiotherapy 등이있다. 보고들에의하면이둘간에치료효과의차이가없거나 49) intensitymodulated radiotherapy가더적은 spinal cord exposure로고용량의방사선을갑상선부위와주위의림프절에주사할수있는장점이있다. 50) 그러나이러한 EBRT 역시단기간의생존율을증가시키고국소재발률을낮출수있지만결국원격전이로사망하게된다. 51,52) ATC 환자는진단시 50% 이상에서원격전이를가지고있고, 국소재발을효과적으로치료하더라도원격전이로사망하게되므로항암제치료는치료에중요한부분을차지한다. 53) 그러나현재까지항암제치료의효과는미미하다. ATC의항암제치료로가장많이이용되는항암제는 doxorubicin이다. doxorubicin 단독요법의효과는약 % 였고, 54,55) 대부분부분관해 (partial remission, PR) 만을보였으며, 완전관해 (complete remission, CR) 는없었다. 51,54,5658) 단독요법에대한다른항암제들로는 bleomycin, etoposide, cisplatin, methotrexate 등이있으나대부분부분관해를보였고 doxorubicin보다효과가적었다. 30,56,59,60) 그리고 doxorubicin은 cisplatin, vincristine, bleomycin, melphalan 등과함께복합요법으로이용되며, Shimaoka 54) 는 doxorubicin과 cisplatin의복합요법시에 33% (3 CR, 3 PR in 19 patients) 를보고하였으나, Williams 등 61) 은한예에서만부분관해를보일뿐이며, 더독성이강하고효과적이지않다는상반된보고를하였다. 이러한 doxorubicin은 doxorubicin을기반으로한복합요법으로도시행되었으나, 그효과는논란의여지가있고, 단독요법에비해서우월하지않다. 51) Doxorubicin을사용하지않은항암제치료로는 taxene계열이있으며, total response는 53%(1 CR, 9 PR) 로보여기존의항암제들보다좋은효과를보였다. 62) 이러한기존의항암제와 taxene계열의차이점은 ATC 세포주와 ATC 종양조직에서시행한항암제내성에관한연구에서원인을확인할수있는데, 항암제내성과관련된인자들로는 Pglycoprotein (MDR1 gene product), MRP (multidrug resistanceassociated protein, MRP1 gene product), LRP (major vault protein), DNA topoisomerase IIalpha (TOPII) 등이있다. 40,63) ATC 세포주들은대부분 MDR1, MRP, LRP 발현을했으며, ATC 종양조직에서는 MRP와 LRP는모두발현이되었으나 MDR1은한개의 ATC 종양조직에서발현이되었고, TOPII은세포주와종양조직모두에서발현이되지만돌연변이는없었다. 40,63) ATC가기존의항암제들에저항을보이는것은항암제를세포안에서세포밖으로운반하는세포막단백질인 MRP, MDR의발현과연관성이있으며, taxene계열은 MRP에의해서세포밖으로운반되지않으므로다른항암제에비해서더좋은효과를보인다. 40,51,62) 아직 taxene계열이생존율을호전시킨다는자료는없으나, 40,62) 새롭게진단된환자에서약간의완화효과를보일수있으므로 taxene계열의항암제를이용한항암요법을시도할수있을것이다. 40,62) ATC에대한분자생물학연구가활발히진행되면서알려진돌연변이유전자 (gene mutation) 를표적으로하는새로운치료방법들이개발되고있다. 아직실용화되지못하였으나, ATC에서 p53 돌연변이로인해 p53 의발현이되지않아세포사멸이억제되는것을발견하여 wild type p53 (wtp53) 을발현하는 adenovirus를 ATC에감염시켜서 doxorubicin 등의항암제에효과를보이게하는방법이연구중이다. 64) 그리고, 임상시험 Vol. 4, No. 2,

5 저분화암및미분화암치료의난제 중인새로운약제로는세포신호전달체제에관여하는유전자인 ras, BRAF, PIK3CA를표적으로하는 kinase inhibitors (sorafenib, imatinib, axitinib) 와 mtor inhibitors (everolimus, sirolimus), 그리고신생혈관에서 microtubule의중합작용 (polymerization) 이나세포와세포의부착을억제하는 combretastatin A4 phosphate (CA4P) 등의신생혈관표적약제들이있으며, peroxisome proliferatoractivated receptors (PPAR) gamma의작용제 (agonist) 인 CS7107이있다. 21,40,51,62) Kinase inhibitor 들의효과는현상유지 (stable disease) 가대부분으로 sorafenib은 4명의 ATC 환자에서완전또는부분관해없이 1명 (25%) 에서만현상유지를보였고, 65) imatinib은 8명의 ATC환자중 2명 (25%) 에서부분관해를, 4명 (50%) 에서현상유지를보였다. 66) Axitinib은진행된갑상선암환자 60명중에 18명 (30%) 에서부분관해를, 23명 (38%) 에서현상유지를보고하였으며 ATC 환자 2명중한명은부분관해되었고, 다른한명에서는병이더악화되었다. 67) Fosbretabulin (CA4P) 는임상제1상시험에서 1명의완전관해를보였고, 68) 임상제2상시험에서는 26명의 ATC 중에 1명 (3.7%) 에서부분관해를, 7명 (26%) 에서현상유지를보였으며, 23% 에서 12개월이상생존하였다. 69) 그러나이러한약제들의 ATC에대한효과는완전또는부분관해를보이기보다는병이더진행하지않은더악화되지않고현상태를유지하는경우가더많았으며, 이약제들이생존에미치는영향력역시더연구가필요하다. 지금까지 ATC 치료에서장기생존을보이는효과적인치료방법은없으나, 모든환자에서다각적인치료를시행하고, 새로운약제에대한임상시험도고려하는등의적극적인치료가필요할것이다. 그리고, 효과적인치료방법에대한연구를위해서다기관연구와새로운약물에대한개발을위한지속적인분자생물학적연구들이필요할것이다. 중심단어 : 저분화암, 미분화암. References 1) Sakamoto A, Kasai N, Sugano H. Poorly differentiated carcinoma of the thyroid. A clinicopathologic entity for a highrisk group of papillary and follicular carcinomas. Cancer 1983; 52(10): ) Carcangiu ML, Zampi G, Rosai J. Poorly differentiated ("insular") thyroid carcinoma. A reinterpretation of Langhans' "wuchernde Struma". Am J Surg Pathol 1984;8(9): ) Akslen LA, LiVolsi VA. Poorly differentiated thyroid carcinomait is important. Am J Surg Pathol 2000;24(2): ) Nishiyama RH. Another dissertation on poorly differentiated carcinomas: is it really necessary? Adv Anat Pathol 1999;6(5): ) Carcangiu ML, Bianchi S. Diffuse sclerosing variant of papillary thyroid carcinoma. Clinicopathologic study of 15 cases. Am J Surg Pathol 1989;13(12): ) Pilotti S, Collini P, Manzari A, Marubini E, Rilke F. Poorly differentiated forms of papillary thyroid carcinoma: distinctive entities or morphological patterns? Semin Diagn Pathol 1995; 12(3): ) SobrinhoSimoes M, Nesland JM, Johannessen JV. Columnarcell carcinoma. Another variant of poorly differentiated carcinoma of the thyroid. Am J Clin Pathol 1988;89(2): ) Volante M, Collini P, Nikiforov E, Sakamoto A, Kakudo K, Katoh R, et al. Poorly differentiated thyroid carcinoma: the Turin proposal for the use of uniform diagnostic criteria and an algorithmic diagnostic approach. Am J Surg Pathol 2007;31(8): ) Patel KN, Shaha AR. Poorly differentiated and anaplastic thyroid cancer. Cancer Control 2006;13(2): ) Volante M, Cavallo GP, Papotti M. Prognostic factors of clinical interest in poorly differentiated carcinomas of the thyroid. Endocr Pathol ;15(4): ) Wreesmann VB, Ghossein RA, Patel SG, Harris CP, Schnaser EA, Shaha AR, et al. Genomewide appraisal of thyroid cancer progression. Am J Pathol 2002;161(5): ) LunaOrtiz K, HurtadoLopez LM, DominguezMalagon H, RamirezMarin R, ZaldivarRamirez FR, HerreraGomez A, et al. Clinical course of insular thyroid carcinoma. Med Sci Monit ;10(3):CR ) van den Brekel MW, Hekkenberg RJ, Asa SL, Tomlinson G, Rosen IB, Freeman JL. Prognostic features in tall cell papillary carcinoma and insular thyroid carcinoma. Laryngoscope 1997; 107(2): ) Papotti M, Botto Micca F, Favero A, Palestini N, Bussolati G. Poorly differentiated thyroid carcinomas with primordial cell component. A group of aggressive lesions sharing insular, trabecular, and solid patterns. Am J Surg Pathol 1993;17(3): ) Lai HW, Lee CH, Chen J, Tseng LM, ang AH. Insular thyroid carcinoma: collective analysis of clinicohistologic prognostic factors and treatment effect with radioiodine or radiation therapy. J Am Coll Surg 2006;203(5): ) Jung TS, Kim T, Kim KW, Oh L, Park do J, Cho B, et al. Clinical features and prognostic factors for survival in patients with poorly differentiated thyroid carcinoma and comparison to the patients with the aggressive variants of papillary thyroid carcinoma. Endocr J 2007;54(2): ) Flynn SD, Forman BH, Stewart AF, Kinder BK. Poorly differentiated ("insular") carcinoma of the thyroid gland: an aggressive subset of differentiated thyroid neoplasms. Surgery 1988;104(6): ) Justin EP, Seabold JE, Robinson RA, Walker WP, Gurll NJ, Hawes DR. Insular carcinoma: a distinct thyroid carcinoma with associated iodine131 localization. J Nucl Med 1991;32(7): ) Chow SM, au S, Kwan CK, Poon PC, Law SC. Local and 91 J Korean Thyroid Assoc

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