대한내분비외과학회지 : 제8권제3호 Vol. 8, No. 3, September 2008 원저 미세유두상갑상선암의예후인자및치료지침 연세대학교원주의과대학외과학교실, 1 국군대구병원외과 김경민ㆍ조민수 1 ㆍ최용현ㆍ배금석ㆍ강성준 The Prognostic Factors and Therapeutic Strategy for Papillary Thyroid Microcarcinoma Kyung Min Kim, M.D., Min Su Cho, M.D. 1, Yong Hyun Choi, M.D., Keum Seok Bae, M.D. and Seong Joon Kang, M.D. Purpose: The objectives of this study were to define the prognostic factors of papillary microcarcinoma of the thyroid (PMCT), to analyse their histopathologic and epidemiologic characteristics and to investigate the optimal therapeutic management. Methods: Our series included 254 consecutive patents who were affected by PMCT and who were operated on by the same surgeon between 1985 and 2002 among a total of 3,100 patients who underwent thyroid surgery. All the surgical specimens were examined in the same Department of Pathology. The prognostic factors were evaluated by uniand multivariate statistical analyses. Results: The histopathologic characteristics such as vascular extension, infiltration into the adjacent parenchyma, a larger primary tumor (size 5 mm) or tumor in the thyroid capsule were all indicative of a poor prognosis. For the patents with poor prognostic factors and who were treated by partial thyroidectomy alone, the prevalence of recurrent disease was higher than that for the patients who were with treated by total thyroidectomy and 131 iodine administration. Conclusion: According to the prognostic factors, different therapeutic modalities could be proposed to treat patients with pillary thyroid microcarcinoma. It is reasonable to perform total thyroidectomy and 131 iodine therapy for patients with PMCT and who have high risk factors. (Korean J Endocrine Surg 2008;8:177-182) 책임저자 : 강성준, 강원도원주시일산동 162 번지 220-701, 연세대학교원주의과대학외과학교실 Tel: 033-741-1306, Fax: 033-741-1815 E-mail: mdkang@yonsei.ac.kr 게재승인일 :2008 년 9 월 16 일본논문의요지는 2007 년대한외과학회추계학술대회에서구연발표되었음. Key Words: Papillary microcarcinoma, Thyroid, Prognosis 중심단어 : 미세유두상암, 갑상선, 예후 Department of Surgery, Yonsei University Wonju College of Medicine, Wonju, 1 The Armed Forces Daegu Hospital, Daegu, Korea 서 미세유두상갑상선암은 1988년 WHO (World Health Organization) 분류에의해종양의최대장경이 1 cm 이하인유두상암으로정의되고있다.(1) 미세유두상암의 WHO 정의가나오기전에는유두상암의크기가 1.5 cm 이하인경우작은유두상암 (small papillary carcinomas) 으로분류하기도하였고, 촉지되지않고임상적으로의심되지않는상태에서부검 (autopsy) 이나갑상선수술후조직에서우연히발견되는경우에는잠재성또는우연성 (occult 또는 incidental) 유두상암으로분류되기도하였다.(2) 미세유두상암을가진환자의예후에대한보고는매우좋은성적을보이는경우가대부분으로,(3-5) 일부보고에서는미세유두상암에의한사망은 1% 이하인것으로보고하기도하였으며,(6,7) 0.25 0.4% 의매우낮은사망률을보고한경우도있다. 하지만적은수이지만미세유두상암환자에서도국소재발또는원격전이를보인다는보고도있으며, 20년장기추적관찰결과재발율이 6% 에이른다는한보고도있다.(4,8-10) 미세유두상암이기는하나림프절전이나원격전이를보이는경우가있어, 갑상선절제범위및림프절곽청술의범위에대해서는아직논란의여지가있다. 또한과거에는대부분양성갑상선질환의수술적절제나부검을통해발견되었던미세유두암이최근에는경부초음파검사와미세침흡인세포검사의보편화되면서발견율이높아지고있다.(6) 이에본연구를통하여미세유두상암으로수술한환자들의임상적및병리학적인특성을파악하고, 예후인자를비교하여치료방법의결정에도움을주고자하였다. 론 177
178 대한내분비외과학회지 : 제 8 권제 3 호 2008 방법 1985년 3월부터 1996년 3월까지본기관에서수술하여미세유두상암을진단받고 10년이상추적관찰이이루어진 254명의환자를대상으로하였다. 모든갑상선수술검체는같은기관의병리학교실에서같은기술적방법으로병리학적인자를조사하였다. 림프절전이는수술검체에서병리학적으로확진된경우로하였으며, 주위조직침윤의판단은수술장소견또는수술검체에서종양이혈관침윤, 주변장기실질침윤및갑상선피막을넘어선경우로하였다. TNM 병기는개정된제6판 AJCC (American Joint Committee on Cancer) 에따라분류하였다.(11) 모든대상환자는나이, 전이, 침윤, 크기 (AMES) 에따라저위험군또는고위험군으로분류하였다.(12) 갑상선아전절제술또는전절제술을시행받은환자는장기간갑상선호르몬대체및억제요법을받았다. 추적관찰은수술방법에따라티로글로블린 (Thyroglobulin), 초음파, 방사성요오드스캔또는양전자단층촬영검사를시행하였다. 추적관찰중재발이확인된모든환자에게는수술또는방사성요오드치료를권고하였다. 통계적인방법은생존율은 Kaplan-Meier 방법, 생존율차이는 Breslow and Mantel-Cox 검정, 예후인자비교는 Logrank 검정, 임상인자비교는 Chi-square 및 t 검정, 상관관계는 Cox regression model을이용하였다. 통계는 SPSS window version 11.0을이용하여분석하였다. 결과전체대상환자의평균추적관찰기간은 15.2년, 평균나이는 48.1세, 여자 213명및남자 41명이었다. 1) 임상및병리학적특징병리학적특징에따라갑상선내에국한된환자군, 림프절전이가확인된환자군및갑상선주위조직침윤이있는환자군으로구분하였다 (Table 1). 갑상선내에국한된환자군은 210명으로평균나이 47.3세 (19 71세) 였고여자 179명, 남자 31명였다. 갑상선절제범위는일엽절제술및협부절제술이 147명, 63명에서는전절제술을시행되었다. 종양의크기는평균 0.59 cm였고유두상암무병생존율 (disease free survival) 은 98.1% 으며, 10명의환자가유두상암이외의질환으로사망하였으나질병특이생존율 (disease specific survival) 은 100% 였다. 처음수술시림프절전이가병리학적으로확인된환자군은 30명으로평균나이 50.2세였고여자 24명, 남자 6명이었다. 갑상선절제범위는일엽절제술및협부절제술이 3명에서, 24명은전절제술을시행받았다. 종양의크기는평균 0.72 cm였고유두상암무병생존율은 93.3% 였으며, 2명의환자가유두상암이외의질환으로사망하였으나질병특이생존율은 100% 였다. 갑상선주위조직침윤이있었던환자는 14명으로평균나이 55.2세였고여자 10명, 남자 4명이었다. 14명모두에서전절제술을시행되었다. 종양의크기는평균 0.83 cm였고유두상암무병생존 (disease free survival) 은 71.4% 였으며, 2 명의환자가유두상암이외의질환으로사망하였으나질병특이생존율은 100% 였다. 주위조직침윤이있는환자군이갑상선내에국한된환자군과림프절전이가있는환자군에비하여국소재발로인해무병생존율이통계학적으로유의하게낮았다. 대상환자모두에서원격전이는확인되지않았다. Table 1. Clinical characteristics of PTM Intrathyroid Lymph node Extrathyroid microcarcinoma (n=210) metastasis (n=30) invasion (n=14) P value* Age at diagnosis (mean±sd, y) 47.3±13.5 50.2±11.2 55.2±8.9 B, C Gender, no. F/M (ratio) 179/31 (5.8:1) 24/6 (4:1) 10/4 (2.5:1) B, C Operative method, 147/63 (2.3:1) 3/27 (0.1:1) 0/14 (0) <.05 no. partial/total thyroidectomy (ratio) Tumor size, mean±sd, cm 0.59±0.04 0.72±0.05 0.83±0.04 A, B Present status, 206/4 (51.5:1) 28/2 (14:1) 10/4 (2.5:1) <.05 no. disease free/non-disease free (ratio) Survival, no. yes/no (ratio) 195/10 (19.5:1) 28/2 (14:1) 12/2 (6:1) <.05 PTM = papillary thyroid microcarcinoma; Extrathyroid invasion = histopathologic characteristics such as the vascular extension, infiltraion into the adjacent parenchyma or in the thyroid capsule; partial = lobectomy and isthmectomy. *A indicates P<.05 for intrathyroid vs lymph node groups; B, P<.05 for intrathyroid vs extrathyroid groups; and C, P<.05 for lymph node vs extrathyroid groups. All patients died of causes other than thyroid cancer.
김경민외 : 미세유두상갑상선암의예후인자및치료지침 179 Table 2. Classification of PTM FNAC, frozen, and final pathology Time of PTM finding (n=254) Preoperative diagnosis Diagnosed during Final histopathological P value* (FNAC) (n=51) operation (Frozen) (n=178) diagnosis (n=25) Age at diagnosis (mean±sd, y) 53.2±9.3 47.5±10.2 41.7±7.3 B, C Operative method, 40/11 (3.6:1) 90/88 (1:1) 20/5 (1:4) <.05 no. partial/total thyroidectomy (ratio) Tumor size, mean±sd, cm 0.71±0.06 0.63±0.04 0.33±0.05 B, C TNM stage, no. stage 1/Stages 2 4 (ratio) 46/5 (9.2:1) 166/12 (13.8:1) 22/3 (7.3:1) B, C Present status, 48/3 (16:1) 171/7 (24.4:1) 25/0 (NA) 0.43 no. disease free/non-disease free (ratio) PTM = papillary thyroid microcarcinoma; FNAC = fine-needle aspiration cytology; NA = not applicable; partial = lobectomy and isthmectomy. *A indicates P<.05 for FNAC vs Frozen; B, P<.05 for FNAC vs final histopathological diagnosis; and C, P<.05 for Frozen vs final histopathological diagnosis. Table 3. Clinical characteristics of PTM categorized into high- or low-risk group Low risk (n=233) High risk (n=21) P value* Age at diagnosis (mean±sd, y) 46.8±9.8 62.3±13.2 <.05 Gender, no. F/M (ratio) 204/29 (7.0:1) 10/11 (0.9:1) <.05 Operative method, 145/88 (1.6:1) 5/16 (0.3:1) <.05 no. partial/total thyroidectomy (ratio) Tumor size, mean±sd, cm 0.60±0.03 0.82±0.01.16 Present status, 231/2 (115.5:1) 13/8 (1.6:1) <.05 no. disease free/non-disease free (ratio) Survival, no. yes/no (ratio) 223/10* 17/4* NS PTM = papillary thyroid microcarcinoma; NS = not significant; partial = lobectomy and isthmectomy. *All patients died of causes other than thyroid cancer. Only compared patients who died of thyroid cancer and patients who survived (223/0 vs 17/0). 2) 미세유두암진단시기별임상적특징미세유두암진단시기에따라수술전미세침흡인세포검사로진단된경우, 동결절편검사로진단된경우및최종조직병리검사에서우연히발견된경우로분류하여임상적특징을파악해보았다 (Table 2). 미세침흡인세포검사또는동결절편검사로진단된경우보다우연히최종조직병리검사에서진단된환자군에서통계학적으로유의하게평균나이 41.7세로젊었고, 미세유두상암의크기도 0.33 cm로작았으며, TNM 병기 1기인환자군의비율이높았다. 3) 고위험군및저위험군분류에따른임상적특징저위험군으로분류할수있었던경우는 233명 (91.7%) 이었고, 고위험군은 21명 (8.3%) 으로분류되었다 (Table 3). 저위험군에비해고위험군환자는평균나이가 62.3세로많았으며, 남자의비율이높았고, 갑상선전절제술을시행빈도가높았으며, 무병생존율이 65% 로통계학적으로유의하게낮았다. 양위험군에서국소재발은있었으나원격전 이는확인되지않았다. 4) 크기에따른임상적특성미세유두상암의크기를 0.5 cm 이하인군과이상인군으로분류하여양군간의특성을비교하였다. 양군간수술당시의평균나이, 원격전이의유무, 남녀비, 다병소성, 림프절곽청술범위의차이는없었으나갑상선주위조직의침윤및림프절전이는크기가 0.5 cm 이상인미세유두상암환자군에서많았고전절제술시행빈도및방사성요오드치료의비율도높았다 (Table 4). 추적관찰결과 0.5 cm 이상인환자군에서국소림프절재발율이 4.9% 로유의하게높았다. 10년무병생존율은 0.5 cm 이상인군에서 97.8% 로낮았으나통계학적의미있는차이는없었다 (Table 5). 고찰건강에대한관심이높아지면서정기적인건강검진을받는사람들이늘어나면서갑상선선별검사의한방법으로
180 대한내분비외과학회지 : 제 8 권제 3 호 2008 Table 4. Comparison of clinical characteristics of PTM, based on the size of primary tumors No. of patients (%) P value* Tumor size Tumor size <5 mm 5 mm Total patients 72 182 - Mean±SD Age (y) 45.8±6.5 49.0±7.5 0.03 Tumor size (cm) 0.39±0.02 0.71±0.04 <.001 Follow-up (y) 14.8±4.4 15.4±4.8 0.6 Gender no. F/M (ratio) 60/12 153/29 0.4 (5:1) (5.3:1) Extrathyroidal extension 2 (2.7) 12 (6.5) <.05 Lymph node metastasis 9 (12.5) 21 (11.5) 0.45 Multifocal disease 4 (5.6) 8 (4.4) 0.17 DM at presentation 0 0 - Thyroid surgery <.05 Total thyroidectomy 23 (31.9) 81 (44.5) - Partial thyroidectomy 49 (68.1) 101 (55.5) - Lymph node surgery 0.21 Not LN excised 31 (43.1) 53 (29.1) - Sampling 20 (27.8) 48 (26.4) - Neck dissection 21 (29.2) 73 (40.1) - Radio iodine ablation 20 (27.8) 78 (42.9) <.05 DM = distant metastasis. 초음파검사가보편적으로시행되어지고있다. 따라서임상적으로촉지되지않는갑상선결절환자도증가하고있다. 1980년미세침흡인세포검사가도입되기이전의시기에는미세유두상암은수술중, 림프절생검, 수술후병리결과상우연히발견되었다.(3) 최근에는초음파유도하에미세침흡인세포검사가보편화되면서 0.2 cm 정도의병변까지도비교적정확하게진단이가능해졌다. 본연구에서도수술후최종조직검사결과에서우연히발견한경우가 25예 (9.8%) 있었고, 미세침흡인세포검사로진단한경우가 51예 (20.1%) 있었다. 미세유두상암은사망률이매우낮은양호한예후를보이며양성적임상경과를보이기때문에치료적방법의선택에있어서도외과의마다이견이있다. 적극적치료를주장하는외과의는국소재발또는원격전이를보이는경우도소수에서있다는근거를제시하고있다.(4,13-19) 주기적인추적관찰이면충분하다는주장을하는임상의는임상암으로진행될가능성이낮아질병관련사망률이매우낮다는근거를제시하고있다.(6,20,21) 본연구에서도 10년이상추적관찰한결과미세유두암으로사망한경우는없어매우양호한예후를보였으나, 전체국소재발한경우는 10명 (3.9%) 에서있었다. Table 5. Comparison of clinical outcome of PTM, based on the size of primary tumors No. of patients (%) P value* Tumor size Tumor size <5 mm 5 mm Recurrences Locoregional Thyroid bed 0 0 - Lymph node 1 (1.4) 9 (4.9) <.05 Distant metastasis 0 0 - Status at last follow-up Alive with no disease 65 (90.3) 175 (96.2) - Alive with disease Locoregional 0 0 - Distant metastasis 0 0 - Died of disease 0 0 - Died of other disease 7 (9.7) 7 (3.8) - Ten year survival (%) Disease-specific survival 100 100 - Local-regional failure-free survival 100 97.8 0.47 Distant metastasis failure-free 100 100 - survival patients who have local-regional failure-free (178/182). 재발및생존율에대한위험인자를분류하여치료지침으로삼고자 AGES (age, tumor grade, extent of disease, size), AMES (age, distant metastasis, extent of primary tumor, size), MACIS (metastasis, age, completeness of resection, invasion, size), EORTC (age, locally advance, distant metastases, microscopic tumor invasion beyond thyroid capsule (pt4), marked cellular atypia) 등이제시되고있다.(12,22-25) 본연구에서는 AMES를이용하여저위험군과고위험군으로분류하였는데, 종양의크기가 1 cm 이하이지만갑상선피막침윤또는주변실질침윤이확인되어고위험군으로분류된경우가 21예 (8.3%) 에서있었다. 고위험군환자는 10년이상추적관찰결과림프절전이로인한국소재발율이저위험군에비해통계적으로의미있게높았다. 하지만 2차수술및방사성요오드치료를통해치료하여재발에의한사망은없었다. 본연구결과에서사망한환자들은 60세이상의고령환자에서심혈관계질환, 다른종양성병변및외상성손상에의한사망이었다. 갑상선유두상암은종양의크기가클수록, 갑상선피막의침범이있을때및림프절전이가동반된경우에사망률이나재발율이높다는보고가있다.(26,27) 본연구에서는크기를기준으로 0.5 cm 이하인환자군 72명과 0.5 cm 이상인환자군 182명으로구분하여조사하였는데수술당시림
김경민외 : 미세유두상갑상선암의예후인자및치료지침 181 프절전이율은각각 9명 (12.5%) 과 21명 (11.5%) 있었으나통계학적유의성은없었다. 평균추적관찰기간인 15.2년동안의림프절전이에의한재발율은각각 1명 (1.4%) 과 9명 (4.9%) 으로통계학적으로유의한차이를보여주었으나, 10 년무병생존율은 100% 와 97.8% 로조사되어양군간의차이는없었다. 유두상암과같은고분화암은늦은성장속도와좋은예후를보여주기때문에 20년추적관찰결과를확인하는후속연구가필요할것으로사료된다. 미세유두상갑상선암의수술범위는이견이존재한다. 일엽절제술을주장하는쪽은재발의양상이원격전이성보다는국소재발성이며, 갑상선기능을보존하여갑상선호르몬대체요법이필요없고, 재수술의합병증도높지않다는근거를들고있다.(28-30) 하지만전절제술을주장하는쪽은미세유두상암은다병소성이많고, 추적관찰시재발의평가를위해방사선동위원소스캔및티로글로블린을활용할수있으며, 숙련된외과의에의해집도되는경우에는수술합병증이높지않다는근거를제시하고있다.(4,6,13,31,32) 본연구대상환자에서는갑상선초음파상단일병변인저위험군환자에서는일엽절제술및협부절제술을시행하였고, 수술장소견상주위실질의침범이있는경우또는다병소성인경우에는전절제술을시행하였다. 그레이브스병으로양측아전절제술을시행한후에최종조직검사보고에서우연히발견되고갑상선내에국한된미세유두상인경우가 5명있었고완결갑상선절제없이추적관찰하였고, 재발의증거없이무병생존상태이다. 저자들의연구결과 0.5 cm 이하이거나 AMES상저위험군환자는부분절제술로도충분하나, 0.5 cm 이상이거나주변실질침윤이있는경우에는경부림프절전이에의한국소재발율이높으므로전절제술및잔여조직소멸을위한방사성요오드치료를시행하는것이합리적치료방침이라고생각한다. 결론 10년이상의장기추적관찰결과미세유두상갑상선암은좋은예후를보임을알수있었다. 하지만국소침윤의소견및크기가 0.5 cm 이상인미세유두상갑상선암은임상암과마찬가지로공격성을보여주어국소재발을할수있다는것을확인하였다. 따라서미세유두상암은크기가 0.5 cm 이상이거나임상병리적특성상갑상선주변조직의침윤소견이있는경우에는국소재발의위험인자로인식하고갑상선전절제술및잔여조직소멸을위한방사성요오드치료와같은적극적인치료전략의수립과재발을발견하기위한면밀한추적관찰이필요하겠다. REFERENCES 1) Hedinger C, Williams ED, Sobin LH. Histological Typing of Thyroid Tumours. WHO International Histological Classification of Tumours. 2nd ed. Berlin: Springer; 1988. p.9-11. 2) Rosen IB, Azadian A, Walfish PG. Adverse aspects of small thyroid cancer and need for treatment. Head Neck 1995; 17:373-6. 3) Hay ID, Grant CS, van Heerden JA, Goellner JR, Ebersold JR, Bergstralh EJ. Papillary thyroid microcarcinoma: a study of 535 cases observed in a 50-year period. Surgery 1992; 112:1139-47. 4) Baudin E, Travagli JP, Ropers J, Mancusi F, Bruno-Bossio G, Caillou B, et al. Microcarcinoma of the thyroid gland: the Gustave-Roussy Institute experience. Cancer 1998;83:553-9. 5) Yamashita H, Noguchi S, Murakami N, Toda M, Uchino S, Watanabe S, et al. Extracapsular invasion of lymph node metastasis. A good indicator of disease recurrence and poor prognosis in patients with thyroid microcarcinoma. Cancer 1999;86:842-9. 6) Ito Y, Uruno T, Nakano K, Takamura Y, Miya A, Kobayashi K, et al. An observation trial without surgical treatment in patients with papillary microcarcinoma of the thyroid. Thyroid 2003;13:381-7. 7) Bramley M, Harrison B. Papillary microcarcinoma of the thyroid gland. Br J Surg 1996;83:1674-83. 8) Appetecchia M, Scarcello G, Pucci E, Procaccini A. Outcome after treatment of papillary thyroid microcarcinoma. J Exp Clin Cancer Res 2002;21:159-64 9) Furlan JC, Bedard Y, Rosen IB. Biologic basis for the treatment of microscopic, occult well-differentiated thyroid cancer. Surgery 2001;130:1050-4. 10) Chow SM, Law SCK, Chan JKC, Au SK, Yau S, Lau WH. Papillary microcarcinoma of the thyroid: prognostic significance of lymph node metastasis and multifocality. Cancer 2006;98:31-40. 11) Shah JP, Kian K, Forastiere A, Garden A, Hoffman HT, Lee J, et al. American Joint Committee on Cancer. Cancer Staging Manual. 6th ed. New York: Springer-Verlag; 2002. p.77-87. 12) Haigh P, Urbach DR, Rotstein LE. AMES prognostic index and extent of thyroidectomy for well-differentiated thyroid cancer in the United States. Surgery 2004;136:609-16. 13) Nagouchi S, Yamashita M, Murakami N. Small carcinoma of the thyroid. A long term follow-up of 876 patients. Arch Surg 1996;13:187-91. 14) Hong SJ, Lee CS, Kim YS. The risk factors of hypocalcemia after total thyroidectomy: what is the main cause of transient hypocalcemia? J Korean Soc Endocrinol 2005;5:87-92. 15) DeGroot LJ, Kaplan EL, McCormick M, Straus FH. Natural history, treatment, and course of papillary thyroid carcinoma. J Clin Endocinol Metab 1990;71:414-24.
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