The Korean Journal of Pathology 2007; 41: 207-12 갑상선에서독립적으로발생한유두암종및수질암종 - 3 예보고 - 유창영 정찬권 권혁상 1 김성헌 2 김민식 3 김승남 4 이교영 가톨릭대학교의과대학병원병리학교실 1 내과학교실, 2 진단방사선과학교실 3 이비인후과학교실, 4 외과학교실 접수 : 2006년 12월 11일게재승인 : 2007년 1월 26일 책임저자 : 정찬권우 137-701 서울시서초구반포동 505 가톨릭대학교강남성모병원병리과전화 : 02-590-1590 Fax: 02-592-4190 E-mail: ckjung@catholic.ac.kr Concurrence of Spatially Separated Medullary Carcinoma and Papillary Carcinoma of the Thyroid Gland - A Report of Three Cases - Changyoung Yoo, Chan-Kwon Jung, Hyeok Sang Kwon 1, Sung Hun Kim 2, Min Sik Kim 3, Seung Nam Kim 4 and Kyo-Young Lee Departments of Hospital Pathology, 1 Internal Medicine, 2 Radiology, 3 Otolaryngology, and 4 Surgery, College of Medicine, The Catholic University of Korea, Seoul, Korea Although medullary thyroid carcinoma (MTC) may coexist with papillary thyroid carcinoma (PTC) as a collision tumor within the same nodule or as two or more spatially separated tumors, these two carcinomas rarely coexist. We encountered three cases of sporadic MTCs spatially separated from PTCs, which occurred concurrently, either within the same thyroid lobe or in different thyroid lobes. In each of the cases the patients underwent total thyroidectomy and neck dissection. PTC metastases of the lymph node were observed in two of the cases and MTC metastasis of the lymph node was observed in one case. Among the multiple thyroid nodules affected by both MTCs and PTCs, only the dominant nodules had spread to the lymph nodes. Because MTC has a different clinical significance from PTC, in patients with multiple thyroid nodules, appropriate diagnostic approaches, such as fine needle aspiration of all possible nodules and measurement of serum calcitonin level, should be performed. Key Words : Papillary carcinoma; Medullary carcinoma; Thyroid gland; Mixed tumor 수질암종은갑상샘에서발생하는대표적인암종가운데하나로여포주위 C 세포에서유래하는악성종양이다. 대부분아무런증상도없는전경부결절로나타나지만주위장기침윤에의한증상, 또는부신생물증후군등다양한임상증상을보일수있다. 수질암종은복합내분비신생물증후군을포함한유전성질환의한부분으로나타나기도하지만산발적으로발생하는예가더흔하다. 1 갑상샘에서가장흔하게발생하는암종은유두암종이지만, 흥미롭게도갑상샘의다발성결절환자의수술검체에서드물게수질암종이우연히발견되기도한다. 2-7 갑상샘에서흔히발견되는유두암종과함께독립적으로수질암종이우연히발견될수있다는사실은, 다발성결절을보이는갑상샘질환환자를대할때다소희귀한수질암종의가능성도염두에두어야한다는것을의미한다. 본논문에서저자들은한갑상샘에서독립적으로발생한수질암종및유두암종 3예를보고하고이들이지니는임상적의의를살펴보고자한다. 증례증례 1 65세여자환자는상기도염증상으로인근병원에갔다가갑상샘의양쪽엽에서종괴가발견되어본원에내원하였다. 내원당시시행한혈청학적검사에서칼시토닌이 69.07 pg/ml로증가한소견을보였다. 그리고초음파검사결과양쪽엽에서종괴세개가확인되었다 (Fig. 1A, B). 이중크기가큰두종괴에각각세침흡인세포검사를시행하였다. 좌측종괴에서시행한세침흡인세포검사결과는유두암종의전형적인세포학적소견을보였다. 우측종괴의세포도말은중등도의세포밀도를보이고다소성근덩어리를이루고있었다. 세포들은경도의다형성을보였으나유두암종에서보이는특징적인핵형태는보이지않았다. 세포블럭으로시행한 calcitonin, carcinoembryonic antigen 207
208 유창영 정찬권 권혁상외 4 인 (CEA), chromogranin에대한면역화학염색결과양성을보여수질암종으로진단하였다. 환자는이후갑상샘전적출술및양측근치목수술을시행받았다. 갑상샘좌엽에서는낭성변화를보이 는종괴가 3.3 2.5 cm 크기로관찰되었으며조직학적검사상유두암종으로진단되었다 (Fig. 2, 3A). 우엽에서는균질한단면을보이는다소경계가뚜렷한옅은황색의종괴가 1.3 1.2 cm A B C D E F G Fig. 1. In the sonogram of the case 1, an about 2.9 2.1 cm sized, oval hypoechoic nodule with microcalcifications is found in the lower portion of the left lobe (A). In the right lobe a smaller nodule, 1.3 1.0 cm, with smooth margin is also noted (B). In the sonogram of the case 2, two irregular hypoechoic nodules with macrocacifications are found in the mid-portion of the right (C) and left lobe (D). Another small hypoechoic nodule, 0.4 0.3 cm, is also found in the right lobe (E). In the case 3, isthmectomy was done three years ago due to papillary carcinoma. Contrast enhanced computed tomogram demonstrates extensive hypodense lymph node metastasis and recurrence in the previous operation bed and left neck (F). A round, heterogeneously enhanced nodule in the left lobe is noted (G).
갑상샘에서독립적으로발생한유두암종및수질암종 209 right left 와경계가나쁜 0.3 0.2 cm 크기의종괴가관찰되었다. 좌엽에서는경계가좋은 2.0 1.0 cm 크기의종괴가관찰되었다 (Fig. 2). 양엽에서관찰된경계가좋은종괴는특징적인조직학적특 Case 1 0.3 0.3 cm 1.3 1.2 cm 3.3 2.5 cm 징과함께콩고레드염색에서아밀로이드의침착이보이고또한면역조직화학염색결과칼시토닌, CEA, chromogranin, synaptophysin에양성반응을보여모두수질암종으로진단되었다 (Fig. 3D, 4B). 우엽의경계가나쁜작은종괴는유두암종으로진단 되었다 (Fig. 3C). 양쪽경부림프절에수질암종의다발성전이 가보였다 (Fig. 2). 수술전혈중칼시토닌은측정하지않았으 0.3 0.2 cm 나혈중칼슘농도는정상이었다. Case 2 2.0 1.5 cm 2.0 1.0 cm 증례 3 Case 3 Fig. 2. The schematic diagram of thyroid glands of three cases. The hollow circles indicate medullary carcinomas and solid circles indicate papillary carcinomas. The circles near the trachea indicate the metastatic tumors in lymph nodes. 의크기로관찰되었고 (Fig. 2), 조직학적으로는원형의세포들이잔가지모양으로배열된특징적인소견이보였으며, 칼시토닌에대한면역조직화학염색에서는세포블럭에서와동일하게양성반응을보였다. 그외 CEA, chromogranin, synaptophysin 에도양성반응을보여수질암종으로진단되었다 (Fig. 3B, 4A). 우엽에는또한수질암종과가까운곳에 0.3 0.3 cm 크기의경계가나쁜종괴가있었는데조직학적으로미세유두암종으로진단되었다. 경부림프절의조직학적검사상왼쪽의림프절에유두암종의전이가있었다 (Fig. 2). 수술후환자의칼시토닌수치는 4.17 pg/ml로정상화되었다. 증례 2 Size unknown papillary carcinoma 1.5 1.5 cm medullary carcinoma 61세여자환자가양쪽갑상샘에서종괴와더불어다발성의경부림프절종대가관찰되어본원에내원하였다. 내원시시행한초음파검사결과, 갑상선양엽에서 2.0 cm 크기의종괴가 2개관찰되었으며우엽에서 0.3 cm 크기의종괴가더관찰되었다 (Fig. 1C-E). 크기가비슷한양측종괴에세침흡인세포검사를시행하였으며양측모두분화가나쁜암종으로진단되었다. 환자는갑상샘전적출술및양측경부림프절절제술을시행받았다. 갑상샘우엽에서는경계가좋은 2.0 1.5 cm 크기의종괴 70세남자환자는수년전갑상샘유두암종과경부림프절및흉골의전이로갑상샘의협부및우엽절제술을포함한완화수술을받았다. 당시유두암종의크기가어느정도였는지는알수없었다. 그러나최근에호흡곤란이심해져서다시내원하였다. 내원당시경부컴퓨터단층촬영을시행하였는데다발성의경부림프절종대및종괴가기관까지침습한소견을보였다 (Fig. 1F, G). 환자는남은갑상샘전적출술및경부림프절절제술그리고기관일부를절제하는수술을받았다. 경부림프절은유두암종의전이가보였다 (Fig. 2, 3E). 기관조직에침윤하는소견도관찰되었다. 갑상샘좌엽에 1.5 1.5 cm 크기의경계가좋은종괴가보였고, 조직학적인특징과함께면역조직화학염색결과칼시토닌, CEA, chromogranin, synaptophysin에양성반응을보여수질암종으로진단하였다 (Fig. 2, 3F, 4C). 내원당시혈중칼슘농도는 7.7 mg/dl이었다. 수술후측정한칼시토닌은 14.7 pg/ml로다소증가하였다. 경부림프절은유두암종의전이를보였다 (Fig. 2, 3E). 고찰수질암종은갑상샘에서발생하는다른종류의암종과함께나타날수있다. 2-8 2004년 WHO 분류에따르면혼합수질-여포세포암종유두암종이따로분류되어있는데, 이는수질암종과여포세포에서유래한종양세포가한종괴내에서서로구분되어동시에존재하는충돌종양 (collision tumor) 을지칭한다. 9 본논문처럼한갑상샘에서수질암종과유두암종이서로떨어져발생한것과는다르다. 기존의보고에따르면수질암종은유두암종과동반되는사례가가장흔하지만, 2-7 여포암종과동반된예도있으며, 10 심지어는세가지암이모두독립적으로발견된예도있다. 11 대다수는특별한가족력이없이산발적으로발생하였다. 한보고에따르면수질암종과유두암종이동반된예의빈도가기존에알려진것보다훨씬높다고한다. 4 미세유두암종이부검시또는양성병변으로인한갑상샘절제시자주관찰되는병변이
210 유창영 정찬권 권혁상외 4 인 A B C D E F Fig. 3. The left column shows the histologic features of the papillary carcinomas in the case 1 (A), 2 (C) and 3 (E). The right column shows the histologic features of the medullary carcinomas in the case 1 (B), 2 (D) and 3 (F). 라는사실을감안하면수질암종환자에게서미세유두암종이함께발생했을가능성은얼마든지있을수있으며, 실제수질암종환자의 11.05% 에서미세유두암종이동반되었다는보고도있다. 4 그러나수질암종환자에게서임상적으로인지할수있는크기 1.0 cm 이상의유두암종이함께발생한예는매우드물었다. 우 리나라에서도유두암종과수질암종이동시에발생한예가문헌상 4예에불과하다. 2,12-14 이중 3예는앞서말한혼합수질-여포세포암종 ( 충돌종양 ) 이었으며, 2,12,14 유두암종과수질암종이독립적으로발생한예는 1예에불과하다. 13 이들은모두가족력이알려지지않은산발적인증례들이었다. 두가지상이한종양이동
갑상샘에서독립적으로발생한유두암종및수질암종 211 A B C 시에발생하는이유에대해서는, 공통의미분화세포에서유래한다는가설과서로다른여포상피세포와 C 세포가각각종양을형성한다는가설이있지만뚜렷한증거는없다. 10,15 미세유두암종의높은발생빈도를감안하면아무런관련없이우연히동시에발생하였을가능성도얼마든지있다. 수질암종은복합내분비신생물증후군과동반될수있기때문에수술전진단이중요하다. 현재우리나라에서수질암종은갑상샘에서발생하는암가운데 2-4% 를차지한다. 16 가족력또는복합내분비신생물증후군과관련되어나타난예가어느정도인지에대해본격적인연구가이루어진적은없지만, 한보고에따르면가족력이있는빈도가전세계적인빈도와비슷한것으로보인다. 17 그러나수질암종은다른갑상샘종양보다가족력을지닌경우가많기때문에가족구성원에대한선별이필요하다. 따라서수질암종환자의가족에게는칼시토닌검사를주기적으로시행할것을권하고있다, 1,18 또수질암종은염색체 10q11.2에있는 RET 원종양유전자 (proto-oncogene) 의돌연변이에의해발생하는것으로생각되기때문에, 1,19,20 RET 원종양유전자돌연변이를검사하여돌연변이가확인된가족에게는예방적갑상샘절제술을권하고있다. 15 다발성갑상샘결절의세포학적검사에서전형적인유두암종 Fig. 4. Representative immunohistochemical findings of medullary carcinomas show positive reaction of calcitonin (A), synaptophysin (B), and CEA (C) in case 1, case 2 and case 3, respectively. 이관찰되거나세포학적진단이어려울경우에는, 수질암종의동반가능성을생각하기란쉽지않다. 증례 1은환자의혈중칼시토닌수치가높게나타났고, 세포블럭에서면역화학염색을시행하여수술전에수질암종을예상할수있었다. 그러나증례 2 는양측종괴에세침흡인세포검사를시행한결과악성을시사하는소견은보였으나수질암종으로진단할수는없었다. 림프절전이를의심하여양측근치목수술을포함한갑상샘전절제술을시행하였고, 조직검사결과수질암종으로진단됨과아울러미세유두암종이우연히발견되었다. 증례 3은유두암종으로이미우엽을절제한후다발성림프절종대가있어림프절및남은갑상선을절제하였으며, 림프절에는유두암종의다발성전이소견을보였다. 수질암종은좌엽에서우연히발견되었다. 수술전수질암종은전혀예상하지못했다. 따라서증례 1을제외하고는모두유두암종에준하여치료가이루어진결과가되었다. 추가적으로, 3예모두에서림프절전이가관찰되었는데모두우세결절을이루는암종의전이였다. 증례 1 및증례 3의경우수질암종이이미상당한크기를이루고있었으나크기가수질암종보다컸던유두암종은림프절에전이된반면수질암종의림프절전이는관찰되지않아서, 만약증대된림프절에서세침흡인세포검사를시행했더라도수질암종의동반가능성을예측하기는더욱어
212 유창영 정찬권 권혁상외 4 인 려울수있다. 수질암종은유두암종과는달리조기림프절전이, 가족력, 복합내분비신생물증후군등상이한임상적특징을보이므로수술전진단이중요하다. 한보고에따르면갑상샘에다발성결절이있을때는유두암종이의심되는부위만검사할것이아니라수질암종이동반되었을가능성도염두에두고모든결절에세침흡인세포검사를시행해야한다고한다. 3 그러나세포도말소견만으로수질암종을진단하기는어렵고다른종양과유사한소견이나올수도있어서진단율은그리높지않다. 17,18 추가로, 갑상샘에다발성결절을보이는환자는칼시토닌수치를측정하여또는칼시토닌수치가정상을약간상회하는경우펜타가스트린자극검사와같은방법을사용하면수질암종을조기에진단할수있다. 18 참고문헌 1. Alsanea O, Clark OH. Familial thyroid cancer. Curr Opin Oncol 2001; 13: 44-51. 2. Ahn JH, Jin SY, Kim HG, Park CI. Medullary carcinoma of thyroid gland with co-existing papillary carcinoma. Korean J Pathol 1988; 22: 443-7. 3. Merchant FH, Hirschowitz SL, Cohan P, Van Herle AJ, Natarajan S. Simultaneous occurrence of medullary and papillary carcinoma of the thyroid gland identified by fine needle aspiration. A case report. Acta Cytol 2002; 46: 762-6. 4. Biscolla RP, Ugolini C, Sculli M, et al. Medullary and papillary tumors are frequently associated in the same thyroid gland without evidence of reciprocal influence in their biologic behavior. Thyroid 2004; 14: 946-52. 5. Nicolas MM, Neto AG, Luna MA. Concurrent papillary and medullary thyroid carcinoma. Arch Pathol Lab Med 2005; 129: 264-5. 6. Younes N, Shomaf M, Al Hassan L. Simultaneous medullary and papillary thyroid carcinoma with lymph node metastasis in the same patient: case report and review of the literature. Asian J Surg 2005; 28: 223-6. 7. Rios A, Rodriguez JM, Ferri B, Balsalobre MD, Parrilla P. Association of medullary and differentiated thyroid carcinomas. Otolaryngol Head Neck Surg 2006; 135: 473-5. 8. Hemminki K, Dong C. Familial relationships in thyroid cancer by histo-pathological type. Int J Cancer 2000; 85:201-5. 9. DeLellis RA, Lloyd RV, Heitz PU, Eng C. The WHO classification of tumors of endocrine organs. 1st ed. Lyon: IARCP press, 2004; 92-3. 10. Matias-Guiu X. Mixed medullary and follicular carcinoma of the thyroid. On the search for its histogenesis. Am J Pathol 1999; 155: 1413-8. 11. Cupisti K, Raffel A, Ramp U, et al. Synchronous occurrence of a follicular, papillary and medullary thyroid carcinoma in a recurrent goiter. Endocr J 2005; 52: 281-5. 12. Kim JK, Chung HW, Seo HS, et al. A case of papillary thyroid carcinoma combined with multiple endocrine neoplasia type 2A. J Korean Soc Endocrinol 2002; 17: 730-8. 13. Choi HS, Lim YC, Kim JY, Chung TY. A case of concurrent medullary and papillary carcinoma of the thyroid gland. Korean J Otolaryngol-Head Neck Surg 2001; 44: 116-8. 14. Hong SJ, Gong KY, Song YK, Ryu JS, Kim KS, Lee JH. Concurrent medullay and papillary carcinoma of the thyroid. J Korean Soc Endocrinol 1998; 13: 634-9. 15. Ardern-Jones A, Harvey RJ, Wilson P, et al. Medullary and non-medullary thyroid cancer in a family. Acta Oncol 2004; 43: 680-1. 16. Lee JH, Shim YS, Lee YS, Lee GH, Park SJ. A clinical study of medullary thyroid carcinoma: 12 cases. Korean J Otolaryngol-Head Neck Surg 1999; 42: 627-33. 17. Oh SK, Kim JS. Medullary carcinoma of the thyroid. J Korean Surg Soc 1999; 56:49-58. 18. Hahm JR, Chung JH, Oh EY, et al. Routine measurement of serum calcitonin concentration is useful in early detection of medullary thyroid carcinoma among patients with nodular thyroid disease. J Korean Soc Endocrinol 2000; 15: 70-84. 19. Kim YK, Kim JW, Ahn SM, et al. A case of familial medullary thyroid carcinoma with a E768D mutation in RET proto-oncogene. J Korean Soc Endocrinol 2005; 20: 375-80. 20. Melillo RM, Cirafici AM, De Falco V, et al. The oncogenic activity of RET point mutants for follicular thyroid cells may account for the occurrence of papillary thyroid carcinoma in patients affected by familial medullary thyroid carcinoma. Am J Pathol 2004; 165: 511-21.