대한내과학회지 : 제 83 권제 2 호 2012 http://dx.doi.org/10.3904/kjm.2012.83.2.226 위장관기질종양으로오인된미분화췌장암 1 예 충남대학교의학전문대학원내과학교실 김규섭 문희석 고광훈 정일순 김설영 성재규 정현용 A Case of Anaplastic Carcinoma of the Pancreas Mimicking a Gastrointestinal Stromal Tumor Kyu Seop Kim, Hee Seok Moon, Kwang Hun Ko, Il Soon Jung, Seul Young Kim, Jae Kyu Seong, and Hyun Yong Jeong Department of Internal Medicine, Chungnam National University School of Medicine, Daejeon, Korea Anaplastic carcinoma of the pancreas is an extremely rare but aggressive, rapidly progressive tumor. It often presents with invasion of adjacent organs and distant metastases. Most cases are inoperable and confirmed by autopsy. A correct diagnosis of stomach invasion by anaplastic carcinoma of the pancreas is important due to the risk of bleeding, perforation by rapid tumor growth, and a poor prognosis. However, an accurate diagnosis is difficult as a result of the various clinical presentations, symptoms, and radiological findings. We herein report a case of anaplastic carcinoma of the pancreas in a 78-year-old woman who presented with stomach invasion mimicking a gastrointestinal stromal tumor. (Korean J Med 2012;83:226-231) Keywords: Anaplastic carcinoma; Gastrointestinal stromal tumor; Pancreas 서론미분화췌장암은남자에호발하며전체외분비췌장암의 0.5-7% 정도를차지하는드문질환이다 [1]. 따라서이에대한조직발생학적및생물학적기원은아직까지는불분명하다. 미분화췌장암은방추세포암 (spindle cell carcinoma), 다형거대세포암 (pleomorphic giant cell carcinoma), 유육성암 (sarcomatoid carcinoma) 등여러이름으로불려왔으나, 1977년 Alguacil- Garcia 등 [2] 이이들을방추세포, 파골세포형거대세포, 다형 거대세포, 그리고구형세포등으로분류하였고, 1996년 WHO 에서미분화췌장암으로정의하고, 파골세포형거대세포암은다른질환군으로분류하였다 [3]. 미분화췌장암은발견당시주변장기로의침윤이나원격전이가있는경우가대부분이어서수술적절제가불가능하고부검후진단되는경우가많다. 또한다양한성장패턴을보이며매우나쁜예후를보이므로조기감별진단이중요하지만, 그임상증상이나방사선적소견이비특이적이고모호한경우가많아다른암으로오인되는경우가많다. 이에저자들은위내시경과방 Received: 2011. 7. 8 Revised: 2011. 7. 26 Accepted: 2011. 8. 12 Correspondence to Hee Seok Moon, M.D. Department of Internal Medicine, Chungnam National University School of Medicine, 282 Munhwa-ro, Jung-gu, Daejeon 301-721, Korea Tel: +82-42-280-7142, Fax: +82-42-257-5753, E-mail: mhs1357@cnuh.co.kr - 226 -
- Kyu Seop Kim, et al. Anaplastic carcinoma of the pancreas - 사선검사에서위장관기질종양이의심되었으나수술후조직검사를통하여미분화췌장암으로진단된증례를경험하였기에문헌고찰과함께보고하는바이다. 증례환자 : 김〇〇, 78세, 여자주소 : 전신쇠약현병력 : 환자는내원 5개월전부터전신쇠약과식사량감소가있었고 1개월전부터증상이악화되어개인병원에서 시행한혈액검사상빈혈 (Hb 8.8 g/dl) 이발견되어내과에의뢰되었고, 원인평가를위해시행한위내시경검사상위장관기질종양이의심되어정밀검사및치료를위해입원하였다. 가족력 : 특이사항은없었다. 과거력 : 3년전고혈압으로진단받고약물치료중이었다. 사회력 : 흡연력이나음주력은없었다. 신체검사소견 : 내원당시의활력징후는혈압은 110/60 mmhg, 맥박은 92회 / 분, 호흡은 20회 / 분, 체온은 37.6 이었다. 의식은명료하였고, 만성병색을보였으며, 결막빈혈이있었으나, 공막은정상이었다. 복부진찰에서장음은정상이었고압통 A B C D Figure 1. Computed tomography (CT) scan of the patient. The CT scan showed a large 12 12 cm heterogenous mass (white arrow) in the posterior wall of the stomach and pancreatic tail (A, B) Transverse view. (C) Coronal view. (D) Sagittal view. - 227 -
- 대한내과학회지 : 제 83 권제 2 호통권제 624 호 2012 - 이나반발통은없었으나, 좌상복부에단단하고고정된 10 cm 가량의종괴가촉지되었다. 검사실소견 : 말초혈액검사에서혈색소 9.0 g/dl, 적혈구용적 26.1%, 백혈구 17,400/uL, 혈소판 638,000/uL이었다. 혈청생화학검사에서혈청총단백 6.6 g/dl, 알부민 2.4 g/dl, AST 17 IU/L, ALT 14 IU/L, 총빌리루빈 0.5 mg/dl, BUN 13 mg/dl, 크레아티닌 0.8 mg/dl, 칼슘 8.4 mg/dl, 알칼라인포스파타제 45 IU/L, 젖산탈수효소 (LDH) 479 IU/L 이었다. 혈청 CEA는 2.3 ng/ml (0-5 ng/ml) 로정상범위였으나, 혈청 CA 19-9가 355 U/mL (0-37 U/mL) 으로상승되어있었다. 방사선소견 : 복부전산화단층촬영에서위와비장을침범하고중심부에괴사를동반한 12 cm 크기의소엽성의거대한종괴가관찰되었다 (Fig. 1). 위내시경소견 : 위분문부에서 5 5 cm 크기의돌출하는 Figure 2. Endoscopic finding of the tumor. Endoscopy revealed a 5 5 cm normal-mucosa covered, fungating mass with convergence of the surrounding folds. A B C D Figure 3. Macroscopic findings of the tumor. (A, C) A bulky mass is observed extending from the pancreatic tail into the gastric posterior wall (solid arrow) and spleen (hollow arrow). (B, D) Cut surface of the specimen revealed central necrotic tissue. - 228 -
- 김규섭외 6 인. 위장관기질종양으로오인된미분화췌장암 1 예 - A B C D Figure 4. Microscopic and immunohistochemical findings of the tumor. (A) Histological examination of the resected specimen revealed that normal mucosa was preserved and undifferentiated neoplasic cells were found in the subepitheial area (hematoxylin and eosin [H&E] staining, 40). (B) The tumor cells were pleomorphic with eccentrically placed nuclei and homogeneous, eosinophilic cytoplasm (H&E staining, 100). Immunohistochemical staining was positive for (C) cytokeratin 7 and (D) cytokeratin 19. 양상의매끈한점막으로덮힌상피하종양이관찰되었으며 (Fig. 2), 내시경하조직검사에서는염증세포외에특이소견은없었다. 육안적소견 : 위의후벽과비장, 췌장을침범하는 12 12 cm 크기의중심부괴사가있는백색종괴가관찰되었다 (Fig. 3). 조직학적소견 : 한쪽으로치우친불규칙한핵과호산구성세포질을동반한다형종양세포들이관찰되었고면역조직화학염색상 CK (cytokeratin) 19와 CK 7 및 vimentin 양성이었다 (Fig. 4). 경과 : 환자는위전절제및비장절제, 췌장미부절제를시행한지 5개월후복막및소장, 횡격막, 좌측신장등다발성전이가발생하였고 2주후사망하였다. 고찰미분화췌장암은관상선암의드문변이형이며생존기간이불과수주에이르는공격적인종양이다 [4]. 이들은고령의남성에흔하고주로 60-80대에호발하는것으로알려져있다 [5,6]. 체중감소, 피로, 식욕감퇴, 복통, 구역, 구토등의일반적인임상증상들을보이며, 특이한임상징후로는황달, 그리고만져지는복부종괴정도이다 [6]. 본증례에서도전신쇠약및피로등의비특이적인증상이었고신체검사에서도복부종괴이외에는특이소견이없었다. 발생부위는췌장의어느곳이나가능하며, 문헌마다호발부위가다양하지만, 관상선암과는달리주로체부와미부에호발하는 - 229 -
- The Korean Journal of Medicine: Vol. 83, No. 2, 2012 - 것으로알려져있다. 방사선적소견은일반적으로복부전산화단층촬영에서조영제주입후중심부에괴사나출혈이동반된소엽상의돌출형종괴형태를보인다 [6]. 크기는 2.5 cm 에서 20 cm까지다양하지만, 평균 9.2 cm으로대부분발견당시 8 cm 이상으로보고된다 [5]. 초기동맥기와문맥기에조영증강되는정상췌장조직에비해저음영으로보이는관상선암과는달리조영후주변부가현저하게조영증강되는것이차이점이다. 이는췌장의점액성낭선종또는낭성종양및내분비종양등과유사한소견으로, Ichikawa 등 [7] 의보고에따르면대부분의증례에서수술전방사선적진단도이와같이잘못판단되었다. 특징적인내시경적소견은없으나도넛모양의융기형병변이나화산분화구모양의궤양형병변이진단에도움을줄수있다. 본증례에서는초기에방사선적및내시경적소견에기초하여위에서기원하는최대직경 12 cm 크기의거대한위장관기질종양을의심하였고, 위와비장및췌장을직접침범하였지만원격전이가없어수술적절제를시행하였으나, 절제후조직검사에서췌장미부에서기원하는미분화암으로최종적으로진단되었다. 국내에서보고된미분화췌장암환자들은총 6예로서이들의임상증상과발생위치및방사선적소견은외국의문헌보고와유사하였다 (Table 1) [8]. 미분화췌장암은우세한세포종류에따라방추세포, 다형거대세포, 구형세포등으로분류할수있으며, 면역조직화학적검사에서상피세포 표식자인 CK 7, EMA, Pancytokeratin 등과반응하여, 전이성암종, 악성흑색종, 횡문근육종, 융모막암종, 미분화거대세포림프종, 상피양육종, 악성섬유성조직구종등과감별할수있으나, 일부에서는간엽세포표식자인 Vimentin, Desmin 에반응하기도한다 [6]. 본증례에서도 CK 7, CK 19, Vimentin 에모두양성소견을보였다. 또한, 미분화췌장암에서는 K-ras 유전자돌연변이가흔하게발견되며돌연변이율은 66.7% 까지보고된다. 모든돌연변이에서 12번염색체단완의 12번째코돈에서 glycine이 valine으로치환된것을관찰할수있으며, 이러한환자들에서불량한예후와상대적으로짧은생존기간을보인다 [5,9-11]. Strobel 등 [12] 은 72예의췌장암을분석하여통계학적유의성은낮지만미분화췌장암과관상선암에서각각 5.7개월과 15.7개월의평균생존기간을그리고근치적절제가불가능한경우관상선암에서보다예후가훨씬불량함을보고하였다. 하지만치료법에대한선택은제한적이다. 근치적절제는대부분발견당시광범위한전이로인해성공적이지못하며, 가능하더라도수술후재발이나간, 폐, 복막등으로의원격전이가빠른편이다 [6]. Paal 등 [5] 은미분화췌장암 35예중수술후 2예에서 14.6년과 7.2년의무병장기생존과 4예에서평균 4.7년의장기생존이있다고하였으나, 나머지 29예에서평균 5.5개월의생존기간을보고하였다. 또한몇몇증례들에서방사선치료가시도되었지만성공적이지못했으며, 환자상태의급격한악화 Table 1. Summary of the clinical, microscopic, and immunohistochemical features of the reported anaplastic carcinomas of the pancreas in the Korean literature Author (yr) Song et al. (1987) Park et al. (2000) Jun et al. (2006) Kim et al. (2006) Chun et al. (2008) Sex/age Symptom Size (cm) Location Invasion Histology 44/F Upper abdominal pain 10 Head None Pleomorphic giant cell 54/F None 3.3 Tail None Pleomorphic giant cell 52/M Upper abdominal pain 2.5 Head Common bile duct 73/F Asthenia 20 Body & tail Stomach, colon, spleen - 230 - Immunohistochemical stain (EMA/CK/Vimentin) NR CEA (+) Survival (mon) Spindle cell NR/+/+ 2 Spindle cell +/+/+ 3 70/M LUQ 11 Body & tail Stomach, colon Spindle cell +/+/- 5 discomfort 65/F Flank pain, Lt 8.5 Tail Spleen, colon Spindle cell +/+/ NR 3 Lt, left; LUQ, left upper quadrant; NR, not recorded; EMA, epithelial membrane antigen; CK, cytokeratin; CEA, carcinoembryonic antigen. NR NR
- Kyu Seop Kim, et al. Anaplastic carcinoma of the pancreas - 등으로항암치료역시좋은대상이되지못했다. 본증례에 서도수술후 6 개월에복막및소장, 신장, 횡격막등다발성 장기전이로사망하였다. 요 미분화췌장암은매우드문질환이나, 치료방법이제한 적이고그진행속도가빠르다. 또한진단당시십이지장, 위, 결장간막등주위조직을침범하는경우가많고간, 폐, 림프절등으로원격전이가많다. 그중위나십이지장의침 범의경우종양자체의불량한예후뿐만아니라종양의급 속한성장에의한출혈과천공의위험성이높기때문에조 기에정확한진단이중요하다. 하지만임상증상및방사선 적, 내시경적소견등이모호하고비특이적이어서그진단이 어렵다. 그러나앞서기술한몇가지소견, 즉, 상복부동통, 황달, 만져지는복부종괴, 복부전산화단층촬영상췌장의 체부나미부에서주변조직들을침범하는거대한중심괴사 성종괴, 특히종양주변부의조영증강소견, 내시경상점 막하종양의형태나외부에서의압박소견등이있을때이 를종합적으로판단하여미분화췌장암을의심해보는것이 필요하리라생각된다. 본증례에서는내시경적, 방사선적으 로위장관기질종양으로판단하였으나, 수술후조직검사에 서최종적으로미분화췌장암으로진단된환자를경험하였 약 기에문헌고찰과함께보고하는바이다. 중심단어 : 미분화췌장암 ; 위장관기질종양 REFERENCES 1. Hakamada K, Miura T, Kimura A, et al. Anaplastic carcinoma associated with a mucinous cystic neoplasm of the pancreas during pregnancy: report of a case and a review of the literature. World J Gastroenterol 2008;14:132-135. 2. Alguacil-Garcia A, Weiland LH. The histologic spectrum, prognosis, and histogenesis of the sarcomatoid carcinoma of the pancreas. Cancer 1977;39:1181-1189. 3. The World Health Organization. Undifferentiated (Anaplastic) carcinoma. In: Klöppel G, Solcia E, Longnecker DS, Capella C, Sobin LH, eds. Histological Typing of Tumors of the Exocrine Pancreas. 2nd ed. Berlin: Springer-Verlag, 1996: 17. 4. Wong M, See JY, Sufyan W, Diddapur RK. Splenic infarction: a rare presentation of anaplastic pancreatic carcinoma and a review of the literature. JOP 2008;9:493-498. 5. Paal E, Thompson LD, Frommelt RA, Przygodzki RM, Heffess CS. A clinicopathologic and immunohistochemical study of 35 anaplastic carcinomas of the pancreas with a review of the literature. Ann Diagn Pathol 2001;5:129-140. 6. Chadha MK, LeVea C, Javle M, Kuvshinoff B, Vijaykumar R, Iyer R. Anaplastic pancreatic carcinoma: a case report and review of literature. JOP 2004;5:512-515. 7. Ichikawa T, Federle MP, Ohba S, et al. Atypical exocrine and endocrine pancreatic tumors (anaplastic, small cell, and giant cell types): CT and pathologic features in 14 patients. Abdom Imaging 2000;25:409-419. 8. Chun KS, Song IS. Anaplastic carcinoma of the pancreas. J Korean Surg Soc 2008;74:462-468. 9. Gocke CD, Dabbs DJ, Benko FA, Silverman JF. KRAS oncogene mutations suggest a common histogenetic origin for pleomorphic giant cell tumor of the pancreas, osteoclastoma of the pancreas, and pancreatic duct adenocarcinoma. Hum Pathol 1997;28:80-83. 10. Hoorens A, Prenzel K, Lemoine NR, Klöppel G. Undifferentiated carcinoma of the pancreas: analysis of intermediate filament profile and Ki-ras mutations provides evidence of a ductal origin. J Pathol 1998;185:53-60. 11. Iguchi H, Sugano K, Fukayama N, et al. Analysis of Ki-ras codon 12 mutations in the duodenal juice of patients with pancreatic cancer. Gastroenterology 1996;110:221-226. 12. Strobel O, Hartwig W, Bergmann F, et al. Anaplastic pancreatic cancer: presentation, surgical management, and outcome. Surgery 2011;149:200-208. - 231 -