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1 대한내과학회지 : 제 91 권제 2 호 HER2 양성간세포양위선암 1 예 울산대학교의과대학서울아산병원 1 내과, 2 병리과, 3 종양내과 김종관 1 신진호 2 이주희 1 권오찬 1 박한빛 1 황인환 1 류민희 3 HER2-Positive Gastric Hepatoid Adenocarcinoma Jong Kwan Kim 1, Jin Ho Shin 2, Joohee Lee 1, Oh Chan Kwon 1, Han-bit Park 1, In Hwan Hwang 1, and Min-Hee Ryu 3 Departments of 1 Internal Medicine, 2 Pathology, and 3 Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea Gastric hepatoid adenocarcinoma is a rare adenocarcinoma that develops in the stomach. The prognosis of gastric hepatoid adenocarcinoma is poorer than that of ordinary gastric adenocarcinoma. Here, we report the first case of human epidermal growth factor receptor 2 (HER2)-positive gastric hepatoid adenocarcinoma in Korea. A 57-year-old male presented with abdominal distension and underwent endoscopic gastric biopsy and percutaneous core needle liver biopsy. The pathological findings were consistent with HER2-positive gastric hepatoid adenocarcinoma. He received six cycles of chemotherapy with cisplatin-capecitabine plus trastuzumab, which is a HER2 targeted agent. After chemotherapy, a follow-up abdominal computed tomography scan showed a partial tumor response. This case emphasizes the importance of using trastuzumab in a patient with HER2-positive gastric hepatoid adenocarcinoma. (Korean J Med 2016;91: ) Keywords: Hepatoid adenocarcinoma; Stomach; HER2; Trastuzumab 서론간세포양위선암 (hepatoid gastric adenocarcinoma) 은 1985 년 Ishikura 등 [1] 에의해명명됐으며간세포양분화와알파태아단백 (Alphafetoprotein, AFP) 을생성하는특징을가진다. 후에다시 Ishikura 등 [1] 은 AFP를생성하지않는간세포양위선암을보고하였으며현재진단은혈중 AFP 측정치보다는조직학적특징에기반하여이루어지고있다 [2]. 전체위 암의 % 를차지하는것으로보고되었으며, 진행된상태에서진단되는경우가많고기타위암에비해불량한예후를보인다. 현재진행한간세포양위선암에대한항암화학요법은정립된바가없다. 일반적인위선암은 5-fluorouracil, cisplatin 병용요법을주로사용하고있으며 Kang 등 [3] 이보고한바에따르면 capecitabine과 cisplatin 병용요법역시만족스러운치료효과를보여많이사용되고있다. 간세포양위선암중인간상피증식인자수용체2 (human epidermal growth Received: Revised: Accepted: Correspondence to Min-Hee Ryu, M.D., Ph.D. Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 05505, Korea Tel: , Fax: , miniryu@amc.seoul.kr Copyright c 2016 The Korean Association of Internal Medicine This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

- The Korean Journal of Medicine: Vol. 91, No. 2, 2016 - factor receptor type 2, HER2) 양성으로 trastuzumab 을통해치료한간세포양위선암의간전이 1예를경험하였기에문헌고찰과함께보고하는바이다.

두경부, 흉부진찰에서특이소견은없었으며복부 Figure 1. Esophagogastroduodenoscopy reveals a 3-cm ulcerative mass lesion at the distal antrum lesser curvature-anterior wall. 례 진찰상복부팽만이확인되었다. 말초혈액검사에서백혈구 7,600/mm 3, 혈색소 9.

종양표지자검사에서는 AFP 7,330 ng/ml, proteins induced by vitamin K absence or antagonist-ii test (PIVKA-II) 147 mau/ml, carcinoembryonic antigen (CEA) 3,869 ng/ml, carbohydrate antigen 19-9 (CA 19-9) 128 U/mL

전신양전자단층촬영에서간내그리고위전정부에대사가증가된병변이확인되어악성종양이의심되었고위주변다수의전이성림프절이관찰되었다. 식도위내시경에서는위전정부 3 cm 크기의궤양성종괴가확인되어조직검사를시행하였고 (Fig. 1), 간내종괴에대하여중심바늘생검을시행하였다. 간종괴의중심바늘생검조직의현미경소견은, 저분화의악성신생물로간세포양분화와샘분화가함께관찰되었으며 (Fig.

2 - The Korean Journal of Medicine: Vol. 91, No. 2, factor receptor type 2, HER2) 양성으로 trastuzumab 을통해치료한간세포양위선암의간전이 1예를경험하였기에문헌고찰과함께보고하는바이다. 증 57세남자가내원 10일전부터복부팽만감이발생하여타병원에서시행한복부초음파에서간내종괴가관찰되어내원하였다. 활력징후는혈압 140/90 mmhg, 맥박 98회 / 분, 호흡 18회 / 분, 체온 36.4 였으며고혈압으로이에대한약물사용중이었고이외에기타과거력및약물복용력은없었다. 신체검진에서전신상태는건강해보였고의식은명료하였다. 두경부, 흉부진찰에서특이소견은없었으며복부 Figure 1. Esophagogastroduodenoscopy reveals a 3-cm ulcerative mass lesion at the distal antrum lesser curvature-anterior wall. 례 진찰상복부팽만이확인되었다. 말초혈액검사에서백혈구 7,600/mm 3, 혈색소 9.5 g/dl, 혈소판 581,000/mm 3 였고, 혈청생화학검사에서총단백 6.4g/dL, 알부민 2.5 g/dl, 총빌리루빈 3.4 mg/dl, 직접빌리루빈 3.2 mg/dl, AST 210 IU/L, ALT 164 IU/L, ALP 1,017 IU/L, gamma glutamyl transpeptidase 714 IU/L였다. 종양표지자검사에서는 AFP 7,330 ng/ml, proteins induced by vitamin K absence or antagonist-ii test (PIVKA-II) 147 mau/ml, carcinoembryonic antigen (CEA) 3,869 ng/ml, carbohydrate antigen 19-9 (CA 19-9) 128 U/mL 였다. B형간염표면항원은음성이었고표면항체양성이었으며 C형간염항체선별검사음성이었다. 복부전산화단층촬영에서간문맥의종양혈전을동반한거대다결절성종괴가관찰되었고뚜렷한동맥기조영증가혹은문맥기조영감소를보이지는않았다. 위하부체벽의불규칙한비후를보였으며주변부림프절종대가관찰되었다. 전신양전자단층촬영에서간내그리고위전정부에대사가증가된병변이확인되어악성종양이의심되었고위주변다수의전이성림프절이관찰되었다. 식도위내시경에서는위전정부 3 cm 크기의궤양성종괴가확인되어조직검사를시행하였고 (Fig. 1), 간내종괴에대하여중심바늘생검을시행하였다. 간종괴의중심바늘생검조직의현미경소견은, 저분화의악성신생물로간세포양분화와샘분화가함께관찰되었으며 (Fig. 2), 위내시경생검조직에서는저분화의간세포양암종이관찰되었다 (Fig. 3). 간생검조직의간세포양분화를보이는부분과위생검조직의저분화암종은 AFP 면역조직화학염색에서양성소견을보였다. 간세포양위선암의간전이로최종진단되었다. 위내시경생검조직및간생검조직에서추가로시행한 HER2 면역조직화학염색에서강양성이확인되었다. 간전이를동반한 Figure 2. Histological findings of the liver biopsy. (A) Core needle biopsy specimen is composed of solid sheet and glandular patterns of polygonal cells with eosinophilic and occasional clear cytoplasm. (Hematoxylin and eosin stain, 200). The tumor cells were positive for (B) alpha fetoprotein (AFP) (AFP immunohistochemical stain original magnification, 200) and (C) human epidermal growth factor receptor 2 (HER2) (HER2 immunohistochemical stain, 200)

- Jong Kwan Kim, et al. HER2-Positive gastric hepatoid adenocarcinoma - Figure 3.

(A) Tumor cells consist of a solid sheet of large polygonal cells with eosinophilic cytoplasm resembling

(B) The tumor cells were positive for alpha fetoprotein (AFP) (AFP immunohistochemical stain original magnification,

Abdominal and pelvic computed tomography scan.

스캔을시행하였고심장독성은확인되지않았다. 총 16주기의항암화학치료를시행하였으며간내전이성종양의크기가눈에띄게감소하였고 1년이상무진행생존을유지하고있다 (Fig. 4).

환자로 cisplatin, capecitabine 에 trastuzumab 을추가하여항암화학요법을 3주간격으로시행하였고 2달간격으로복부전산화단층촬영을추적관찰하였다.

3 - Jong Kwan Kim, et al. HER2-Positive gastric hepatoid adenocarcinoma - Figure 3. Histological findings of the stomach biopsy. (A) Tumor cells consist of a solid sheet of large polygonal cells with eosinophilic cytoplasm resembling hepatocellular carcinoma. (Hematoxylin and eosin stain, 200). (B) The tumor cells were positive for alpha fetoprotein (AFP) (AFP immunohistochemical stain original magnification, 200) and (C) human epidermal growth factor receptor 2 (HER2) (HER2 immunohistochemical stain, 200). Figure 4. Abdominal and pelvic computed tomography scan. Before chemotherapy (A), after three cycles of chemotherapy (B), and after 16 cycles of chemotherapy (C). 스캔을시행하였고심장독성은확인되지않았다. 총 16주기의항암화학치료를시행하였으며간내전이성종양의크기가눈에띄게감소하였고 1년이상무진행생존을유지하고있다 (Fig. 4). 또한초기 7,330 ng/ml 이던 AFP 역시 2 ng/ml 까지감소하였다 (Fig. 5). 고 찰 Figure 5. Serum alpha-fetoprotein (AFP) level. 환자로 cisplatin, capecitabine 에 trastuzumab 을추가하여항암화학요법을 3주간격으로시행하였고 2달간격으로복부전산화단층촬영을추적관찰하였다. 항암화학치료를시행하는동안 10주기이후 2단계의말초신경병증이발생하여 cisplatin을중단하였으며 capecitabine 및 trastuzumab 은감량또는중단없이유지하였다. 치료개시전후게이트심장혈액풀 간세포양위선암의평균발병연령은 63.5세이며여성에비해남성에서호발하는것으로보고되었다 (2.32:1) [4]. 위에서호발하며 (83.9%) 담낭 (3.7%), 자궁 (3.2%), 폐 (2.3%) 그리고드물지만식도및복막에서도발생한다. 일반적인위선암에비해불량한예후를보이는데 Liu 등 [5] 은 1년, 3년, 5년생존율을각각 53%, 35%, 28% 로보고하였다. 이는 AFP를분비하지않는기타위암의 95%, 57%, 38% 과비교하여불량하다. 간세포양위선암의예후가불량한이유에대해몇가지가설이제시되었다. Inagawa 등 [6] 은간세포양위선암이 AFP와더불어알파-1 항트립신및알파-1 항키모트립신을분비하는

4 - 대한내과학회지 : 제 91 권제 2 호통권제 672 호 것을보고하였다. 이물질이면역억제작용을하며단백분해효소억제를통해주위조직으로의침투성이높아지고이에따라정맥침범이많으며또한간전이가흔한것으로생각된다. 본증례에서도간문맥의종양혈전을동반하고있었다. 또한치료적절제술이불가능한경우더욱불량한데이경우일반적인위선암의생존중앙값인 개월인것에비해 [3] 간세포양위선암의생존중앙값은 개월에불과하다 [4,7]. 수술이불가능한경우항암치료가주된치료지만아직까지만족할만한치료효과를보인예가없어일반적인위선암의항암화학요법에기반하여치료하고있다. 5-fluorouracil, cisplatin 병용요법과 capecitabine, cisplatin 병용요법을주로사용하며이외에도 S-1 단독또는 paclitaxel, cisplatin 병용요법항암화학요법을시행한다 [4]. 하지만현재효과적인항암화학요법이정리되지않아치료하는데어려움을겪고있다. 국내에서는수술후 1년만에재발한증례가있었고 [8], Baek 등 [7] 에의하면항암화학요법에부분반응이상을보인경우가 8.3% 에불과한데국내일반적인위선암의부분반응률 32-46% 에비해매우불량하다 [3]. 외국보고에서도마찬가지로불량한예후를확인할수있다. Lin 등 [4] 이보고한바에따르면 87.1% 의환자가진단당시림프절전이나원격전이를동반하고있었으며, 5-fluorouracil 기반의항암화학요법을시행했지만중앙생존기간은 7.2에불과했다. Su 등 [9] 이시행한메타분석에서는생존자료가확인된환자 125 명중 51.2% 의환자가진단 12개월내에사망하였다. 현재까지발표된보고에는 HER2 양성을보인증례가없으며 trastuzumab을사용한예역시없다. 본증례는간세포양위선암에서 HER2 양성을보인첫증례이다. Bang 등 [10] 은진행한일반적인위선암에서 HER2 양성일경우기존항암화학요법에 trastuzumab 을추가하는것이좀더우수한치료효과를나타내는것으로보고하였다. 이에본증례에서도 trastuzumab 을사용하였고무진행생존을 1년이상유지하고있다. 간세포양위선암환자중 8.3% 만이항암화학치료에반응하였고생존중앙값이 8개월미만, 1차항암화학치료의무진행생존값이 5개월미만임을고려하면만족할만한치료경과로판단할수있다. 일반적으로간세포양위선암은치료성적이좋지않지만본증례에서와같이 HER2 면역화학검사를시행하고표적치료제인 trastuzumab 을사용함으로써좀더좋은치료성적을기대해볼수있다. 요 간세포양위선암은매우드물며일반적인위선암에비해예후가불량하다. 진단당시림프절전이및간전이를동반한경우가많아초치료로항암화학요법을시행하는경우가많지만현재까지정립된항암화학요법은제시된바없다. 또한문헌보고에따르면그효과가위선암에비해좋지않다. 본증례는국내에서 HER2 양성을보인간세포양위선암의첫증례이다. 기존항암화학요법에 HER2 표적치료제인 trastuzumab 을추가하여사용하였고현재복부전산화단층촬영및 AFP 검사상호전소견을보이고있다. 중심단어 : 간세포양선암 ; 위 ; 인간상피증식인자수용체2; 트라스투주맙 약 REFERENCES 1. Ishikura H, Fukasawa Y, Ogasawara K, Natori T, Tsukada Y, Aizawa M. An AFP-producing gastric carcinoma with features of hepatic differentiation. A case report. Cancer 1985;56: Ye MF, Tao F, Liu F, Sun AJ. Hepatoid adenocarcinoma of the stomach: a report of three cases. World J Gastroenterol 2013;19: Kang YK, Kang WK, Shin DB, et al. Capecitabine/cisplatin versus 5-fluorouracil/cisplatin as first-line therapy in patients with advanced gastric cancer: a randomised phase III noninferiority trial. Ann Oncol 2009;20: Lin CY, Yeh HC, Hsu CM, Lin WR, Chiu CT. Clinicopathologial features of gastric hepatoid adenocarcinoma. Biomed J 2015;38: Liu X, Cheng Y, Sheng W, et al. Clinicopathologic features and prognostic factors in alpha-fetoprotein-producing gastric cancers: analysis of 104 cases. J Surg Oncol 2010;102: Inagawa S, Shimazaki J, Hori M, et al. Hepatoid adenocarcinoma of the stomach. Gastric Cancer 2001;4: Baek SK, Han SW, Oh DY, Im SA, Kim TY, Bang YJ. Clinicopathologic characteristics and treatment outcomes of hepatoid adenocarcinoma of the stomach, a rare but unique subtype of gastric cancer. BMC Gastroenterol 2011;11: Moon JY, Kim GH, Cheong JH, Lee BE, Ryu DY, Song GA. A case of hepatic metastasis of gastric hepatoid adenocarcinoma mistaken for primary hepatocellular carcinoma. Korean J Gastroenterol 2012;60: Su JS, Chen YT, Wang RC, Wu CY, Lee SW, Lee TY. Clinicopathological characteristics in the differential diag

5 - 김종관외 6 인. HER2 양성간세포양위선암 - nosis of hepatoid adenocarcinoma: a literature review. World J Gastroenterol 2013;19: Bang YJ, Van Cutsem E, Feyereislova A, et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet 2010;376:

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내시경 conference 부울경소화기내시경학회 6월집담회 고신대학교복음병원소화기내과전임의서광일 F/63 CASE C.C) epigastric pain for 2 wks P. I) 2014.04.16 EGD at LMC adm via OPD for further evaluation. P. Hx) CASE HTN/DM/Hepatitis/Tbc (+/+/-/-) S. Hx) N-S ROS)