REVIEW ISSN 1738-3331 eissn 2671-826X, https://doi.org/10.7704/kjhugr.2020.0063 The Korean Journal of Helicobacter and Upper Gastrointestinal Research, [Epub ahead of print] Epstein-Barr virus 관련위암 이봉은 부산대학교의과대학내과학교실 Epstein-Barr Virus-associated Gastric Carcinoma Bong Eun Lee Department of Internal Medicine, Pusan National University School of Medicine, Busan, Korea Epstein-Barr virus-associated gastric carcinoma (EBVaGC) comprises approximately 10% of all gastric cancers and is now defined as one of the four subtypes of gastric cancer according to the molecular classification proposed by the Cancer Genome Atlas project. EBVaGC has characteristic genetic profiles that harbor a DNA methylation phenotype, frequent mutations in PIK3CA and ARID1A, and amplification of JAK2 and programmed death-ligand (PD-L)1/PD-L2. Therefore, EBVaGC shows several distinct clinicopathological features, including a male predominance, proximal stomach location, gastric carcinoma with lymphoid stroma histology, low risk of lymph node metastasis, and favorable prognosis. In clinical practice, patients with early EBVaGC might be good candidates for endoscopic resection or minimally invasive surgery since the rate of lymph node metastasis is very low, even with deep submucosal invasion. Furthermore, in the case of advanced EBVaGC, the applicability of immunotherapy has been investigated based on its increased expression of PD-L1 and high immunogenicity. In conclusion, EBV can serve as a biomarker in gastric cancer, and further identification of other molecular characteristics of EBVaGC is essential for new potential therapeutic targets. (Korean J Helicobacter Up Gastrointest Res 2021 Feb 22. [Epub ahead of print]) Key Words: Epstein-Barr virus; Gastric cancer; Gastric carcinoma with lymphoid stroma 서론 Epstein-Barr virus (EBV) 는 Herpes virus에속하는이중나선형의 DNA 바이러스이고, 구인두의상피세포에서증식하면서주로타액을통해전파된다. 원발성감염은소아기에별다른증상없이지나가고, 이후로는 B림프구에무증상의잠복감염형태를보이는데, 전세계성인인구의 90% 이상에서양성혈청반응을보이는것으로알려져있다. 1 EBV 감염의두가지주표적세포는잠복감염을나타내는 B림프구와바이러스증식이일어나는인후두상피세포로버키트림프종 (Burkitt s lymphoma), 비호지킨림프종 (non-hodgikin s lymphoma), 호지킨림프종 (Hodgikin s lymphoma), 이식후림프증식성질환 (post-transplant lymphoproliferative disorder), 비인두암 (nasopharyngeal carcinoma) 과같은악성종양을유발할수있어 International Agency for Research on Cancer 에서는 EBV 를 group-1 carcinogen으로분 류하고있다. 2 1990년 Burke 등이 EBV와연관된위암 (EBV-associated gastric carcinoma, EBVaGC) 을처음으로보고한이후이에대한여러연구들이있었다. 최근보고에따르면 EBVaGC 는 EBV 연관악성종양가운데가장흔하고, 전세계적으로연간 75,000-90,000예정도발생하는것으로알려져있다. 이는전체위암중 10% 를차지하며, 우리나라에서는전체위암의 5.6~13% 가 EBV 감염과연관성이있다고보고되고있다. 3-5 EBVaGC 는위암의분자학적분류에따라별도의유형으로분류하고있으며, 다른유형의위암과는다른유전적, 임상병리학적인특성을보이는것으로알려져있다 (Table 1). 3 본고에서는 EBVaGC 의병인과임상병리학적특징을고찰해보고실제진료에서그임상적의의에대해알아보고자하였다. 본 론 Received: December 10, 2020 Revised: January 6, 2021 Accepted: January 14, 2021 Corresponding author: Bong Eun Lee Department of Internal Medicine, Pusan National University Hospital, Pusan National University School of Medicine and Biomedical Research Institute, 179 Gudeok-ro, Seo-gu, Busan 49241, Korea Tel: +82-51-240-7869, Fax: +82-51-244-8180, E-mail: bongsul@daum.net 1. 병인 EBV 가어떤경로로위점막상피세포에침입하는지에대해서는아직도불분명하다. 위점막상피세포에는 CD21 antigen (C3d/EBV-re- Copyright 2021 Korean College of Helicobacter and Upper Gastrointestinal Research The Korean Journal of Helicobacter and Upper Gastrointestinal Research is an Open-Access Journal. All articles are distributed under the terms of the Creative Commons Attribution Non-Commercial License (http:// creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Korean J Helicobacter Up Gastrointest Res: 2021 Feb 22. [Epub ahead of print] ceptor) 이없기때문에바이러스에의한위점막상피세포로의직접감염가능성은낮고, EBV 에감염된위점막고유층의 B림프구에의하여위점막상피세포와세포융합을일으키거나 EBV-specific IgA 를매개체로하여바이러스를위점막상피세포로전달할것이라는가설이유력하다. 6 하지만아직알려지지않은바이러스수용체를매개로하여 EBV 가위점막상피세포로직접침투할수있다는의견도있다. 6 한편 EBV 감염은암화과정 (carcinogenesis) 에서 Table 1. Clinicopathological and Genetic Features of Epstein-Barr Virus-associated Gastric Carcinoma Epidemiology Approximately 10% of all gastric carcinomas Male predominance (2:1 or 3:1) Predominantly younger age High frequency in postsurgical gastric stump (4 times) Molecular features DNA hypermethylation PIK3CA, ARID1A, BCOR mutations PD-L1 and PD-L2 amplification JAK2 amplification Intact TP53 Microsatellite stable phenotype Macroscopic features Located in proximal stomach Superficially depressed or ulcerated SMT-like feature or marked thickening of gastric wall Endosonographic feature Hypoechoic submucosal nodule or mass in early stage Microscopic features Diffuse type Moderate to poorly differentiated adenocarcinoma Prominent lymphoid stroma (tumor infiltrating lymphocytes) including lymphoepithelioma-like histology Prognosis Low rate of lymph node metastasis Favorable overall survival PD-L, programmed death-ligand; SMT, submucosal tumor. 초기에일어나는것인지, 아니면위점막상피세포의암성변환후에감염이일어나는것인지에대해서도논란은있지만, EBVaGC 의거의모든종양세포가 EBV 에균일하게감염되어있으면서단클론성 (monoclonality) 의 EBV DNA 를나타내는것으로보아상피세포가악성으로변형되기이전에바이러스감염이선행할것으로추정한다. 7 EBV 잠복감염 (latent infection) 은잠복유전자 (latent gene) 의표현형에따라 3가지아형으로나누어지는데, EBVaGC 에서는 EBV encoded small RNAs (EBERs), Epstein-Barr nuclear antigen-1 (EBNA-1), BamHI-A rightward transcripts (BARTs), BART mirna 가나타나며, 약반수에서 latent membrane protein-2a (LMP-2A) 가발현되어잠복제1형또는제2 형 (latency type 1 or 2) 을나타낸다 (Table 2). 8 EBNA-1 은세포사멸과숙주면역반응을저해하고 genome 불안정화를유도하여세포의초기변형에주요한역할을하는반면, LMP-2A 는 phosphatase and tensin homolog (PTEN) 과같은종양억제유전자 (tumor suppressor gene) 를억제하여세포증식과이동에관여함으로써침습성상피암에서종양의진행을촉진하는것으로알려져있다. 9 2. 분자적특성 EBVaGC 은임상병리학적으로특이한성향을보이는데, 이것은다른유형의위선암과는암발생기전이다르기때문으로생각한다. 2014년발표된 Cancer Genome Atlas (TCGA) project는종합적인분자적분석 (comprehensive molecular analysis) 을통해위선암을다음의 4가지아형으로분류하였다 (Fig. 1): 10 1) EBVaGC, 2) gastric carcinoma with microsatellite instability (MSI), 3) gastric carcinoma with chromosomal instability, 4) genetically stable gastric carcinoma. EBVaGC 는다른아형과는다르게높은빈도의 DNA hypermethylation 을보이면서 CpG island methylator phenotype 발현이높았으며, 특히 CDKN2A (p16ink4a) promoter hypermethylation 을거의모든경우에서확인할수있었다. 10 또한 EBVaGC 의 80% 에서 PIK3CA mutation 이관찰되었으며, JAK2, CD274 (programmed death-ligand [PD-L] 1), PDCD1LG2 (PD-L2) 의증폭과 ARID1A Table 2. Latent Gene Expression Patterns in Different EBV Latency Types EBERs EBNA-1 EBNA-2, 3A-C, LP LMP-1 LMP-2A, B BARTs BART mirnas Latency 1 + + - - - + + Latency 2 + + - + + + + Latency 3 + + + + + + + EBV, Epstein-Barr virus; EBER, EBV encoded small RNA; EBNA-1, EBV nuclear antigen-1; LMP, latent membrane protein; BART, BamHI-A rightward transcripts. 2
Bong Eun Lee: Epstein-Barr Virus-associated Gastric Carcinoma (55%) 와 BCOR (23%) 유전자변이도흔하게보이는것으로보고하였다. 10 반면 TP53 과발현이나 MSI 와의관련성은매우낮은것으로알려져있다. 6 이러한분자적특성의차이가다른아형과는다른기전으로암발생과진행에관여하여특징적인임상병리학적소견을나타낼것으로생각된다. 3. 위험인자 최근 39개의환자- 대조군연구 (case-control study) 를분석한메타분석에따르면 EBVaGC 의위험도는지역에따라다르며, 위암발생률이높은극동아시아지역에서높았다. 11 흡연도 EBVaGC 의발생의위험인자로알려져있으며, 비흡연자와비교하였을때현재흡연자 (current smoker) 에서 2.4배, 과거흡연자 (former smoker) 에서 2배정도 EBVaGC 의발병이높다. 12 또한, human immunodeficiency virus나 Helicobacter pylori (H. pylori) 와동반감염된경우에서위암발생이증가할수있는데, 4 한연구에따르면 H. pylori 와 EBV 의중복감염이일어난경우에각각의단독감염에비하여중증위염 (severe polymorphonuclear and mononuclear cell infiltration according to Sydney system) 과의연관성이유의하게높았다. 13 이는 H. pylori 와 EBV 의중복감염에서조직손상을일으키는각각의염증반응이단순히더해진결과인지 H. pylori 와 EBV 유전자사이의밀접한상호작용으로인한것인지에대해서는명확하지않으며, 일부연구 14 는 EBV 와 H. pylori 간의상호연관이없었다고하여이에대해서는좀더연구가필요할것으로보인다. 이전한연구는위궤양병력이 EBVaGC 의위험을증가시킨다고하였으며, 위절제술후잔위에서발생한위암가운데 35% 가 EBVaGC 였음을근거로하여 EBVaGC 의발생에있어위점막의화학적손상이중요한요인임을제시하였다. 15 또다른연구에서는악성빈혈 (pernicious anemia) 이있는환자에서 EBVaGC 의빈도가 2배정도높아위축성위염과악성빈혈이발생을증가시키는요인일것으로주장하였다. 16 4. 임상병리학적특징 EBVaGC 는전체위암가운데약 10% (1.3~20.1%) 로보고되고있으며, 남성에서 2~3 배정도발생빈도가높고, 특히젊은연령에서흔하게발견된다. 4 특정지역에서호발하는버키트림프종이나비인두암과는달리전세계적분포를보이나전체위암에서 EBVaGC 가차지하는비율은지역별로차이를보이는데, 우리나라의경우전체위암의 5.6~13% 에서 EBV 감염과연관성이있음을보고하였다. 5 위근위부에서많이발생하고, 국내의한보고에따르면 EBVaGC 의 84.4% 가위의중상부에위치하였다. 17 Lauren 분류법에따른조직학적형태는미만형 (diffuse type) 이흔하며, World Health Organization 분류법에따르면중등도- 저분화 (moderate to poorly differentiated) 선암의특성을보이는데한연구에서는 EBVaGC 의 76.2% 가저분화위암임을보고하였다. 4 특징적으로림프상피종성암종 (lymphoepithelioma-like carcinoma, LELC) 이라고도불리는림프성기질을가진위암종 (gastric carcinoma with lymphoid stroma, GCLS) 의 80% 에서 EBV 양성을보이는것으로알려져있다. 18 GCLS 는전체위암에서는 1~4% 를차지하는드문조직형으로림프구침윤 (lymphoid infiltration) 이동반된특별한형태의위암종이다. 비결합조직성간질에많은림프구및형질세포가미만성으로전종양에걸쳐일정하게침윤되어있고, 다양한배열을보이는비교적작은양의종양세포가사이사이의간질에의해나눠지는모양 (lace-like or small nested patten) 을가진다. 19 이러한림프성기질반응은주로세포독성 CD8+ T림프구에의해일어나는데, EBV 자체에대한직접반응이기보다는 EBV 에감염된세포에표현된바이러스항원에대한항원 -항체반응, 즉숙주세포면역반응 (host cellular immune response) 이활성화된결과로예상한다. 20 림프구침윤정도에따라 EBVaGC 를 typical LELC, Crohn s disease-like lymphocytic reaction (CLR), conventional type adenocarcinoma (CA) 의세가지유형으로분류할수있으며, 일반적으로 GCLS 는 typical LELC 에 CLR 조직형을포함한개념으로받아들여지고있다 (Fig. 2). 20 EBVaGC 는육안적으로표면함몰형 (superficially depressed) EBV - PIK3CA mutation - PD-L1/2 overexpression - EBV-CIMP - CDKN2A silencing - Immune cell signaling CIN - Intestinal histology - TP53 mutation - RTK-RAS activation MSI - Hypermutation - Gastric-CIMP - MLHI silencing - Mitotic pathways GS - Diffuse histology - CDHI, RHOA mutation - CLDN18-ARHGAP fusion - Cell adhesion Fig. 1. Molecular subtypes of gastric carcinoma. The four molecular subtypes of gastric carcinoma (GC) are as follows: 1) Epstein-Barr virus (EBV)-positive GC, 2) GC with microsatellite instability (MSI), 3) GC with chromosomal instability (CIN), and 4) genetically stable (GS) GC. CIMP, CpG island methylator phenotype; PD-L, programmed deathligand; RTK, receptor tyrosine kinase. 3
Korean J Helicobacter Up Gastrointest Res: 2021 Feb 22. [Epub ahead of print] A C 4 B D A B C D Fig. 2. Endoscopic findings of EpsteinBarr virus-associated gastric carcinoma. (A) Superficially depressed lesion on the anterior wall of the antrum. (B) Ulcerative lesion on the greater curvature/ posterior wall of the upper body. (C) Submucosal tumor-like morphology on the posterior wall of the angle. (D) Marked gastric wall thickening with ulceration on the greater curvature of the lower body. Fig. 3. Histologic findings of EpsteinBarr virus-associated gastric carcinoma (EBVaGC) with lymphoid stroma. (A) Typical lymphoepithelioma-like carcinoma shows dense lymphocytic infiltration, accompanied by a syncytial growth pattern with poorly formed glandular structures (hematoxylin and eosin [H&E], 40). (B) In Crohn s disease-like lymphocytic reaction, tumor cells show frequent tubule formation with fewer lymphoid stroma than tumor cells (H&E, 40). (C, D) EBV in situ hybridization highlights tumor cells ( 40). Adapted from the article of Shin et al. Surg Endosc 2017;31:4156-4164, with permission.23
Bong Eun Lee: Epstein-Barr Virus-associated Gastric Carcinoma 또는궤양형 (ulcerative) 이흔하며, 많은경우에서위벽비후가두드러지면서점막하종양유사위암 (submucosal tumor-like carcinoma) 의형태로보인다 (Fig. 3). 21 이러한육안형은종양세포에동반된풍부한림프성기질로인하여발생하며내시경초음파에서특징적인저에코성점막하결절 (hypoechoic submucosal nodule) 을관찰할수있다 (Fig. 4). 22,23 5. 진단 EBVaGC 을진단하기위해서는종양세포에서 EBV가검출되어야한다. 조직에서의 EBV 검출은제자리부합법 (in situ hybridization, ISH) 과중합효소연쇄반응 (polymerase chain reaction, PCR) 을이용하여다음의진단표지자 (diagnostic marker) 를확인한다 : 1) small RNA EBER1/EBER2 for ISH, 2) EBNA-1, Bam-M, BamHI-W viral antigens for PCR. 24 일반적인유전물질검출에는유전자증폭이수반되는 PCR 이민감도가높지만, 종양조직내잠복감염된 B림프구에의해위양성을초래하기도한다. 이러한이유로 ISH 방법이비교적민감도는낮지만 EBVaGC 를진단하는데있어표준진단법 (gold standard) 이라하겠다. 24 6. 예후 EBV 음성위암과비교하여종양의침윤정도 (T stage) 와림프절전이 (N state) 빈도가낮아일반적으로좋은예후를보인다. 4 조기 (early stage) EBVaGC 에서의림프절전이율은점막암과점막하침윤암에서각각 2.2~4.2% 와 14.0~23.6% 로보고되었고, 17 한메타분석에따르면 EBVaGC 환자군에서생존기간의중앙값 (median survival time) 이길었다 (8.5 년 vs. 5.3년 ). 25 다른연구에서도 EBVaGC 환자군에서대조군보다 1기환자의비율이더많으면서 (37.4% vs. 4.9%), 더나은생존율을보임을주장하였다 (5-year overall survival rate: 71.4% vs. 56.1%; 5-year disease-free survival rate: 67.5% vs. 55.2%). 20 TCGA project 에따라위암을분류하여분석한최근국내연구에서도진행성 EBVaGC 환자에서화학요법 (chemotherapy) 후전체생존기간 (overall survival) 과무재발생존기간 (relapse-free survival) 이더나은결과를보여주었다. 26 EBVaGC 의예후는종양의크기, 림프절전이여부외에도환자의염증반응이중요한역할을하는것으로알려져있다. EBVaGC 를림프구침윤정도에따라전형적인 LELC 와 CLR, CA 로분류하였을때 LELC 와 CLR 조직형에서더긴전체생존기간 (hazard ratio 각각 0.09 와 0.42) 과무질병생존기간 A B C D E F G H Fig. 4. Endosonographic images of early Epstein-Barr virus-associated gastric carcinoma (EBVaGC) with lymphoid stroma. (A, E) Marked hypoechogenicity in the mucosal layer at the center of the tumor (arrow); mucosal cancer (confined to muscularis mucosa) on the gastric fundus. (B, F) A hypoechoic round submucosal nodule; SM3 cancer (2,000 µm invasion from the muscularis mucosa) on the upper body. (C, G) Hypoechoic submucosal nodules; SM3 cancer (3,125 µm invasion from the muscularis mucosa) on the lower body. (D, H) A hypoechoic submucosal mass; SM3 cancer (6,500 µm invasion from the muscularis mucosa) on the prepylorus. Adapted from the article of Shin et al. Surg Endosc 2017;31:4156-4164, with permission. 23 5
Korean J Helicobacter Up Gastrointest Res: 2021 Feb 22. [Epub ahead of print] (disease-free survival; hazard ratio 각각 0.05와 0.46) 을보였다. 20 이것은 EBVaGC 의예후가환자의염증반응 (host inflammatory response) 에의존한다는근거로서림프구성침윤이숙주의세포면역과체액성면역반응을반영하며암세포에대한일종의방어기전으로작용할것으로생각한다. 27 최근연구에서도 EBVaGC 에서종양침윤성림프구 (tumor infiltrating lymphocytes, TILs) 가환자의무재발생존기간 (hazard ratio, 12.193) 과무질병생존기간 (hazard ration, 4.836) 을향상시켰으며, 낮은 TILs 은국소림프절전이와나쁜예후를예측할수있는인자라고보고하였다. 28 GCLS 의형태를보이는 EBVaGC 가항암제에도더잘반응하는것으로도보고하였는데, 이는간질에림프구침윤이풍부하여종양기질내결체조직과섬유화가거의없기때문에항암제가종양세포로더잘침투할수있다는점과종양세포가 EBV 에감염됨으로써항암제에대해높은예민도를가지게된것으로추측한다. 29 이외에도종양의크기 (>5 cm), PD-L1 overexpression, PTEN 과 ARID1A 와같은종양억제유전자의소실, PIK3CA 증폭과같은유전자변이가있는경우에서는 EBVaGC 의예후가나쁜것으로알려져있다. 4,30 7. 임상적의의 EBVaGC 는대부분에서미만형또는저분화선암의조직형을보이기때문에조기위암이라하더라도 Gotoda 등 31 이제시한내시경절제술의일반적인적응증이되지않는다. 하지만 GCLS 의형태를보이는조기위암 (early gastric carcinoma with lymphoid stroma, EGCLS) 의경우에서는분화암과비교하여림프절전이의위험이같거나오히려더낮다고보고되고있으며점막하침윤이있는경우에서도림프절전이의빈도가매우낮았다. 23,32,33 국내연구들에서도 EGCLS 의침윤깊이에따른림프절전이여부를분석하였을때 SM1/SM2 침윤암에서림프절전이가발견되지않았다. 23,32 이러한결과를종합해보면 EGCLS 의조직형을보이는 EBVaGC 의경우에서미만형의조직형을보이거나점막하침윤이있다하더라도내시경절제술이효과적인치료가될수있음을조심스럽게생각해볼수있다. 하지만내시경절제술의적응증으로정립되기위해서는좀더많은전향적연구가필요하며, 현재로서는기저질환으로인하여전신상태가좋지않은환자또는위전절제술의부담이있는환자에서내시경절제술을효과적인대안으로고려해볼수있겠다. 한편 EBVaGC 는면역원성 (immunogenicity) 이높은위암으로 PD-L1/PD-L2 의발현이높고, CD8+ TILs 가풍부하여면역관문억제제 (immune check point inhibitor) 에반응이좋을것으로기대되어왔다. 27 Anti-PD-L1 antibody 인 pembrolizumab 을사용한 phase II trial 은 PD-L1 양성위암환자에서 PD-L1 음성위암환자와비교하여약제의전체반응률 (overall response rate) 이높았음 (15.5% vs. 5.5%) 을보고하였고, nivolumab을이용한 phase III trial에서는 EBVaGC 환자의전체생존기간의중앙값 (median overall survival) 이향상된것으로나타났다 (5.3 vs. 4.1 months). 4 이외에도 PIK3K 억제제나 demethylating agent 의치료효과를확인하기위한연구들도시도되고있지만, 현재까지일관된결과를보여주고있지않아후속연구들의결과를기다려보아야할것이다. 결 론 EBVaGC 는다른유형의위암과는다른유전적, 임상병리학적특성을보이며, 특징적으로 GCLS 형태의조직형을관찰할수있다. GCLS 에서동반되는림프구성기질은 EBV 감염종양세포에대한일종의숙주면역반응으로항종양효과 (anti-tumor effect) 를나타내어 EBVaGC 의좋은예후와연관된인자로생각한다. GCLS 의 80% 에서 EBV 양성을보이기때문에 GCLS 의조직형을보이는위암조직에서 EBV 를진단하는것이필요한데, EBER ISH 가 EBVaGC 를진단하는적합한표준검사법이다. 임상적인측면에서 GCLS 의조직형을보이는조기 EBVaGC 의경우다른유형의암과비교하여림프절전이율이매우낮기때문에점막하침윤이있다하더라도내시경절제술의효과적인대상으로고려해볼수있으며, 진행성 EBVaGC 의경우 PD-L1 의발현이높아면역관문억제제치료효과에대한기대를하고있으며많은면역억제제치료연구를진행하고있다. 결론으로 EBV 는위암진단에있어예후를예측하고치료계획을결정하는새로운생체표지자 (novel biomarker) 로서중요하고, EBVaGC 에서실제예후를향상시킬수있는새로운표적항원의개발과연구가필요하다. CONFLICT OF INTEREST No potential conflict of interest relevant to this article was reported. Bong Eun Lee ORCID https://orcid.org/0000-0003-2734-2134 REFERENCES 1. Ning S. Innate immune modulation in EBV infection. Herpesviridae 6
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