HAYASHI Momoko

KATSUBE Takao

KONO Teppei

KUHARA Kotaro

MIYAUCHI Tatsuomi

NARITAKA Yoshihiko

SHIMAKAWA Takeshi

SHIMOJIMA Yukio

SHIOZAWA Shunichi

TSUCHIYA Akira

USUI Takebumi

YAMAGUCHI Kentaro

YOKOMIZO Hajime

YOSHIMATSU Kazuhiko

Tokyo Women’s Medical University

Diffuse Intracystic Papillary NeoplasmIndistinguishable from Gallbladder Cancer: ACase Report著者名 SHIOZAWA Shunichi, KUHARA Kotaro, USUITakebumi, TSUCHIYA Akira, MIYAUCHI Tatsuomi,KONO Teppei, SHIMOJIMA Yukio, HAYASHI Momoko,YAMAGUCHI Kentaro, YOKOMIZO Hajime, SHIMAKAWATakeshi, YOSHIMATSU Kazuhiko, KATSUBE Takao,NARITAKA Yoshihikojournal orpublication titleTokyo Women's Medical University Journalvolume 2page range 45-50year 2018-12-25URL http://hdl.handle.net/10470/00032124doi: 10.24488/twmuj.2018006(https://doi.org/10.24488/twmuj.2018006)45―45―J.TWMU 2: 45-50, 2018Case ReportDiffuse Intracystic Papillary Neoplasm Indistinguishable from GallbladderCancer: A Case ReportShunichi SHIOZAWA, Kotaro KUHARA, Takebumi USUI, Akira TSUCHIYA, Tatsuomi MIYAUCHI,Teppei KONO, Yukio SHIMOJIMA, Momoko HAYASHI, Kentaro YAMAGUCHI,Hajime YOKOMIZO, Takeshi SHIMAKAWA, Kazuhiko YOSHIMATSU,Takao KATSUBE, and Yoshihiko NARITAKADepartment of Surgery, Tokyo Women’s Medical University Medical Center East, Tokyo, Japan(Accepted August 22, 2018)(Advance Publication by J-STAGE October 25, 2018)This report describes a patient who underwent resection for an intracystic papillary neoplasm (ICPN) classified by the WorldHealth Organization in 2010 as a pre-cancerous or early cancerous tumor of the gallbladder. The patient was a 70-year-oldJapanese woman who was hospitalized for hepatic dysfunction and jaundice. Various imaging tests revealed multiple papil-lary tumors, present mainly in the gallbladder lumen as well as infiltrating the intra- and extra-hepatic bile ducts and the liver.Advanced gallbladder cancer was suspected. The patient underwent extended right hepatectomy and resection of the extrahe-patic bile duct and regional lymph nodes along with hepatico-jejunostomy. However, the gallbladder tumor was diagnosedimmuno-histopathologically as intestinal-type ICPN with high-grade dysplasia. ICPN has been described as a gallbladder pa-pilloma (papillomatosis), comparable to benign gallbladder lesions. To date, however, there have been no reports of patientswith multiple tumors in the gallbladder lumen resulting in an ICPN of large diameter. As ICPN is regarded as a pre-cancerousor early cancerous tumor of the gallbladder, the method of diagnosis and histopathological classification require standardiza-tion.Key Words: intracystic papillary neoplasm (ICPN), intraductal papillary neoplasm of bile duct (IPNB), gallbladder papillo-matosis, gallbladder cancerIntroductionTo date, most papilliform tumors growing in the intra-and extra-hepatic bile duct epithelium have been recog-nized as benign lesions１）２）, although some tumors are re-garded as borderline-low grade malignancies３）. Intracys-tic papillary neoplasms (ICPN) are papilliform growthsof tumorous lesions in the gallbladder. These tumors in-clude intrabiliary lesions, called intraductal papillary neo-plasms of the bile duct (IPNB), classified by the WorldHealth Organization in 2010 WHO as pre-cancerous /early cancerous lesions of the gallbladder４）５）. The pa-thologic morphology and clinical characteristics of IPNBare similar to those of intraductal papillary mucinousneoplasms (IPMN)６）, which are regarded as a pancreaticdisease. To date, however, little is known about the car-Corresponding Author: Shunichi Shiozawa, Department of Surgery, Tokyo Women’s Medical University Medical Center East, 2-1-10Nishiogu, Arakawa-ku, Tokyo 116-8567, JapanE-mail: tansiosu@twmu.ac.jpdoi: 10.24488/twmuj.2018006CopyrightⒸ 2018 Society of Tokyo Women’s Medical University46―46―Fig.　1　Abdominal ultrasonographyAbdominal ultrasonography, showing multiple papilliform tumors at mixed echo level in the gallbladder lumen (arrows). The borderbetween the gallbladder and liver was unclear, which was evidence of liver infiltration by the tumors (arrowheads).GB, gallbladder.Fig.　2　Multi detector-row computed tomographyMulti detector-row computed tomography (CT), showing the growth of multiple tumors in the lumen due to the contrast effect in the gallbladder (arrowheads). The coronal cross-sectional CT shows that the right primary branch of the portal vein was stenosed, a finding suggesting direct tumor infiltration (arrow).cinogenetic mechanisms and progression of ICPN.We recently encountered a patient who underwent re-section of diffuse ICPN in the gallbladder, accompaniedby intra- and extra-hepatic bile duct infiltration. The le-sion was found to be a papillomatous tumor indistin-guishable from advanced gallbladder cancer. This reportdescribes our findings in this patient.Case ReportA 70-year-old Japanese woman was urgently admitted toour department in December 2012 for upper abdominalpain after eating. Her prior history included emphysemadue to long-term smoking. Her family history was unre-markable. Blood tests showed a white blood cell (WBC)count of 18,700 / μl, and a serum C-reactive protein(CRP) concentration of 8.63 mg/dl, indicating a seriousinflammatory reaction. Her serum aspartate aminotrans-ferase (AST), alanine aminotransferase (ALT), alkalinephosphatase (ALP ) , and total bilirubin concentrationswere 1,100 IU/l, 627 IU/l, 1,426 IU/l, and 6.3 mg/dl, re-spectively, indicating hepatic dysfunction, and jaundicewas observed. Her carcinoembryonic antigen (CEA) andcancer antigen 19-9 (CA 19-9) concentrations were 16.2ng/ml and 369 U/ml, respectively, both of which werehigh. We determined that the inflammation was causedby mild acute cholangitis, but this gradually resolvedwith conservative treatment. Abdominal ultrasound (US)revealed swelling of the gallbladder, to 114 × 45 mm,and a papillomatous tumor with widespread growth inthe lumen. In addition, the border between the gallblad-der and liver was unclear, which is evidence of suspectedliver invasion by the tumor (Fig. 1). Multi detector-rowcontrast-enhanced computed tomography (CT) revealedmany multiple papilliform tumors in the swollen gall-bladder. Coronal cross-sectional CT showed marked re-traction of the right branch and right hepatic duct of theportal vein, along with enlargement of the secondarybranches of the intrahepatic bile ducts at the periphery(Fig. 2) . Magnetic resonance imaging (MRI) revealedthat the tumor in the gallbladder lumen was of low inten-47―47―Fig.　3　Abdominal magnetic resonance imagingT2 weighted image (WI) showing shrinkage of the common hepatic duct and right hepatic duct (arrow-heads) due to retraction by the multiple tumors (arrows) in the gallbladder lumen. Diffusion weighted imaging (DWI) of the gallbladder tumors yielded high signals, and the apparent diffusion coefficient (ADC) was low.CBD, common bile duct; GB, gallbladder.sity in T 1 and high intensity in T 2 and diffusionweighted images. On the latter, however, the apparentdiffusion coefficient (ADC) map was decreased, result-ing in the diagnosis of a tumor with malignant potential(Fig. 3). Endoscopic retrograde cholangiography (ERC)showed enlargement of the extrahepatic bile duct diame-ter to 12 mm, as well as stenosis due to retraction in thedownwards direction from the right hepatic bile ductthrough the common hepatic bile duct. Because the cysticduct was interrupted behind the common bile duct, imag-ing of the gallbladder was not feasible. Cytologic assess-ment showed that the bile sampled from the bile duct in-terior was class IIb, with no malignant cells detected. Fi-nally, we strongly suspected that the tumor was gallblad-der cancer of papillary infiltrating type from these find-ings. And the liver function just before operation waswithin liver damage A.After obtaining written informed consent from the pa-tient, surgery was performed in January 2015. Operativefindings included a markedly swollen gallbladder withwhitened serosa. Perioperative US revealed that the bor-der between the gallbladder and liver was unclear. Theright side of the hepatic portal area was strongly adherentto the neck region of the gallbladder making it impossi-ble to visualize the gallbladder. These operative findingssuggested gallbladder cancer and direct invasion of theright hepatic lobe. Therefore, extended right hepatectomyand resection of the extrahepatic bile duct and regionallymph nodes with hepatico-jejunostomy were performed.The operative time was 382 min and the volume of bloodlost was 1,015 ml.Macroscopic examination of the resected specimen re-vealed irregular thickening of the gallbladder wall andthe aggregation of multiple pedunculated-semipedunculated papillomatous tumors in the lumen.These tumors were confined to the gallbladder neck andstrongly adhered to the right hepatic bile duct (Fig. 4).However, microscopic examination showed that the tu-48―48―Fig.　4　Macroscopic analysis of the resected specimen.Macroscopic analysis of the resected specimen, showing that the gallbladder lumen was packed with swollen papilliform growth(arrows). The gallbladder cervix showed extensive adherencefrom the common hepatic duct to the right porta hepatis, forming a tumor mass.CBD, common bile duct; GB, gallbladder.Fig.　5　Histopathological findings in our patient.Histoimmunopathologic findings, showing that most cells retained polarity and the nuclei and chroma-tin showed no clear evidence of malignancy on hematoxylin-eosin (HE) staining (× 40, × 100, × 400). The tumor consisted mainly of non-invasive, highly deformed papillotubular mucosal epithelium. Ki-67 proliferation-index (MIB-1) staining showed that the density of the neoplastic duct was low (× 40, × 400). The tumor was diagnosed as an intracystic papillary neoplasm with high-grade intraepithelial neoplasia.mor cells had cuboid or cylindrical nuclei, with no evi-dence of nucleolar enlargement. The part thought to bedirect invasion from the gallbladder cancer was strongbenign inflammatory findings. Moreover, the Ki-67proliferation-index (MIB-1) of one area was higher thanthose of the other areas; although mixed with areas ofhigh neoplastic ducts, there was no evidence of vascular,lymph duct or lymph node metastasis. On immunostain-ing, the cells were focally positive for mucin core protein(MUC) 1, diffusely positive for cytokeratin (CK) 20, andnegative for MUC2, MUC6, and CK7. Based on thesefindings, the tumor was diagnosed as intestinal-typeICPN with high-grade dysplasia (Fig. 5). Her postopera-tive course was uneventful, with no complications, andthe patient was discharged on day 22. To date, 5 yearsand 4 months after surgery, the patient has shown no re-currence of symptoms. Her high preoperative CEA andCA19-9 concentrations decreased rapidly after surgeryand have since remained in their normal ranges.DiscussionMost gallbladder cancers are diagnosed at an advancedstage, with few patients being candidates for surgical re-section. Therefore, diagnosis at an early or preneoplasticstage can enhance treatment outcomes. Lesions with pa-49―49―pilliform growth have been described as papillary adeno-mas (adenomatosis) and papillomas (papillomatosis) ofthe gallbladder based on the degree of cellular atypia andmorphological characteristics７）. There is no internationalconsensus on their histopathological category and itsidentification has therefore been chaotic. All tumors withpapilliform development in the biliary lumen were foundto be either highly differentiated papilliform adenocarci-nomas or borderline lesions with a morphology and clini-cal condition similar to those of IPMN８）９）. This led to pro-posals that bile duct lesions be defined as IPNBs andgallbladder lesions as ICPN. The 2010 World Health Or-ganization classification of tumors of the digestive sys-tem categorized ICPN as early or preneoplastic forms ofbiliary cancer４）５）. Therefore, the tumor in our patient cor-responded to a gallbladder papillomatosis in western pa-tients７）or to an ICPN. Gallbladder papillomatoses re-ported to date are comparatively rare benign tumors１０）１１）,although an ICPN was recently reported to be a border-line low-grade malignant lesion. Gallbladder lesions maydevelop into cancers via ICPN. The clinicopathologicalcharacteristics of ICPN include (a) an intramucosal loca-tion, (b) non-infiltrative properties, (c) a papilliform mor-phology, (d) size 10 mm, (e) a compact appearance,and (f) a clear surrounding mucosa and border. As in ourpatient, ICPN with abnormal findings in the intra- andextra-hepatic bile ducts occupying most of the gallblad-der lumen are very rare１２）. ICPN usually arise from intra-biliary lesions and, in the absence of cholecystitis, pa-tients appear asymptomatic during early stages, with cho-lestasis and jaundice usually not observed even on bloodbiochemistry tests. Tumor enlargement, as in our patient,can induce inflammation in the surrounding organs, withserum CEA and CA19-9 concentrations increasing due tocholestasis. The tumor may not always contribute to a di-agnosis of malignant potential. Moreover, although im-aging frequently shows characteristic papillomatous ele-vated lesions, as in our patient, most of the tumors arepresent in the gallbladder lumen. The occurrence of ab-normal findings in the surrounding organs makes it verydifficult to differentiate ICPN and gallbladder cancer.Positron emission tomography (PET)-CT and endoscopicUS-fine needle aspiration (EUS-FNA)１３）will likely con-tribute in future to the preoperative diagnosis of ICPN.The recommended treatment in patients with suspectedICPN is surgical resection, based on the malignant neo-plasm of the gallbladder and the high potential for malig-nant transformation. Our patient underwent surgery dueto the suspicion of advanced gallbladder cancer with in-vasion of the intra- and extra-hepatic bile ducts and liverinfiltration. However, the extent of resection of large,multiform tumors is based on preoperative imaging１４）. Inthe future, for a similar case, there is scope for investigat-ing how to avoid excessive invasive surgery, and consid-ering the malignant potential of ICPN, perfect surgicalresection aimed at total biopsy of the lesioned area is re-quired. Curative surgical resection of ICPN in the ab-sence of invasion has been associated with a 3-year over-all survival rate of 90%, which is comparatively good１２）.Two carcinogenic pathways have been identified ingallbladder cancer, the adenoma-carcinoma sequence andde novo carcinogenesis１５）. The characteristics of gallblad-der lesions, however, are similar to those of tumors de-rived from the epithelium of other organs１６）. However,characteristics that can lead to early diagnosis have notbeen determined. Assessment of additional patients withthis condition will likely contribute to improvements inprognosis.ConclusionThis report describes a patient with an ICPN indistin-guishable from a gallbladder cancer. Histopathologically,ICPN are early or preneoplastic lesions of the gallblad-der, suggesting a need for surgical treatment. Accumula-tion of data on patients diagnosed early and those withICPN may improve treatment outcomes in patients withgallbladder cancer.AcknowledgementsThe authors thank Professor Mariko Fujibayashi for provid-ing pathological and technical assistance in the immunohisto-chemical studies.Conflicts of Interest: The authors declare that there is noconflict of interest regarding the publication of this article.References1）Yeung YP, AhChong K, Chung CK et al: Biliary papil-50―50―lomatosis: report of seven cases and review of Englishliterature. 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Diffuse Intracystic Papillary Neoplasm Indistinguishable from Gallbladder Cancer: A Case Report

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Diffuse Intracystic Papillary Neoplasm Indistinguishable from Gallbladder Cancer: A Case Report

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