CAP Cancer Protocol Intrahepatic Bile Ducts
Protocol for the Examination of Specimens From Patients With Carcinoma of the Intrahepatic Bile DuctsVersion: IntrahepaticBileDuct 4.1.0.0Protocol Posting Date: February 2020CAP Laboratory Accreditation Program Protocol Required Use Date: November 2020Includes pTNM requirements from the 8th Edition, AJCC Staging ManualFor accreditation purposes, this protocol should be used for the following procedures AND tumor types:ProcedureDescriptionResectionIncludes specimens designated hepatic resection, partial or totalTumor TypeDescriptionCarcinomaInvasive carcinomas including combined hepatocellular-cholangiocarcinoma, small cell and large cell (poorly differentiated) neuroendocrine carcinomaThis protocol is NOT required for accreditation purposes for the following:ProcedureBiopsyPrimary resection specimen with no residual cancer (eg, following neoadjuvant therapy)Cytologic specimensThe following tumor types should NOT be reported using this protocol:Tumor TypeIntraductal papillary neoplasm without associated invasive carcinomaMucinous cystic neoplasm without associated invasive carcinomaWell-differentiated neuroendocrine tumors of liverHepatocellular carcinoma and fibrolamellar carcinoma (consider the Hepatocellular Carcinoma protocol)Lymphoma (consider the Hodgkin or non-Hodgkin Lymphoma protocols)Sarcoma (consider the Soft Tissue protocol)AuthorsLawrence J. Burgart, MD*; Chanjuan Shi, MD, PhD*; Oyedele A. Adeyi, MBBS; Wendy L. Frankel, MD; Dhanpat Jain, MD; Sanjay Kakar, MD; Alyssa M. Krasinskas, MD; Mari Mino-Kenudson, MD; Timothy Pawlik, MD, MPH, PhD; Vaibhav Sahai, MD; Michael S Torbenson, MD; Jean-Nicolas Vauthey, MD; Mary K. Washington, MD, PhDWith guidance from the CAP Cancer and CAP Pathology Electronic Reporting Committees.* Denotes primary author. All other contributing authors are listed alphabetically.Accreditation RequirementsThis protocol can be utilized for a variety of procedures and tumor types for clinical care purposes. For accreditation purposes, only the definitive primary cancer resection specimen is required to have the core and conditional data elements reported in a synoptic format. Core data elements are required in reports to adequately describe appropriate malignancies. For accreditation purposes, essential data elements must be reported in all instances, even if the response is “not applicable” or “cannot be determined.”Conditional data elements are only required to be reported if applicable as delineated in the protocol. For instance, the total number of lymph nodes examined must be reported, but only if nodes are present in the specimen.Optional data elements are identified with “+” and although not required for CAP accreditation purposes, may be considered for reporting as determined by local practice standards.The use of this protocol is not required for recurrent tumors or for metastatic tumors that are resected at a different time than the primary tumor. Use of this protocol is also not required for pathology reviews performed at a second institution (ie, secondary consultation, second opinion, or review of outside case at second institution).Synoptic ReportingAll core and conditionally required data elements outlined on the surgical case summary from this cancer protocol must be displayed in synoptic report format. Synoptic format is defined as:Data element: followed by its answer (response), outline format without the paired "Data element: Response" format is NOT considered synoptic.The data element should be represented in the report as it is listed in the case summary. The response for any data element may be modified from those listed in the case summary, including “Cannot be determined” if appropriate. Each diagnostic parameter pair (Data element: Response) is listed on a separate line or in a tabular format to achieve visual separation. The following exceptions are allowed to be listed on one line:Anatomic site or specimen, laterality, and procedurePathologic Stage Classification (pTNM) elementsNegative margins, as long as all negative margins are specifically enumerated where applicableThe synoptic portion of the report can appear in the diagnosis section of the pathology report, at the end of the report or in a separate section, but all Data element: Responses must be listed together in one locationOrganizations and pathologists may choose to list the required elements in any order, use additional methods in order to enhance or achieve visual separation, or add optional items within the synoptic report. The report may have required elements in a summary format elsewhere in the report IN ADDITION TO but not as replacement for the synoptic report ie, all required elements must be in the synoptic portion of the report in the format defined above.Summary of ChangesVersion 4.1.0.0Histologic Type (WHO 2019)Surgical Pathology Cancer Case SummaryProtocol posting date: February 2020Intrahepatic Bile Ducts: Select a single response unless otherwise indicated. Procedure (Note A)___ Wedge resection___ Partial hepatectomy ___ Total hepatectomy___ Other (specify): _______________________________ Not specifiedTumor SizeGreatest dimension (centimeters): ___ cm+ Additional dimensions (centimeters): ___ x ___ cm___ Cannot be determined (see “Comment”)Tumor Focality (Note B)___ Solitary (specify location): _______________________________ Multiple (specify locations): ____________________________Histologic Type (Note C)___ Large duct intrahepatic cholangiocarcinoma___ Small duct intrahepatic cholangiocarcinoma___ Combined hepatocellular-cholangiocarcinoma___ Intraductal papillary neoplasm with an associated invasive carcinoma___ Mucinous cystic neoplasm with an associated invasive carcinoma___ Undifferentiated carcinoma___ Large cell neuroendocrine carcinoma___ Small cell neuroendocrine carcinoma___ Mixed neuroendocrine-non-neuroendocrine neoplasm (MiNEN)___ Other histologic type not listed (specify): ___________________________Histologic Grade (Note D)___ G1: Well-differentiated___ G2: Moderately differentiated___ G3: Poorly differentiated___ Other (specify): _______________________________ GX: Cannot be assessed___ Not applicable+ Tumor Growth Pattern (Note E)+ ___ Mass-forming+ ___ Periductal infiltrating+ ___ Mixed mass-forming and periductal infiltrating+ ___ Cannot be determinedTumor Extension (select all that apply)___ No evidence of primary tumor___ Tumor confined to the intrahepatic bile ducts (carcinoma in situ/high-grade dysplasia)___ Tumor confined to hepatic parenchyma___ Tumor involves visceral peritoneal surface___ Tumor directly invades gallbladder ___ Tumor directly invades adjacent organs other than the gallbladder (specify):?____________________________ Cannot be assessedMargins (Note F)Hepatic Parenchymal Margin___ Cannot be assessed___ Uninvolved by invasive carcinoma+ Distance of invasive carcinoma from margin (millimeters or centimeters): ___ mm or ___ cm___ Involved by invasive carcinomaBile Duct Margin (required only if applicable)___ Not applicable___ Cannot be assessed___ Uninvolved by invasive carcinoma and high-grade intraepithelial neoplasia+ Distance of invasive carcinoma from margin (millimeters or centimeters): ___ mm or ___cm___ Uninvolved by invasive carcinoma+ Distance of invasive carcinoma from margin (millimeters or centimeters): ___ mm or ___cm___ Involved by invasive carcinoma___ Involved by high-grade intraepithelial neoplasiaOther Margin (required only if applicable)Specify margin: _______________________________ Cannot be assessed___ Uninvolved by invasive carcinoma___ Involved by invasive carcinomaLymphovascular Invasion ___ Not identified___ Present___ Cannot be determined+ Perineural Invasion+ ___ Not identified+ ___ Present+ ___ Cannot be determinedRegional Lymph Nodes___ No lymph nodes submitted or foundLymph Node Examination (required only if lymph nodes are present in the specimen)Number of Lymph Nodes Involved: _______ Number cannot be determined (explain): ______________________Number of Lymph Nodes Examined: _______ Number cannot be determined (explain): ______________________Pathologic Stage Classification (pTNM, AJCC 8th Edition) (Note G)Note: Reporting of pT, pN, and (when applicable) pM categories is based on information available to the pathologist at the time the report is issued. Only the applicable T, N, or M category is required for reporting; their definitions need not be included in the report. The categories (with modifiers when applicable) can be listed on 1 line or more than 1 line.TNM Descriptors (required only if applicable) (select all that apply)___ m (multiple primary tumors)___ r (recurrent)___ y (posttreatment)Primary Tumor (pT)___ pTX:Primary tumor cannot be assessed___ pT0:No evidence of primary tumor___ pTis: Carcinoma in situ (intraductal tumor)___ pT1: Solitary tumor without vascular invasion, ≤5 cm or >5 cm___ pT1a: Solitary tumor ≤5 cm without vascular invasion ___ pT1b: Solitary tumor >5 cm without vascular invasion___ pT2:Solitary tumor with intrahepatic vascular invasion, or multiple tumors, with or without vascular invasion___ pT3:Tumor perforating the visceral peritoneum ___ pT4: Tumor involving local extrahepatic structures by direct invasion Regional Lymph Nodes (pN) (Note H)___ pNX:Regional lymph nodes cannot be assessed___ pN0:No regional lymph node metastasis___ pN1:Regional lymph node metastasis presentDistant Metastasis (pM) (required only if confirmed pathologically in this case) ___ pM1:Distant metastasisSpecify site(s), if known: ____________________________+ Additional Pathologic Findings (select all that apply) (Note I)+ Fibrosis:+___ Cirrhosis+___ Extent of fibrosis (specify name of the scheme and scale used for assessing stage of fibrosis): _________________________+ ___ Primary sclerosing cholangitis+ ___ Biliary stones+ ___ Chronic hepatitis (specify type): ____________________________+ ___ Other (specify): ____________________________+ ___ None identified+ Ancillary Studies + Specify: ___________________________________+ Comment(s)Explanatory NotesA. ApplicationThis protocol applies only to hepatic resection specimens containing intrahepatic cholangiocarcinoma, combined hepatocellular-cholangiocarcinoma and primary high grade neuroendocrine carcinomas. Hepatocellular carcinomas and carcinomas arising in the perihilar bile ducts are staged using separate TNM systems. ADDIN EN.CITE <EndNote><Cite><Author>Edge</Author><Year>2009</Year><RecNum>838</RecNum><record><rec-number>838</rec-number><ref-type name="Edited Book">28</ref-type><contributors><authors><author>Edge, S. E. </author><author>Byrd, D. R.</author><author>Carducci, M. A.</author><author>Compton, C. A. </author></authors></contributors><titles><title>AJCC Cancer Staging Manual</title></titles><edition>7th </edition><dates><year>2009</year></dates><pub-location>New York, N. Y.</pub-location><publisher>Springer</publisher><urls></urls></record></Cite></EndNote>1 Anatomically, the intrahepatic bile ducts extend from the periphery of the liver to the second-order bile ducts (Figure 1). The perihilar bile ducts extend from the hepatic duct bifurcation to include the extrahepatic biliary tree proximal to the origin of the cystic duct. The distal extrahepatic bile duct extends from the junction of the cystic duct-common hepatic duct to the ampulla of Vater. ADDIN EN.CITE <EndNote><Cite><Author>Edge</Author><Year>2009</Year><RecNum>838</RecNum><record><rec-number>838</rec-number><ref-type name="Edited Book">28</ref-type><contributors><authors><author>Edge, S. E. </author><author>Byrd, D. R.</author><author>Carducci, M. A.</author><author>Compton, C. A. </author></authors></contributors><titles><title>AJCC Cancer Staging Manual</title></titles><edition>7th </edition><dates><year>2009</year></dates><pub-location>New York, N. Y.</pub-location><publisher>Springer</publisher><urls></urls></record></Cite></EndNote>1Figure 1. Anatomy of the intrahepatic and extrahepatic biliary system.References ADDIN EN.REFLIST 1.Amin MB, Edge SB, Greene FL, et al, eds. AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer; 2017. B. Tumor FocalitySections should be prepared from each major tumor nodule, with representative sampling of smaller nodules. For purposes of staging, satellite nodules, multifocal primary cholangiocarcinomas, and intrahepatic metastases are considered to be multiple tumors. ADDIN EN.CITE <EndNote><Cite><Author>Edge</Author><Year>2009</Year><RecNum>838</RecNum><record><rec-number>838</rec-number><ref-type name="Edited Book">28</ref-type><contributors><authors><author>Edge, S. E. </author><author>Byrd, D. R.</author><author>Carducci, M. A.</author><author>Compton, C. A. </author></authors></contributors><titles><title>AJCC Cancer Staging Manual</title></titles><edition>7th </edition><dates><year>2009</year></dates><pub-location>New York, N. Y.</pub-location><publisher>Springer</publisher><urls></urls></record></Cite></EndNote>1 In intrahepatic cholangiocarcinoma, multiple tumor deposits have been associated with poorer survival. ADDIN EN.CITE <EndNote><Cite><Author>Ohtsuka</Author><Year>2002</Year><RecNum>98</RecNum><record><rec-number>98</rec-number><ref-type name='Journal Article'>17</ref-type><contributors><authors><author>Ohtsuka, M.</author><author>Ito, H.</author><author>Kimura, F.</author><author>Shimizu, H.</author><author>Togawa, A.</author><author>Yoshidome, H.</author><author>Miyazaki, M.</author></authors></contributors><titles><title>Results of surgical treatment for intrahepatic cholangiocarcinoma and clinicopathological factors influencing survival</title><secondary-title>British Journal of Surgery</secondary-title></titles><pages>1525-31</pages><volume>89</volume><number>12</number><dates><year>2002</year><pub-dates><date>Dec</date></pub-dates></dates><accession-num>12445060</accession-num><urls></urls></record></Cite><Cite><Author>Sano</Author><Year>2008</Year><RecNum>844</RecNum><record><rec-number>844</rec-number><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Sano, T.</author><author>Shimada, K.</author><author>Sakamoto, Y.</author><author>Ojima, H.</author><author>Esaki, M.</author><author>Kosuge, T.</author></authors></contributors><titles><title>Prognosis of perihilar carcinoma: hilar bile duct cancer versus intrahepatic cholangiocarcinoma involving the hepatic hilus.</title><secondary-title>Annals of Surgical Oncology</secondary-title></titles><pages>590-599</pages><volume>15</volume><number>2</number><dates><year>2008</year></dates><urls></urls></record></Cite></EndNote>2,3References ADDIN EN.REFLIST 1.Amin MB, Edge SB, Greene FL, et al, eds. AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer; 2017. 2.Ohtsuka M, Ito H, Kimura F, et al. Results of surgical treatment for intrahepatic cholangiocarcinoma and clinicopathological factors influencing survival. Br J Surg. 2002;89(12):1525-1531.3.Sano T, Shimada K, Sakamoto Y, Ojima H, Esaki M, Kosuge T. Prognosis of perihilar carcinoma: hilar bile duct cancer versus intrahepatic cholangiocarcinoma involving the hepatic hilus. Ann Surg Oncol. 2008;15(2):590-599.C. Histologic Type The protocol recommends the following modified classification of the World Health Organization (WHO).1 In the United States, approximately 30% of the primary malignant tumors of the liver are biliary carcinomas.1For intrahepatic cholangiocarcinoma iCCA, origin in large duct versus small duct correlates with several clinicopathologic correlations.1 Large duct iCCA tend to form hilar masses, present with obstructive cholestasis and share risk factors with extrahepatic bile duct adenocarcinomas. Small duct iCCA form peripheral liver masses, present with larger tumors and share risk factors with hepatocellular bined or mixed hepatocellular-cholangiocarcinoma should show histologic evidence of both hepatocellular and biliary differentiation by morphology, and supported by immunohistochemistry.1 Hepatocellular markers with high sensitivity and specificity such as arginase-1 should be included in the panel (in addition to markers like Hep Par 1),2 and a cholangiocarcinoma component should not be diagnosed based solely on immunoreactivity with markers like CK7, CK19, and/or MOC31, which can be positive in a subset of HCC, especially in variants like scirrhous HCC.3 Discrete gland formation with or without mucin, positive staining of these areas with CK7, CK19, and/or MOC31, and negative results in these areas with hepatocellular markers is the most reliable evidence of a cholangiocarcinoma component. The proportion of each component can be provided. The size of the entire tumor is used for staging. The demographics and clinical features of combined HCC-cholangiocarcinoma such as age, sex, viral hepatitis status, and cirrhosis tend to resemble that of HCC,4,5 while some studies have reported molecular changes similar to cholangiocarcinomaPFJlZm1hbj48Q2l0ZT48QXV0aG9yPkxlZTwvQXV0aG9yPjxZZWFyPjIwMDY8L1llYXI+PFJlY051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ADDIN REFMGR.CITE PFJlZm1hbj48Q2l0ZT48QXV0aG9yPkxlZTwvQXV0aG9yPjxZZWFyPjIwMDY8L1llYXI+PFJlY051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ADDIN EN.CITE.DATA .6 Many studies show that combined HCC-cholangiocarcinoma is more aggressive compared to classical HCC and has a higher recurrence rate after liver transplantation.7,8 Carcinosarcoma is mentioned as a histologic type in the AJCC 8th edition.References ADDIN EN.REFLIST 1.WHO Classification of Tumours Editorial Board. Digestive system tumours. Lyon (France): International Agency for Research on Cancer; 2019. (WHO classification of tumours series, 5th ed.; vol. 1)2.Nguyen T, Phillips D, Jain D, et al. Comparison of 5 Immunohistochemical Markers of Hepatocellular Differentiation for the Diagnosis of Hepatocellular Carcinoma. Arch Pathol Lab Med. 2015;139(8):1028-1034.3.Krings G, Ramachandran R, Jain D, et al. Immunohistochemical pitfalls and the importance of glypican 3 and arginase in the diagnosis of scirrhous hepatocellular carcinoma. Mod Pathol. 2013;26(6):782-791.4.Yano Y, Yamamoto J, Kosuge T, et al. Combined hepatocellular and cholangiocarcinoma: a clinicopathologic study of 26 resected cases. Jpn J Clin Oncol. 2003;33:283-287.5.Tang D, Nagano H, Nakamura M, et al. Clinical and pathological features of Allen's type C classification of resected combined hepatocellular and cholangiocarcinoma: a comparative study with hepatocellular carcinoma and cholangiocellular carcinoma. J Gastrointest Surg. 2006;10:987-998.6.Cazals-Hatem D, Rebouissou S, Bioulac-Sage P, et al. Clinical and molecular analysis of combined hepatocellular-cholangiocarcinomas. J Hepatol. 2004;41(2):292-298.7.Wu CH, Yong CC, Liew EH, et al. Combined hepatocellular carcinoma and cholangiocarcinoma: diagnosis and prognosis after resection or transplantation. Transplant Proc. 2016;48(4):1100-1104. 8. Sapisochin G, Fidelman N, Roberts JP, Yao FY. Mixed hepatocellular cholangiocarcinoma and intrahepatic cholangiocarcinoma in patients undergoing transplantation for hepatocellular carcinoma. Liver Transpl. 2011;17(8):934-942.D.Histologic GradeFor cholangiocarcinomas, definitive criteria for histologic grading have not been established; however, the following quantitative grading system based on the proportion of gland formation within the tumor is suggested: Grade XGrade cannot be assessedGrade 1Well differentiated (more than 95% of tumor composed of glands)Grade 2Moderately differentiated (50% to 95% of tumor composed of glands)Grade 3Poorly differentiated (less than 49% of tumor composed of glands)Undifferentiated category is rarely used and is reserved for tumors that do not show obvious glandular, squamous, or neuroendocrine differentiation on morphology and/or immunohistochemistry. It is more appropriate to categorize these as undifferentiated carcinomas rather than cholangiocarcinoma. This category is not included in the AJCC scheme. There is no separate grading scheme for combined hepatocellular-cholangiocarcinoma; both the components can be separately graded. This grading system is not applicable to poorly differentiated neuroendocrine carcinoma.E. Tumor Growth Pattern Three tumor growth patterns of intrahepatic cholangiocarcinoma are described: the mass-forming type, the periductal infiltrating type, and mixed mass-forming/periductal-infiltrating type. Mass-forming intrahepatic cholangiocarcinoma (60% of cases) forms a well-demarcated nodule growing in a radial pattern and invading the adjacent liver parenchyma (Figure 2). In contrast, the periductal-infiltrating type of cholangiocarcinoma (20% of cases) spreads in a diffuse longitudinal growth pattern along the bile duct. The remaining 20% of cases of intrahepatic cholangiocarcinoma grow in a mixed mass-forming/periductal-infiltrating pattern. Earlier studies suggested a poor outcome for diffuse periductal-infiltrating type, while some recent studies have suggested a relatively favorable prognosis.1-4 Figure 2. Tumor growth pattern in intrahepatic cholangiocarcinoma. From Amin MB et al.5 Used with permission of the?American Joint Committee on Cancer (AJCC), Chicago, Illinois. The original source for this material is the AJCC?Cancer Staging Manual, 8th edition (2017), published by Springer Science and Business Media LLC, .References ADDIN EN.REFLIST 1.Hirohashi K, Uenishi T, Kubo S, et al. Macroscopic types of intrahepatic cholangiocarcinoma: clinicopathologic features and surgical outcomes. Hepatogastroenterology. 2002;49(44):326-329. 2.Shimada K, Sano T, Sakamoto Y, Esaki M, Kosuge T, Ojima H. Surgical outcomes of the mass-forming plus periductal infiltrating types of intrahepatic cholangiocarcinoma: a comparative study with the typical mass-forming type of intrahepatic cholangiocarcinoma. World J Surg. 2007;31(10):2016-2022.3.Imai K, Yamamoto M, Ariizumi S. Surgery for periductal infiltrating type intrahepatic cholangiocarcinoma without hilar invasion provides a better outcome than for mass-forming type intrahepatic cholangiocarcinoma without hilar invasion. Hepatogastroenterology. 2010;57(104):1333-1336. 4. Uno M, Shimada K, Yamamoto Y, et al. Periductal infiltrating type of intrahepatic cholangiocarcinoma: a rare macroscopic type without any apparent mass. Surg Today. 2012;42(12):1189-1194.5.Amin MB, Edge SB, Greene FL, et al, eds. AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer; 2017. F. MarginsThe evaluation of margins for total or partial hepatectomy specimens depends on the method and extent of resection. It is recommended that the surgeon be consulted to determine the critical foci within the margins that require microscopic evaluation. The transection margin of a partial hepatectomy may be large, rendering it impractical for complete examination. In this setting, grossly positive margins should be microscopically confirmed and documented. If the margins are grossly free of tumor, judicious sampling of the cut surface in the region closest to the nearest identified tumor nodule is indicated. In selected cases, adequate random sampling of the cut surface may be sufficient. The histologic examination of the bile ducts at the cut margin is recommended to evaluate the lining epithelium for in situ carcinoma or dysplasia. If the neoplasm is found near the surgical margin, the distance from the margin should be reported. For multiple tumors, the distance from the nearest tumor should be reported.G.Pathologic Stage ClassificationAccording to AJCC/UICC convention, the designation “T” refers to a primary tumor that has not been previously treated. The symbol “p” refers to the pathologic classification of the TNM, as opposed to the clinical classification, and is based on gross and microscopic examination. pT entails a resection of the primary tumor or biopsy adequate to evaluate the highest pT category, pN entails removal of nodes adequate to validate lymph node metastasis, and pM implies microscopic examination of distant lesions. Clinical classification (cTNM) is usually carried out by the referring physician before treatment during initial evaluation of the patient or when pathologic classification is not possible.Pathologic staging is usually performed after surgical resection of the primary tumor. Pathologic staging depends on pathologic documentation of the anatomic extent of disease, whether or not the primary tumor has been completely removed. If a biopsied tumor is not resected for any reason (eg, when technically infeasible) and if the highest T and N categories or the M1 category of the tumor can be confirmed microscopically, the criteria for pathologic classification and staging have been satisfied without total removal of the primary cancer. TNM DescriptorsFor identification of special cases of TNM or pTNM classifications, the “m” suffix and “y,” “r,” and “a” prefixes are used. Although they do not affect the stage grouping, they indicate cases needing separate analysis.The “m” suffix indicates the presence of multiple primary tumors in a single site and is recorded in parentheses: pT(m)NM.The “y” prefix indicates those cases in which classification is performed during or after initial multimodality therapy (ie, neoadjuvant chemotherapy, radiation therapy, or both chemotherapy and radiation therapy). The cTNM or pTNM category is identified by a “y” prefix. The ycTNM or ypTNM categorizes the extent of tumor actually present at the time of that examination. The “y” categorization is not an estimate of tumor before multimodality therapy (ie, before initiation of neoadjuvant therapy).The “r” prefix indicates a recurrent tumor when staged after a documented disease-free interval and is identified by the “r” prefix: rTNM.The “a” prefix designates the stage determined at autopsy: aTNM.T Category ConsiderationsT includes high-grade biliary intraepithelial neoplasia (BilIn-3), intraductal papillary neoplasm with high-grade dysplasia, and mucinous cystic neoplasm with high-grade dysplasia. For intraepithelial lesions, a 3-tier biliary intraepithelial neoplasia classification has been proposed.1The T categories are based on size, vascular invasion and extrahepatic spread. For invasive carcinoma associated with intraductal papillary neoplasms and mucinous cystic neoplasms, only the size of the invasive component should be used to determine the T category. The synoptic report is not required for intraductal papillary neoplasms and mucinous cystic neoplasms in the absence of an invasive component. For invasive carcinoma associated with intraductal papillary neoplasms and mucinous cystic neoplasms, only the size of the invasive component should be used to determine the T category. The invasive portion in these cases can be multifocal. The size of the largest focus as well as cumulative size of all invasive carcinoma foci should be included in the report. Till further data becomes available, the T category should be determined based on size of the largest invasive focus. Vascular invasion includes either gross or microscopic involvement of vessels. Major vascular invasion is defined as invasion of the branches of the main portal vein or hepatic artery (first and second order branches) or as invasion of 1 or more of the 3 hepatic veins (right, middle or left). Direct invasion of visceral peritoneum is considered as T3, while adjacent organs, including colon, duodenum, stomach, common bile duct, portal lymph nodes, abdominal wall, and diaphragm, is considered as T4 disease. Due to inconsistent criteria for defining tumors with periductal growth pattern and its unclear association with outcome, this growth pattern is no longer a part of the T classification.Additional DescriptorsLymphovascular InvasionLymphovascular invasion (LVI) indicates whether microscopic lymphovascular invasion is identified in the pathology report. LVI includes lymphatic invasion, vascular invasion, or lymphovascular invasion. References ADDIN EN.REFLIST 1.Zen Y, Adsay NV, Bardadin K, et al. Biliary intraepithelial neoplasia: an international interobserver agreement study and proposal for diagnostic criteria. Mod Pathol. 2007;20(6):701-709.H. Lymph NodesLymph node metastases have consistently been identified as an important predictor of outcome for intrahepatic cholangiocarcinoma.1-3 The lymph node involvement pattern for intrahepatic cholangiocarcinomas varies with location in the liver (Figure 3). For carcinomas arising in the right lobe of the liver (segments 5-8), the regional lymph nodes include the hilar (common bile duct, hepatic artery, portal vein, and cystic duct), periduodenal, and peripancreatic lymph nodes. For tumors arising in the left lobe, the regional lymph nodes are the hilar, inferior phrenic and gastrohepatic lymph nodes. Nodal involvement of the celiac, periaortic, or pericaval lymph nodes is considered to be distant metastasis (pM1). ADDIN EN.CITE <EndNote><Cite><Author>Edge</Author><Year>2009</Year><RecNum>838</RecNum><record><rec-number>838</rec-number><ref-type name="Edited Book">28</ref-type><contributors><authors><author>Edge, S. E. </author><author>Byrd, D. R.</author><author>Carducci, M. A.</author><author>Compton, C. A. </author></authors></contributors><titles><title>AJCC Cancer Staging Manual</title></titles><edition>7th </edition><dates><year>2009</year></dates><pub-location>New York, N. Y.</pub-location><publisher>Springer</publisher><urls></urls></record></Cite></EndNote>1 Figure 3. Segmental anatomy of the liver. From Greene et al.4 Used with permission of the American Joint Committee on Cancer (AJCC), Chicago, Illinois. The original source for this material is the AJCC Cancer Staging Atlas (2006) published by Springer Science and Business Media LLC, .References ADDIN EN.REFLIST 1.Amin MB, Edge SB, Greene FL, et al, eds. AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer; 2017. 2.Ohtsuka M, Ito H, Kimura F, et al. Results of surgical treatment for intrahepatic cholangiocarcinoma and clinicopathological factors influencing survival. Br J Surg. 2002;89(12):1525-1531.3.Mavros MN, Economopoulos KP, Alexiou VG and Pawlik TM (2014). Treatment and prognosis for patients with intrahepatic cholangiocarcinoma: systematic review and meta-analysis. JAMA Surg. 149(6):565-574. 4.Greene FL, Compton, CC, Fritz AG, et al, eds. AJCC Cancer Staging Atlas. New York, NY: Springer; 2006.I. Additional Pathologic FindingsThe extent of fibrosis should be reported as cirrhosis or advanced fibrosis have an adverse effect on outcome. The scoring system described by Ishak1 is recommended by the AJCC Cancer Staging Manual, 8th edition,2 but other commonly used schemes (Batts-Ludwig, Metavir) can be used. The name of the staging scheme and its scale should be included.The presence of underlying disease, such as primary sclerosing cholangitis,3 should be included in the pathology report. Biliary parasites and recurrent pyogenic cholangitis may be present along with cholangiocarcinoma in Asian countries. Hepatitis C infection, nonalcoholic fatty liver disease, obesity, and smoking are also risk factors for cholangiocarcinoma.4,5References ADDIN EN.REFLIST 1.Ishak K, Baptista A, Bianchi L, et al. Histologic grading and staging of chronic hepatitis. J Hepatol. 1995;22:696-699.2.Amin MB, Edge SB, Greene FL, et al, eds. AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer; 2017. 3.Shaib Y, El-Serag HB. The epidemiology of cholangiocarcinoma. Semin Liver Dis. 2004;24(2):115-125.4.Welzel TM, Graubard BI, El-Serag HB, et al. Risk factors for intrahepatic and extrahepatic cholangiocarcinoma in the United States: a population-based case-control study. Clin Gastroenterol Hepatol. 2007;5(10):1221-1228.5.Ben-Menachem T. Risk factors for cholangiocarcinoma [comment]. Eur J Gastroenterol Hepatol. 2007;19(8):615-617. ................
................
In order to avoid copyright disputes, this page is only a partial summary.
To fulfill the demand for quickly locating and searching documents.
It is intelligent file search solution for home and business.