|Year : 2017 | Volume
| Issue : 4 | Page : 501-504
|Accuracy of vascular invasion reporting in hepatocellular carcinoma before and after implementation of subspecialty surgical pathology sign-out
Aaron R Huber1, Raul S Gonzalez1, Mark S Orloff2, Christopher T Barry3, Christa L Whitney-Miller1
1 Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY, USA
2 Department of Solid Organ Transplant and Hepatobiliary Surgery, University of Rochester Medical Center, Rochester, NY, USA
3 Adjunct Professor and Transplant Consultant, Mahatma Gandhi Hospital, Jaipur, Rajasthan, India
Click here for correspondence address and email
|Date of Web Publication||12-Jan-2018|
| Abstract|| |
Context: Liver cancers (including hepatocellular carcinoma [HCC] and cholangiocarcinoma) are the fifth most common cause of cancer death. The most powerful independent histologic predictor of overall survival after transplantation for HCC is the presence of microscopic vascular invasion (VI). Aims: Given that VI is known to have somewhat high interobserver variability in both HCC and other tumors, we hypothesized that pathologists with special interest and training in liver pathology would be more likely to identify and report VI in HCC than would general surgical pathologists. Settings and Design: We searched our departmental surgical pathology archives for transplant hepatectomies performed for HCC. Subjects and Methods: We identified 143 such cases with available sign-out reports and hematoxylin and eosin-stained slides. Statistical Analysis Used: Kappa results (level of agreement) were calculated. Results: Before surgical pathology subspecialty sign-out (SSSO) implementation, 49 of 88 HCC cases were reported as negative for VI; on rereview, 20 of these had VI. After SSSO implementation, 39 of 55 cases were reported as negative for VI; on our review, 8 of these had VI. Kappa (agreement) between general SO and subspecialty rereview was 0.562 (95% confidence interval [CI] = 0.411–0.714) “weak agreement.” Kappa (agreement) between SSSO and rereview by select liver pathologists was 0.693 (95% CI = 0.505–0.880) “moderate agreement.” Conclusions: Our study is one of only a few so far that have suggested improved accuracy of certain parameters under SSSO.
Keywords: Hepatocellular carcinoma, subspecialty sign-out, vascular invasion
|How to cite this article:|
Huber AR, Gonzalez RS, Orloff MS, Barry CT, Whitney-Miller CL. Accuracy of vascular invasion reporting in hepatocellular carcinoma before and after implementation of subspecialty surgical pathology sign-out. Indian J Pathol Microbiol 2017;60:501-4
|How to cite this URL:|
Huber AR, Gonzalez RS, Orloff MS, Barry CT, Whitney-Miller CL. Accuracy of vascular invasion reporting in hepatocellular carcinoma before and after implementation of subspecialty surgical pathology sign-out. Indian J Pathol Microbiol [serial online] 2017 [cited 2019 Nov 16];60:501-4. Available from: http://www.ijpmonline.org/text.asp?2017/60/4/501/222996
| Introduction|| |
Liver cancers (including hepatocellular carcinoma [HCC] and cholangiocarcinoma) are the 13th most common malignancy diagnosed in the United States and the fifth most common cause of cancer death. Liver cancer is more common in Asian/Pacific Islanders and American Indians/Alaskan Natives. Studies show rates for new liver and intrahepatic bile duct cancer cases have been rising on average 3.0% each year for the past 10 years. Liver cancers have high mortality (overall 5-year relative survival of 17.5%).
The only potentially curative therapies for HCC are resection and liver transplantation; due to underlying liver disease, many patients are not candidates for resection, meaning liver transplantation is their only option for cure. Tumor-associated features that have the most impact on long-term survival in liver transplant patients with HCC include tumor size and number, bilobar tumors, tumor differentiation, satellite lesions, and vascular invasion (VI);,, in fact, the most powerful independent histologic predictor of overall survival after transplantation for HCC is the presence of microscopic VI, and therefore, tumors with VI are assigned a higher stage. Specifically, under American Joint Commission on Cancer staging criteria, VI upstages a solitary tumor from pT1 to pT2, and tumor(s) involving a major branch of the hepatic or portal vein automatically categorizes a tumor as pT3b.
Pathological assessment of the explanted liver is critical, as radiographic pretransplant staging of an HCC has demonstrated only 34% accuracy compared to the pathological examination of the explanted liver specimen. All patients with HCC are screened for recurrent tumor posttransplant and it has been suggested that patients with a tumor demonstrating VI should be screened at more frequent intervals.
In recent years, there has been a movement, particularly in academic medical centers, toward subspecialty sign-out (SSSO) in surgical pathology; in this model, attending pathologists generally focus on only one or two subspecialties, rather than doing “general sign-out” and being responsible for cases from all organ systems. Recently, our department transitioned from general sign-out to SSSO in July 2015 after utilizing a hybrid model for 6 years. Given that VI is known to have somewhat high interobserver variability in both HCC and other tumors,,, we hypothesized that pathologists with special interest and training in liver pathology would be more likely to identify and report VI in HCC than would general surgical pathologists and that our SSSO model would reflect this.
| Subjects and Methods|| |
With appropriate Institutional Research Board approval, we searched our departmental surgical pathology archives for transplant hepatectomies performed for HCC. We identified 143 such cases with available sign-out reports and hematoxylin and eosin-stained slides: 88 cases before implementation of SSSO and 55 cases after SSSO implementation. All slides were reviewed for the presence or absence of VI by two pathologists (ARH and CWM) with fellowship training in gastrointestinal (GI) and liver pathology whose practice is limited to that subspecialty. VI was defined as tumor cells within or adherent to the wall of an unequivocal endothelial-lined vascular space. If immunohistochemical staining to highlight vessels was performed at the time of original sign-out, those slides were reviewed as well; no additional immunostains were performed.
The following metrics were tabulated for each case: whether it was signed out before or after SSSO, whether VI was present or absent as per the original report, whether VI was present or absent after rereview, and whether the signing pathologist had special training in GI/liver pathology. The results were compared using Cohen's kappa analysis to compare agreement between the cases signed out before and after SSSO implementation in GraphPad Software online (http://graphpad.com/quickcalcs, GraphPad Software, San Diego, CA, USA, last accessed 10/12/2016). The Kappa results and level of agreement were interpreted as suggested by McHugh as follows: 0.01–0.20 as “no agreement,” 0.21–0.39 as “minimal agreement,” 0.40–0.59 as “weak agreement,” 0.60–0.79 as “moderate agreement,” 0.80-0.90 as “strong agreement,” and above 0.90 as “almost perfect.”
| Results|| |
Findings are summarized in [Table 1]. Before SSSO implementation, 49 of 88 HCC cases were reported as negative for VI; on rereview, 20 of these had VI. The other 39 cases were originally reported as positive for VI; we agreed with all cases, meaning that no cases were switched from positive to negative for VI. Fourteen cases signed out before implementation of SSSO were done so by a GI/liver pathologist; these were distributed proportionately among the groups (3 negative/negative; 3 negative/positive; and 8 positive/positive). After SSSO implementation, 39 of 55 cases were reported as negative for VI; on our review, 8 of these had VI. Missed foci were usually small and subtle but were adjacent to the main tumor mass [Figure 1]a and [Figure 1]b. Sixteen cases were originally reported as positive for VI; we agreed with all 16 cases. Again, no cases were switched from positive to negative for VI. Overall, the VI status was correct in 69 of 88 cases (78%) before SSSO, while it was correct in 47 of 55 cases (85%) after SSSO. Kappa (agreement) between general SO and subspecialty rereview was 0.562 (95% confidence interval [CI] = 0.411–0.714) “weak agreement;” these values did not change if the 14 cases that happened to be signed out by a GI/liver pathologist were excluded. Kappa (agreement) between SSSO and rereview by select liver pathologists was 0.693 (95% CI = 0.505–0.880) “moderate agreement.”
|Figure 1: (a and b) Two examples of foci of small vessel vascular invasion by hepatocellular carcinoma identified on rereview of cases that were originally not identified (H and E, ×400)|
Click here to view
|Table 1: Impact of subspecialty sign-out on identification of vascular invasion in hepatocellular carcinoma: summary of results|
Click here to view
| Discussion|| |
There is a movement afoot for surgical pathology units to implement SSSO, not only in academic centers but also in community practice. SSSO is appealing because it allows pathologists to focus their clinical efforts on one or two organ systems, rather than trying to keep up with the ever-increasing available knowledge of every organ system. It also may foster closer relationships with clinicians, perhaps leading to improved communication and in academic institutions, stronger research collaborations. Transitioning from general to SSSO requires a careful balancing act, considering pathologist preferences, departmental case mix, and coverage/staffing needs. Because of this, SSSO can be burdensome to implement and maintain, as we have experienced at our institution. After SSSO, it can be difficult for pathologists to “cross-cover” during staff shortages. Staffing needs may increase because depth is required in each subspecialty. Remaining proficient in frozen section interpretation across subspecialties requires special attention.
In the field of GI and liver pathology, SSSO has become an expectation among gastroenterologists and hepatologists. This has received particular attention as regarding the identification of dysplasia in Barrett's esophagus. In fact, the American Gastroenterological Association position statement on Barrett's esophagus states, “the diagnosis of dysplasia in Barrett's esophagus should be confirmed by at least one additional pathologist, preferably one who is an expert in esophageal histopathology.” Other authors have also been recommended that “consultants with particular expertise in GI pathology” be utilized “before institution of definitive management in patients with Barrett's esophagus (sic) with 'atypical' biopsy specimens.” These recommendations have been made even though interobserver variability remains high in the assessment of dysplasia in Barrett's esophagus, even among expert GI pathologists.,
Despite this trend, only a handful of studies in the literature have evaluated the quality of sign-out reports generated under an SSSO model compared to a general sign-out model. One study has suggested that SSSO improves the diagnosis of pleural involvement in lung cancer. Similarly, GI pathologists appear better than non-GI pathologists at detecting VI in colorectal carcinoma, whether using ancillary stains or just hematoxylin and eosin. Another study showed that dedicated breast pathologists were significantly more likely than nonbreast pathologists to make a diagnosis on core biopsy that correlated with the final diagnosis on excision. It has also been observed that SSSO can decrease the rate of extramural expert consultants disagreeing with original diagnoses given by the department employing SSSO.
While a variety of immunohistochemical stains (including CD31, D2-40, and ERG ), as well as a special stain for elastin, have been proposed to help increase the detection of lymphatic invasion and VI, we hypothesized that SSSO could also improve the overall accuracy of assessing for VI. Our study found improved recognition and reporting of VI in patients with HCC who underwent liver transplantation. Specifically, we found that among HCC cases signed out before SSSO, the likelihood of a case harboring overlooked VI was higher than among cases signed out under SSSO. Fortunately, the majority of cases reported as negative for VI were indeed negative, and no case reported as positive for VI was found to in actuality be negative for VI.
Because of the role VI plays in predicting long-term survival in patients with HCC treated with liver transplantation, institutions that perform liver transplants may want to consider the benefits of adopting SSSO. If complete SSSO is not feasible, institutions may also consider a hybrid model in which select cases are given to a pathologist with subspecialty expertise; for instance, before implementation of full SSSO at our institution, we utilized such a hybrid model. Under that system, all GI/liver resection specimens, liver biopsies, biopsies for Barrett's esophagus, and biopsies for inflammatory conditions of the luminal GI tract were funneled to an expert GI pathologist, while specimens from other procedures (such as upper endoscopies for nonspecific symptoms and screening colonoscopies) could be distributed to any pathologist in the department. The differences in identifying VI may be related to the attentiveness of a particular pathologist in the search for VI. In addition, the retrospective nature of the study with unlimited time to review the slides may have increased detection of VI. However, the careful examination of transplant hepatectomies with HCC requires a meticulous search for lymphoVI regardless of whether they are subspecialty trained or not. This is especially true given the clinical implications for the patient.
Our study is one of only a few so far that have suggested improved accuracy of certain parameters under SSSO. As this sign-out model continues to be adopted across the country and the world, it is prudent that its advantages be studied and quantified, to offer maximum benefit to patients. Its disadvantages (or areas of no advantage) should also be studied so that institutional steps can be taken to minimize their impact.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Maggs JR, Suddle AR, Aluvihare V, Heneghan MA. Systematic review: The role of liver transplantation in the management of hepatocellular carcinoma. Aliment Pharmacol Ther 2012;35:1113-34.
Clavien PA, Lesurtel M, Bossuyt PM, Gores GJ, Langer B, Perrier A, et al.
Recommendations for liver transplantation for hepatocellular carcinoma: An International Consensus Conference Report. Lancet Oncol 2012;13:e11-22.
Tsai TJ, Chau GY, Lui WY, Tsay SH, King KL, Loong CC, et al.
Clinical significance of microscopic tumor venous invasion in patients with resectable hepatocellular carcinoma. Surgery 2000;127:603-8.
Lauwers GY, Terris B, Balis UJ, Batts KP, Regimbeau JM, Chang Y, et al.
Prognostic histologic indicators of curatively resected hepatocellular carcinomas: A multi-institutional analysis of 425 patients with definition of a histologic prognostic index. Am J Surg Pathol 2002;26:25-34.
Edge SB, Byrd DR, Carducci MA, Compton CC, editors. AJCC Cancer Staging Manual. 7th
ed. New York: Springer; 2009.
Adler M, De Pauw F, Vereerstraeten P, Fancello A, Lerut J, Starkel P, et al.
Outcome of patients with hepatocellular carcinoma listed for liver transplantation within the Eurotransplant allocation system. Liver Transpl 2008;14:526-33.
Roberts JP. Tumor surveillance-what can and should be done? Screening for recurrence of hepatocellular carcinoma after liver transplantation. Liver Transpl 2005;11 Suppl 2:S45-6.
Harris EI, Lewin DN, Wang HL, Lauwers GY, Srivastava A, Shyr Y, et al.
Lymphovascular invasion in colorectal cancer: An interobserver variability study. Am J Surg Pathol 2008;32:1816-21.
Fan L, Mac MT, Frishberg DP, Fan X, Dhall D, Balzer BL, et al.
Interobserver and intraobserver variability in evaluating vascular invasion in hepatocellular carcinoma. J Gastroenterol Hepatol 2010;25:1556-61.
Longacre TA, Ennis M, Quenneville LA, Bane AL, Bleiweiss IJ, Carter BA, et al.
Interobserver agreement and reproducibility in classification of invasive breast carcinoma: An NCI breast cancer family registry study. Mod Pathol 2006;19:195-207.
McHugh ML. Interrater reliability: The kappa statistic. Biochem Med (Zagreb) 2012;22:276-82.
Sarewitz SJ. Subspecialization in community pathology practice. Arch Pathol Lab Med 2014;138:871-2.
Groppi DE, Alexis CE, Sugrue CF, Bevis CC, Bhuiya TA, Crawford JM, et al.
Consolidation of the north shore-LIJ health system anatomic pathology services: The challenge of subspecialization, operations, quality management, staffing, and education. Am J Clin Pathol 2013;140:20-30.
American Gastroenterological Association, Spechler SJ, Sharma P, Souza RF, Inadomi JM, Shaheen NJ, et al.
American gastroenterological association medical position statement on the management of Barrett's esophagus. Gastroenterology 2011;140:1084-91.
Odze RD. Diagnosis and grading of dysplasia in Barrett's oesophagus. J Clin Pathol 2006;59:1029-38.
Kerkhof M, van Dekken H, Steyerberg EW, Meijer GA, Mulder AH, de Bruïne A, et al.
Grading of dysplasia in barrett's oesophagus: Substantial interobserver variation between general and gastrointestinal pathologists. Histopathology 2007;50:920-7.
Jung G, Hwang HS, Jang SJ, Ro JY. Are elastic stain and specialty sign out necessary to evaluate pleural invasion in lung cancers? Ann Diagn Pathol 2012;16:250-4.
Kirsch R, Messenger DE, Riddell RH, Pollett A, Cook M, Al-Haddad S, et al.
Venous invasion in colorectal cancer: Impact of an elastin stain on detection and interobserver agreement among gastrointestinal and nongastrointestinal pathologists. Am J Surg Pathol 2013;37:200-10.
Jakate K, De Brot M, Goldberg F, Muradali D, O'Malley FP, Mulligan AM, et al.
Papillary lesions of the breast: Impact of breast pathology subspecialization on core biopsy and excision diagnoses. Am J Surg Pathol 2012;36:544-51.
Liu Y, Kessler M, Zander D, Karamchandani D. Trends in extramural consultation: Comparison between subspecialty vs. general surgical pathology service models. Am J ClinPathol 2015;144 Suppl 2:A395.
Alexander-Sefre F, Singh N, Ayhan A, Salveson HB, Wilbanks G, Jacobs IJ, et al.
Detection of tumour lymphovascular space invasion using dual cytokeratin and CD31 immunohistochemistry. J Clin Pathol 2003;56:786-8.
Arnaout-Alkarain A, Kahn HJ, Narod SA, Sun PA, Marks AN. Significance of lymph vessel invasion identified by the endothelial lymphatic marker D2-40 in node negative breast cancer. Mod Pathol 2007;20:183-91.
Kim S, Park HK, Jung HY, Lee SY, Min KW, Kim WY, et al.
ERG immunohistochemistry as an endothelial marker for assessing lymphovascular invasion. Korean J Pathol 2013;47:355-64.
Dr. Aaron R Huber
Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, 601 Elmwood Avenue, Box 626, Rochester, NY
Source of Support: None, Conflict of Interest: None
|This article has been cited by|
||SPAG5 promotes hepatocellular carcinoma progression by downregulating SCARA5 through modifying ß-catenin degradation
| ||Hongliang Liu,Junwen Hu,Ran Wei,Longfei Zhou,Hua Pan,Hongchao Zhu,Mingwen Huang,Jun Luo,Wei Xu |
| ||Journal of Experimental & Clinical Cancer Research. 2018; 37(1) |
|[Pubmed] | [DOI]|
| Article Access Statistics|
| Viewed||1898 |
| Printed||30 |
| Emailed||0 |
| PDF Downloaded||76 |
| Comments ||[Add] |
| Cited by others ||1 |