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Study Characterizes Peripheral Nerve Invasion in HCCA With Novel WHLS Method


Analyzing whole-mount histologic large sections is not a new practice, but a new strategy was needed to fully characterize peripheral nerve invasion in hilar cholangiocarcinoma.

Technology to evaluate whole-mount histologic large sections (WHLS) of tissue has been used to diagnose and stage several cancer types for decades, and a recent study published in Frontiers in Oncology aimed to fill the need for a WHLS system capable of assessing peripheral nerve invasion (PNI) in hilar cholangiocarcinoma (HCCA).

Patients with HCCA, the most common type of cholangiocarcinoma, typically have a poor prognosis, high morbidity, and high mortality rates. PNI is present in an estimated 38.8% to 84.5% of HCCA cases and significantly reduces survival compared with HCCA sans PNI, according past studies. Because the scope of nerve invasion is larger in more advanced HCCA, traditional WHLS technology that only accommodates samples up to 5 cm is insufficient to assess whether there are differences between intrahepatic and extrahepatic PNI.

“We have developed a WHLS system that includes dehydration, tissue embedding, sectioning, hematoxylin and eosin (H&E), immunohistochemical (IHC) staining and digital scanning for hepatectomy specimens larger than 10 × 10cm,” the authors wrote. “Through this system, we can observe the characteristics of intrahepatic and extrahepatic PNI in Bismuth III and IV types of HCCA.”

Between July 2018 and February 2021, 20 patients diagnosed with Bismuth types III and IV HCCA underwent hemihepatectomy (75%) or trisegmenthepatectomy (25%), then samples were prepared for WHLS analysis with fixation, dehydration, embedding, sectioning, H&E and IHC staining. Given the 10 cm and larger size of the samples, a 3-stage fixation system was used to prevent autolysis, and prolonged dehydration at low alcohol concentrations minimized tissue shrinkage. Staining was done manually and successfully showed adenocarcinoma and its nuclear morphology, surrounding liver tissues, blood vessels, lymphatic tissues, and nerve tissues.

In this cohort, 100% of patients showed PNI. Extrahepatic PNI was present in all 20 cases, and intrahepatic PNI in 1 patient. In 16 patients, vessel density decreased when the nerve tissue was invaded by tumors, and 4 patients saw no change in density. This result is contrary to a previous study that saw blood vessel numbers increase following tumor cell invasion into nerve fibers and suggests that the types of HCCA in this study might not rely on blood supply to invade surrounding nerves.

Tumor differentiation was strongly correlated with decreased vessel density in PNI, with 100% of tumors with low differentiation and 83% of tumors with moderate differentiation showing PNI independent of blood supply. However, vessel density decrease was not associated with tumor size, Bismuth type, vascular invasion, carbohydrate antigen 19-9, or microvascular invasion.

Overall, the study gives significant insight into the pattern of types III and IV HCCA and provides a novel WHLS technology capable of analyzing larger samples of hepatectomy tissue.

“This study established a WHLS of the liver that can be used for clinical diagnosis and research and confirmed that extrahepatic PNI is prevalent in types III and IV HCCA, but intrahepatic PNI is rare and does not accompany the invasion scope of the bile duct,” the authors concluded.


Wang S, Jiang N, Zeng J, Yu S, Xiao Y, Jin S. Characteristic of perineural invasion in hilar cholangiocarcinoma based on whole-mount histologic large sections of liver. Front Oncol. Published online March 8, 2022. doi:10.3389/fonc.2022.855615

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