Study on the Pattern and Extent of Intrahepatic Infiltration in Perihilar Cholangiocarcinoma

Academic Background

Perihilar cholangiocarcinoma (PHCC) is one of the most common malignancies of the biliary system, and its treatment primarily relies on radical surgical resection. However, despite advancements in surgical techniques, the postoperative recurrence rate of PHCC remains high, particularly for in situ and intrahepatic recurrences. This suggests that the intrahepatic biological boundaries of PHCC are not yet fully understood, affecting the extent and efficacy of radical surgical resection. Previous studies have indicated that the proximal bile duct infiltration range of PHCC is typically within 10 millimeters. Nevertheless, the postoperative recurrence rate remains high, hinting at potential intrahepatic infiltration patterns that have not been fully recognized.

To address this issue, this study aims to comprehensively assess the intrahepatic infiltration patterns and extent of PHCC using the Whole-Mount Digital Liver Pathology System (WDLPS), thereby guiding surgical treatment and pathological research.

Source of the Paper

This paper was co-authored by Shuo Jin and Nan Jiang from the Hepatopancreatobiliary Center of Beijing Tsinghua Changgung Hospital, along with Jing-Min Zhao from the Fifth Medical Center of the Chinese PLA General Hospital, among others. The paper was published online on August 14, 2024, in the International Journal of Surgery, titled “Pattern and Extent of Intrahepatic Infiltration of Perihilar Cholangiocarcinoma – A Case–Control Study Based on Liver Panoramic Digital Pathology.”

Research Process and Results

1. Study Design and Patient Selection

This study included 62 patients diagnosed with PHCC who underwent major hepatectomy between April 2018 and December 2021. All patients underwent hemihepatectomy or trisectionectomy combined with caudate lobectomy. The study utilized WDLPS to panoramically evaluate liver resection specimens larger than 10×10 cm, quantifying the intrahepatic infiltration extent of PHCC.

2. Pathological Specimen Processing and WDLPS Construction

The research team developed WDLPS to panoramically display tumors and surrounding liver tissues in liver resection specimens. The specific workflow is as follows: - Specimen Processing: Liver specimens resected during surgery were immediately injected with 10% neutral formalin through blood vessels and bile ducts, followed by immersion in formalin for 24 hours. - Section Preparation: Specimens were continuously sliced along the long axis at a thickness of 8-10 mm and immersed in formalin for another 24 hours. Subsequently, the slice thickness was adjusted to 4-5 mm and immersed in formalin for 48 hours. - Digital Scanning and Analysis: Sections were prepared using the Sakura IVS-410 microtome, stained with H&E and immunohistochemistry, scanned using the VS200 panoramic digital scanner, and digitally measured using the Olyvia analysis system.

3. Assessment of Intrahepatic Infiltration Extent

The study focused on two intrahepatic infiltration patterns of PHCC: Distal Intrahepatic Infiltration (DIHI) and Radial Liver Invasion (RLI). - RLI was defined as the maximum straight-line distance from the infiltrated liver parenchyma to the hepatic hilar plate. - DIHI was defined as intrahepatic infiltration greater than 1 cm from the margin of the main tumor.

4. Key Findings

• RLI: 75.8% of PHCC patients exhibited RLI, with all RLI distances within 15,000 µm. Among them, 65.9% of patients had RLI distances less than 5,000 µm, 23.4% had RLI distances between 5,000-10,000 µm, and 10.6% had RLI distances between 10,000-15,000 µm.
• DIHI: 62.9% of PHCC patients exhibited DIHI, predominantly located in the terminal portal area. Among them, 56.4% of patients had DIHI distances between 10,000-20,000 µm, 30.8% had DIHI distances between 20,000-30,000 µm, and 12.8% had DIHI distances exceeding 30,000 µm.
• Survival Analysis: Patients with DIHI had significantly lower recurrence-free survival (RFS) and overall survival (OS) rates compared to those without DIHI (p<0.0001 and p=0.0038, respectively). Additionally, RLI patients had significantly lower RFS and OS rates compared to non-RLI patients (p=0.037 and p=0.011, respectively).

5. Liver Lobe Infiltration

The study resected 105 liver lobes from 62 PHCC patients. The infiltration rates of the left lateral lobe, left medial lobe, right anterior lobe, and right posterior lobe were 79%, 100%, 100%, and 69%, respectively. The liver lobe infiltration rate was significantly higher in DIHI patients than in non-DIHI patients.

Conclusions and Significance

This study demonstrates that the presence of DIHI is a significant factor contributing to poor survival in PHCC patients, and arterial invasion on the resected side is a predictor of DIHI. Based on the extent of intrahepatic infiltration, minor hepatectomy is unsuitable as a curative surgery for PHCC, while major hepatectomy and liver transplantation are ideal radical treatments.

Research Highlights

• Innovative Methodology: The introduction of WDLPS overcomes the limitations of traditional pathological techniques, enabling panoramic visualization of intrahepatic infiltration patterns in PHCC and precise measurement of infiltration extent.
• Clinical Implications: The study provides critical pathological evidence for the surgical treatment of PHCC, supporting major hepatectomy and liver transplantation as the preferred radical surgeries.
• Prognostic Prediction: Arterial invasion, as a predictor of DIHI, exhibits high specificity and positive predictive value, which can guide surgical planning and postoperative adjuvant therapy.

Study Limitations

Despite overcoming the limitations of traditional pathological techniques, this study has some limitations: - Small Sample Size: The study included only 62 patients, and future plans involve incorporating data from multiple centers to strengthen the conclusions. - Measurement of Spatial Infiltration Distance: Since DIHI is mainly located in the terminal portal area, millimeter-thick slices cannot fully reconstruct its spatial infiltration distance, potentially leading to partial information loss.

Summary

This study comprehensively assessed the intrahepatic infiltration patterns and extent of PHCC using WDLPS, revealing the significance of DIHI and RLI in PHCC and providing critical pathological evidence for its surgical treatment. The study supports major hepatectomy and liver transplantation as radical treatments for PHCC and offers new indicators for postoperative prognosis prediction.