In an effort to ensure the accuracy of pathological diagnosis, a standardized process of pathological examination is required to provide a valuable frame of reference for the clinical assessment of the risk of postoperative recurrence, long-term prognosis, as well as individualized treatment regimens. However, most current practice guidelines for PLC focus on the clinical treatment[ 3 , 4 ]. To our best knowledge, no consensus guidelines for the pathological diagnosis of PLC have ever been published. The lack of such guidelines has led to many contradictions and inconsistencies in the pathological characteristics and diagnostic criteria for PLC.
To address this gap, Chinese pathologists developed an expert consensus on the pathological diagnosis of PLC in [ 5 ]. Since the development of these guidelines, much progress in the clinical management and pathological assessment of PLC has yielded many new concepts, such as tumor heterogeneity, pathobiological characteristics, molecular classification, personalized therapy and precision medicine, etc.
The inclusion of these new concepts has become the cornerstone for the clinical management of PLC, placing greater demands on more stringent criteria and standards for hepatic pathological diagnosis. Therefore, in April 18, , under the guidance of renowned academicians Prof. Wu Meng-Chao, Prof.
Tang Zhao-You and Prof. Liu Tong-Hua, a Guideline Committee consisting of 40 specialists supplementary materials from Chinese Pathology, Surgery, Hepatology and Oncology Societies was created for the formulation of updated guidelines for the standardization of the pathological diagnosis of PLC. To meet these goals, the Guideline Committee organized several seminars for guideline formulation, mainly focusing on the following topics: gross specimen sampling, concepts and diagnostic criteria of small HCC SHCC , microvascular invasion MVI , satellite nodules, immunohistochemical and molecular diagnosis.
The final version of the guidelines was approved at the last Guideline Committee meeting, which was held in February 1, in Shanghai, China. Peritumoral zones are representative of tumor heterogeneity in that they are rich in highly invasive cells, susceptible to the formation of MVI and satellite nodules and, therefore, more likely to impact liver cancer metastasis, postoperative recurrence and prognosis[ 7 , 8 ].
Therefore, sampling around the periphery of tumor tissues is critical for objectively evaluating the biological behaviors of PLC. Regarding tissue fixation, the following recommendations were made to assure the quality of the tissues for pathological and immunopathological examination[ 9 ]. The surgical margin, suspected lesions, important vessels and bile duct margin should be marked with a dye or suture by surgeons. Small resected tissues, such as lymph nodes, should be placed into different containers and labeled with corresponding descriptions; 2 to maximally preserve the integrity of intracellular nucleic acids and proteins for avoiding autocytolysis, tumor specimens should be transferred to the Department of Pathology as soon as possible after resection, ideally within 30 min after surgical removal for sectioning and fixation[ 10 ]; 3 the fresh specimens should be cut consecutively into 1-cm-thick multiple sections at the maximal diameter; a portion should remain unfixed fresh or cryopreserved for molecular examination; and 4 at room temperature, tissues should be fixed in a neutral formalin solution v:v, for h and embedded in paraffin.
Recommendations: 1 Hepatic tumor samples should be collected using the 7-point baseline sampling protocol; 2 the location and number of liver tissues collected should be determined as appropriate according to the size, shape and number of the liver tumors as well as the adjacent liver tissues; 3 because the detection rate of MVI and satellite nodules is related to the extent of adjacent liver tissues, it is necessary to describe the size of the adjacent liver tissues, and the suspected lesions should be sampled after reviewing several sections C, I ; and 4 when the tumor tissue is close to the surgical margin, sampling should be done at the region vertical to the margin closest to the cancer.
When the tumor tissue is far away from the surgical margin, sampling should be done parallel to the surgical margin. The status of the surgical margin should be determined using the section with maximal area C, I. In the description of general hepatic tissue characteristics, pathologists should emphasize the size, number, color and texture of the tumor, its relationship with blood vessels and the bile duct, tumor capsule, tumor involvement, peripheral liver lesions, type of hepatic cirrhosis, the shortest distance between the tumor and surgical margin, and the status of the surgical margin.
For tumor tissues with atypical morphology, the tissues should be photographed. According to the classification system proposed by the World Health Organization WHO , ICCs are classified as mass-forming, periductal-infiltrating, and intraductal growth[ 14 ]. However, the definition of SHCC varies greatly by international criteria - from 2 cm to 5 cm in diameter[ 15 ]. Studies indicating that HCC growing near to or larger than 3 cm in diameter is an important turning point in the transformation of a tumor from having relatively benign features to more aggressive behaviors[ 16 , 17 ].
Thus, radical therapy should be initiated at an early stage before the tumor becomes highly invasive B, I ; and 2 in a small number of cases, SHCC may be poorly differentiated, invasive, or containing MVI and satellite nodules, which is indicative of highly malignant behavior. Previous studies have described the analysis of microscopic tissue characteristics that include the following[ 14 , 23 ]: 1 histological types of HCC, including common histological types e.
Although there are many systems for grading and staging chronic viral hepatitis[ 24 - 29 ], a simple histologic scoring system is recommended for routine pathological diagnosis, such as the Scheuer scoring system, etc. Liver cell dysplasia refers to either large cellular changes, including increased cellular and nuclear volumes, nuclear pleomorphism, hyperchromatic chromatin and multinucleation, and small cellular changes, including decreased cell volume, increased nuclear-to-cytoplasm ratio with mild pleomorphism and hyperchromasia, but showing crowded nuclei.
LGDN is a nodule mainly comprising large cellular changes without obvious atypia, isolated interstitial arteries, or expansive growth patterns. In contrast, HGDN is composed of small cellular changes with increased atypia, isolated interstitial arteries, and expansive growth.
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BilIN is usually graded as BilIN-1 low-grade lesions , BilIN-2 intermediate-grade lesions , and BilIN-3 high-grade lesions or carcinoma in situ , according to the degree of nuclear atypia observed in biliary epithelial cells. IPBN refers to tubular papillary tumors with growth confined to the bile duct lumen.
Recommendations: It is important to conduct a differential diagnosis between HGDN and well-differentiated SHCC, the latter of which may manifest morphologically as varying degrees of increased cellular density and nuclear-to-cytoplasmic ratio, widened trabecular space, pseudoglandular structures, infiltrative growth, increased MVD as assessed by CD34 staining, higher Ki index, and positive expression of p53 and glypican-3 GPC-3 , etc B, I. MVI is also known as microvascular cancer embolus and refers to the cancer cell nest in vessels lined with endothelial cells.
MVI is most frequently found in the small branches of the portal vein in the adjacent liver tissues including vessels of the cancer capsule because these vessels are the major ones exiting the tumor, as the portal vein shows disordered hemodynamics[ 34 , 35 ]. Branches of the hepatic vein are the secondary vessels exiting the tumor and may also develop MVI. Occasionally, the hepatic tumor may invade the hepatic artery, bile duct and lymphatic vessels, which should be reported independently[ 33 , 36 ].
Clinical studies indicate that MVI is related to poor prognosis in patients with HCC, including increased risk for postoperative recurrence and reduced long-term survival. In patients with HCC, a correlation between higher MVI grade and shorter disease-specific survival and recurrence-free survival has been noted[ 37 ]. Furthermore, Pawlik et al[ 39 ] found that the occurrence of MVI was positively correlated with the size of HCC, suggesting that the size and number of tumors are important predictive indices for MVI.
Satellite nodules refer to the macroscopic or microscopic tumor cell nests located around or near, but separated from the main tumor with similar histological features as observed in the primary tumor. Generally, satellite nodules are derived from MVI. While difficult to distinguish from each other histologically, a diagnosis of satellite nodules is appropriate.
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Moreover, the presence of satellite nodules is also an important predictor of postoperative recurrence[ 42 ]. The presence of MVI and satellite nodules may also provide a reference for the selection of clinical therapeutic modules.
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For example, Meniconi et al[ 43 ] found that in the absence of MVI and satellite nodules in the first resected HCC, a second hepatectomy or radiofrequency ablation for early intrahepatic recurrence predicted a better overall survival as compared to hepatic arterial chemoembolization. Pathological diagnosis of satellite nodules should include the following pathological parameters[ 44 ]: 1 number; 2 distribution and extent; and 3 presence of cancerous nodes in the distant adjacent liver tissues, including multinodular HCC MNHCC , which may represent either intrahepatic metastases or de novo HCC arising from a polycentric origin.
Molecular cloning detection may then be helpful to elucidate the origin of the satellite nodules B, I. Regarding the diagnosis of hepatic space-occupying lesions, a gauge puncture needle is usually used to obtain a biopsy specimen containing junctional areas between the tumor and peritumoral zones or one from each zone. A relatively longer biopsy sample is required for the assessment of the degree of hepatic fibrosis or cirrhosis in the setting of chronic viral hepatitis.
The appropriate tissue length should be longer than 1. Although Hep Par-1, CD10, arginase-1 and pCEA are hepatocyte-specific antigens, they cannot be used to distinguish benign and malignant hepatocellular tumors[ 47 ]. For the immunohistochemical diagnosis of ICC, staining with antibodies specific for biliary cytokeratins, such as CK19, CK7 and mucin-1, is commonly employed.
Although some reported biomarkers may aid in the evaluation and prediction of certain biological features of liver cancer, including risk for invasiveness, recurrence and long-term survival[ 50 , 51 ], but further studies are required to confirm their clinical importance in multiple patient populations.
For instance, a diffuse staining pattern is indicative for HCC, a scattered staining pattern for ICC, a patchy staining pattern for HCA, and a cord-like staining pattern for focal nodular hyperplasia, etc B, I. Development of molecular classification techniques, including the detection of molecular targets and assessment of clonal origin, represents a promising new development in the field. Although many new systems based on molecular typing and predictive biomarkers have been reported in the literature[ 52 ], validation of their clinical significance is still required through the use of controlled studies across multiple centers with large sample sizes.
Specifically, the selection, detection and clinical significance of molecular targets for targeted drug therapy for PLC are still under investigation, but the results of preliminary clinical trials are worthy of high expectations[ 53 , 54 ]. Regarding risk evaluation of precancerous lesions, molecular identification may be better suited than histopathological evaluation to detect the genomic instability for hepatocarcinogenesis and impact of clinical treatment modalities for patients with precancerous lesions, such as HGDN and HCA[ 55 ].
Molecular pathology detection is conducive to optimization and choice of clinical treatment modalities[ 56 ]. Based on the clonal origin theory, a RHCC may originate from either a monocentric monoclonal origin or multicentric polyclonal origin. Theoretically, interventional therapy and targeted drug therapy are more suitable for RHCC that originate from residual cancer cells monoclonal origin after initial tumor resection, while repeated resections or liver transplantation are more appropriate for RHCC of multicentric origin that resembles a new primary tumor arising from a de novo tumor clone[ 57 ].
Although other researchers have proposed histological criteria for the clonal evaluation of RHCC[ 59 ], the accuracy of such morphological criteria requires further validation of the molecular detection. Finkelstein et al[ 60 ] reported that postoperative survival after LT was significantly better in patients with multicentric MNHCC than in those with monocentric MNHCC, indicating that genotyping has the potential to serve as a reference for LT recipient screening and prognostic evaluation.
Gehrau et al[ 61 ] also recommended a diagnostic and therapeutic roadmap based on the clonal detection of MNHCC that would assist with patient selection for LT. Specifically, patients with MNHCC derived from multicentric origins could be ranked in the waiting lists to receive a LT, while those patients with monocentric MNHCC would be better suited for interventional treatment or targeted drug therapy using sorafenib[ 61 ]. A standardized pathological diagnostic process is the first precondition required for a correct pathological diagnosis, scientific clinical decision-making and precision treatment of PLC from the origin.
Considering the high prevalence of PLC worldwide, especially in China, we report updated guidelines for pathological diagnosis of PLC, which includes standardized guidelines for specimen fixation, 7-point baseline sampling protocol and examination, a grading system for MVI in a routine pathology diagnosis, and immunohistochemical diagnostic panels, as well as molecular diagnostic principles, such as the importance of clonal typing of RHCC and MNHCC for determining therapeutic strategy and evaluating clinical prognosis.
Manuscript source: Unsolicited manuscript. Specialty type: Gastroenterology and hepatology.
Surgical Pathology of Liver Tumors
Country of origin: China. Peer-review report classification. Grade A Excellent : 0. Grade B Very good : B, B. Conflict-of-interest statement: The authors declare that they have no conflicts of interest related to this work.
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Peer-review started: March 3, First decision: April 14, Article in press: August 8, National Center for Biotechnology Information , U. Journal List World J Gastroenterol v. World J Gastroenterol. Published online Nov Author information Article notes Copyright and License information Disclaimer. Published by Baishideng Publishing Group Inc. All rights reserved.
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. This article has been cited by other articles in PMC. Abstract In , a panel of Chinese pathologists reported the first expert consensus for the pathological diagnosis of primary liver cancers to address the many contradictions and inconsistencies in the pathological characteristics and diagnostic criteria for PLC. Keywords: Liver cancer, Hepatocellular carcinoma, Intrahepatic cholangiocarcinoma, Practice guidelines, Pathology, Diagnosis.
Table 1 Grades of evidence and classes of recommendations. Open in a separate window.
Figure 1. Description of macroscopic characteristics and clinical significance of SHCC In the description of general hepatic tissue characteristics, pathologists should emphasize the size, number, color and texture of the tumor, its relationship with blood vessels and the bile duct, tumor capsule, tumor involvement, peripheral liver lesions, type of hepatic cirrhosis, the shortest distance between the tumor and surgical margin, and the status of the surgical margin. Description of microscopic characteristics Previous studies have described the analysis of microscopic tissue characteristics that include the following[ 14 , 23 ]: 1 histological types of HCC, including common histological types e.
Description of precancerous lesions The main types of precancerous HCC lesions include the following[ 23 , 31 , 32 ]: liver cell dysplasia, dysplastic foci, low-grade dysplastic nodule LGDN , and high-grade dysplastic nodule HGDN. Recommendations Pathological diagnosis of satellite nodules should include the following pathological parameters[ 44 ]: 1 number; 2 distribution and extent; and 3 presence of cancerous nodes in the distant adjacent liver tissues, including multinodular HCC MNHCC , which may represent either intrahepatic metastases or de novo HCC arising from a polycentric origin.
Recommendations 1 Currently used biomarkers for liver cancer are somewhat imperfect in their diagnostic specificity and sensitivity; thus, a biomarker panel in combination with other tissue-specific markers could represent a useful tool for diagnosis and differential diagnosis between benign and malignant hepatocellular tumors, HCC and ICC, other specific types of hepatic tumors, and primary and metastatic liver cancer B, I ; and 2 although immunohistochemical staining for CD34 does not directly label hepatic parenchymal cells, it is valuable for determining the extent of MVD and examining its unique distribution pattern in different liver tumors.
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