The application of markers (HSP70 GPC3 and GS) in liver biopsies is useful for detection of hepatocellular carcinoma

Di Tommaso, Luca,Destro, Annarita,Seok, Jae Yeon,Balladore, Emanuela,Terracciano, Luigi,Sangiovanni, Angelo,Iavarone, Massimo,Colombo, Massimo,Jang, Ja June,Yu, Eunsil,Jin, So Young,Morenghi, Emanuela Elsevier 2009 Journal of hepatology Vol.50 No.4

<P><B>Background/Aims</B></P><P>Liver biopsy for hepatocellular carcinoma (HCC) detection is largely restricted to small hepatocellular lesions, which are often morphologically challenging, requiring careful distinction between dysplastic nodules (high-grade) and well-differentiated HCC.</P><P><B>Methods</B></P><P>We investigated the diagnostic accuracy of a panel of markers (HSP70 GPC3 and GS), previously tested in resection specimens, in a series of liver biopsies of large regenerative nodules (<I>n</I>=13), low-grade dysplastic nodules (<I>n</I>=21), high-grade dysplastic nodules (<I>n</I>=50), very well-differentiated (VWD) (<I>n</I>=17), well-differentiated (WD-G1) (<I>n</I>=40) and G2-3 (<I>n</I>=35) HCC.</P><P><B>Results</B></P><P>Almost all cases of large regenerative and low-grade dysplastic nodules did not stain while high-grade dysplastic nodules showed 1 marker (22%) but never 2 or 3. For HCC detection the overall accuracy of marker combination was 60.8% (3 markers) and 78.4% (2 markers) with 100% specificity. When restricted to VWD+WD-G1 HCC the accuracy was 57% (3 markers) and 72.9% (2 markers) with 100% specificity.</P><P><B>Conclusions</B></P><P>This panel proved useful to detect well-differentiated HCC in biopsy. Two immunoreactive markers (out of 3) are recommended as the most valuable diagnostic combination for HCC detection. The diagnostic accuracy of the panel could be improved using additional markers, as suggested by studies of expression profiling in other human models.</P>

Diagnostic value of HSP70, glypican 3, and glutamine synthetase in hepatocellular nodules in cirrhosis

Di Tommaso, Luca,Franchi, Giada,Park, Young Nyun,Fiamengo, Barbara,Destro, Annarita,Morenghi, Emanuela,Montorsi, Marco,Torzilli, Guido,Tommasini, Maurizio,Terracciano, Luigi,Tornillo, Luigi,Vecchione, Wiley Subscription Services, Inc., A Wiley Company 2007 Hepatology Vol.45 No.3

<P>Hepatocellular nodules in cirrhosis include regenerative (large regenerative, LRN) and dysplastic (low and high grade, LGDN and HGDN) nodules, early and grade 1 HCC (eHCC-G1), and overt HCC. The differential diagnosis may be particularly difficult when lesions such as HGDN and eHCC-G1 are involved. We investigated the diagnostic yield of a panel of 3 putative markers of hepatocellular malignancy such as HSP70, glypican 3 (GPC3), and glutamine synthetase (GS). We selected 52 surgically removed nonmalignant nodules (15 LRNs, 15 LGDNs, 22 HGDNs) and 53 HCCs (10 early, 22 grade 1, and 21 grade 2-3) and immunostained them for HSP70, GPC3, and GS. The sensitivity and specificity of the individual markers for the detection of eHCC-G1 were 59% and 86% for GS, 69% and 91% for GPC3, and 78% and 95% for HSP70. We identified 2 main phenotypes: (1) all negative, seen in 100% LRN and LGDN, 73% HGDN and 3% eHCC-G1; (2) all positive, a feature detected in less than half the eHCC-G1. Using a 3-marker panel, when at least 2 of them, regardless which, were positive, the sensitivity and specificity for the detection of eHCC-G1 were respectively 72% and 100%; the most sensitive combination was HSP70+/GPC3+ (59%) when a 2-marker panel was used. Conclusion: The adopted panel of 3 markers is very helpful in distinguishing eHCC-G1 from dysplastic nodules arising in cirrhosis. (HEPATOLOGY 2007;45:725–734.)</P>

Benign hepatocellular nodules of healthy liver: focal nodular hyperplasia and hepatocellular adenoma

( Massimo Roncalli ),( Amedeo Sciarra ),( Luca Di Tommaso ) 대한간학회 2016 Clinical and Molecular Hepatology(대한간학회지) Vol.22 No.2

Owing to the progress of imaging techniques, benign hepatocellular nodules are increasingly discovered in the clinical practice. This group of lesions mostly arises in the context of a putatively normal healthy liver and includes either pseudotumoral and tumoral nodules. Focal nodular hyperplasia and hepatocellular adenoma are prototypical examples of these two categories of nodules. In this review we aim to report the main pathological criteria of differential diagnosis between focal nodular hyperplasia and hepatocellular adenoma, which mainly rests upon morphological and phenotypical features. We also emphasize that for a correct diagnosis the clinical context such as sex, age, assumption of oral contraceptives, associated metabolic or vascular disturbances is of paramount importance. While focal nodular hyperplasia is a single entity epidemiologically more frequent than adenoma, the latter is representative of a more heterogeneous group which has been recently and extensively characterized from a clinical, morphological, phenotypical and molecular profile. The use of the liver biopsy in addition to imaging and the clinical context are important diagnostic tools of these lesions. In this review we will survey their systematic pathobiology and propose a diagnostic algorithm helpful to increase the diagnostic accuracy of not dedicated liver pathologists. The differential diagnosis between so-called typical and atypical adenoma and well differentiated hepatocellular carcinoma will also be discussed. (Clin Mol Hepatol 2016;22:199-211)

A clinical and pathological update on hepatocellular carcinoma

( Salvatore Lorenzo Renne ),( Luca Di Tommaso ) 대한간암학회 2022 대한간암학회지 Vol.22 No.1

It is estimated that more than 1 million individuals will be affected annually by hepatocellular carcinoma (HCC) by 2025. HCC can be broadly grouped into two major molecular subgroups, each of which is characterized by specific morphological and phenotypic features that mirror the genetic background. The use of these tissue biomarkers in the daily practice of pathologists promises to better allocate patients with HCC with adequate treatments. In turn, this will likely boost the attitude of clinicians toward obtaining a pre-treatment biopsy. (J Liver Cancer 2022;22:14-22)

Ductular reaction is helpful in defining early stromal invasion, small hepatocellular carcinomas, and dysplastic nodules

Park, Young Nyun,Kojiro, Masamichi,Di Tommaso, Luca,Dhillon, Amar P.,Kondo, Fukuo,Nakano, Masayuki,Sakamoto, Michiie,Theise, Neil D.,Roncalli, Massimo John Wiley & Sons 2007 Cancer Vol.109 No.5

<B>BACKGROUND.</B><P>Stromal invasion is 1 of the main features used to distinguish high-grade dysplastic nodules (DNs) from well-differentiated hepatocellular carcinomas (HCCs). The authors hypothesized that ductular reaction (DR) takes place around noninvasive hepatocellular nodules but not within the stroma contiguous to invasive HCC.</P><B>METHODS.</B><P>DR/cytokeratin 7 (CK7)-positive patterns were evaluated in 105 resected small hepatic nodules according to the level of invasion. The nodules were classified histologically prior to immunostaining as noninvasive (large regenerative nodules, low-grade DNs, and high-grade DNs), minimally invasive (early HCCs with a vaguely nodular type), and overtly invasive (typical HCCs with a distinctly nodular type) in a review by expert pathologists, the current gold standard. Intranodular DR (inner DR) and DR around the nodule periphery (outer DR) were assessed separately on a semiquantitative scale from 0 to 4+.</P><B>RESULTS.</B><P>DR was 3 or 4+ in the majority of noninvasive nodules (inner DR, 81%; outer DR, 91%), whereas DR was 0 or 1+ in overtly invasive HCCs (inner DR, 96%; outer DR, 81%). Minimally invasive HCCs showed an intermediate DR pattern (2 or 3+ inner DR, 75%; 2+ outer DR, 67%). DR characteristically was absent at the stromal-invasive, leading edge of tumor cells in both minimally invasive HCCs (focal loss of DR/CK7) and overtly invasive HCCs (diffuse loss of DR/CK7). The DR patterns in 41 needle-biopsy samples were similar to the patterns observed in resected nodules.</P><B>CONCLUSIONS.</B><P>DR/CK7 immunostaining may help to identify small foci of invasion and to distinguish noninvasive, high-grade DNs from both minimally invasive and overtly invasive HCCs. Cancer 2007 © 2007 American Cancer Society.</P>

Filamin-A Expression Predicts Recurrence of Mass- Forming Cholangiocarcinoma after Hepatectomy

( Flavio Milana ),( Atteo Donadon ),( Artina Nebbia ),( Ristiana Soldani ),( Barbara Franceschini ),( Michela Anna Polidoro ),( Luca Di Tommaso ),( Ana Lleo De Nalda ),( Guido Torzilli ) 대한간학회 2020 춘·추계 학술대회 (KASL) Vol.2020 No.1

Aims: Recurrence of mass-forming cholangiocarcinoma (MFCCC) after hepatectomy is very high. A predictive marker of recurrence capable of personalizing follow-up and developing new targeted therapy would be beneficial. The overexpression of Filamin-A (FlnA), a cytoskeleton protein with scaffolding properties, has recently been associated with cell signalling, migration and adhesion in different tumors. The aim of this study was to test the expression of FlnA in a cohort of patients operated for MFCCC. Methods: A retrospective cohort of patients who underwent hepatic resection for MFCCC at Humanitas Clinical and Research Center between January 2004 and December 2018 was analyzed. FlnA expression was measured by calculating its intensity score at immunohistochemistry on paraffin-embedded tumor tissue sections for each patient. Such expression was then correlated with prognostic parameter of disease-free survival (DFS) by using survival analyses. Results: A total of 82 patients were considered. Median DFS in patients with low expression of FlnA was significantly increased in comparison with patients with high expression of FlnA (27 months vs. 10 months). Similarly, 5-year DFS was 30.8% vs. 10.9% (P=0.008). At the multivariate analysis number of tumor (HR=2.18; CI95% 1.98-3-21; P=0.004), tumor grade (HR=2.81; CI95% 1.77-5.12; P=0.001) and high expression of FlnA (HR=1.81; CI95% 0.98-2.31; P=.0.005) were found to be independently associated with worse DFS. Conclusions: FlnA expression is associated with higher risk of recurrence of MFCCC after hepatectomy. This finding provides important insights that would help physicians to personalize follow-up strategies and develop targeted therapy.