Gastric-Type Expression Signature in Hepatocellular Carcinoma.

It is known that V-set and immunoglobulin domain containing 1 (VSIG1) is a cell-cell adhesion molecule that can serve as an indicator of better survival in patients with gastric cancer. Its interaction with cytoplasmic thyroid transcription factor 1 (TTF-1) has been hypothesized to characterize gastric-type HCC, but its clinical importance is far from understood. As VSIG1 has also been supposed to be involved in the epithelial-mesenchymal transition (EMT) phenomenon, we checked for the first time in the literature the supposed interaction between VSIG1, TTF-1, and Vimentin (VIM) in HCCs. Immunohistochemical (IHC) stains were performed on 217 paraffin-embedded tissue samples that included tumor cells and normal hepatocytes, which served as positive internal controls. VSIG1 positivity was seen in 113 cases (52.07%). In 71 out of 217 HCCs (32.71%), simultaneous positivity for VSIG1 and TTF-1 was seen, being more specific for G1/G2 carcinomas with a trabecular architecture and a longer OS (p = 0.004). A negative association with VIM was revealed (p < 0.0001). Scirrhous-type HCC proved negative for all three examined markers. The present paper validates the hypothesis of the existence of a gastric-type HCC, which shows a glandular-like architecture and is characterized by double positivity for VSIG1 and TTF-1, vimentin negativity, and a significant OS.

Interaction between cadherins, vimentin, and V-set and immunoglobulin domain containing 1 in gastric-type hepatocellular carcinoma.

In hepatocellular carcinomas (HCCs), the role of the cell surface protein V-set and immunoglobulin domain containing 1 (VSIG1), which is known as a specific marker of the gastric mucosa and testis, has not yet been determined. We examined VSIG1 immunohistochemical (IHC) expression in 105 consecutive samples provided by HCC patients, along with the IHC expression of three of the biomarkers known to be involved in the epithelial-mesenchymal transition (EMT): vimentin (VIM), and E- and N-cadherin (encoded by CDH1 and CDH2 genes). IHC subcellular localization of thyroid transcription factor 1 (TTF1), in which nuclear-to-cytoplasmic translocation is known to cause a lineage shift from lung to gastric-type adenocarcinoma, was also checked. The obtained data were validated using the miRNET program. In the examined HCC samples, VSIG1 expression was observed in the cytoplasm of normal hepatocytes and downregulated in 47 of the 105 HCCs (44.76%). In 29 cases (27.62%), VSIG1 was co-expressed with cytoplasmic TTF1. VSIG1 expression was positively correlated with both E-cadherin and N-cadherin and negatively correlated with VIM (p < 0.0001). The VSIG1+/E-cadherin+/N-cadherin-/VIM phenotype was seen in 13 cases (12.4%) and was characteristic of well-differentiated (G1/2) carcinomas diagnosed in pT1/2 stages. Like pulmonary carcinomas, simultaneous cytoplasmic positivity of HCC cells for VSIG1 and TTF1 may be a potential indicator of a lineage shift from conventional to gastric-type HCC. The E-cadherin/VSIG1 complex can help suppress tumor growth by limiting HCC dedifferentiation. The miRNET-based interaction between VSIG1/VIM/CDH1/CDH2 genes might be interconnected by miR-200b-3p, a central regulator of EMT which also targets VIM and VSIG1.

Combined hepatocellular-cholangiocarcinoma: from genesis to molecular pathways and therapeutic strategies.

Hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) are the most common primary liver cancers. Little is known about the combined hepatocellular-cholangiocarcinoma (cHCC-ICC) variant and the proper therapeutic strategies. Out of over 1200 available studies about cHCC-ICC, we selected the most representative ones that reflected updated information with application to individualized therapy. Based on literature data and own experience, we hypothesize that two molecular groups of cHCC-ICC can be identified. The proposed division might have a significant therapeutic role. Most cases develop, like HCC, on a background of cirrhosis and hepatitis and share characteristics with HCC; thus, they are named HCC-type cHCC-ICC and therapeutic strategies might be like those for HCC. This review also highlights a new carcinogenic perspective and identifies, based on literature data and the own experience, a second variant of cHCC-ICC called ICC-type cHCC-ICC. Contrary to HCC, these cases show a tendency for lymph node metastases and ICC components in the metastatic tissues. No guidelines have been established yet for such cases. Individualized therapy should be, however, oriented toward the immunoprofile of the primary tumor and metastatic cells, and different therapeutic strategies should be used in patients with HCC- versus ICC-type cHCC-ICC.

Benefits of the 8th American Joint Committee on Cancer System for Hepatocellular Carcinoma Staging.

PURPOSE: We aimed to emphasize the prognostic impact of differences included in the 8th versus the previous 7th edition of AJCC (American Joint Committee on Cancer) Cancer Staging manual for hepatocellular carcinoma (HCC). METHODS: A number of 87 consecutive HCCs were retrospectively evaluated and staged, using the 7th and 8th edition of AJCC staging systems. The clinicopathological parameters were correlated with the overall survival rate. No preoperative chemotherapy was received by any of the patients. RESULTS: According to the 7th edition of AJCC manual, 52 of the 87 cases were staged as pT2 and 35 as pT1. After restaging, according to the 8th edition, 23 of the 52 pT2 cases were understaged as pT1b, and the rest of the 29 remained as pT2. Regarding the 35 HCCs classified as pT1, using 7th edition, all of them were restaged as pT1a. Compared to the 7th staging system, using the 8th edition of AJCC manual, the percentage of pT2 tumors significantly decreased, from 59.77 to 33.33%. The patient's gender, age, tumor focality, and grade of differentiation did not prove to have any prognostic value. Regarding pT stage, it does not influence the overall survival rate, independently from the used staging system. CONCLUSION: The staging criteria, in the most recent edition of AJCC, are simplified and allowed tumor understaging. These changes do not have independent prognostic value. The prognostic impact of pT understaging should be evaluated in larger cohorts.

Maspin subcellular expression in wild-type and mutant TP53 gastric cancers.

BACKGROUND: Although the role of p53 in the evolution and prognosis of gastric cancer (GC) has been extensively examined, the exact mechanism of action is incompletely understood. In the last years, p53-target genes were supposed to be involved in the p53 pathway. One of them is the tumor-suppressor gene Maspin, which codifies the protein with the same name. Maspin activity depends on its subcellular localization. To our knowledge, the possible role of TP53 gene in Maspin subcellular localization, in GC cells, has not yet been studied in a large number of human samples. AIM: To evaluate the possible role of wild-type and mutated p53 in Maspin subcellular localization. METHODS: The present study included 266 consecutive patients with GC in which TP53 gene status, and mutations in exons 2 to 11, respectively, were analyzed and correlated with immunohistochemical expression of p53 and Maspin. RESULTS: None of the 266 cases showed mutations in exon 9. The rate of TP53 mutations was 33.83%. The mutation rate was slightly higher in distally-located GCs, with a lower degree (≤ 5 buds/ high power fields) of dyscohesivity (P < 0.01). The wild-type cases had a longer survival, compared with mutant GCs, especially in patients without lymph node metastases, despite the high depth of tumor infiltration (P = 0.01). The Dukes-MAC-like staging system was proved to have the most significant independent prognostic value (P < 0.01). The statistical correlations proved that TP53 gene mutations in exon 7 might induce knockdown of Maspin, but wild-type p53 can partially restore nuclear Maspin expression and decrease the metastatic potential of gastric adenocarcinoma cells. CONCLUSION: Downregulated Maspin might be induced by mutations in exon 7 of the TP53 gene but wild-type p53 can partially restore nuclear Maspin expression. These findings should be proved in experimental studies.

Primary rhabdomyosarcoma: An extremely rare and aggressive variant of male breast cancer.

BACKGROUND: Rhabdomyosarcoma (RMS) of the breast, a mesenchymal neoplasm with skeletal muscle differentiation, is an extremely rare tumour in males, with less than 30 cases published in English-language literature. We report on the first case of a male breast RMS, with an unusual ectomesenchymal/neuroectodermal component. CASE SUMMARY: A 55-year-old, previously healthy male, underwent a radical left mastectomy for an ulcerated tumour mass, occupying the breast and left anterior thoracic wall. The biopsy specimen indicated the presence of a tumour with neural origins, namely a peripheral neuroectodermal tumour (PNET). The surgical specimens identified two components. The rhabdomyosarcomatous component (over 70%) was represented by large pleomorphic cells with positivity for desmin, sarcomeric actin and myogenin. The PNET-like ectomesenchymal component, which was admixed with the RMS cells, and was also revealed during the preoperative biopsy, consisted of small cells which expressed neurofilament, neuron specific enolase and CD99. The microscopic examination, along with the immunohistochemical profile, allowed the diagnosis of an RMS, with unusual ectomesenchymal differentiation. The patient refused the postoperative oncologic therapy and died three months after surgery. CONCLUSION: In patients with RMS of the breast, the PNET-like ectomesenchymal component increases the diagnosis difficulty, especially in biopsy specimens. This differentiation can be immunohistochemically proven and might highlight the possible development of high-grade sarcoma of the breast from remnants of the embryological ectodermal layer.

Primary gastric choriocarcinoma - a rare and aggressive tumor with multilineage differentiation: A case report.

BACKGROUND: Primary choriocarcinoma of the stomach (PCCS) is a rare tumor, with fewer than 60 cases published in the English-language literature up to December 2018. In this paper, we present the complex immunoprofile of one PCCS and a hypothesis regarding its histogenesis. CASE SUMMARY: A 66-year-old previously healthy male underwent an emergency palliative gastrectomy for a gastric obstructive tumor. The histologic examination and immunoprofile of tumor cells showed a mixed tumor that consisted of choriocarcinoma (90%) and moderate differentiated adenocarcinoma (10%), with hepatic metastases (Stage pT2NxM1L1V1R0) and microsatelite stable status. The patient died one month after surgery. The tumor cells showed focal positivity for CDX2 (adenocarcinoma component), HCG (choriocarcinoma) and CD138 (plasmacytoid carcinoma component) and were negative for HER-2, α-fetoprotein, VEGF, maspin and markers of epithelial-mesenchymal transition. The gastric mucosa cells displayed positivity for CDX2, Hepar A and CD138. The complex immunoprofile and literature data synthesis prove that the gastric mucosa cells can present a multilineage differentiation. CONCLUSION: PCCS should be considered as an aggressive variant of microsatellite stable gastric adenocarcinoma of an epithelial type, and not a germ cell tumor.