Histologic growth pattern of hepatocellular carcinoma: Relationship to orcein(hepatitis B surface antigen)-positive cells in cancer tissue

Nakashima, Toshiro; Kojiro, Masamichi; Kawano, Yoshiro; Shirai, Fumio; Takemoto, Norishige; Tomimatsu, Hisanobu; Kawasaki, Hiroshi; Okuda, Kunio

doi:10.1016/s0046-8177(82)80272-4

Cited by 77 publications

(28 citation statements)

References 18 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Based on histopathological criteria defined for liver metastases and HCCs (13,29), we observed that control and sensitive tumors had a predominantly ‘pushing’ growth pattern characterized by compression of the hepatocyte plates parallel to the tumor-liver interface (Figure 4A). By early resistance, the tumor growth pattern became highly infiltrative.…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Co-option of Liver Vessels and Not Sprouting Angiogenesis Drives Acquired Sorafenib Resistance in Hepatocellular Carcinoma

Kuczynski

Yin

Bar‐Zion

et al. 2016

JNCI J Natl Cancer Inst

152

153

View full text Add to dashboard Cite

Background: The anti-angiogenic Sorafenib is the only approved systemic therapy for advanced hepatocellular carcinoma (HCC). However, acquired resistance limits its efficacy. An emerging theory to explain intrinsic resistance to other anti-angiogenic drugs is ‘vessel co-option,’ ie, the ability of tumors to hijack the existing vasculature in organs such as the lungs or liver, thus limiting the need for sprouting angiogenesis. Vessel co-option has not been evaluated as a potential mechanism for acquired resistance to anti-angiogenic agents.Methods: To study sorafenib resistance mechanisms, we used an orthotopic human HCC model (n = 4-11 per group), where tumor cells are tagged with a secreted protein biomarker to monitor disease burden and response to therapy. Histopathology, vessel perfusion assessed by contrast-enhanced ultrasound, and miRNA sequencing and quantitative real-time polymerase chain reaction were used to monitor changes in tumor biology.Results: While sorafenib initially inhibited angiogenesis and stabilized tumor growth, no angiogenic ‘rebound’ effect was observed during development of resistance unless therapy was stopped. Instead, resistant tumors became more locally infiltrative, which facilitated extensive incorporation of liver parenchyma and the co-option of liver-associated vessels. Up to 75% (±10.9%) of total vessels were provided by vessel co-option in resistant tumors relative to 23.3% (±10.3%) in untreated controls. miRNA sequencing implicated pro-invasive signaling and epithelial-to-mesenchymal-like transition during resistance development while functional imaging further supported a shift from angiogenesis to vessel co-option.Conclusions: This is the first documentation of vessel co-option as a mechanism of acquired resistance to anti-angiogenic therapy and could have important implications including the potential therapeutic benefits of targeting vessel co-option in conjunction with vascular endothelial growth factor receptor signaling.

show abstract

Section: Resultsmentioning

confidence: 99%

“…A second limitation is the lack of corroborating data suggesting that vessel co-option occurs clinically in sorafenib-resistant HCC patients. A ‘replacement’ growth pattern in which sinusoidal vessels are co-opted by infiltrating HCC cells has been observed in HCC patients (29,42). …”

Section: Discussionmentioning

confidence: 99%

Co-option of Liver Vessels and Not Sprouting Angiogenesis Drives Acquired Sorafenib Resistance in Hepatocellular Carcinoma

Kuczynski

Yin

Bar‐Zion

et al. 2016

JNCI J Natl Cancer Inst

152

153

View full text Add to dashboard Cite

show abstract

“…The latter comprised hepatocytes showing nuclear atypia relative to surrounding liver and irregular or sparse portal tracts. Atypical nodules were histologically heterogeneous, with areas of normotrabecular, compact, pseudoglandular and/or scirrhous patterns and showed expansive or replacing growth (or both) (202) into the surrounding liver. Atypical hepatocytes also infiltrate the fibrous septa and portal tracts.…”

Section: Histopathology Of Early Hccmentioning

confidence: 99%

Hepatocellular Carcinoma: Recent Progress

1992

Self Cite

View full text Add to dashboard Cite

HCC is not a major killer among malignant diseases in Western countries, and until recently few Western hepatologists were interested in this cancer. After the demonstration of an etiologic role for HBV infection in hepatocarcinogenesis, interest surged even in lowincidence countries, particularly among molecular biologists and oncologists. A large body of literature now exists dealing with molecular mechanism in HBVrelated human HCC and hepadnavirus-induced HCC in animals. The recent identification and cloning of hepatitis C virus (HCV) has focused interest on chronic C hepatitis which, under the name of non-A, non-B (NANB) hepatitis, had for some time been suspected as another etiological factor for HCC in certain areas of the world. It did not take long before well-documented evidence linked HCV to HCC. Imaging diagnosis of small-mass lesions in the liver has progressed remarkably in recent years, as emphasized in a previous review in this JOURNAL (1). In countries where detection and resection of small HCCs in cirrhotic livers are common practice, pathologists are discussing how to differentiate large, benign, hyperplastic nodules; adenomatous hyperplastic nodules with potential to transform; and early HCC lesions histopathologically. Radiologists are attempting to make similar diagnostic distinction by imaging alone with limited success. This review attempts to update the recent progress made in the basic study of HCC. EPIDEMIOLOGY AND ETIOLOGYAccording to Muiioz and Bosch (2), no clear indication of a change has appeared in the incidence rate of HCC in developed Western countries in the past 20 yr or so as far as cancer registry data are concerned. However, in Japan, incidence of HCC began to increase about 20 yr ago; the increase was accounted for by non-HBV-related cases, and an etiologic role of chronic NANB hepatitis was suspected in the early 1980s (3). All cancer registries in Japan have clearly shown significant increases in HCC because of non-HBV-related cases. HBsAgpositive patients accounted for more than 40% of all HCC cases in the early 1970s, when testing was by the immunoprecipitation techniques. This figure is currently less than 20% as tested by the much more sensitive methods (4). At the autopsy table, the numbers of patients with HCC and of those with cirrhosis alone were about the same in early 1960s, but HCC now far exceeds cirrhosis in number. The frequency of complicating HCC among all cirrhotic livers autopsied used to be 20% to 40% and is currently about 80% (5). A similar trend of increase has been observed among autopsies in northern Italy (6) and the United States (7). A number of studies in Japan have shown that the frequency with which HCC develops in cirrhotic patients during follow-up is more than 6%/yr (8) among all cirrhotic patients. In a recent study in northern Italy, HCC developed in 29 (7%) of 417 patients with cirrhosis (62% viral) during follow-up periods averaging 33 mo (9).Shortly after the identification of HCV by the group at Chiron Laboratories and the developmen...

show abstract

“…In those tumors, as the arterial tumor vessels (unpaired artery) and sinusoidal vascularization are not well developed, most of them are not hypervascular at angiography [9][10][11][12][13]. Well-differentiated cancer cells proliferate as if they are replacing the liver cell cords at the tumor-nontumor boundary (replacing growth pattern) [14]. Histologic features of well-differentiated HCC of the early stage are characterized by increased cell density with an increased nuclear to cytoplasm ratio and irregular thin-trabecular pattern, frequent pseudoglandular pattern and frequent fatty change.…”

Section: Pathomorphologic Characteristics Of Small Hcc In the Early Smentioning

confidence: 99%

‘Nodule-in-Nodule’ Appearance in Hepatocellular Carcinoma: Its Significance as a Morphologic Marker of Dedifferentiation

Kojiro¹

2004

Intervirology

Self Cite

View full text Add to dashboard Cite

Small hepatocellular carcinoma (HCC) of the early stage can be divided into 2 types: small nodular HCC with distinct margins and small HCC with indistinct margins. The latter consists uniformly of well-differentiated cancerous tissue with a replacing growth at the boundary, and many portal tracts are retained in the tumor. When such tumors reach around 1.5–2.0 cm in diameter, moderately or poorly differentiated cancer tissues develop within the well-differentiated cancer tissue, and well-differentiated cancerous tissues are replaced by less differentiated cancerous tissues. Such a dedifferentiation seems to be closely related to tumor proliferation. When less differentiated cancerous tissues within the well-differentiated cancer nodules proliferate in an expansive fashion, a ‘nodule-in-nodule’ appearance is frequently seen. Thus, a ‘nodule-in-nodule’ appearance in early-stage HCC could be interpreted as a morphologic marker of dedifferentiation of early HCC.

show abstract

Histologic growth pattern of hepatocellular carcinoma: Relationship to orcein(hepatitis B surface antigen)-positive cells in cancer tissue

Cited by 77 publications

References 18 publications

Co-option of Liver Vessels and Not Sprouting Angiogenesis Drives Acquired Sorafenib Resistance in Hepatocellular Carcinoma

Co-option of Liver Vessels and Not Sprouting Angiogenesis Drives Acquired Sorafenib Resistance in Hepatocellular Carcinoma

Hepatocellular Carcinoma: Recent Progress

‘Nodule-in-Nodule’ Appearance in Hepatocellular Carcinoma: Its Significance as a Morphologic Marker of Dedifferentiation

Contact Info

Product

Resources

About