|Year : 2015 | Volume
| Issue : 3 | Page : 712-717
Hepatocellular carcinoma in cirrhotic and noncirrhotic liver: Clinicopathological differences
Moshira M Abd El-Wahed1, Mohamad T Badr2, El Sayed A Soliman2, Asmaa G Abdou1, Doha M Taie2
1 Department of Pathology, Faculty of Medicine, Menoufyia University, Shebin El Kom, Egypt
2 Department of Pathology, National Liver Institute, Menoufyia University, Shebin El Kom, Egypt
|Date of Submission||03-Apr-2014|
|Date of Acceptance||25-Apr-2014|
|Date of Web Publication||22-Oct-2015|
Doha M Taie
Department of Pathology, National Liver Institute, Menoufyia University, 32511 Shebin El Kom
Source of Support: None, Conflict of Interest: None
The present study aimed to explore the differences between hepatocellular carcinoma (HCC) that arise in cirrhotic and noncirrhotic liver in terms of the demographical, clinical, and pathological parameters.
HCC is the sixth most common cancer worldwide. Its overall incidence has increased progressively in the last two decades. Cirrhosis from any cause remains one of the strongest known risk factors for HCC. However, HCC also occurs in noncirrhotic livers.
Materials and methods
This study investigated the demographical and clinicopathological differences between 86 cases of HCC in cirrhotic liver and 17 cases of HCC in noncirrhotic liver.
The main differences between the groups studied were the predominance of men among the patients with HCC in noncirrhotic livers (P = 0.04) and the large size of the tumor mass in the same group (P = 0.04) in comparison with HCC in cirrhotic livers.
The present study shows that HCCs arising in cirrhotic livers do not differ considerably from those occurring without cirrhosis in most demographical, clinical, and pathological criteria. However, the large size of HCC in noncirrhotic livers could be because of its late detection.
Keywords: Cirrhosis, hepatocellular carcinoma, HCV
|How to cite this article:|
Abd El-Wahed MM, Badr MT, Soliman EA, Abdou AG, Taie DM. Hepatocellular carcinoma in cirrhotic and noncirrhotic liver: Clinicopathological differences. Menoufia Med J 2015;28:712-7
|How to cite this URL:|
Abd El-Wahed MM, Badr MT, Soliman EA, Abdou AG, Taie DM. Hepatocellular carcinoma in cirrhotic and noncirrhotic liver: Clinicopathological differences. Menoufia Med J [serial online] 2015 [cited 2020 Apr 3];28:712-7. Available from: http://www.mmj.eg.net/text.asp?2015/28/3/712/165822
| Introduction|| |
Hepatocellular carcinoma (HCC), the predominant form of primary liver cancer, is the sixth most common cancer worldwide and the third leading cause of cancer-related deaths. Its overall incidence has been increasing over the past two decades in Europe and North America . In Egypt, HCC contributes to 14.8% of all cancer mortality, with a higher incidence in men (17.3%) than in women (11.5%). It is the second most frequent cancer type in Egyptian men after bladder cancer and the eighth most frequent cancer type in Egyptian women ,.
HCC is multifactorial in etiology and complex in pathogenesis. The major risk factor for the development of HCC is liver cirrhosis associated with chronic hepatitis C (HCV) and hepatitis B (HBV) infections, nonalcoholic fatty liver disease, aflatoxin B exposure, alcohol intake, and several metabolic disorders ,. Despite this, not all cirrhotic livers progress to HCC, and tumors may appear at any stage of liver disease ,. Less than 20% of HCC develops in the noncirrhotic liver (HCC-NC) . In high-incidence areas, HCC-NC mostly relates to chronic HBV infection and may occur in children. HBV can be directly oncogenic, leading to HCC through integration of the viral genome into the host genome . In addition, the X protein of HBV is a potent transactivator that can interact with p53, interfering with its tumor-suppressor activity . In part because of these properties of HBV, liver cirrhosis in HBV-infected patients is not a prerequisite for hepatocarcinogenesis . In low-incidence areas, the etiology of HCC-NC is more heterogeneous, including HBV, synthetic gonadal steroids, chemicals, and some metabolic disorders such as glycogen storage disease. The etiology of many cases of HCC-NC is yet to be discovered .
The underlying molecular mechanisms for the differences between these two types of HCC (with and without cirrhosis) are poorly understood .
| Aim|| |
Therefore, the present study aimed to evaluate the differences between HCC in the cirrhotic and noncirrhotic liver in terms of the demographic, clinical, and pathological parameters.
| Patients and methods|| |
This is a retrospective study that included 103 liver specimens obtained surgically by partial hepatectomy from Egyptian patients who presented with HCC. Paraffin blocks of those specimens were retrieved from the Archives of the Pathology Department, National Liver Institute, Menofiya University, during the period between March 2007 and April 2013. The cases were selected randomly on the basis of the availability of paraffin-embedded blocks for serial cutting and histologic examination. According to the presence or absence of cirrhosis, the cases were divided into two groups: (a) HCC in cirrhotic liver (HCC-C). There were 86 HCC specimens including tumorous and nontumorous tissue. (b) HCC in noncirrhotic liver (HCC-NC). Those were 17 HCC specimens including tumorous and nontumorous tissue (excluding liver specimens positive for chronic HBV infection or those diagnosed with fibrolamellar carcinoma). The following data were collected from patients' medical records:
- Age (years).
- Laboratory investigations:
- Serum a-fetoprotein, when available, was recorded as the highest value available within the 6 months before surgical resection .
- Hepatitis C virus antibody (anti-HCV) and hepatitis B virus antibody (anti-HBV), detected by enzyme-linked immunosorbent assay, third generation.
- Computed topography:
- Tumor focality: single or multifocal.
- Tumor size: the greatest dimension in centimeters.
- Tumor site: right lobe, left lobe, or both right and left lobes.
From each representative paraffin block of the cases studied, two 4-μm thick sections were cut; one was stained by hematoxylin and eosin and the other by Masson Trichrome stain to re-evaluate the histopathological findings and to assess the following parameters:
(1) Histopathological type (WHO, 2010) :
- Classical type: divided according to the architectural pattern into:
- Trabecular pattern.
- Pseudoglandular (acinar) pattern.
- Compact (solid) pattern.
- Other histologic subtypes such as schirrous carcinoma, sarcomatoid HCC, clear cell change, undifferentiated carcinoma.
(2) Tumor grading (WHO, 2010) :
- Well differentiated: the lesions are composed of cells with minimal atypia and increased nuclear/cytoplasmic (N/C) ratio in a thin trabecular pattern, with frequent pseudoglandular or acinar structures and frequent fatty change.
- Moderately differentiated: tumor cells are arranged in trabeculae of three or more cells in thickness. Tumor cells have abundant eosinophilic cytoplasm and round nuclei with distinct nucleoli. A pseudoglandular pattern is also frequent, and pseudoglands frequently contain bile or proteinaceous fluid.
- Poorly differentiated: tumors proliferate in a solid pattern without distinct sinusoid-like blood spaces, and only slit-like blood vessels are observed in large tumor nests. Neoplastic cells show an increased N/C ratio and frequent pleomorphism, including bizarre giant cells.
- Undifferentiated: tumors show solid growth. Cells are spindle or round, with little cytoplasm and a high N/C ratio.
(3) Lymphovascular invasion:
(a) Microscopic (small vessel) invasion: present or absent.
(4) Parenchymal margin (edge of excision) (microscopic): involved or uninvolved with carcinoma.
(5) Regional lymph node: number of lymph nodes involved if available.
(6) Pathologic staging (AJCC, 7th ed., 2010) :
- Stage I: T1: solitary tumor without vascular invasion.
- Stage II: T2: solitary tumor with vascular invasion or multiple tumors, none more than 5 cm.
- Stage IIIA: T3a: multiple tumors, with one or more greater than 5 cm.
- Stage IIIB: T3b: solitary tumor or multiple tumors of any size involving a major branch of the portal or the hepatic vein.
- Stage IIIC: T4: tumor(s) with direct invasion of adjacent organs other than the gall bladder or with perforation of visceral peritoneum.
- Stage IVA: any T; N1: regional lymph node metastasis.
- Stage IVB: any T; any N; M1: distant metastasis.
(7) Determination of the status of the adjacent non-neoplastic liver tissue as to whether it is cirrhotic or not: according to the Ishak scoring system, the cirrhotic stage is identified by the presence of variable-sized regenerative parenchymal nodules surrounded by porto-portal and porto-central fibrous links . The adjacent non-neoplastic liver is defined as noncirrhotic if no or mild to moderate fibrosis (stage 1-4/6 by the Ishak scoring system) is observed .
Data were collected, tabulated, and analyzed statistically using the 'statistical package for the social science' program for windows, version 16 (SPSS Inc., Chicago, Illinois, USA). Fisher's exact and χ2 tests were used for comparison between qualitative variables, whereas the Mann-Whitney test was used for comparison between quantitative variables. All P values were two sided; P values of up to 0.05 were considered statistically significant and highly significant when P value was 0.01 or less, whereas P values greater than 0.05 were considered statistically nonsignificant .
| Results|| |
Studied HCC group
(1) Age: the age of the patients studied ranged between 30 and 75 years, with 56.44 ± 8.08 as mean ± SD and 57 years as the median value.
(2) Sex: eighty-five (82.5%) out of 103 patients were men, whereas the remaining 18 (17.5%) patients were women, with a male to female ratio of 8.5 : 1.8.
(3) Laboratory findings
- a-Fetoprotein level ranged between 2 and 200 10 ng/l, with 1042.05 ± 3131.8 as mean ± SD and 236 as the median value.
- By enzyme-linked immunosorbent assay, 95/103 (92%) cases were positive for HCV infection and 2/103 (2%) cases were positive for HBV infection and 8/103 (8%) cases were negative for both HCV and HBV infections.
(4) Radiologic findings
- Tumor focality: eighty-three (80.6%) cases had single focal lesions, whereas the remaining 20 cases (19.4%) showed multiple focal lesions.
- Site of tumor: fifty-one (49.5%) cases were found in the left lobe, 47 (45.6%) cases were in the right lobe, and 5 (4.9%) cases were found in both the right and the left lobes.
- Size of tumor: the greatest dimension of the HCC mass ranged between 0.5 and 24 cm, with 6.4 ± 4.3 as mean ± SD and 5 cm as the median value.
(5) Histopathological data
- Histopathological type of tumors: 101 out of 103 HCC cases studied (98%) had a classic histology, whereas the remaining 2 (2%) cases were of special HCC subtypes, including one case of the schirrous subtype and the other of the sarcomatoid subtype.
- Pattern of classical HCC: fifty-five out of 101 cases showed a trabecular pattern (54.5%) [Figure 1], 37 cases showed trabecular and acinar pattern (36.6%) [Figure 2], and nine cases showed a solid pattern (9%) [Figure 3].
- Grading of tumors: 10 cases out of 103 HCC cases studied were well differentiated (10%) [Figure 1], 83 were moderately differentiated (80.6%) [Figure 2], and only 10 cases were poorly differentiated (9.7%) [Figure 3].
- Adjacent non-neoplastic liver: out of 103 HCC cases studied, 86 (83.5%) showed cirrhotic liver and 17 (16.5%) showed noncirrhotic liver [Figure 4],[Figure 5],[Figure 6] and [Figure 7].
- Parenchymal margin (edge of excision): the parenchymal margin was involved in 35 cases (34%).
- Lymphovascular invasion: was present in 27 (26%) HCC cases.
- Tumor pathologic staging: according to AJCC, 2010 classification of HCC, 65 (63%) HCC cases represented stage T1, 29 (28%) cases represented stage T2, and the remaining 9 (9%) cases represented stage T3a.
|Figure 1: A case of classic well-differentiated HCC showing thin trabeculae (one to two cells in thickness) separated by sinusoid-like spaces (H and E, ×100). HCC, hepatocellular carcino ma.|
Click here to view
|Figure 2: A case of classic moderately differentiated HCC with mixed trabecular and acinar patterns with pseudoglandular structures (H and E, ×200). HCC, hepatocellular carcin oma.|
Click here to view
|Figure 3: A case of classic poorly differentiated HCC showing a solid pattern with indistinct sinusoid-like spaces (H and E, ×200). HCC, hepatocellular carcinoma.|
Click here to view
|Figure 4: A case of HCC arising in cirrhotic liver. The adjacent non-neoplastic liver shows complete regenerative cirrhotic nodules (H and E, ×100). HCC, hepatocellular carci noma.|
Click here to view
|Figure 5: Masson Trichrome stain of the previous slide showed a disturbed architecture with the formation of cirrhotic nodules in the adjacent non-neoplastic liver (Masson Trichrome, × 100).|
Click here to view
|Figure 6: A case of HCC arising in noncirrhotic liver. The adjacent nonneoplastic liver showed preserved lobular architecture (H and E, ×100). HCC, hepatocellular carcinoma.|
Click here to view
|Figure 7: Masson Trichrome stain of the previous slide showing minimal fibrous expansion of portal tracts in the adjacent non-neoplastic liver (Masson Trichrome, ×100).|
Click here to view
Male sex was exclusively seen in HCC cases in noncirrhotic liver (100%) in comparison with 80% of male predominance in HCC cases in cirrhotic liver (P = 0.04) [Table 1]. In addition, the median size of the HCC tumor mass was significantly larger in HCC cases in cirrhotic liver (median = 6) than that of HCC in noncirrhotic liver (median = 5) (P = 0.04).
|Table 1: Comparison between HCC-C and HCC-NC groups in the clinicopathological parameters studied|
Click here to view
| Discussion|| |
In Egypt, hospital-based studies have reported that HCC constitutes greater than 95% of liver cancers . Although many of the specific etiologies that lead to HCC are well known, the underlying molecular mechanisms leading to hepatocarcinogenesis remain incompletely defined. Nevertheless, cirrhosis from any cause remains one of the strongest known risk factors for HCC .
In cirrhosis, the prevailing opinion is that HCC develops by a step-wise progression from large regenerative nodules to dysplastic nodules to well-differentiated HCC and subsequently to less differentiated tumors .
Nevertheless, a certain number of HCCs arise in noncirrhotic livers (HCC-NC). This form of hepatic carcinogenesis occurs in a proportion of cases that ranges widely from 7 to 54% across the geographic areas and according to the etiology of liver disease . In high-incidence areas, HCC-NC mostly relates to chronic HBV infection and may occur in children. HBV can be directly oncogenic, leading to HCC through integration of the viral genome into the host genome. In addition, the X protein of HBV is a potent transactivator that can interact with p53, interfering with its tumor-suppressor activity. In part because of these properties of HBV, liver cirrhosis in HBV-infected patients is not a prerequisite for hepatocarcinogenesis. Moreover, fibrolamellar HCC is a variant of HCC with distinct clinicopathologic features. It occurs at a young age and lacks the common risk factors for HCC.
Study population characteristics of this work showed a statistically significant difference between the studied groups, HCC-C and HCC-NC, in sex (P = 0.04). Male sex was exclusively seen in HCC-NC (100%) in comparison with 80% in HCC-C. In contrast, some series of noncirrhotic HCCs have reported a lower male preponderance (male/female ratio: 1.3-2 : 1) as compared with the cirrhotic counterparts, where this ratio ranges from 3.2 to 8 : 1. However, this was not confirmed by other studies . In our study, 16 out of 17 HCC-NC cases proved to be positive for HCV by serologic tests and so the high predominance of men could be explained by the fact that men are usually the main income earners in the family in Egyptian community and many patients discover that they have HCV infection through blood tests when applying to work abroad. Thirty-one percent of Egyptians applying to work were found to be positive for the anti-HCV antibody . Many other patients discover that they have an infection while donating blood. Studies have shown the high seroprevalence of anti-HCV among Egyptian blood donors, and it is predominantly men who usually donate blood . These results are in agreement with many Egyptian epidemiological studies that have shown the prevalence of HCV to be higher among men than women .
Also, there was a statistically significant difference between HCC-C and HCC-NC in the tumor size (P = 0.04), where the median size of the HCC tumor mass was significantly larger in HCC-NC cases (median = 6) than that of HCC-C (median = 5). The larger tumor size of the HCC-NC group is in agreement with the result of Trevisani et al. , who found that the size of an HCC mass without cirrhosis is indeed larger than that of HCC with cirrhosis, likely because of the delayed diagnosis as they do not participate in screening programs and so presented with an advanced stage.
However, the results of this study are in agreement with other studies  on the absence of a statistical difference between HCC-C and HCC-NC in clinical and pathological criteria such as patients' age, histological type, grade, multiplicity, vascular invasion, tumor stage, or surgical margins.
In conclusion, in terms of most of the demographical and clinicopathological parameters studied, no considerable difference was found between HCC that occur in cirrhotic and noncirrhotic liver.
| Acknowledgements|| |
Conflicts of interest
There are no conflicts of interest.
| References|| |
Scaggiante B, Kazemi M, Pozzato G, Dapas B, Farra R, Grassi M, et al.
Novel hepatocellular carcinoma molecules with prognostic and therapeutic potentials. World J Gastroenterol 2014; 20
Anwar WA, Khaled HM, Amra HA, El-Nezami H, Loffredo CA. Changing pattern of hepatocellular carcinoma (HCC) and its risk factors in Egypt: possibilities for prevention. Mutat Res 2008; 659
Rashad NM, El-Shal AS, Abd Elbary EH, Abo Warda MH, Hegazy O. Impact of insulin-like growth factor 2, insulin-like growth factor receptor 2, insulin eceptor substrate 2 genes polymorphisms on susceptibility and clinicopathological features of hepatocellular carcinoma. Cytokine 2014; 68
Noda K, Yoshihara H, Suzuki K, Yamada Y, Kasahara A, Hayashi N, et al.
Progression of type C chronic hepatitis to liver cirrhosis and hepatocellular carcinoma its relationship to alcohol drinking and the age of transfusion. Alcohol Clin Exp Res 1996; 20
Tretiakova MS, Shabani-Rad MT, Guggisberg K, Hart J, Robert A, Gao Z. Genomic and immunophenotypical differences between hepatocellular carcinoma with and without cirrhosis. Histopathology 2010; 56
Fattovich G, Stroffolini T, Zagni I, Donato F. Hepatocellular carcinoma in cirrhosis: incidence and risk factors. Gastroenterology 2004; 127
Alkofera B, Lepennecb V, Chichea L. Hepatocellular cancer in the non-cirrhotic liver. J Visc Surg 2011; 148
Buendia MA. Hepatitis B viruses and hepatocellular carcinoma. Adv Cancer Res 1992; 59
Wang XW, Forrester K, Yeh H, Feitelson MA, Gu JR, Harris CC. Hepatitis B virus X protein inhibits p53 sequence-specific DNA binding, transcriptional activity, and association with transcription factor ERCC3. Proc Natl Acad Sci USA 1994; 91
Yeh MM, Daniel HD, Torbenson M. Hepatitis C associated hepatocellular carcinomas in non-cirrhotic livers. Mod Pathol 2010; 23
Hamilton SR, Altonen LA. In: Bosman FT, Carneiro F, Hruban RH, Theise ND, eds. Hepatocellular carcinoma. WHO classification of tumors of the digestive system. 4th ed. Lyon: International agency of research on cancer; 2010. 205-216.
Salomao M, McMillen E, Lefkowitch JH. Recent advances in the classification of hepatocellular carcinoma. Diagn Histopathol 2011; 18
Ishak K, Baptista A, Bianchi L, Callea F, De Groote J, Gudat F, et al.
Histological grading and staging of chronic hepatitis. J Hepatol 1995; 22
Dawson B, Trapp R. In: Basic and clinical biostatistics. Large medical books. 3rd ed. Oxford, London, Boston: Amazon; 2001. 87.
Lehman EM, Wilson ML. Epidemiology of hepatitis viruses among hepatocellular carcinoma cases and healthy people in Egypt: a systematic review and meta-analysis. Int J Cancer 2009; 124
Trevisani F, Frigerio M, Santi V, Grignaschi A, Bernardi M. Hepatocellular carcinoma in non-cirrhotic liver: a reappraisal. Dig Liver Dis 2010; 42
Mohamed MK, Hussein MH, Massoud AA, Sheir S, Aoun AA, Naser MA. Study of the risk factors for viral hepatitis C infection among Egyptians applying for work abroad. J Egypt Public Health Assoc 1996; 71
Arthur RR, Hassan NF, Abdallah MY, El-Sharkawy MS, Saad MD, Hackbart BG, et al.
Hepatitis C antibody prevalence in blood donors in different governorates in Egypt. Trans R Soc Trop Med Hyg 1997; 91
El-Sadawy M, Ragab H, El-Toukhy H, El-Mor Ael-L, Mangoud AM, Eissa MH, et al.
Hepatitis C virus infection at Sharkia Governorate, Egypt: seroprevalence and associated risk factors. J Egypt Soc Parasitol 2004; 34
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7]