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Figure 1.
Role of host and known environmental factors in the pathogenesis of cirrhosis and hepatocellular carcinoma (HCC) and potential unknown factors in the pathogenesis of HCC. HBV indicates hepatitis B; HCV, hepatitis C.

Role of host and known environmental factors in the pathogenesis of cirrhosis and hepatocellular carcinoma (HCC) and potential unknown factors in the pathogenesis of HCC. HBV indicates hepatitis B; HCV, hepatitis C.

Figure 2.
Age-specific incidence rates per 100 000 population of hepatocellular carcinoma in Kentucky.

Age-specific incidence rates per 100 000 population of hepatocellular carcinoma in Kentucky.

Figure 3.
Hepatocellular carcinoma incidence by county in Kentucky for the total population age adjusted to the 2000 US standard population.

Hepatocellular carcinoma incidence by county in Kentucky for the total population age adjusted to the 2000 US standard population.

Table 1. 
Clinical and Pathologic Demographic Characteristics of Patients With Cirrhotic and Noncirrhotic Hepatocellular Carcinoma*
Clinical and Pathologic Demographic Characteristics of Patients With Cirrhotic and Noncirrhotic Hepatocellular Carcinoma*
Table 2. 
Percentage Distribution of Stage at Diagnosis and 5-Year Survival Rates of Patients With Hepatocellular Carcinoma
Percentage Distribution of Stage at Diagnosis and 5-Year Survival Rates of Patients With Hepatocellular Carcinoma
1.
Greenlee  RTMurray  TBolden  S  et al.  Cancer statistics, 2000. CA Cancer J Clin 2000;507- 33
PubMedArticle
2.
McGlynn  KATsao  LHsing  AW  et al.  International trends and patterns of primary liver cancer. Int J Cancer 2001;94290- 296
PubMedArticle
3.
Botha  JFLangnas  AN Liver transplantation for hepatocellular carcinoma: an update. J Natl Compr Canc Netw 2006;4762- 767
PubMed
4.
El-Serag  HBDavila  JAPetersen  NJ  et al.  The continuing increase in the incidence of hepatocellular carcinoma in the United States: an update. Ann Intern Med 2003;139817- 823
PubMedArticle
5.
Davila  JAMorgan  ROShaib  Y  et al.  Hepatitis C infection and the increasing incidence of hepatocellular carcinoma: a population-based study. Gastroenterology 2004;1271372- 1380
PubMedArticle
6.
 Kentucky Cancer Registry. http://www.kcr.uky.edu/. Accessed October 15, 2006
7.
 Surveillance, Epidemiology, and End Results.  Bethesda, Md National Cancer Institute, Cancer Surveillance Research Program, Cancer Statistics Branch2006;
8.
Liu  JHChen  PWAsch  SM  et al.  Surgery for hepatocellular carcinoma: does it improve survival? Ann Surg Oncol 2004;11298- 303
PubMedArticle
9.
World Health Organization, International Classification of Diseases, Ninth Revision (ICD-9).  Geneva, Switzerland World Health Organization1977;
10.
Goldsmith  NAWoodburne  RT The surgical anatomy pertaining to liver resection. Surg Gynecol Obstet 1957;105310- 318
PubMed
11.
Wantz  GEPayne  MA Experience with portacaval shunt for portal hypertension. N Engl J Med 1961;265721- 728
PubMedArticle
12.
Pugh  RNMurray-Lyon  IMDawson  JL  et al.  Transection of the oesophagus for bleeding oesophageal varices. Br J Surg 1973;60646- 649
PubMedArticle
13.
Okuda  KOhtsuki  TObata  H  et al.  Natural history of hepatocellular carcinoma and prognosis in relation to treatment: study of 850 patients. Cancer 1985;56918- 928
PubMedArticle
14.
Reichman  TWBahramipour  PBarone  A  et al.  Hepatitis status, Child-Pugh classification, and serum AFP levels predict survival in patients treated with transarterial embolization for unresectable hepatocellular carcinoma. J Gastrointest Surg 2005;9638- 645
PubMedArticle
15.
Fong  YSun  RLJarnagin  W  et al.  An analysis of 412 cases of hepatocellular carcinoma at a Western center. Ann Surg 1999;229790- 799
PubMedArticle
16.
Figueras  JRamos  EIbanez  L  et al.  Surgical treatment of hepatocellular carcinoma in cirrhotic and noncirrhotic patients. Transplant Proc 1999;312455- 2456
PubMedArticle
17.
Torzilli  GMakuuchi  MInoue  K  et al.  No-mortality liver resection for hepatocellular carcinoma in cirrhotic and noncirrhotic patients: is there a way? a prospective analysis of our approach. Arch Surg 1999;134984- 992
PubMedArticle
18.
Tsukioka  GKakizaki  SSohara  N  et al.  Hepatocellular carcinoma in extremely elderly patients: an analysis of clinical characteristics, prognosis and patient survival. World J Gastroenterol 2006;1248- 53
PubMed
Paper
May 01, 2007

Kentucky HepatomaEpidemiologic Variant or Same Problem in a Different Region?

Author Affiliations

Author Affiliations: Division of Surgical Oncology, Department of Surgery, and James Graham Brown Cancer Center, University of Louisville School of Medicine, Louisville, Ky.

Arch Surg. 2007;142(5):431-437. doi:10.1001/archsurg.142.5.431
Abstract

Background  Hepatitis and cirrhosis are common etiologic factors in hepatocellular carcinoma (HCC) in the United States. However, noncirrhotic, nonfibrotic HCC has been recognized more frequently in Kentucky. The aim of this study was to evaluate the epidemiologic features of this variant of HCC.

Hypothesis  Kentucky hepatoma, defined as a noncirrhotic, nonfibrotic, hepatitis-negative HCC, occurs in an older population with more favorable preoperative factors when compared with other patients with HCC.

Design  A prospective review of our 1002 hepatopancreaticobiliary patients, the Kentucky Cancer Registry, and the Surveillance, Epidemiology, and End Results database.

Setting  An academic referral center.

Patients  All patients with HCC treated from January 1, 1999, through September 30, 2005, were reviewed for clinicopathologic factors, recurrence, and outcome.

Results  In a review of the region's 703 patients with HCC, we have seen a 4-fold increase in age-specific HCC diagnosis, with the most rapid increase seen in the 60- to 69-year-old age group. In our institution's 103 patients with HCC, 62 (60.2%) were without hepatitis or cirrhosis. These noncirrhotic, hepatitis-free patients were found to be significantly older (70 vs 55 years; P = .001), to be more often female (40.3% vs 24.4%; P = .01), to have a larger tumor size (6.5 vs 3.9 cm; P = .004), to have fewer liver lesions (1 vs 3; P = .22), and to more frequently undergo surgical therapy (75.6% vs 53.8%; P = .01) than the patients with cirrhosis or hepatitis (n = 41).

Conclusions  A larger percentage of the patients with HCC seen in our region are significantly different from those in other reports throughout the United States in preoperative clinical and pathologic presentation. The reason for this change is as yet unknown, but the incidence continues to rise annually.

Hepatocellular carcinoma (HCC) is one of the top 5 most common cancers in the world and remains one of the top 3 most common causes of cancer mortality, with an incidence reported in excess of 560 000 cases.1 Most HCC cases (>80%) occur in either sub-Saharan Africa or East Asia. Aggressive attempts at prevention and public awareness have demonstrated encouraging trends in these high-incidence areas, with decreases in incidence having been reported in China, Hong Kong, and Singapore.2 In contrast and more alarmingly, HCC incidence in a number of low–incidence rate areas, including Australia, the United States, Canada, and the United Kingdom, has increased significantly and has not been easily explained by changes in immigration alone.

It is widely know that chronic hepatitis B and C virus infection remains the most dominant risk factor in HCC incidence (Figure 1). Other known hepatocellular carcinoma risk factors include alcoholic cirrhosis, hemochromatosis, and the consumption of aflatoxin B1–contaminated foodstuffs. The universal belief has always been that cirrhosis precedes the development of HCC (Figure 1), even in the United States, where continued reports state that approximately 95% of HCC arises in the background of cirrhosis.3 Another challenge has been to determine the cause of HCC in patients without chronic hepatitis infection or without chronic cirrhosis but who still develop primary HCC (Figure 1). This etiologic question may be one of the reasons why there has been a 2-fold increase in the age-adjusted incidence rate of HCC in the United States between 1985 and 2002.4 This incidence has caused an increase of 1.3 per 100 000 population during 1978 to 1980 to 3.3 per 100 000 population during 1999 to 2001.4 Interestingly, the largest increase during this time has occurred in white individuals (including Hispanic persons), whereas the lowest increase has been within the Asian population. More recent reports have demonstrated that as much as 40% of the HCC diagnosed in the United States is of unknown cause (ie, not by alcohol, hepatitis, or cirrhosis).5

The origin of HCC in patients without chronic hepatitis infection or chronic cirrhosis from other causes remains unclear. To date, because of the overwhelming acceptance of hepatitis or cirrhosis as the cause of HCC, little attention has been paid to the increasing incidence of patients who present with nonhepatitic, noncirrhotic HCC. Because we have witnessed this etiologic variant of HCC so commonly in our practice during the past decade, we have termed it the Kentucky hepatoma. Thus, the aim of our study was to evaluate the incidence of this variant HCC.

METHODS

A prospective review of our center's 1000 hepatopancreaticobiliary patients, the Kentucky Cancer Registry, and the Surveillance, Epidemiology, and End Results (SEER) database was conducted for both incident rates and overall survival in patients with HCC.

The Kentucky Cancer Registry was searched from January 1, 1999, to September 30, 2005, to look at age-adjusted rates for HCC in patients 20 years and older.6 In addition, incidence rates per 100 000 persons were also searched by county to evaluate epidemiologic trends in certain areas of the state.6 The Kentucky Cancer Registry does not delineate HCC based on hepatitis, cirrhosis, or other etiologic factors. The evaluation of the Kentucky Cancer Registry was to evaluate trends in incidence rates and trends among the 65 counties in a predominantly rural state.

De-identified patient-level data were obtained from the population-based SEER database maintained by the National Cancer Institute. Evaluation of the database included the 17 SEER areas: San Francisco, Calif; Connecticut; Detroit, Mich; Hawaii; Iowa; New Mexico; Seattle, Wash; Utah; Atlanta, Ga; San Jose–Monterey, Calif; Los Angeles, Calif; Alaska; rural Georgia; California (excluding the cities already mentioned); Kentucky; Louisiana; and New Jersey.

The population captured by the SEER database is representative of the US population.7,8 To ensure the accuracy of the data, medical record abstractors undergo extensive training as described in the National Cancer Institute SEER publications. Malignancies are encoded based on the International Classification of Diseases, Ninth Revision (ICD-9)9 for oncology. The SEER database does not distinguish between patients with HCC who are diagnosed as having hepatitis B or C and those with underlying cirrhosis. The reason for the use of the SEER database is to compare the 5-year survival of patients in our region with that of others.

All patients with HCC treated in the Department of Surgery at the University of Louisville from January 1, 1999, through September 30, 2005, were identified from the Division of Surgical Oncology's prospective hepatopancreaticobiliary database. At the University of Louisville, the care of HCC is planned under the auspices of a multidisciplinary hepatopancreaticobiliary disease management team that includes Society of Surgical Oncology–accredited and trained surgical oncologists with a specialty in hepatopancreaticobiliary malignancies, medical oncologists, gastroenterologists, interventional radiologists, transplant surgeons, and radiation oncologists. One hundred three patients with HCC were considered for treatment in this period. Data for these patients were then extracted from the database for review. Data examined included extensive demographics (age, sex, medical history, surgical history, social history, tobacco history, alcohol history, medication use, family history, and any other possible etiologic factors), pathologic findings of the liver lesion, pathologic or nonneoplastic liver parenchyma, hepatitis serologic test results, α-fetaprotein level, and outcome. Follow-up was obtained by the treating physician and is up to date from the end of the study.

Nomenclature for the extent of resection was defined by Goldsmith and Woodburne.10 Evaluation of liver function was by the Childs-Pugh classification.11,12 Clinical staging of disease was performed by using the 2002 American Joint Committee on Cancer staging criteria and the Okuda staging criteria.13 Additional criteria in the form of extent of liver involvement were also used based on review of all cross-sectional imaging for each patient by 2 independent radiologists for extent of disease.

The diagnosis of hepatitis was defined as the presence of hepatitis C antibody or the presence of hepatitis B surface antigen. Alcoholic cirrhosis was defined as excessive alcohol use in combination with either radiologic demonstration or pathologic demonstration of hepatic cirrhosis.

A patient with Kentucky hepatoma was defined as an individual who was without hepatitis, had no history of excessive alcohol use, and had normal nonneoplastic hepatic parenchyma for patients who underwent resection or ablation, or normal hepatic parenchyma on computed tomography or magnetic resonance imaging for patients treated without resection or ablation.

The χ2, t, and Mann-Whitney U tests for nominal, continuous, and ordinal variables, respectively, were used to evaluate the association of independent variables with surgical complications. Proportional hazards analysis was performed using all variables found to be significant by univariate analysis. Relative risks with 95% confidence intervals were calculated as a measure of association. Multiple logistic regression analysis was used to determine overall outcome and differences. P<.05 was considered statistically significant. Statistical analysis was performed using JMP software (SAS Institute Inc, Cary, NC).

RESULTS

A review of the Kentucky Cancer Registry has demonstrated a near 4-fold increase in age-specific HCC rates in Kentucky, with the most rapid rise seen in the 60- to 69-year-old age group (Figure 2). In addition, a consistently increasing incidence of age-specific HCC has been seen in Kentucky in patients 70 years or older compared with other age groups. The incidence of HCC in Kentucky is evenly distributed among the north central counties, the eastern counties, and the western counties (Figure 3), without any 1 area as the dominant hotbed of incidence.

In a review of our 103 patients with HCC at the University of Louisville, 62 (60.2%) were found to be without hepatitis or cirrhosis compared with 41 patients (39.8%) who had either underlying hepatitis infection or other etiologically induced cirrhosis. In a comparison of these 2 groups, patients who were without hepatitis or cirrhosis were found to be significantly older (70 vs 55 years; P = .001) (Table 1). Furthermore, in the patients without hepatitis or cirrhosis, a significantly greater proportion of women (40.3% vs 24.4%; P = .01) and a trend toward an increase in diabetes mellitus (37.1% vs 19.5%; P = .05) were seen when compared with patients with cirrhosis. Patients without underlying hepatitis or cirrhosis were less often smokers (40.3% vs 70.7%; P = .002) and had significantly lower α-fetoprotein levels at initial diagnosis (median level, 16 vs 320 ng/mL; P = .02).

Patients who were found to be free of hepatitis and cirrhosis had a significantly greater tumor size (6.5 vs 3.9 cm; P = .02) and fewer tumors (median, 1) when compared with the patients with hepatitis or cirrhosis (median, 3). This translated into a trend toward a greater percentage of the patients with Kentucky hepatoma (57.6%) having less than 25% liver parenchymal involvement when compared with the cirrhotic patients (48.4%), which was not statistically significant (P = .58).

These preoperative factors led to a greater use of surgical therapy in the patients with Kentucky hepatoma. The patients without hepatitis or cirrhosis underwent major liver resection more frequently (34.4% vs 2.0%; P<.001), with a similar fraction of patients who underwent minor resection (5.0% vs 4.7%) and a greater number of liver radiofrequency ablation procedures (27.3% vs 12.1%). Conversely, the hepatitis and cirrhosis population had a greater incidence of transplantation (39.3% vs 10.9%) when compared with the patients with Kentucky hepatoma.

A similar T stage was seen in both groups, with a nonsignificant trend toward greater T1 stage in the patients with Kentucky hepatoma (50.0% vs 35.7%). This similar T stage also translated into similar Okuda stage and Childs-Pugh status (Table 1). In patients with Kentucky hepatoma, a trend was seen toward a greater incidence of vascular invasion, but this finding was not statistically significant (P = .06).

In a review of the SEER database in regard to incidence, there has been a consistent age-adjusted incidence of more than 20 per 100 000 population for those 65 years and older for both men and women of all races. The 65 years and older aggregate incidence is 26.5 per 100 000 population. This increase has led to the third largest increase in the trend of SEER incidence rates by primary cancer site from 1994 to 2003, 1.6 per 100 000 population, with only thyroid (5.5) and melanoma (3.1) being greater. When we then compared our institutional data with the 17 SEER supporting data sites, there was a greater incidence of localized stage at diagnosis in the SEER database (33%) when compared with the University of Louisville patients (9.4%). A similar distribution was found of regional (25% vs 26%) and distant (21% vs 38%) disease in the SEER data areas compared with our institutional data. Interestingly, the 5-year survival rate by stage was significantly improved in the University of Louisville patients for localized disease (53.3% vs 21.9%; P = .001) and regional disease (26.3% vs 7.2%; P = .001), with similar survival for distant disease (5.4% vs 4.1%; P = .90) (Table 2).

COMMENT

The incidence of HCC has risen markedly in the United States during the past 2 decades, with an average yearly age-adjusted incidence rate of HCC (verified by histologic or cytologic analysis) from 1.3 per 100 000 population during 1978 to 1980 to 3.3 per 100 000 population during 1999 to 2001.4 This increase has been widely hypothesized to be related to the dormancy or latency of hepatitis B and C in patients infected in the 1960s and 1970s who are now developing underlying cirrhosis and HCC.4 The incidence of nonhepatitic, noncirrhotic HCC in the United States has not been evaluated. This report represents the first evaluation at a tertiary referral center of the incidence of this variant HCC (ie, nonhepatitic and noncirrhotic), which we have labeled Kentucky hepatoma. It is possible that a national increase in the incidence of HCC reflects similar increases in HCC among patients without hepatitis or cirrhosis in other regions.5

One reason for the increased incidence of HCC may be related to changes in the diagnostic criteria used in the SEER database. In the 1970s and early 1980s, the SEER database recorded only histologically confirmed cases of HCC. Although this is highly specific, it may underestimate the true number of patients with HCC. The average yearly age-adjusted incidence rates of all HCC captured by the SEER database irrespective of the method of diagnosis has increased approximately 30%. Because the diagnosis of HCC can now occur without histologic confirmation, based on the presence of underlying cirrhosis, a nodular mass seen on computed tomography or magnetic resonance imaging, and an elevated α-fetoprotein level, the corresponding increased incidence in the SEER database may be partially related to these changes in diagnostic criteria.

Similarly, with the rapid rise in hepatic resections now being performed in all age groups, patients who were initially diagnosed as having and being treated for cancer of unknown primary are now being appropriately diagnosed as having HCC. Perhaps the incidence of HCC is not actually increasing, but the incidence of carcinoma of unknown primary is decreasing as a result of our ability to appropriately diagnose these patients as having either HCC or intrahepatic cholangiocarcinoma. The willingness to be surgically aggressive in patients who are initially diagnosed as having unknown primary cancers has led to more precise and accurate diagnosis and staging in patients with these primary malignancies. This may partially explain the relatively large proportion of patients at the University of Louisville diagnosed as having HCC who do not have underlying hepatitis and are free of any type of hepatic parenchymal abnormalities.

Other potential causes for the increasing incidence of this variant HCC may be the ever increasing age of the US population. Elderly people (defined as those ≥65 years) will account for more than 61% of all new cancer cases and 70% of all annual cancer deaths.6 It has recently been estimated that the elderly patient population has 11 times the cancer risk of people younger than 65 years. It also has been estimated that in 2030, approximately 20% of the US population will be older than 65 years.7 These changes alone (age of the liver) coupled with environmental exposure and potential genetic effects may be other potential causes for this change in incidence rates.

This reasoning is further solidified by the significant differences in the clinical and pathologic features of the patients with Kentucky hepatoma when compared with the common cirrhotic patient with HCC. Those with Kentucky hepatoma are significantly older, are more commonly female, are less often smokers, have a lower α-fetoprotein level, have a greater incidence of a normal α-fetoprotein level, have larger tumors, and have a smaller number of tumors (most commonly a single liver tumor). These criteria have led to an ability to be more surgically aggressive in these patients because of their underlying normal hepatic parenchyma and minimal comorbidities. This variant histologic presentation responds well to aggressive surgical resection.

The variant HCC or Kentucky hepatoma has also shown an alarming rate of increase in the older patient (60-69 years of age) and remains high in the 70- to 79-year age group (Figure 1). In an attempt to evaluate specific regions of Kentucky that would elucidate this increase, a similar increase in HCC has been seen among all 5 major regions in Kentucky (Figure 2).

Compared with other studies that have presented the incidence of this variant HCC, our study demonstrates the single largest incidence rate. A recent report from Reichman et al14 demonstrated an incidence of 26%, with a worse overall survival when compared with the cirrhotic population. A similar high incidence (31%) was reported by Fong et al,15 without a difference in overall survival. Both of these reports were from the United States, in New Jersey and New York, respectively, which has a higher incidence of Asian immigrants and thus a probable higher incidence of hepatitis. A similar low (<15%) incidence of this variant HCC is seen in Europe and Asia.1618 Consistently, however, all of these studies, as well as ours, did not demonstrate a significant survival effect in patients with HCC. The underlying hepatic parenchyma did not affect the biologic features of this disease in our study or in previous studies evaluated.

The fact that 60.2% of the patients evaluated at the Department of Surgery of the University of Louisville are without evidence of hepatitis or cirrhosis is markedly different from the experience of other centers. This finding certainly may reflect referral bias to our center and the fact that our surrounding area does not include a large population of patients with endemic hepatitis B and C. Because only 2 centers in Kentucky perform major hepatectomy, we reason that the referral of patients with HCC (with and without hepatitis or cirrhosis) is probably evenly distributed. Admittedly, our study does not capture all of the patients diagnosed with this condition in our region but only those referred for surgical consultation. However, because our center uses a multidisciplinary team approach to the evaluation and treatment of these patients and because the surgeons in our department treat all of the patients undergoing nonoperative liver-directed therapies (eg, embolization, chemoembolization, radioactive microsphere therapy, and percutaneous radiofrequency ablation), we believe that the results presented herein are probably an accurate reflection of the patients treated for HCC in our area. In addition, in other areas where multiple centers provide liver-directed therapy, it may be more common to refer patients with cirrhosis to larger institutions that have transplantation as an option and to treat older patients without cirrhosis in the smaller centers.

The increased incidence of HCC in noncirrhotic, nonhepatitic patients with HCC may be common to other regions as well but may not be as well recognized in centers where there is a greater population at risk for hepatitis B and C. Whether our high proportion of patients with HCC who are without hepatitis or cirrhosis represents differences in diagnosis, surgical treatment, or as-yet-undiscovered etiologic factors remains to be elucidated. Other environmental exposures and genetic factors are being evaluated to delineate this epidemiologic variant.

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Article Information

Correspondence: Robert C. G. Martin II, MD, University of Louisville School of Medicine, 315 E Broadway, Room 313, Louisville, KY 40202 (Robert.martin@louisville.edu).

Accepted for Publication: December 13, 2006.

Author Contributions:Study concept and design: Martin. Acquisition of data: Martin, Loehle, Scoggins, and McMasters. Analysis and interpretation of data: Martin. Drafting of the manuscript: Martin. Critical revision of the manuscript for important intellectual content: Martin, Loehle, Scoggins, and McMasters. Statistical analysis: Martin. Administrative, technical, and material support: Martin, Loehle, and McMasters. Study supervision: Scoggins.

Financial Disclosure: None reported.

Previous Presentation: This study was presented at the 114th Annual Meeting of the Western Surgical Association; November 14, 2006; Los Cabos, Mexico. The discussions that follow this article are based on the originally submitted manuscript and not the revised manuscript.

References
1.
Greenlee  RTMurray  TBolden  S  et al.  Cancer statistics, 2000. CA Cancer J Clin 2000;507- 33
PubMedArticle
2.
McGlynn  KATsao  LHsing  AW  et al.  International trends and patterns of primary liver cancer. Int J Cancer 2001;94290- 296
PubMedArticle
3.
Botha  JFLangnas  AN Liver transplantation for hepatocellular carcinoma: an update. J Natl Compr Canc Netw 2006;4762- 767
PubMed
4.
El-Serag  HBDavila  JAPetersen  NJ  et al.  The continuing increase in the incidence of hepatocellular carcinoma in the United States: an update. Ann Intern Med 2003;139817- 823
PubMedArticle
5.
Davila  JAMorgan  ROShaib  Y  et al.  Hepatitis C infection and the increasing incidence of hepatocellular carcinoma: a population-based study. Gastroenterology 2004;1271372- 1380
PubMedArticle
6.
 Kentucky Cancer Registry. http://www.kcr.uky.edu/. Accessed October 15, 2006
7.
 Surveillance, Epidemiology, and End Results.  Bethesda, Md National Cancer Institute, Cancer Surveillance Research Program, Cancer Statistics Branch2006;
8.
Liu  JHChen  PWAsch  SM  et al.  Surgery for hepatocellular carcinoma: does it improve survival? Ann Surg Oncol 2004;11298- 303
PubMedArticle
9.
World Health Organization, International Classification of Diseases, Ninth Revision (ICD-9).  Geneva, Switzerland World Health Organization1977;
10.
Goldsmith  NAWoodburne  RT The surgical anatomy pertaining to liver resection. Surg Gynecol Obstet 1957;105310- 318
PubMed
11.
Wantz  GEPayne  MA Experience with portacaval shunt for portal hypertension. N Engl J Med 1961;265721- 728
PubMedArticle
12.
Pugh  RNMurray-Lyon  IMDawson  JL  et al.  Transection of the oesophagus for bleeding oesophageal varices. Br J Surg 1973;60646- 649
PubMedArticle
13.
Okuda  KOhtsuki  TObata  H  et al.  Natural history of hepatocellular carcinoma and prognosis in relation to treatment: study of 850 patients. Cancer 1985;56918- 928
PubMedArticle
14.
Reichman  TWBahramipour  PBarone  A  et al.  Hepatitis status, Child-Pugh classification, and serum AFP levels predict survival in patients treated with transarterial embolization for unresectable hepatocellular carcinoma. J Gastrointest Surg 2005;9638- 645
PubMedArticle
15.
Fong  YSun  RLJarnagin  W  et al.  An analysis of 412 cases of hepatocellular carcinoma at a Western center. Ann Surg 1999;229790- 799
PubMedArticle
16.
Figueras  JRamos  EIbanez  L  et al.  Surgical treatment of hepatocellular carcinoma in cirrhotic and noncirrhotic patients. Transplant Proc 1999;312455- 2456
PubMedArticle
17.
Torzilli  GMakuuchi  MInoue  K  et al.  No-mortality liver resection for hepatocellular carcinoma in cirrhotic and noncirrhotic patients: is there a way? a prospective analysis of our approach. Arch Surg 1999;134984- 992
PubMedArticle
18.
Tsukioka  GKakizaki  SSohara  N  et al.  Hepatocellular carcinoma in extremely elderly patients: an analysis of clinical characteristics, prognosis and patient survival. World J Gastroenterol 2006;1248- 53
PubMed

Steven C. Stain, MD, Albany, NY: The authors from Louisville make the argument that HCC in Kentucky somehow differs from the rest of the country because of differences in clinical and pathologic presentation. This conclusion comes from analysis of data from 3 sources: a database maintained by the Division of Surgical Oncology, the Kentucky Cancer Registry, and the SEER database. There were 103 patients with HCC in the Louisville database and 703 patients in the Kentucky Cancer Registry. The authors contend that compared with a nationwide SEER 17 sample, the patients seen at the University of Louisville were more likely to have localized disease and that those with localized disease had significantly longer survival than patients in the SEER database. The authors have coined the term Kentucky hepatoma to describe a variant HCC that occurs in patients without hepatitis or cirrhosis.

The Kentucky Cancer Registry became a SEER site in 2001, and the increased incidence of HCC identified in this registry appears to mirror national trends. Although it has been suggested that the national increase is likely due to hepatitis B and C infections secondary to transfusions received more than 30 years ago, today on the SEER Web site, I compared the rising incidence of liver and intrahepatic bile duct cancer in Kentucky with the nationwide sample, and increases seemed quite similar. To the authors, have you done statistical analyses to determine if the increasing incidence in Kentucky is greater than the trend observed in the nationwide SEER data?

In the Louisville database, 60% of the patients did not have hepatitis or cirrhosis. I am unclear what the histological requirements for Kentucky hepatoma are. In 1956, Hugh Edmondson, MD, from the University of Southern California first described fibrolamellar HCC as a distinct, well-differentiated cancer with specific histologic characteristics that occurred in normal livers and most often in younger patients. Are there specific histologic features of Kentucky hepatoma that pathologists can identify, or are the authors referring to any HCC in the absence of cirrhosis or hepatitis serology? It would be useful to have some more information about the data available in the Louisville database. Did all patients with HCC in this database have serologic testing for hepatitis B or C? How did you determine the absence of cirrhosis? Was biopsy of normal liver required for patients who did not have resection?

The authors compare the stage distribution and survival rate of patients in the Louisville database with the SEER data. While I am confident that the Louisville database included all patients seen by surgeons, did this database include all patients with HCC seen by all physicians within the region or even within the University of Louisville? I have concerns about comparing a surgical database with a population-based sample such as the SEER data set for both stage distribution and survival analysis. Surgeons might be much more likely to evaluate the patients who referring physicians believed were candidates for therapy.

The authors point out that the Kentucky Cancer Registry does not contain data regarding hepatitis serology or cirrhosis histology. Do the authors believe that the increase in patients with HCC in Kentucky is primarily due to the increased prevalence of hepatitis that is seen nationally, or does Kentucky have an increase in the number of noncirrhotic hepatocellular carcinomas in the absence of hepatitis? Could this also be simply a change in referral patterns to the University of Louisville? I do not know if any of these are true, but I do not believe that this question can be answered by analysis of a single institutional database.

Dr Martin: First, do we believe that our increasing trend in hepatocellular cancers is higher than the SEER database? The limitations of my comment are that I do not know why.

The reason for this limitation is the difficulty with the SEER database and how much of the incidence is influenced by cholangiocarcinoma. One of the limitations with the SEER database, and hopefully one that can be easily corrected in the future, is that it includes in the data both HCC and cholangiocarcinoma as primary liver cancers. This limits the ability of the SEER database to evaluate trends in both of these diseases.

The histologic characteristics of the HCC of these patients were all confirmed pathologically. None of these patients had the fibrolamellar variant, which is seen in the younger population and which is different from our data, since a majority of our patients with HCC were older.

All patients did undergo serologic testing both for hepatitis as well as for α-fetoprotein levels. The hepatic parenchyma for the nonsurgically treated patients were evaluated by percutaneous biopsy to establish the diagnosis or were defined based on their lack of serologic, social, and radiologic characteristics for cirrhosis.

We have established an inclusive referral pattern based on our multidisciplinary conferences, and since our division has established all of the new liver-directed therapies, this allows us to be confident that this is a true denominator. In addition, since there is really only 1 other academic center, and that is Lexington, which draws more toward the east of the state, we have been fortunate to be able to see a lot of these patients at the initial management.

So I think our denominator is fairly robust. I think we probably do lose some patients south to Nashville as well as north to Cincinnati, but I would also argue that both the cirrhotic and noncirrhotic patients are probably being referred to those other centers because they may actually be closer geographically.

The increasing incidence of HCC: yes, I think there is obviously the latency period of hepatitis B and C, but I do believe that this rising incidence of this variant HCC is real. The main focus of this manuscript is hopefully awareness, greater acceptance of it, and, more important, greater accuracy in treating these patients, since, as I have said before, systemic chemotherapy is really not beneficial for them.

John J. Brems, MD, Burr Ridge, Ill: This is a phenomenon that I think others are seeing, too. One of my thoughts is, since you are seeing it in older patients and since this group seems to have a higher proportion of female patients, as opposed to your cirrhotic patients, do you think these could be hepatic adenomas that are undergoing malignant transformation?

Dr Martin: Without a doubt, I think it is a possibility. The other is simply a new genetic distribution because of the aging population. Are we seeing that type of dedifferentiation or loss of that consistent regeneration as patients are getting older? It is a possibility. Obviously it remains to be seen.

William C. Chapman, MD, St Louis, Mo: We live only a few hours west of you, and I will tell you that we do not see this phenomenon. Eighty percent of our patients who have HCC have associated liver disease. I think that is more in keeping, as you point out, with what has been published. I would be very skeptical, based on your single-center experience, to conclude that 60% of your patients with HCC are unassociated with liver disease. This point was mentioned earlier by Dr Stain: I would be pretty skeptical on the basis of 1 report.

I think your point of saying to consider that your patient may be noncirrhotic and may be able to undergo standard resection is an important one, but I think you need a lot more data before you can jump to the conclusion that the epidemiology is changing. We are seeing a big increase in HCC, as are others. In our experience it is in large part related to increased incidence of nonalcoholic steatohepatitis and hepatitis C.

A question for you: Who are you considering for liver transplantation? You mentioned that in your group you had transplant surgeons and, I guess, hepatologists involved. How do you structure that? You also have a pretty high recurrence rate. Are you considering transplantation in any of your noncirrhotic patients? You pointed out that 11%, I think, had had transplantations. Could you comment a little on how transplantation is factored in in your center?

Dr Martin: I understand your skepticism, but we also mentioned that there must be a referral bias to a transplant center as well known as yours (ie, only cirrhotic patients). Obviously, the rate of 60% is probably higher than seen in other centers, but I think obviously the national trends have shown that the incidence rate is far higher than the 5%, or even the 10%, that continues to be quoted. I think the main issue is to keep it in mind, keep it aware. We have had some fairly stringent evaluation of our hepatic parenchyma, so we are very confident of our diagnosis.

In regard to whom we perform transplantations on, transplantation, again, falls under the Milan criteria. I think there are few data to suggest that transplantation should be the first treatment option in a noncirrhotic patient with resectable disease. Some of our patients do undergo, as you reported in the Journal of American College of Surgeons, pretransplant therapy to better assess the biology of disease and to evaluate if transplantation would be indicated. The majority of these patients, though, do present with lesions greater than 5 cm as presented in the data, so they obviously fall outside the established Milan criteria.

Stephen G. Jolley, MD, Anchorage, Alaska: In your nonhepatitic, noncirrhotic patients with hepatoma, are any of them related by blood?

Dr Martin: A great question. I cut out a slide for the interest of time. Family history was not a factor in our incidence, and we take a thorough family history as part of the database just to begin to sort out those trends.

Financial Disclosure: Dr Chapman is a founder of Pathfinder Therapeutics, Inc.

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