Focal nodular hyperplasia (FNH) and hepatocellular adenoma (HCA) are benign hepatocellular tumors. The risk of bleeding and malignant transformation of HCA are strong arguments to differentiate HCA from FNH. Despite great progress that has been made in the differential radiological diagnosis of the 2 types of nodules, liver biopsy is sometimes necessary to separate the 2 entities. Identification of HCA subtypes using immunohistochemical techniques, namely, HNF1A-inactivated HCA (35–40%), inflammatory HCA (IHCA), and beta-catenin-mutated inflammatory HCA (b-IHCA) (50–55%), beta-catenin-activated HCA (5–10%), and unclassified HCA (10%) has greatly improved the diagnostic accuracy of benign hepatocellular nodules. If HCA malignant transformation occurs in all HCA subgroups, the risk is by far the highest in the β-catenin-mutated subgroups (b-HCA, b-IHCA). In the coming decade the management of HCA will be more dependent on the identification of HCA subtypes, particularly for smaller nodules (<5？cm) in terms of imaging, follow-up, and resection. 1. Introduction The knowledge of benign hepatocellular tumors, that is, focal nodular hyperplasia (FNH) and hepatocellular adenoma (HCA), has considerably progressed in the last 10 years, thanks to molecular biology, followed by immunohistochemical applications. Following these advances, new classification is now largely used, first in France, and more recently in other European, American, and East countries. The aims of this study are (1) to make a brief general overview of these 2 entities [2–8]; (2) to report results of a survey through different academic centers in France and throughout the world; (3) to report applications of the molecular/immunohistochemical data and of the new HCA classification in practice through the Bordeaux experience. 2. A Brief Overview of Focal Nodular Hyperplasia and Hepatocellular Adenoma 2.1. Focal Nodular Hyperplasia It is the second most frequent benign liver nodule (after hemangioma), occurring in 0.8% of an adult autopsy population and has been reported in 0.6–3% of the general population. In 80–90% of cases, FNH is discovered in women in their third or fourth decade. In countries (i.e., China) where OC use has been less prevalent, FNH tends to be a lesion of adult men or children of either gender. FNH is solitary in 2/3 of cases. Most lesions are asymptomatic and are therefore discovered as incidental findings during surgery, autopsy, or imaging procedures for unrelated symptoms. Large lesions can present with abdominal pain or compression of adjacent organs. Reports of
References
[1]
P. Bioulac-Sage, G. Cubel, S. Taouji, et al., “Immunohistochemical markers on needle biopsies are helpful for the diagnosis of focal nodular hyperplasia and hepatocellular adenoma subtypes,” American Journal of Surgical Pathology, vol. 36, no. 11, pp. 1691–1699, 2012.
[2]
S. Rebouissou, P. Bioulac-Sage, and J. Zucman-Rossi, “Molecular pathogenesis of focal nodular hyperplasia and hepatocellular adenoma,” Journal of Hepatology, vol. 48, no. 1, pp. 163–170, 2008.
[3]
J. Zucman-Rossi, E. Jeannot, J. T. Van Nhieu et al., “Genotype-phenotype correlation in hepatocellular adenoma: new classification and relationship with HCC,” Hepatology, vol. 43, no. 3, pp. 515–524, 2006.
[4]
A. K. Shanbhogue, S. R. Prasad, N. Takahashi, R. Vikram, and D. V. Sahani, “Recent advances in cytogenetics and molecular biology of adult hepatocellular tumors: implications for imaging and management,” Radiology, vol. 258, no. 3, pp. 673–693, 2011.
[5]
P. Bioulac-Sage, C. Balabaud, P. Bedossa et al., “Pathological diagnosis of liver cell adenoma and focal nodular hyperplasia: Bordeaux update,” Journal of Hepatology, vol. 46, no. 3, pp. 521–527, 2007.
[6]
V. Paradis, A. Benzekri, D. Dargére et al., “Telangiectatic focal nodular hyperplasia: a variant of hepatocellular adenoma,” Gastroenterology, vol. 126, no. 5, pp. 1323–1329, 2004.
[7]
V. Paradis, A. Laurent, J. F. Flejou, M. Vidaud, and P. Bedossa, “Evidence for the polyclonal nature of focal nodular hyperplasia of the liver by the study of X-chromosome inactivation,” Hepatology, vol. 26, no. 4, pp. 891–895, 1997.
[8]
P. Bioulac-Sage, S. Rebouissou, A. Sa Cunha et al., “Clinical, morphologic, and molecular features defining so-called telangiectatic focal nodular hyperplasias of the liver,” Gastroenterology, vol. 128, no. 5, pp. 1211–1218, 2005.
[9]
S. Rebouissou, G. Couchy, L. Libbrecht et al., “The β-catenin pathway is activated in focal nodular hyperplasia but not in cirrhotic FNH-like nodules,” Journal of Hepatology, vol. 49, no. 1, pp. 61–71, 2008.
[10]
P. Bioulac-Sage, S. Taouji, L. Possenti, and C. Balabaud, “Hepatocellular adenoma subtypes: the impact of overweight and obesity,” Liver International, vol. 32, no. 8, pp. 1217–1221, 2012.
[11]
V. Paradis, A. Champault, M. Ronot et al., “Telangiectatic adenoma: an entity associated with increased body mass index and inflammation,” Hepatology, vol. 46, no. 1, pp. 140–146, 2007.
[12]
M. Sasaki and Y. Nakanuma, “Overview of hepatocellular adenoma in Japan,” International Journal of Hepatology, vol. 2012, Article ID 648131, 6 pages, 2012.
[13]
H. Lin, J. Van Den Esschert, C. Liu, and T. M. Van Gulik, “Systematic review of hepatocellular adenoma in China and other regions,” Journal of Gastroenterology and Hepatology, vol. 26, no. 1, pp. 28–35, 2011.
[14]
P. Bioulac-Sage, H. Laumonier, and C. Balabaud, “Benign hepatocellular tumors,” in Practical Hepatic Pathology, R. Saxena, Ed., pp. 473–488, Elsevier Saunders, Philadelphia, Pa, USA, 2010.
[15]
P. Bioulac-Sage, C. Balabaud, and I. Wanless, “Focal nodular hyperplasia and hepatocellular adenoma,” in Tumors of the Digestive Tract, World Health Organization, F. Bosman, F. Carneiro, R. Hruban, and N. D. Theise, Eds., pp. 198–204, IARC, Lyon France, 2nd edition, 2010.
[16]
P. Bioulac-Sage, G. Cubel, C. Balabaud, and J. Zucman-Rossi, “Revisiting the pathology of resected benign hepatocellular nodules using new immunohistochemical markers,” Seminars in Liver Disease, vol. 31, no. 1, pp. 91–103, 2011.
[17]
P. Bioulac-Sage, G. Cubel, and C. Balabaud, “Pathological diagnosis of hepatocellular adenoma in clinical practice,” Diagnostic Histopathology, vol. 17, no. 12, pp. 521–529, 2011.
[18]
P. Bioulac-Sage, S. Rebouissou, C. Thomas et al., “Hepatocellular adenoma subtype classification using molecular markers and immunohistochemistry,” Hepatology, vol. 46, no. 3, pp. 740–748, 2007.
[19]
P. Bioulac-Sage, H. Laumonier, A. Rullier et al., “Over-expression of glutamine synthetase in focal nodular hyperplasia: a novel easy diagnostic tool in surgical pathology,” Liver International, vol. 29, no. 3, pp. 459–465, 2009.
[20]
S. Van Der Borght, L. Libbrecht, A. Katoonizadeh et al., “Nuclear β-catenin staining and absence of steatosis are indicators of hepatocellular adenomas with an increased risk of malignancy,” Histopathology, vol. 51, no. 6, pp. 855–856, 2007.
[21]
A. F. Manichon, B. Bancel, M. Durieux-Millon et al., “Hepatocellular adenoma: evaluation with contrast-enhanced ultrasound and MRI and correlation with pathologic and phenotypic classification in 26 lesions,” HPB Surgery, vol. 2012, Article ID 418745, 12 pages, 2012.
[22]
M. Sasaki, N. Yoneda, S. Kitamura, Y. Sato, and Y. Nakanuma, “Characterization of hepatocellular adenoma based on the phenotypic classification: the Kanazawa experience,” Hepatology Research, vol. 41, no. 10, pp. 982–988, 2011.
[23]
S. M. van Aalten, J. Verheij, T. Terkivatan, R. S. Dwarkasing, R. A. De Man, and J. N. M. Ijzermans, “Validation of a liver adenoma classification system in a tertiary referral centre: implications for clinical practice,” Journal of Hepatology, vol. 55, no. 1, pp. 120–125, 2011.
[24]
C. O. C. Bellamy, R. S. Maxwell, S. Prost, I. A. Azodo, J. J. Powell, and J. R. Manning, “The value of imunophenotyping hepatocellular adenomas—consecutive resections at one UK centre,” Histopathology, vol. 62, no. 3, pp. 431–445, 2012.
[25]
P. Bioulac-Sage, H. Laumonier, G. Couchy et al., “Hepatocellular adenoma management and phenotypic classification: the Bordeaux experience,” Hepatology, vol. 50, no. 2, pp. 481–489, 2009.
[26]
M. Ronot, S. Bahrami, J. Calderaro et al., “Hepatocellular adenomas: accuracy of magnetic resonance imaging and liver biopsy in subtype classification,” Hepatology, vol. 53, no. 4, pp. 1182–1191, 2011.
[27]
H. Laumonier, P. Bioulac-Sage, C. Laurent, J. Zucman-Rossi, C. Balabaud, and H. Trillaud, “Hepatocellular adenomas: magnetic resonance imaging features as a function of molecular pathological classification,” Hepatology, vol. 48, no. 3, pp. 808–818, 2008.
[28]
S. M. van Aalten, M. G. Thomeer, T. Terkivatan et al., “Hepatocellular adenomas: correlation of MR imaging findings with pathologic subtype classification,” Radiology, vol. 261, pp. 172–181, 2011.
[29]
M. Bieze, J. W. van den Esschert, C. Y. Nio et al., “Diagnostic accuracy of MRI in differentiating hepatocellular adenoma from focal nodular hyperplasia: prospective study of the additional value of gadoxetate disodium,” American Journal of Roentgenology, vol. 199, no. 1, pp. 26–34, 2012.
[30]
L. Grazioli, M. P. Bondioni, H. Haradome et al., “Hepatocellular adenoma and focal nodular hyperplasia: value of gadoxetic acid-enhanced MR imaging in differential diagnosis,” Radiology, vol. 262, pp. 520–529, 2012.
[31]
H. Laumonier, H. Cailliez, C. Balabaud et al., “Role of contrast-enhanced sonography in differentiation of subtypes of hepatocellular adenoma: correlation with MRI findings,” American Journal of Roentgenology, vol. 199, no. 2, pp. 341–348, 2012.
[32]
T. Denecke, I. G. Steffen, S. Agarwal et al., “Appearance of hepatocellular adenomas on gadoxetic acid-enhanced MRI,” European Radiology, vol. 22, no. 8, pp. 1769–1775, 2012.
[33]
J. W. van den Esschert, T. M. Van Gulik, and S. S. K. S. Phoa, “Imaging modalities for focal nodular hyperplasia and hepatocellular adenoma,” Digestive Surgery, vol. 27, no. 1, pp. 46–55, 2010.
[34]
V. S. Katabathina, C. O. Menias, A. K. Shanbhogue, J. Jagirdar, R. M. Paspulati, and S. R. Prasad, “Genetics and imaging of hepatocellular adenomas: 2011 update,” Radiographics, vol. 31, no. 6, pp. 1529–1543, 2011.
[35]
N. Yoneda, O. Matsui, A. Kitao et al., “Beta-catenin-activated hepatocellular adenoma showing hyperintensity on hepatobiliary-phase gadoxetic-enhanced magnetic resonance imaging and overexpression of OATP8,” Japanese Journal of Radiology, vol. 30, no. 9, pp. 777–782, 2012.
[36]
S. Dokmak, V. Paradis, V. Vilgrain et al., “A single-center surgical experience of 122 patients with single and multiple hepatocellular adenomas,” Gastroenterology, vol. 137, no. 5, pp. 1698–1705, 2009.
[37]
S. M. van Aalten, C. D. Witjes, R. A. de Man, J. N. Ijzermans, and T. Terkivatan, “Can a decision-making model be justified in the management of hepatocellular adenoma?” Liver International, vol. 32, no. 1, pp. 28–37, 2012.
[38]
T. Terkivatan and J. N. M. Ijzermans, “Hepatocellular adenoma: should phenotypic classification direct management?” Nature Reviews Gastroenterology and Hepatology, vol. 6, no. 12, pp. 697–698, 2009.
[39]
S. M. van Aalten, M. E. Br？ker, J. J. van Busschbach et al., “Pregnancy and liver adenoma management: PALM study,” BMC Gastroenterology, vol. 12, p. 82, 2012.
[40]
S. M. van Aalten, R. A. de Man, J. N. IJzermans, and T. Terkivatan, “Systematic review of haemorrhage and rupture of hepatocellular adenomas,” British Journal of Surgery, vol. 99, no. 7, pp. 911–916, 2012.
[41]
V. A. L. Huurman and A. F. M. Schaapherder, “Management of ruptured hepatocellular adenoma,” Digestive Surgery, vol. 27, no. 1, pp. 56–60, 2010.
[42]
Y. C. Bo and M. H. Nguyen, “The diagnosis and management of benign hepatic tumors,” Journal of Clinical Gastroenterology, vol. 39, no. 5, pp. 401–412, 2005.
[43]
J. F. Gibbs, A. M. Litwin, and M. S. Kahlenberg, “Contemporary management of benign liver tumors,” Surgical Clinics of North America, vol. 84, no. 2, pp. 463–480, 2004.
[44]
L. Chiche, T. Dao, E. Salamé et al., “Liver adenomatosis: reappraisal, diagnosis, and surgical management: eight new cases and review of the literature,” Annals of Surgery, vol. 231, no. 1, pp. 74–81, 2000.
[45]
H. Yoshidome, K. M. McMasters, and M. J. Edwards, “Management issues regarding hepatic adenomatosis,” American Surgeon, vol. 65, no. 11, pp. 1070–1076, 1999.
[46]
A. Perrakis, V. Muller, K. Oeckl et al., “Indications and long-term outcome after elective surgery for hepatocellular adenoma,” The American Surgeon, vol. 78, pp. 80–85, 2012.
[47]
M. Abu Hilal, F. Di Fabio, R. D. Wiltshire, M. Hamdan, D. M. Layfield, and N. W. Pearce, “Laparoscopic liver resection for hepatocellular adenoma,” World Journal of Gastrointestinal Surgery, vol. 27, no. 3, pp. 101–105, 2011.
[48]
M. Abu Hilal, F. Di Fabio, M. J. Teng, D. A. Godfrey, J. N. Primrose, and N. W. Pearce, “Surgical management of benign and indeterminate hepatic lesions in the era of laparoscopic liver surgery,” Digestive Surgery, vol. 28, pp. 232–236, 2011.
[49]
C. H. Wilson, D. M. Manas, and J. J. French, “Laparoscopic liver resection for hepatic adenoma in pregnancy,” Journal of Clinical Gastroenterology, vol. 45, no. 9, pp. 828–833, 2011.
[50]
S. Dardenne, C. Hubert, C. Sempoux et al., “Conservative and operative management of benign solid hepatic tumours: a successful stratified algorithm,” European Journal of Gastroenterology and Hepatology, vol. 22, no. 11, pp. 1337–1344, 2010.
[51]
J. F. Buell, H. Tranchart, R. Cannon, and I. Dagher, “Management of benign hepatic tumors,” Surgical Clinics of North America, vol. 90, no. 4, pp. 719–735, 2010.
[52]
A. G. Lopes Jr. and A. C. M. Duarte, “Clinical presentation and management of liver adenoma hemorrhagic complications,” American Surgeon, vol. 76, no. 6, pp. 654–655, 2010.
[53]
M. A. F. Ribeiro Junior, E. Chaib, W. A. Saad, L. A. C. D'Albuquerque, and I. Cecconello, “Surgical management of spontaneous ruptured hepatocellular adenoma,” Clinics, vol. 64, no. 8, pp. 775–779, 2009.
[54]
S. W. Cho, J. W. Marsh, J. Steel et al., “Surgical management of hepatocellular adenoma: take it or leave it?” Annals of Surgical Oncology, vol. 15, no. 10, pp. 2795–2803, 2008.
[55]
J. F. Gigot, C. Hubert, R. Banice, and M. L. Kendrick, “Laparoscopic management of benign liver diseases: where are we?” HPB Journal, vol. 6, no. 4, pp. 197–212, 2004.
[56]
C. Toso, P. Majno, A. Andres et al., “Management of hepatocellular adenoma: solitary-uncomplicated, multiple and ruptured tumors,” World Journal of Gastroenterology, vol. 11, no. 36, pp. 5691–5695, 2005.
[57]
K. J. Evason, J. P. Grenert, L. D. Ferrell, and S. Kakar, “Atypical hepatocellular adenoma-like neoplasms with β-catenin activation show cytogenetic alterations similar to well-differentiated hepatocellular carcinomas,” Human Pathology, 2012.
[58]
J. H. Stoot, R. J. Coelen, M. C. De Jong, and C. H. Dejong, “Malignant transformation of hepatocellular adenomas into hepatocellular carcinomas: a systematic review including more than 1600 adenoma cases,” HPB Journal, vol. 12, no. 8, pp. 509–522, 2010.
[59]
O. Farges, N. Ferreira, S. Dokmak et al., “Hepatocellular carcinoma arising from hepatocellular adenoma in a hepatitis B virus-associated cirrhotic liver,” Clinical Radiology, vol. 67, no. 4, pp. 329–333, 2012.
[60]
M. Sasaki, N. Yoneda, S. Kitamura, Y. Sato, and Y. Nakanuma, “A serum amyloid A-positive hepatocellular neoplasm arising in alcoholic cirrhosis: a previously unrecognized type of inflammatory hepatocellular tumor,” Modern Pathology, vol. 25, no. 12, pp. 1584–1593, 2012.
