CANCER BIOLOGY & THERAPY 2016, VOL. 17, NO. 7, 727–731 http://dx.doi.org/10.1080/15384047.2016.1177682
RESEARCH PAPER
Synchronous giant hepatic adenoma in siblings-A case report and brief literature review Chengsheng Zhanga,b,*, Xuetao Shia,*, and Lei Zhaoa a Shandong Provincial Cancer Hospital and Institute, Shandong Academy of Medical Science, Jinan, China; bSchool of Medicine and Life Sciences, University of Jinan-Shandong Academy of Medical Sciences, Jinan, China
ABSTRACT
ARTICLE HISTORY
A 47-year-old woman was referred to our department for a hepatic mass. She denied history of hepatitis or alcohol consumption and regular oral contraceptive use, except for the emergency contraceptive pill taken once a decade ago. Hepatitis B surface antigen and anti-hepatitis C antibody were negative, a-fetoprotein was within normal limit. CT scan revealed an enormous mass measuring 26.0£16 5£13 0 cm that almost totally replaced the right hepatic lobe. The neoplasm was completely resected and pathologically diagnosed as hepatic adenoma. Literature review indicates this is the largest hepatic adenoma reported so far. At the same time, clinical examination also revealed a hepatic mass in the patient’s 42-year-old brother, which was pathologically confirmed as hepatic adenoma, too. He denied history of anabolic steroid use. Immunohistochemical analysis revealed the subtypes of both tumors as the inflammatory hepatic adenoma. Literature review indicates this is the first report of synchronous hepatic adenomas in siblings.
Received 11 January 2016 Revised 15 March 2016 Accepted 8 April 2016
Introduction Hepatocellular adenoma (HA; also known as hepatic adenoma, liver cell adenoma, etc.) is a very rare primary benign neoplasm originated from hepatocytes. HAs are seen principally in women during the period of reproductive activity. Its incidence is significantly lower in men than in women.1 The pathogenesis of HA has generally been associated with the use of steroid. In females, oral intake of contraceptive pills is the dominating source2; while in males (mainly bodybuilders), anabolic steroid intake is the most common reason.3-5 Here we report a case of HAs synchronously diagnosed and surgically treated across siblings.
Case report A 47-year-old woman was referred to our specialist tertiary referral center following a diagnosis of primary liver cancer at her local hospital. Routine clinical examination at the local hospital revealed a giant palpable abdominal mass, while abdominal ultrasonography (US) revealed a giant neoplastic lesion in her liver, and the finding of which was confirmed by computed tomography (CT). Despite evidence advanced pathology, the patient was asymptomatic, except for a vague right upper quadrant fullness. She denied a history of regular oral contraceptive use, except for the emergency contraceptive pill taken once a decade ago. There was no history of hepatitis or alcohol consumption. Liver functional tests revealed a slight elevation in conjugated and unconjugated bilirubin (conjugated bilirubin, 4.0 mmol/L, reference range 0–3.4 mmol/L; unconjugated bilirubin, 12.8 mmol/L, reference range 1.7–10.2 mmol/L); alanine CONTACT Lei Zhao [email protected] * These authors equally contributed to this work. © 2016 Taylor & Francis Group, LLC
KEYWORDS
Environment and public health; hepatocellular adenoma; steroid
transaminase (ALT) and aspartate transaminase (AST) were within normal ranges, while alkaline phosphatase (ALP) and g-glutamyl transpeptidase (g-GGT) levels were both significantly elevated (ALP, 380 U/L, reference range 40–150 U/L; g-GGT, 267 U/L, reference range 7–32 U/L). Hepatitis B surface antigen, e antigen and anti-hepatitis C antibody were negative while the hepatitis B surface antibody, e antibody and hepatitis B core antibody were all positive. Carcinoembryonic antigen, a-fetoprotein, CA19–9 and CA125 were all within normal limits. Fasting blood glucose was normal (4.9 mmol/L, reference range 3.9–6.1 mmol/L). A CT scan performed at our institution revealed an enormous heterogeneous mass measuring 26.0 £ 16 .5 £ 13 .0 cm which totally replaced the right hepatic lobe. On unenhanced CT, the mass was slightly hypoattenuating and well defined, containing irregular, hypodense regions and a limited degree of calcification. On contrast-enhanced CT scan, the mass exhibited significant heterogeneous enhancement during the arterial phase, which decreased and became isoattenuating during portal and delayed phase scans (Fig. 1A). Some irregular hypodense regions in unenhanced CT showed no enhancement in the arterial and portal phases. There was no concurrent cirrhosis and the mass did not appear to invade local vasculature. Based on the imaging findings, we considered this a benign, non-vascular hepatic tumor. A right hemihepatectomy was performed to remove the mass. At surgery, we found the mass had nearly replaced the whole right hepatic lobe; it abutted and compressed the middle hepatic veins and the retrohepatic inferior vena cava, and extended inferiorly from hepatic segment
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Figure 1. Giant hepatic adenoma of the sister. (A) CT scan; clockwise from upper-left: Unenhanced scan, arterial phase of contrast enhanced scan, delayed phase of contrast enhanced scan, portal phase of contrast enhanced scan. (B) In situ hepatic adenoma. (C) View of resected hepatic adenoma. (D) Histology of resected hepatic adenoma.
VI pushing the right kidney toward the midline (Fig. 1B–C). The patient recovered without complications. Macroscopically, the mass appeared as a well-demarcated greyish red and yellow tumor with large surface vessels. Hemorrhagic regions were discovered in the middle of the tumor. No fibrous capsule was found and the surrounding liver tissue was normal. Microscopically, the tumor was composed of cells closely resembled mature hepatocytes, which organized in plates, mainly 1 to 2 cells thick. The tumor hepatocytes had normal cytoplasm and nucleus, and the nuclear atypia or mitoses were not found. There was a notable absence of fibrosis, and no bile duct or portal vein was found. The neoplasm was pathologically diagnosed as hepatic adenoma (HA) (Fig. 1D). Before the patient was discharged, her 42-year-old brother described vague abdominal pain and ultrasound revealed a hepatic neoplastic lesion. While the brother consumed 40–75 g of alcohol per day for the preceding 25 y there was no history of anabolic steroid use and physical examination was unremarkable. Liver functional tests revealed a normal bilirubin and ALP but elevated ALT (80U/L, reference range 5–40 U/L), AST (50U/L, reference range 8–40 U/L) and g-GGT (131 U/L, reference range 11– 50 U/L). Hepatitis B surface antigen, e antigen and anti-hepatitis C antibody were negative while the hepatitis B surface antibody, e antibody and hepatitis B core antibody were positive. Tumor markers were again negative. Fasting blood glucose was normal.
Unenhanced CT confirmed low density liver parenchyma and an isoattenuating mass measuring 5.2 £ 3 .8 £ 4 .8 cm in the right lobe, containing hypodense regions. On contrast-enhanced scan, there was moderate enhancement in the arterial and portal phases, without significant clearance in the delayed scan. On Magnetic Resonance imaging, the mass appeared hypointense in T1-weighted, T2-weighted, diffusion weighted and fat-suppressed images (Fig. 2A). It showed heterogeneous, mild enhancement in the arterial phase on dynamic gadolinium-enhanced imaging, remained enhanced in the portal and hepatic parenchymal phases turning hypointense in the delayed scan. Similarly to his sibling, a diagnosis of benign non-vascular hepatic tumor was made, and at surgery (Fig. 2B–C) a tumor later confirmed histologically as a HA (Fig. 2D) was resected. The tumor had similar pathologic features as that of his siblings but showed the following different features: significant inflammatory infiltration, sinusoidal dilatation and frequent steatosis. He recovered without complication. To further confirm the diagnosis of HA, as well as to clarify their molecular subtypes, immunohistochemistry on tissue samples from both cases were performed with the following four markers: liver fatty acid binding protein (LFABP), C reactive protein (CRP), b-catenin and glutamine synthase (GS). The results were carefully examined and interpreted by two pathologists.
CANCER BIOLOGY & THERAPY
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Figure 2. Hepatic adenoma of the brother. (A) Magnetic Resonance imaging; clockwise from upper-left: T1-weighted image, T2-weighted image, fat suppressed image, diffusion weighted image. (B) In situ hepatic adenoma. (C) View of resected hepatic adenoma. (D) Histology of resected hepatic adenoma.
In the tumor from the brother, both LFABP and CRP showed diffuse positive cytoplasmic staining; b-catenin staining was confined in membrane, while the bona fide positive staining should be cytoplasmic /nuclear, so it was negative; positive GS staining were confined in hepatocytes around veins. When these added up, together with its pathological features in H&E staining, the brother’s HA was classified as typical IHA (Fig. 3A). In the tumor from the sister, staining patterns of LFABP and b-catenin were very similar to the brother’s HA; the CRP staining was also positive; the GS staining was heterogeneous, it was strong and diffuse in some regions, but confined around veins in other regions; in this case, b-catenin mutation should rely on b-catenin staining, which was negative. When taken together, both pathologists agreed to still classify its subtype as IHA (Fig. 3B).
Discussion On average, HAs measure between 8 and 15 cm6; with reports of giant HA >20 cm being seldom.1,7 Thus this case of familial HA describes the largest reported in the literature. The main complications of HA are rupture, hemorrhage and malignant transformation, the incidence of which increase with increasing adenoma size.8,9 For giant HAs, surgical excision at an experienced liver surgery unit is the gold standard treatment option.1
Our literature review also indicates that this is the first report of HA in siblings. Maturity onset diabetes of the young type 3 (MODY3) is an autosomal dominantly inherited form of diabetes, it is associated with heterozygous mutations in the HNF1a gene, which is also related to HA.10,11 A clinical study revealed that all subjects with MODY3 had been diagnosed before 25 y of age and required drug therapy for blood glucose control, so it was concluded that a diabetes diagnosis after 25 y of age or the absence of a need for drug therapy to control glycaemia from this age should exclude a MODY3 diagnosis.12 In this case, the age of the patients was 47 and 42 y old, respectively, and both of them showed normal fasting blood glucose. Close questioning about the family history revealed that the two patients have other two siblings, and totally they have 6 children, the ages of the children ranges from 10s to 20s; the two patients’ father has 2 brothers, their mother has one brother, and none of these 15 family members is diabetic. Taking together, the diagnosis of MODY3 can be safely excluded. Thanks to the recent progress in the molecular biology of HA, through the exploration of its genotype–phenotype correlation, Zucman-Rossi et al. classified HA into three subgroups based on the mutation status of HNF1a (hepatocytes nuclear factor 1a) and b-catenin. Their featured phenotypic and molecular characteristics are summarized in Table 1.13 To date four major subtypes of HA have been identified, they are HNF1a mutated HA (H-HA), b-catenin mutated HA (b-HA), inflammatory HA (IHA); IHA can be also b-catenin mutated (b-IHA). Less than
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Figure 3. Subtype classification by immunohistochemical analysis. (A) The brother’s HA; (B) The sister’s HA. From upper panels to lower panels: LFABP, b-catenin, CRP and GS. All original magnifications are 100£; the magnification of the insets in b-catenin is 200£ to show the sub-cellular distribution of the positive staining, and the magnification of the insets in GS is 40£ to show the homogeneous or heterogeneous distribution of the positive staining.
10% of HA remain unclassified.14 A phenotypic classification using a panel of immunohistochemistry has been developed from these molecular characterizations. LFABP, SAA(serum amyloid A)/CRP, GS and b-catenin immunohistochemical analyses performed on surgical samples can discriminate FNH (focal nodular hyperplasia) from HA and identify the different HA subtypes.14
According to the immunohistochemical results, both tumors were confirmed to be HA; the brother’s tumor showed typical features of the inflammatory HA, although the sister’s tumor was less typical, it was still classified to the same subtype (Fig. 3). The pathogenesis of hepatic adenoma is strongly associated with the long-term use of oral contraceptives,2 while the risk of HA following short-term use (less than 2 years) is debatable.15 Leese et al. report a case of HA following oral contraceptive use for only 15 d predating presentation by 2 decades.1 In our female patient the emergency contraceptive pill was taken once 10 y prior to presentation, and we believe that it is therefore unlikely the development of HA resulted from iatrogenic estrogen exposure. HA is a very rare, benign neoplasm with significant female preponderance; its incidence in males is 10-fold lower than females.1 It is less likely that these two cases of HA in siblings were just sporadic. Considering the simultaneous onset and the same molecular subtype, we suspect that same exogenous factors may contribute to the development of HAs in the siblings. Closer questioning revealed that the siblings have been raising pigs since 2008. Interestingly, she raises 4 sows among all 60 pigs. The waste of livestock has been proved to be one of the major sources of environmental estrogen,16,17 and compared with piglets and barrows, sows produce varied classes of steroids, including estrogens and androgens, at much higher concentrations.18 The onset of HA in fish has been reported to be associated with the environmental contamination including steroids.19 We therefore suspect whether the environmental steroid exposure might, to some extent, contribute to the simultaneous development of HA in two siblings. Here we could not confirm this speculation with convincing evidence, and indeed it could just be a simple while extremely rare coincidence. Further carefully designed, large-scale clinical investigation is needed to confirm or deny the connection between environmental contamination and the pathogenesis of HA.
Table 1. Phenotypic and molecular characteristics of four subgroups of hepatic adenoma Molecular Characteristics
HNF1a Mutated HA Germline
HNF1a Mutation B-Catenin Mutation
Yes, Germline No
Inflammatory Infiltration Morphological Features Steatosis Pseudo-Glandular Formation Cytological Abnormalities Tumor Clinical Features Connection With HCC Age Of Patients Oral Contraception History Female Dominancy Familiar Adenomatosis
b-Catenin Mutated HA Somatic
Non-Mutated HA
Inflammatory
No No
No
Infrequent
Yes, Somatic Yes; Overexpressing B-Catenin Target Genes Less Frequent
Yes; Focal Or Diffuse
No
Marked Steatosis Less Frequent Infrequent Larger, More Numerous
Infrequent Frequent Frequent Smaller, Less Numerous
Less Frequent Infrequent Frequent More Solitary
Infrequent Younger Frequent Significant Frequent
Significant Elder Less Frequent Less Significant Less Frequent
Infrequent No Specific Frequent Significant No Specific
Non-Inflammatory
No Specific
More Solitary No Specific No Specific Frequent No Specific
CANCER BIOLOGY & THERAPY
Disclosure of potential conflicts of interest No potential conflicts of interest were disclosed.
References 1. Leese T, Farges O, Bismuth H. Liver cell adenomas. A 12-year surgical experience from a specialist hepato-biliary unit. Annals Surg 1988; 208:558-64; PMID:3190282; http://dx.doi.org/10.1097/00000658198811000-00003 2. Rooks JB, Ory HW, Ishak KG, Strauss LT, Greenspan JR, Hill AP, Tyler CW, Jr. Epidemiology of hepatocellular adenoma. The role of oral contraceptive use. JAMA 1979; 242:644-8; PMID:221698; http:// dx.doi.org/10.1001/jama.1979.03300070040020 3. Martin NM, Abu Dayyeh BK, Chung RT. Anabolic steroid abuse causing recurrent hepatic adenomas and hemorrhage. World J Gastroenterol 2008; 14:4573-5; PMID:18680242; http://dx.doi.org/10.3748/ wjg.14.4573 4. Socas L, Zumbado M, Perez-Luzardo O, Ramos A, Perez C, Hernandez JR, Boada LD. Hepatocellular adenomas associated with anabolic androgenic steroid abuse in bodybuilders: a report of two cases and a review of the literature. Br J Sports Med 2005; 39:e27; PMID:15849280; http://dx.doi.org/ 10.1136/bjsm.2004.013599 5. Soe KL, Soe M, Gluud C. Liver pathology associated with the use of anabolic-androgenic steroids. Liver 1992; 12:73-9; PMID:1535676; http://dx.doi.org/10.1111/j.1600-0676.1992.tb00560.x 6. Chaib E, Gama-Rodrigues J, Ribeiro MA, Jr, Herman P, Saad WA. Hepatic adenoma. Timing for surgery. Hepato-Gastroenterol 2007; 54:1382-7; PMID:17708259 7. von Riedenauer WB, Shanti CM, Abouljoud MS. Resection of giant liver adenoma in a 17-year-old adolescent boy using venovenous bypass, total hepatic vascular isolation, and in situ cooling. J Pediatr Surg 2007; 42:E23-7; PMID:17706483; http://dx.doi.org/10.1016/j. jpedsurg.2007.05.045 8. Deneve JL, Pawlik TM, Cunningham S, Clary B, Reddy S, Scoggins CR, Martin RC, D’Angelica M, Staley CA, Choti MA, et al. Liver cell adenoma: a multicenter analysis of risk factors for rupture and malignancy. Annals Surg Oncol 2009; 16:640-8; PMID:19130136; http://dx.doi.org/10.1245/ s10434-008-0275-6 9. Farges O, Dokmak S. Malignant transformation of liver adenoma: an analysis of the literature. Digestive Surg 2010; 27:32-8; PMID:20357449; http:// dx.doi.org/10.1159/000268405 10. Reznik Y, Dao T, Coutant R, Chiche L, Jeannot E, Clauin S, Rousselot P, Fabre M, Oberti F, Fatome A, et al. Hepatocyte nuclear factor-1 a
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gene inactivation: cosegregation between liver adenomatosis and diabetes phenotypes in two maturity-onset diabetes of the young (MODY)3 families. J Clin Endocrinol Metab 2004; 89:1476-80; PMID:15001650; http://dx.doi.org/10.1210/jc.2003-031552 Bacq Y, Jacquemin E, Balabaud C, Jeannot E, Scotto B, Branchereau S, Laurent C, Bourlier P, Pariente D, de Muret A, et al. Familial liver adenomatosis associated with hepatocyte nuclear factor 1alpha inactivation. Gastroenterol 2003; 125:1470-5; PMID:14598263; http://dx. doi.org/10.1016/j.gastro.2003.07.012 Pines Corrales PJ, Lopez Garrido MP, Louhibi Rubio L, Aznar Rodriguez S, Lopez Jimenez LM, Lamas Oliveira C, Lozano Garcıa JJ, Alfaro Martınez JJ, Hernandez L opez A, Requejo Castillo R, et al. Importance of clinical variables in the diagnosis of MODY2 and MODY3. Endocrinol Nutr 2011; 58:341-6; PMID:21737366; http://dx.doi.org/ 10.1016/j.endonu.2011.05.002 Zucman-Rossi J, Jeannot E, Nhieu JT, Scoazec JY, Guettier C, Rebouissou S, Bacq Y, Leteurtre E, Paradis V, Michalak S, et al. Genotype-phenotype correlation in hepatocellular adenoma: new classification and relationship with HCC. Hepatol 2006; 43:515-24; PMID:16496320; http://dx.doi.org/10.1002/hep.21068 Bioulac-Sage P, Balabaud C, Zucman-Rossi J. Will the pathomolecular classification of hepatocellular adenomas improve their clinical management? J Hepatol 2011; 55:8-10; PMID:21300118; http://dx.doi.org/ 10.1016/j.jhep.2011.01.016 Naduka CC. Hepatic adenoma following short period of oral contraceptive use. J Am Board Family Practice / Am Board Family Practice 1999; 12:337-9; PMID:10477198; http://dx.doi.org/10.3122/ jabfm.12.4.337 Chen TS, Chen TC, Yeh KJ, Chao HR, Liaw ET, Hsieh CY, Chen KC, Hsieh LT, Yeh YL. High estrogen concentrations in receiving river discharge from a concentrated livestock feedlot. Sci Total Envir 2010; 408:3223-30; PMID:20451953; http://dx.doi.org/10.1016/j. scitotenv.2010.03.054 Yin GG, Kookana RS, Ru YJ. Occurrence and fate of hormone steroids in the environment. Envir Int 2002; 28:545-51; PMID:12503920; http://dx.doi.org/10.1016/S0160-4120(02)00075-2 Liu S, Ying GG, Zhou LJ, Zhang RQ, Chen ZF, Lai HJ. Steroids in a typical swine farm and their release into the environment. Water Res 2012; 46:3754-68; PMID:22591816; http://dx.doi.org/10.1016/j. watres.2012.04.006 Mirbahai L, Yin G, Bignell JP, Li N, Williams TD, Chipman JK. DNA methylation in liver tumorigenesis in fish from the environment. Epigenetics 2011; 6:1319-33; PMID:22048251; http://dx.doi.org/10.4161/ epi.6.11.17890
RESEARCH PAPER
Synchronous giant hepatic adenoma in siblings-A case report and brief literature review Chengsheng Zhanga,b,*, Xuetao Shia,*, and Lei Zhaoa a Shandong Provincial Cancer Hospital and Institute, Shandong Academy of Medical Science, Jinan, China; bSchool of Medicine and Life Sciences, University of Jinan-Shandong Academy of Medical Sciences, Jinan, China
ABSTRACT
ARTICLE HISTORY
A 47-year-old woman was referred to our department for a hepatic mass. She denied history of hepatitis or alcohol consumption and regular oral contraceptive use, except for the emergency contraceptive pill taken once a decade ago. Hepatitis B surface antigen and anti-hepatitis C antibody were negative, a-fetoprotein was within normal limit. CT scan revealed an enormous mass measuring 26.0£16 5£13 0 cm that almost totally replaced the right hepatic lobe. The neoplasm was completely resected and pathologically diagnosed as hepatic adenoma. Literature review indicates this is the largest hepatic adenoma reported so far. At the same time, clinical examination also revealed a hepatic mass in the patient’s 42-year-old brother, which was pathologically confirmed as hepatic adenoma, too. He denied history of anabolic steroid use. Immunohistochemical analysis revealed the subtypes of both tumors as the inflammatory hepatic adenoma. Literature review indicates this is the first report of synchronous hepatic adenomas in siblings.
Received 11 January 2016 Revised 15 March 2016 Accepted 8 April 2016
Introduction Hepatocellular adenoma (HA; also known as hepatic adenoma, liver cell adenoma, etc.) is a very rare primary benign neoplasm originated from hepatocytes. HAs are seen principally in women during the period of reproductive activity. Its incidence is significantly lower in men than in women.1 The pathogenesis of HA has generally been associated with the use of steroid. In females, oral intake of contraceptive pills is the dominating source2; while in males (mainly bodybuilders), anabolic steroid intake is the most common reason.3-5 Here we report a case of HAs synchronously diagnosed and surgically treated across siblings.
Case report A 47-year-old woman was referred to our specialist tertiary referral center following a diagnosis of primary liver cancer at her local hospital. Routine clinical examination at the local hospital revealed a giant palpable abdominal mass, while abdominal ultrasonography (US) revealed a giant neoplastic lesion in her liver, and the finding of which was confirmed by computed tomography (CT). Despite evidence advanced pathology, the patient was asymptomatic, except for a vague right upper quadrant fullness. She denied a history of regular oral contraceptive use, except for the emergency contraceptive pill taken once a decade ago. There was no history of hepatitis or alcohol consumption. Liver functional tests revealed a slight elevation in conjugated and unconjugated bilirubin (conjugated bilirubin, 4.0 mmol/L, reference range 0–3.4 mmol/L; unconjugated bilirubin, 12.8 mmol/L, reference range 1.7–10.2 mmol/L); alanine CONTACT Lei Zhao [email protected] * These authors equally contributed to this work. © 2016 Taylor & Francis Group, LLC
KEYWORDS
Environment and public health; hepatocellular adenoma; steroid
transaminase (ALT) and aspartate transaminase (AST) were within normal ranges, while alkaline phosphatase (ALP) and g-glutamyl transpeptidase (g-GGT) levels were both significantly elevated (ALP, 380 U/L, reference range 40–150 U/L; g-GGT, 267 U/L, reference range 7–32 U/L). Hepatitis B surface antigen, e antigen and anti-hepatitis C antibody were negative while the hepatitis B surface antibody, e antibody and hepatitis B core antibody were all positive. Carcinoembryonic antigen, a-fetoprotein, CA19–9 and CA125 were all within normal limits. Fasting blood glucose was normal (4.9 mmol/L, reference range 3.9–6.1 mmol/L). A CT scan performed at our institution revealed an enormous heterogeneous mass measuring 26.0 £ 16 .5 £ 13 .0 cm which totally replaced the right hepatic lobe. On unenhanced CT, the mass was slightly hypoattenuating and well defined, containing irregular, hypodense regions and a limited degree of calcification. On contrast-enhanced CT scan, the mass exhibited significant heterogeneous enhancement during the arterial phase, which decreased and became isoattenuating during portal and delayed phase scans (Fig. 1A). Some irregular hypodense regions in unenhanced CT showed no enhancement in the arterial and portal phases. There was no concurrent cirrhosis and the mass did not appear to invade local vasculature. Based on the imaging findings, we considered this a benign, non-vascular hepatic tumor. A right hemihepatectomy was performed to remove the mass. At surgery, we found the mass had nearly replaced the whole right hepatic lobe; it abutted and compressed the middle hepatic veins and the retrohepatic inferior vena cava, and extended inferiorly from hepatic segment
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Figure 1. Giant hepatic adenoma of the sister. (A) CT scan; clockwise from upper-left: Unenhanced scan, arterial phase of contrast enhanced scan, delayed phase of contrast enhanced scan, portal phase of contrast enhanced scan. (B) In situ hepatic adenoma. (C) View of resected hepatic adenoma. (D) Histology of resected hepatic adenoma.
VI pushing the right kidney toward the midline (Fig. 1B–C). The patient recovered without complications. Macroscopically, the mass appeared as a well-demarcated greyish red and yellow tumor with large surface vessels. Hemorrhagic regions were discovered in the middle of the tumor. No fibrous capsule was found and the surrounding liver tissue was normal. Microscopically, the tumor was composed of cells closely resembled mature hepatocytes, which organized in plates, mainly 1 to 2 cells thick. The tumor hepatocytes had normal cytoplasm and nucleus, and the nuclear atypia or mitoses were not found. There was a notable absence of fibrosis, and no bile duct or portal vein was found. The neoplasm was pathologically diagnosed as hepatic adenoma (HA) (Fig. 1D). Before the patient was discharged, her 42-year-old brother described vague abdominal pain and ultrasound revealed a hepatic neoplastic lesion. While the brother consumed 40–75 g of alcohol per day for the preceding 25 y there was no history of anabolic steroid use and physical examination was unremarkable. Liver functional tests revealed a normal bilirubin and ALP but elevated ALT (80U/L, reference range 5–40 U/L), AST (50U/L, reference range 8–40 U/L) and g-GGT (131 U/L, reference range 11– 50 U/L). Hepatitis B surface antigen, e antigen and anti-hepatitis C antibody were negative while the hepatitis B surface antibody, e antibody and hepatitis B core antibody were positive. Tumor markers were again negative. Fasting blood glucose was normal.
Unenhanced CT confirmed low density liver parenchyma and an isoattenuating mass measuring 5.2 £ 3 .8 £ 4 .8 cm in the right lobe, containing hypodense regions. On contrast-enhanced scan, there was moderate enhancement in the arterial and portal phases, without significant clearance in the delayed scan. On Magnetic Resonance imaging, the mass appeared hypointense in T1-weighted, T2-weighted, diffusion weighted and fat-suppressed images (Fig. 2A). It showed heterogeneous, mild enhancement in the arterial phase on dynamic gadolinium-enhanced imaging, remained enhanced in the portal and hepatic parenchymal phases turning hypointense in the delayed scan. Similarly to his sibling, a diagnosis of benign non-vascular hepatic tumor was made, and at surgery (Fig. 2B–C) a tumor later confirmed histologically as a HA (Fig. 2D) was resected. The tumor had similar pathologic features as that of his siblings but showed the following different features: significant inflammatory infiltration, sinusoidal dilatation and frequent steatosis. He recovered without complication. To further confirm the diagnosis of HA, as well as to clarify their molecular subtypes, immunohistochemistry on tissue samples from both cases were performed with the following four markers: liver fatty acid binding protein (LFABP), C reactive protein (CRP), b-catenin and glutamine synthase (GS). The results were carefully examined and interpreted by two pathologists.
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Figure 2. Hepatic adenoma of the brother. (A) Magnetic Resonance imaging; clockwise from upper-left: T1-weighted image, T2-weighted image, fat suppressed image, diffusion weighted image. (B) In situ hepatic adenoma. (C) View of resected hepatic adenoma. (D) Histology of resected hepatic adenoma.
In the tumor from the brother, both LFABP and CRP showed diffuse positive cytoplasmic staining; b-catenin staining was confined in membrane, while the bona fide positive staining should be cytoplasmic /nuclear, so it was negative; positive GS staining were confined in hepatocytes around veins. When these added up, together with its pathological features in H&E staining, the brother’s HA was classified as typical IHA (Fig. 3A). In the tumor from the sister, staining patterns of LFABP and b-catenin were very similar to the brother’s HA; the CRP staining was also positive; the GS staining was heterogeneous, it was strong and diffuse in some regions, but confined around veins in other regions; in this case, b-catenin mutation should rely on b-catenin staining, which was negative. When taken together, both pathologists agreed to still classify its subtype as IHA (Fig. 3B).
Discussion On average, HAs measure between 8 and 15 cm6; with reports of giant HA >20 cm being seldom.1,7 Thus this case of familial HA describes the largest reported in the literature. The main complications of HA are rupture, hemorrhage and malignant transformation, the incidence of which increase with increasing adenoma size.8,9 For giant HAs, surgical excision at an experienced liver surgery unit is the gold standard treatment option.1
Our literature review also indicates that this is the first report of HA in siblings. Maturity onset diabetes of the young type 3 (MODY3) is an autosomal dominantly inherited form of diabetes, it is associated with heterozygous mutations in the HNF1a gene, which is also related to HA.10,11 A clinical study revealed that all subjects with MODY3 had been diagnosed before 25 y of age and required drug therapy for blood glucose control, so it was concluded that a diabetes diagnosis after 25 y of age or the absence of a need for drug therapy to control glycaemia from this age should exclude a MODY3 diagnosis.12 In this case, the age of the patients was 47 and 42 y old, respectively, and both of them showed normal fasting blood glucose. Close questioning about the family history revealed that the two patients have other two siblings, and totally they have 6 children, the ages of the children ranges from 10s to 20s; the two patients’ father has 2 brothers, their mother has one brother, and none of these 15 family members is diabetic. Taking together, the diagnosis of MODY3 can be safely excluded. Thanks to the recent progress in the molecular biology of HA, through the exploration of its genotype–phenotype correlation, Zucman-Rossi et al. classified HA into three subgroups based on the mutation status of HNF1a (hepatocytes nuclear factor 1a) and b-catenin. Their featured phenotypic and molecular characteristics are summarized in Table 1.13 To date four major subtypes of HA have been identified, they are HNF1a mutated HA (H-HA), b-catenin mutated HA (b-HA), inflammatory HA (IHA); IHA can be also b-catenin mutated (b-IHA). Less than
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Figure 3. Subtype classification by immunohistochemical analysis. (A) The brother’s HA; (B) The sister’s HA. From upper panels to lower panels: LFABP, b-catenin, CRP and GS. All original magnifications are 100£; the magnification of the insets in b-catenin is 200£ to show the sub-cellular distribution of the positive staining, and the magnification of the insets in GS is 40£ to show the homogeneous or heterogeneous distribution of the positive staining.
10% of HA remain unclassified.14 A phenotypic classification using a panel of immunohistochemistry has been developed from these molecular characterizations. LFABP, SAA(serum amyloid A)/CRP, GS and b-catenin immunohistochemical analyses performed on surgical samples can discriminate FNH (focal nodular hyperplasia) from HA and identify the different HA subtypes.14
According to the immunohistochemical results, both tumors were confirmed to be HA; the brother’s tumor showed typical features of the inflammatory HA, although the sister’s tumor was less typical, it was still classified to the same subtype (Fig. 3). The pathogenesis of hepatic adenoma is strongly associated with the long-term use of oral contraceptives,2 while the risk of HA following short-term use (less than 2 years) is debatable.15 Leese et al. report a case of HA following oral contraceptive use for only 15 d predating presentation by 2 decades.1 In our female patient the emergency contraceptive pill was taken once 10 y prior to presentation, and we believe that it is therefore unlikely the development of HA resulted from iatrogenic estrogen exposure. HA is a very rare, benign neoplasm with significant female preponderance; its incidence in males is 10-fold lower than females.1 It is less likely that these two cases of HA in siblings were just sporadic. Considering the simultaneous onset and the same molecular subtype, we suspect that same exogenous factors may contribute to the development of HAs in the siblings. Closer questioning revealed that the siblings have been raising pigs since 2008. Interestingly, she raises 4 sows among all 60 pigs. The waste of livestock has been proved to be one of the major sources of environmental estrogen,16,17 and compared with piglets and barrows, sows produce varied classes of steroids, including estrogens and androgens, at much higher concentrations.18 The onset of HA in fish has been reported to be associated with the environmental contamination including steroids.19 We therefore suspect whether the environmental steroid exposure might, to some extent, contribute to the simultaneous development of HA in two siblings. Here we could not confirm this speculation with convincing evidence, and indeed it could just be a simple while extremely rare coincidence. Further carefully designed, large-scale clinical investigation is needed to confirm or deny the connection between environmental contamination and the pathogenesis of HA.
Table 1. Phenotypic and molecular characteristics of four subgroups of hepatic adenoma Molecular Characteristics
HNF1a Mutated HA Germline
HNF1a Mutation B-Catenin Mutation
Yes, Germline No
Inflammatory Infiltration Morphological Features Steatosis Pseudo-Glandular Formation Cytological Abnormalities Tumor Clinical Features Connection With HCC Age Of Patients Oral Contraception History Female Dominancy Familiar Adenomatosis
b-Catenin Mutated HA Somatic
Non-Mutated HA
Inflammatory
No No
No
Infrequent
Yes, Somatic Yes; Overexpressing B-Catenin Target Genes Less Frequent
Yes; Focal Or Diffuse
No
Marked Steatosis Less Frequent Infrequent Larger, More Numerous
Infrequent Frequent Frequent Smaller, Less Numerous
Less Frequent Infrequent Frequent More Solitary
Infrequent Younger Frequent Significant Frequent
Significant Elder Less Frequent Less Significant Less Frequent
Infrequent No Specific Frequent Significant No Specific
Non-Inflammatory
No Specific
More Solitary No Specific No Specific Frequent No Specific
CANCER BIOLOGY & THERAPY
Disclosure of potential conflicts of interest No potential conflicts of interest were disclosed.
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