Abstract
Hepatocellular adenomas are rare in children. A large study focused on pediatric patients has not been undertaken. A natural language search was performed at 5 institutions for hepatocellular adenomas in patients less than 21 years old. Clinical characteristics as well as immunohistochemical staining profile was reviewed and adenomas subtyped per standard classification. Patients were divided into pre- and post-pubescent age group. Thirty-one patients were included. 11 (35%) were male and 10 (32%) were pre-pubescent. 15 (54%) of 28 patients with known clinical histories had adenomas associated with a syndrome. The percentage of the different adenoma subtypes was: 23% β-catenin activated, 3% combined inflammatory and β-catenin activated, 29% HFN1α-inactivated, 35% inflammatory, and 10% unclassified subtype by immunohistochemical staining. Interestingly 47% of patients with syndromes were male, while 85% of patients in the non-syndromic group were female. The total number of β-catenin activated tumors was greater in the syndromic group (5 of 15, 33%) and pre-pubescent group (5 of 10, 50%) than in the non-syndromic group (2 of 13, 16%) and post-pubescent group (3 of 21, 14%), p=0.4 and p=0.07 respectively. Inflammatory type adenoma was more frequent in the post-pubescent (10 of 21, 48%) than in the pre-pubescent group (1 of 10, 10%), p=0.06, trending towards significance. Pediatric patients with hepatocellular adenomas frequently have syndromes, especially in the pre-pubescent group. In patients with syndromes a greater percentage of adenomas were β-catenin activated. In patients without a known syndrome the distribution of hepatocellular adenoma sub-types appears similar to adults.
Keywords: hepatocellular adenoma, pediatric, immunohistochemistry, syndrome
Introduction
The classification of hepatocellular adenomas based on genotype and phenotype has undergone significant change in recent years. While hepatocellular adenomas are considered benign lesions, those with β-catenin mutations are now known to have an increased risk for malignant transformation.1-4
Hepatocellular adenomas removed from adult patients undergo classification based on morphologic features and immunohistochemical staining as part of standard practice.1 Immunohistochemical staining acts as a surrogate for molecular alteration. HNF1α-mutated lesions demonstrate loss of liver fatty-acid binding protein (L-FABP) staining; inflammatory hepatocellular adenomas have mutations resulting in STAT3 activation and correlate with C-reactive protein (CRP) and serum amyloid A (SAA) staining; mutations in CTNNB1 result in β-catenin nuclear positivity and/or glutamine synthetase diffuse positivity; and, finally, unclassified hepatocellular adenomas lack a defined molecular abnormality and staining pattern and hence are designated as such.1,3,5,6 In the largest study of adenomas subclassified using immunohistochemistry the distribution of various types was as follows: HNF1α mutated adenomas 33%, β-catenin activated 19%, inflammatory 39%, and unclassified 8%.3
There are case reports using immunohistochemical staining in pediatric hepatocellular adenomas,7 but an extensive study characterizing pediatric lesions based on immunohistochemical subtyping has not been done. Hepatocellular adenomas are rare in children, and while some occur in the context of increased steroid hormone levels/or steroid usage, similar to adults, they frequently occur in patients with other syndromes affecting the liver.7-12 The largest comprehensive published study to date with clinical information on pediatric adenomas in children was reported in 1995. The study involved 8 patients with lesions ranging in size from 0.1-14.5 cm arising in patients with a variety of associated disorders.12 Immunohistochemical staining for the current subtyping was not available at that time.
The purpose of our study was to determine whether the distribution of different types of hepatocellular adenomas was affected by age and/or background medical conditions in the pediatric/adolescent population. Additionally, we aimed to determine whether adenomas with malignant potential were more or less likely to occur in this unique population.
Materials and Methods
This study was approved by the institutional review board at the University of Washington, Mayo Clinic, University of California San Francisco, Yale University, and Seattle Children’s Hospital. The electronic pathology records at all institutions were queried for cases of hepatic adenoma diagnosed between June 1, 2009 and May 1, 2020 using a natural language search. The electronic medical record was used to obtain the following information for included patients: age, sex, relevant clinical diagnoses, size of lesion, presence of focal versus multiple tumor nodules, and presenting signs when available. The pathology report was used to discern whether the specimen received in pathology was a resection or a biopsy. Slides were reviewed and when immunohistochemical staining had not been done clinically, staining was performed on available resection specimens. Results of β-catenin, C-reactive protein and/or serum amyloid A, liver fatty acid binding protein, and glutamine synthetase were recorded along with reticulin and glypican-3 staining when performed. The diagnosis of hepatocellular adenoma was made based on morphology, and, when available, reticulin preservation throughout the lesion, and lack of glypican-3 immunohistochemical staining, while malignant transformation was defined by thickening of cell plates, cellular pleomorphism, and small cell change as well as convincing loss of reticulin, and strong diffuse glypican-3 positivity when available. The results from all institutions were collected, and based on reported staining results, a hepatic adenoma subtype was assigned at the consensus of two authors (MCP and MMY) according to current literature.13,1 Patients greater than 21 years of age, were excluded as were patients without the aforementioned immunohistochemical stains necessary for subtyping. When needle and resection specimens were both available for review, only the case on which staining was performed was used for study.
For analysis age 13 years or greater was defined as post-pubertal. The hepatocellular adenoma subtypes of the entire group, pre-pubertal, and post-pubertal patients were analyzed along with syndromic and non-syndromic patients. The Fischer exact test with two-tailed p was performed using VassarStats.14
Results
During the period of study, 172 case of hepatocellular adenoma were identified across all institutions, of which 36 (22%) patients were under 21 years of age. Five pediatric patients were excluded because of lack of immunohistochemical staining or resection tissue for review/staining. The detailed clinical and pathologic features of each case are listed in Table 1. The average age of patients was 14 years (range 3-20 years) and 20 (63%) were female. Because outside consultations were included, some cases had limited information. Of the 28 with available history, Glycogen Storage Disease Type 1 was the most frequent pre-existing condition occurring in 5 (17%) of these patients. Seventeen (59%) of the 29 patients with information regarding whether their lesions were single or multiple had a single lesion. The largest lesion recorded was 19.5 cm. Of our cases with reticulin and glypican-3 staining available, 3 cases had partial loss of reticulin, 1 case had patchy positive glypican-3 staining, and one case had partial loss of reticulin and patchy positive glypican-3, Table 1. In case 103 the focal weak glypican-3 staining prompted consideration of hepatoblastoma; whereas in cases 107, 113, and 123 the loss of reticulin, and, in case 101 the loss of reticulin coupled with patchy positive glypican-3 staining, were suggestive of early malignant transformation.
Table 1.
Hepatocellular adenoma: clinical history, features, and subtype.
| Study # |
age | sex | relevant clinical diagnoses | BMI | size of lesion(s) |
single vs multiple |
presentation | E/R/B | Reticulin | adenoma type |
|---|---|---|---|---|---|---|---|---|---|---|
| 101 | 1 | M | 80% XY; 20% XX; uniparental disomy*+ | 16.7 | 1 | single | BWS suveillance | R | intact | HA-U |
| 102 | 3 | F | GSD type 1 | NA | 0 | single | NA | R | NA | b-HCA |
| 103 | 4 | M | ciliary dyskinesia/situs inversus totalis+ | 15.4 | 14 | single | incidental | R | intact | b-HCA |
| 104 | 5 | M | Alagille syndrome | 17 | NA | single | incidental | E | intact | IHCA |
| 105 | 7 | F | biliary atresia | 15.3 | 4.5 | single | jaundice | E | intact | H-HCA |
| 106 | 9 | M | Abernethy | NA | 5.5 | multiple | incidental | R | intact | b-IHCA |
| 107 | 9 | F | Abernethy syndrome; protein S deficiency* | 13.1 | 9.5 | multiple | FTT | R | loss | b-IHCA |
| 108 | 9 | M | GSD1A | 17 | 0.9 | single | incidental | E | NA | b-HCA |
| 109 | 10 | M | Alagille syndrome (NOTCH2 mutation) | 17.1 | 5.1 | single | incidental | R | intact | H-HCA |
| 110 | 11 | F | Treated Ewing | NA | 18.5 | multiple | incidental | R | intact | H-HCA |
| 111 | 15 | F | ARPKD s/p kidney txp | 21.6 | 5 | single | incidental | R | intact | H-HCA |
| 112 | 15 | F | OCP | NA | 9.3 | multiple | NA | B | intact | H-HCA |
| 113 | 15 | F | Kabuki syndrome* | NA | 19.5 | multiple | incidental | E | loss | HA-U |
| 114 | 16 | F | none | NA | 3.5 | single | NA | R | intact | b-IHCA |
| 115 | 16 | F | GSD type 1 | NA | 4-Jan | multiple | incidental | E | NA | IHCA |
| 116 | 17 | M | GSD 1a | 23.21 | 1.2 | single | GSD complications | E | intact | IHCA |
| 117 | 17 | F | none | 24.1 | 0.9-18 | multiple | hemorrhage | R | intact | H-HCA |
| 118 | 17 | M | Obesity | NA | 12 | single | NA | B | intact | IHCA |
| 119 | 17 | F | congenital hepatic fibrosis | NA | NA | single | incidental | B | intact | H-HCA |
| 120 | 17 | F | none | 36 | 0.6-9 | multiple | incidental | E | NA | IHCA |
| 121 | 17 | F | none | 25 | NA | NA | incidental | B | intact | IHCA |
| 122 | 18 | M | AML treated | NA | 6.5 | single | NA | B | intact | IHCA |
| 123 | 18 | F | none* | 19 | 6.4 | single | incidental | R | E loss | b-HCA |
| 124 | 18 | M | GSD1 | NA | 0.2-2 | multiple | incidental | E | NA | IHCA |
| 125 | 18 | F | NA | NA | NA | single | NA | R | intact | b-HCA |
| 126 | 19 | F | none | NA | 4.3 | single | incidental | R | intact | IHCA |
| 127 | 19 | F | none | 29 | NA | multiple | incidental | B | intact | IHCA |
| 128 | 19 | F | none | 27 | NA | NA | incidental | B | intact | HA-U |
| 129 | 19 | F | none | NA | NA | single | incidental | B | NA | IHCA |
| 130 | 19 | F | NA | 25 | 0.6-11.5 | multiple | NA | R | intact | H-HCA |
| 131 | 20 | M | NA | 29 | 17 | multiple | hemorrhage | R | intact | H-HCA |
Abbreviations:
M=male; F=female; GSD=glycogen storage disease; AML=acute myeloid leukemia; NA=not available; BWS=Beckwith Wiedemann Syndrome; E=explant; R=resection; B=biopsy; HA-U=hepatocellular adenoma unclassified; b-HCA=beta-catenin hepatocellular adenoma; IHCA=hepatocellular adenoma inflammatory; H-HCA=HNF1A-inactivated hepatocellular adenoma; b-IHCA=combined beta-catenin and inflammatory hepatocellular adenoma;
=patchy/focal reticulin loss;
=patchy glypican-3 staining
In our cohort 7 (23%) of 31 patients had β-catenin activated hepatocellular adenomas, 1 (3%) had a combined inflammatory and β-catenin activated hepatocellular adenoma, 9 (29%) had HFN1α-inactivated hepatocellular adenomas, 11 (35%) had inflammatory hepatocellular adenomas, and 3 (10%) patients had unclassified hepatocellular adenomas by immunohistochemical staining (Table 1, Figures 1-4). Ten (34%) of 31 patients were less than 13 years of age, and within this group the average age was 6.8 years, and 55% were male. This group was enriched with β-catenin activated tumors which comprised 50% (5 of the 10) of cases, when compared to the post-pubertal group (p=0.02) (Table 2A). The total β-catenin activated tumors was greater in the pre-pubertal group as opposed to the post-pubertal group, and this trended towards significance, p=0.07. The post-pubertal group included 21 patients, average age 17.2 years, 76% female, and had a predominance of the inflammatory subtype, 48% (10 of the 21 cases), p=0.06 trending toward significance, when compared to the pre-pubescent group (Table 2A). The difference in the number of unclassified and HNF1α-inactivated hepatocellular adenomas was not statistically different (Table 2A).
Figure 1.
β-catenin activated hepatocellular adenoma, H&E 100x.
Figure 4.
Hepatocellular adenoma immunohistochemistry. A, B) β-catenin activated hepatocellular adenoma: A) Glutamine synthetase with diffuse staining, 100x; and B) β-catenin with membranous and nuclear staining, 200x. C, D) Inflammatory hepatocellular adenoma: C) C-reactive protein, 100x, adenoma on top and background liver on bottom; and D) Glutamine synthetase, 100x, adenoma on top and background liver on bottom. E, F) HNF1α-inactivated adenoma: E) Liver fatty acid binding protein (LFABP), 100x, on adenoma, and F) LFABP, 100x, on background liver.
Table 2A.
Comparison of different hepatocellular adenoma types between in the pre- and post-pubescent groups.
| Adenoma Sub-Type | <13 years, n=10 | ≥13 years, n=21 | p |
|---|---|---|---|
| HA-U | 1 (10%) | 2 (10%) | 1 |
| b-HCA | 5 (50%) | 2 (10%) | 0.02 |
| IHCA | 1 (10%) | 10 (48%) | 0.06 |
| H-HCA | 3 (30%) | 6 (29%) | 1 |
| b-IHCA | 0 | 1 (5%) | 1 |
| Total b-catenin activated | 5 (10%) | 3 (15) | 0.07 |
In the pre-pubertal group 9 (90%) of the 10 patients had syndromes, whereas in the post-pubertal group only 6 (33%) of the 18 patients with known clinical histories had syndromes, p=0.01. Interestingly 2 (40%) of the 5 patients with glycogen storage disease had β-catenin activated lesions while the remaining 3 (60%) patients had inflammatory subtype. In this group of patients with glycogen storage disease type 1, the 2 patients with β-catenin activation were 3 and 9 years of age; whereas the patients with inflammatory adenomas were ages 16, 17, and 18 years. While there was a difference in the percentage of the different adenoma subtypes between those with and without background clinical syndromes, the difference in the distribution did not reach statistical significance, Table 2B.
Table 2B.
Comparison of different hepatocellular adenoma types between the syndromic and non-syndromic groups.
| Adenoma Sub-Type | Syndromic, n=15* | Non-syndromic, n=13* | p |
|---|---|---|---|
| HA-U | 2 (13%) | 1 (8%) | 1 |
| b-HCA | 5 (33%) | 1 (8%) | 0.17 |
| IHCA | 4 (27%) | 7 (54%) | 0.24 |
| H-HCA | 4 (27%) | 3 (23%) | 1 |
| b-IHCA | 0 (0%) | 1 (8%) | 0.46 |
| Total b-catenin activated | 5 (33%) | 2 (16%) | 0.40 |
Abbreviations: HA-U=hepatocellular adenoma unclassified; b-HCA=beta catenin hepatocellular adenoma; IHCA=hepatocellular adenoma inflammatory; H-HCA=HNF1A-inactivated hepatocellular adenoma; b-IHCA=combined beta-catenin and inflammatory hepatocellular adenoma
While the total number of cases in the study was n=31, the total number of cases with clinical information available was n=28. Therefore 3 cases were excluded from Table 2B.
Discussion
Hepatocellular adenoma is generally a tumor seen in adults. This is the largest study of pediatric hepatocellular adenomas to date and the first to incorporate the immunohistochemical staining widely used in adult patients. We found β-catenin activated tumors to be the predominant subtype in the pre-pubescent group. The one patient in this group without a syndrome or background process affecting the liver had been treated for Ewing sarcoma, Table 1. The post-pubescent group more closely mirrored the distribution of adenomas described by Biolac-Sage and colleagues, with inflammatory hepatocellular adenomas and HNF1α-mutated adenomas comprising the bulk of the adenomas.3 Additionally in the post-pubertal group, of 11 patients without a known syndrome, 10 (91%) were female, 1 of whom was documented to be on oral contraceptives, and the lone male was clinically obese. This is similar to the overwhelming majority of female patients (85%) in the study by Nault, et al which included 533 adenomas from 411 patients ranging in age from 7-82 years.2 Because the true puberty status of the patients studied was not known, but instead assigned based on age, it is possible that the difference in adenoma subtypes between the pre- and post-pubescent groups was affected. This may have resulted in a trending, rather than significant difference, in the total β-catenin activated hepatocellular adenomas and the inflammatory hepatocellular adenomas.
In the pediatric age group, well-differentiated fetal hepatoblastoma and hepatocellular carcinoma pose the greatest diagnostic dilemmas with hepatocellular adenomas. Distinguishing hepatocellular adenomas from these entities can be difficult because the morphology of these low-grade tumors can be similar. Glutamine synthetase staining, which is characteristically positive in well-differentiated fetal hepatoblastoma, is also positive in β-catenin activated hepatocellular adenomas and in hepatocellular carcinomas.15,16,1 Glypican-3 staining has been found to be positive in hepatocellular carcinomas and negative in hepatocellular adenomas.17,3 Additionally, well-differentiated epithelial hepatoblastoma is characterized by diffuse pericanalicular cytoplasmic staining with glypican-3.15 Reticulin staining has long been used to assess hepatocellular lesions because loss of the reticulin framework supports the diagnosis of hepatocellular carcinoma. Some low-grade lesions demonstrate partial loss of reticulin and patchy glypican-3 staining suggesting adenomas undergoing malignant transformation. Three of the 4 patients with partial reticulin loss had syndromes, uniparental disomy, Abernethy syndrome, and Kabuki syndrome, and of these, 2 patients had unclassified hepatocellular adenomas, while 1 patient had a β-catenin activated hepatocellular adenoma. The patient without a syndrome and with reticulin loss had a β-catenin activated lesion, Table 1. These represent lesions that are undergoing malignant transformation from adenoma to carcinoma. One of the tumors had focal, weak granular cytoplasmic glypican-3 staining with retained reticulin. This lesion was in the patient with ciliary dyskinesia and was β-catenin activated. Due to staining with glypican-3 and age, hepatoblastoma was considered, however the sclerotic vessels and lack of extramedullary hematopoiesis along with only focal, weak glypican-3 seemed to favor hepatocellular adenoma.
Five (17%) of 29 patients in the study had a diagnosis of glycogen storage disease type 1. Glycogen storage disease type 1a is caused by mutations in G6PC which leads to glucose-6-phosphatase deficiency.18 This in turn leads to glycogen accumulation within the liver and hepatomegaly with subsequent adenoma formation. In patients with glycogen storage disease Type 1, 15 years is the average age at which adenomas are first identified.19 The 2 pre-pubescent patients had β-catenin activated adenomas; whereas the 3 post-pubescent patients had inflammatory type adenomas. Three of the patients were reported to have single lesions whereas the other 2 had multiple. Immunohistochemical profiles are consistent with the findings of Calderaro, et al. in which β-catenin activation and inflammatory type adenomas were the most common subtypes in glycogen storage type 1 disease patients.20
Fifteen (48%) of the 31 patients had associated syndromes and of these 15, 8 (53%) were male. The near equal distribution of hepatocellular adenomas in males and females with syndromes is notable when compared to other studies. As discussed previously there is a well-known association of glycogen storage disease and hepatocellular adenomas.19 A literature review also found reports of hepatic adenomas arising in the setting of Alagille syndrome,7 Abernethy malformation,21 biliary atresia,22 and congenital hepatic fibrosis.23 Interestingly, our patients with autosomal polycystic kidney disease and congenital hepatic fibrosis had HNF1α-mutated adenomas, which is the same pathway as reported in an adult case in the literature.23 The background liver in the patient with Kabuki syndrome showed focal equivocal portal fibrosis and mild sinusoidal dilatation, but was otherwise histologically normal. Overall, it appears that the adenomas associated with syndromes likely arose in a milieu of abnormal liver and this predisposition probably explains the more equal distribution of male and female cases. Notably five (33%) of the 15 syndromic patients had β-catenin activation suggesting an increased risk of malignancy in adenomas arising within syndromes affecting the liver, though the difference between those with and without syndromes did not reach statistical significance.
In the 13 patients who had clinical information available and did not have a documented syndrome, 11 (85%) of the patients were female. The one male was obese, which can lead to a state of higher estrogen. Only 1 (8%) of the female patients was known to be on oral contraceptives. Of these non-syndromic cases, 1 (8%) patient had a β-catenin activated hepatocellular adenoma, 1 (8%) had a combined inflammatory and β- catenin activated hepatocellular adenoma, 3 (23%) had HFN1α-inactivated hepatocellular adenomas, 7 (54%) had inflammatory hepatocellular adenomas, and 1 (8%) had unclassified subtype of hepatocellular adenoma. Although the number of patients on oral contraceptives was much lower in this study, 8% (1 of 13 patients without a known syndrome) versus 65% in the Nault, et al., the percentage of female patients was the same as in the Nault study. Additionally, the percentage of each adenoma subtype was similar.2 This suggests that in pediatric patients without background liver pathology, hepatocellular adenomas are similar to those arising in adults.
Pediatric patients with hepatocellular adenomas frequently have syndromes, especially in the pre-pubescent group. In patients with syndromes a greater percentage of lesions were β-catenin activated. All syndromes seen in patients included in our study are known to affect the liver either primarily or secondarily. This background injury may contribute to the formation of adenomas. In patients without a known syndrome the distribution of sub-types appears similar to that seen in the adult literature.
Figure 2.
Inflammatory hepatocellular adenoma, H&E 100x, adenoma in top portion of photo with normal liver in bottom portion separated by fibrosis.
Figure 3.
HNF1α-inactivated adenoma, H&E 100x.
Acknowledgments
Funding: None
References
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