Multiple Inflammatory and Serum Amyloid A Positive Telangiectatic Hepatic Adenomas with Glycogenated Nuclei Arising in a Background of Nonalcoholic Steatohepatitis

• ABSTRACT
• CASE REPORT
• GROSS FINDINGS
• MICROSCOPIC FINDINGS
• IMMUNOHISTOCHEMICAL FINDINGS
• DISCUSSION
• CONCLUSION
• ABBREVIATIONS
• REFERENCES

ABSTRACT

The authors describe multiple telangiectatic or inflammatory adenomas in a 53-year-old woman with steatohepatitis who presented with acute right upper quadrant abdominal pain. Magnetic resonance imaging revealed 6 lesions consistent with multiple hepatic adenomas, 2 of which showed hemorrhage. She underwent right lobectomy and nonanatomical segment 2 liver resections and seven nodules ranging in size from 1.0 to 5.0 cm were identified. All nodules contained portal-like structures and ductular reaction, features seen in focal nodular hyperplasia, as well as significant inflammation, telangiectatic sinusoids and immunoreactivity for serum amyloid A, placing them according to a recently described classification systems as telangiectatic or inflammatory adenomas. The diffuse positivity of the serum amyloid A staining results in this case suggests an important diagnostic role of this stain in smaller tissue samples, such as in core biopsy specimens.

Benign hepatocytic liver tumors can be roughly divided into hepatocellular adenoma (HA), a clonal proliferation of hepatocytes, and focal nodular hyperplasia (FNH), a nonclonal proliferation of hepatocytes with fibrous septa and eccentrically thickened vessels. The distinction may be difficult on needle biopsy and is important as hepatic adenomas are more likely to harbor foci of hepatocellular carcinoma and to hemorrhage. More recently, this distinction has become complicated by lesions that share features with both entities.

Wanless et al first described a lesion with telangiectatic vessels that otherwise resembled FNH, but showed a propensity for hemorrhage. This lesion was termed telangiectatic focal nodular hyperplasia (TFNH)[1] [2] and has been traditionally classified as a variant of FNH.[3] Recent molecular studies have demonstrated that TFNH is clonal and is now classified as a variant of hepatic adenoma.[4] Bioulac-Sage et al have further divided these lesions and have proposed a classification for hepatocellular adenoma using molecular and immunohistochemical markers.[5] Adenomas are grouped into those with (1) hepatocyte nuclear factor (HNF)-1α mutations, which are liver fatty acid binding protein (L-FABP) negative and are often markedly steatotic; (2) beta catenin activating mutations, which are glutamine synthetase (GS) positive and have a greater propensity for malignant transformation; (3) inflammatory adenomas with telangiectatic features (IA), which are serum amyloid A (SAA) positive and most closely resemble TFNH histologically; and (4) those that are negative for all the previous mentioned markers. Paradis et al described an association of adenomas with telangiectatic features they termed telangiectatic adenoma (TA) with increased body mass index and inflammation.[6] We use the term IA for the multiple SAA positive lesions with inflammatory and telangiectatic features seen in our patient.

CASE REPORT

A 53-year-old woman presented with acute right upper-quadrant abdominal pain. On examination she was afebrile. Her blood pressure was 134/90 mm Hg, her weight was 130 lbs, and her height was 62 inches. Cardiorespiratory examination was normal. The abdomen was soft with mild tenderness over the right upper quadrant and epigastrium. No guarding was noted. She had previous laparoscopic cholecystectomy and caesarian section for her 2 children. She had a 20-year history of previous oral contraceptive use. There was no history of excessive alcohol consumption or diabetes mellitus.

Hepatitis B and C serologies were negative. Liver enzyme activities were normal. A magnetic resonance imaging (MRI) scan of the abdomen revealed multiple lesions in the liver. There were 4 lesions that demonstrated increased signal intensity on the fat saturated T2-weighted images and isointense to the liver on the non-fat-saturated single shot weighted images. The lesions measured 1.4, 1.5, 1.7, and 2.8 cm and were situated in segments 6, 8, 3, and 2. Another two lesions that were predominantly composed of fluid were identified in segment 6 and segment 5 and measured 3.4 and 3.6 cm. The impression was that of multiple adenomas, 2 of which were with hemorrhage. The background liver showed diffuse dropout of signal on the out-of-phase T1-weighted images when compared with the in-phase T1-weighted images compatible with diffuse fatty infiltration. Right lobectomy and nonanatomic segment 2 liver resections were performed.

A summary of the radiologic and pathologic findings are presented in Table [1].

1 Nodule 4 was not identified on radiology.

GROSS FINDINGS

The right lobe of the liver weighed 1065 g and contained 5 nodules ranging from 1.0 cm to 5.0 cm. The nodules were all nonencapsulated with ill-defined borders. The cut surface of the lesions was tan with focal red congested areas. Two lesions (nodules 2 and 3) were acutely hemorrhagic, and nodule 3 was completely infarcted. The segment 2 specimen weighed 120 g and contained two similar nodules measuring 1.7 and 1.9 cm (Fig. [1]). The lesions were well circumscribed with no capsule separating them from the adjacent liver. The lesions were soft and appeared a slightly deeper red in comparison to the adjacent liver. Both lesions contained areas of congestion and hemorrhage.

In the absence of hemorrhage, the size on imaging corresponded with the actual measurement of the lesions, while there was discrepancy in the 2 lesions with extensive hemorrhage. A 1-cm lesion identified after resection was not identified on imaging. Microscopic foci of hemorrhage in nodule 6 were not identified on imaging studies.

MICROSCOPIC FINDINGS

Hematoxylin and eosin (H&E) and trichrome stained slides were examined, and immunohistochemistry for serum amyloid A (SAA) (1:50 dilution, Dako), glutamine synthetase (GS) (1:400, Abcam), and anti-liver fatty acid binding protein (L-FABP) (1:50, Biogenex) was performed. Positivity for SAA was assessed as cytoplasmic staining greater than the background liver, and positive staining for GS was assessed as more than 50% of staining within the lesion.[5] [7] L-FABP was considered normal if it stained positive, similar to nontumor hepatocytes, and was interpreted as negative if the staining was lost within the lesion.[5]

The histological features of all the nodules are presented in Table [2].

2 Nodules 2 and 3 show extensive hemorrhage and fibrosis with little residual lesion for proper histological assessment.

The evaluation of the histological features of nodules 2 and 3 were incomplete due to significant hemorrhage and infarction. The remaining 5 nodules showed portal-like structures with abnormal arteries, thick- and thin-walled vessels, ductular reaction, unpaired arteries, steatosis, inflammation, and glycogenated nuclei. Dilated sinusoids, vessels draining directly into sinusoids and ectatic vessels were present in 4 out of 5 nodules. No central scar was identified in any of the nodules. Old and/or recent hemorrhage was seen in 4 out of 7 nodules. Of the lesions that bled only lesion 2 were > 3.0 cm. The other 3 lesions ranged from 1.5 to 2.8 cm. This seems to imply that bleeding may not be related to large size, but related to the abnormal vasculature. Ductular reaction accompanied by neutrophils was noted adjacent to the portal tract-like structures. Bile ducts, however, were missing. Inflammatory cells, which consisted predominantly of lymphocytes, were seen in the portal tract-like structures and sometimes in aggregates replacing the adenoma cells (Fig. [2]). Some of the nodules also contained clusters of histiocytes within the portal tract-like structures (Fig. [2]).

The background liver showed moderate macrovesicular steatosis (affecting ~50% of hepatocytes) with ballooned hepatocytes and mild neutrophilic infiltrates in the lobules. Glycogenated nuclei were present. No Mallory bodies were seen. The trichrome stain showed mild perivenular fibrosis. The findings were consistent with moderate steatohepatitis grade 2/3, stage 1/4.

IMMUNOHISTOCHEMICAL FINDINGS

SAA was found in all 6 nodules with no staining in the adjacent liver (Fig. [3]). Although only a slim rim of lesional tissue around the hemorrhagic area was preserved in nodule 2, this also showed strong cytoplasmic staining for SAA (Fig. [3]). GS showed patchy positivity similar to the surrounding steatotic liver and no nodules showed more than 50% staining. L-FABP showed weak cytoplasmic staining in the all the nodules and the surrounding liver indicating that there was no loss of L-FABP staining to suggest HNF-1α mutations.

DISCUSSION

In the literature, these lesions have been called a variety of terms including telangiectatic focal nodular hyperplasia (TFNH), inflammatory adenoma (IA), and telangiectatic adenoma (TA). Due to the consistent reactivity of SAA, which is a marker for inflammation in all lesions in our patient, we are referring to them as IA.

The patient in this report is a 53-year-old woman, who is slightly older than the mean age reported in the 2 series of IA/TFNH.[4] [5] Otherwise female gender and oral contraceptive use are all in keeping with reported findings. Our patient's body mass index (BMI) was 23.9 and was below the mean BMI of 28, but within the range of 18 to 49 that was reported by Paradis et al.[6]

The MRI findings of the lesions were strong increased intensity on T2-weighted images and absence of a central scar. Several radiologic features in TFNH have been reported in the literature and include heterogeneous enhancement on contrast-enhanced computed tomography (CT), absence of a central scar, heterogeneous appearance, increased signal intensity on T1-weighted MRI scans, hyperintense T2-weighted MRI scans and prolonged contrast enhancement on delayed phase contrast-enhanced CT or T1-weighted MRI scans.[8] [9] [10]

The gross pathologic findings of ill-defined soft nodules slightly darker than the adjacent liver with areas of hemorrhage are classical and have been reported before.[6] Our case had multiple lesions, a total of 7 were resected, 2 showed extensive hemorrhage and 2 showed microscopic areas of hemorrhage, in keeping with the reported behavior of TA/TFNH.[4] [5] [11] [12]

The histological features of TFNH/TA/IA are intermediate between that of FNH and HA. It shares some features with the other two entities and yet has features that are also not seen including dilated sinusoids, vessels draining directly into sinusoids, and ectatic vessels. Some of these features have been reported in a case of TFNH detected at birth.[13] In FNH the vessels are mostly thick walled, and in adenomas the vessels are thin walled. In TA/IA both thick-walled and thin-walled vessels are present simultaneously. We postulate that it is these thin-walled vessels seen in TA/IA and other subtypes of HA that give rise to the increased propensity to bleed. We also identified collections of histiocytes within portal tract-like structures, similar to the noncaseating granulomas seen around arterial vessels reported by Guindi et al in TFNH.[11]

In our case the nodules showed mild steatosis and inflammation. There was also moderate steatohepatitis in the adjacent liver. A case of TA containing a focus of well-differentiated hepatocellular carcinoma has been reported in a patient with metabolic syndrome.[6] Whether there is an increased risk of malignant change in TA in general or in TA arising in a background of steatohepatitis remains to be elucidated. Glycogenated nuclei were identified in the nodules as well as in the surrounding liver. To the best of the authors' knowledge this feature has not been described in TA/IA. Because glycogenated nuclei are often seen in metabolic syndrome, their occurrence in TA/IA may indicate some role in their pathogenesis.

Hepatic adenomas with β-catenin mutations are associated with high risk to malignant change.[14] These often show an overexpression of GS and are categorized separately from steatotic adenomas that harbor an inactivating HNF-1α mutation and consequently show loss of L-FABP staining. HNF-1α germ line mutations have been described in several reports involving patients with maturity onset diabetes of the young (MODY 3) and multiple liver adenomas.[15] [16] [17] There is a high incidence of hemorrhage and possible fatal outcome. Liver adenomas in these MODY 3 patients often show steatosis. Our patient has no history of diabetes mellitus or family history of diabetes or liver adenomas. Screening of families of patients with MODY 3 is suggested. The IA nodules in this case show mild steatosis with glycogenated nuclei in most nodules, and with moderate steatosis and steatohepatitis in the surrounding parenchyma. Because the GS immunostains did not show any overexpression, and the L-FABP positive immunostain is retained within the nodules, this indicates that the nodules in our case are not associated with either HNF-1α or β-catenin mutations.

The presence of significant inflammation and strong SAA staining in all nodules places this case in the inflammatory hepatocellular adenoma group.[4] [5] [12] However, these lesions are usually not associated with steatosis or steatohepatitis. Paradis et al[6] did not include SAA staining in their series of TA with steatosis. TA may be a more heterogeneous group of tumors than the current proposed classification assumes.

CONCLUSION

Inflammatory adenoma/telangiectatic adenoma of the liver may be distinguished from hepatocellular adenoma and focal nodular hyperplasia by the following histological features: the presence of thick- and thin-walled vessels, dilated sinusoids, vessels draining directly into sinusoids and ectatic vessels, the presence of significant inflammation, and SAA immunoreactivity.

We describe the presence of glycogenated nuclei in IA, which we believe has not been previously reported. Our case also demonstrates the association of IA with steatohepatitis and oral contraceptive use and a possible pathogenesis. Based on proposed molecular and immunohistochemical classification of hepatocellular adenomas, this case falls into the SAA positive, HNF-1α and β-catenin negative hepatocellular adenoma group, albeit with steatohepatitis.

ABBREVIATIONS

• BMI body mass index

• CT computed tomography

• FNH focal nodular hyperplasia

• GS glutamine synthetase

• HA hepatocellular adenoma

• HNF hepatocyte nuclear factor

• IA inflammatory adenoma

• MRI magnetic resonance imaging

• L-FABP liver fatty acid binding protein

• SAA serum amyloid A

• TA telangiectatic adenoma

• TFNH telangiectatic focal nodular hyperplasia

REFERENCES

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• 15 Yamagata K, Oda N, Kaisaki P J et al.. Mutations in the hepatocyte nuclear factor-1alpha gene in maturity-onset diabetes of the young (MODY3).  Nature. 1996;  384 458-460
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  CrossrefPubMedSearch in Google Scholar
• 17 Reznik Y, Dao T, Coutant R et al.. Hepatocyte nuclear factor-1 alpha gene inactivation: cosegregation between liver adenomatosis and diabetes phenotypes in two maturity-onset diabetes of the young (MODY3) families.  J Clin Endocrinol Metab. 2004;  89 1476-1480
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Stephen C WardM.D. Ph.D. 

Department of Pathology, The Mount Sinai Medical Center

One Gustave L. Levy Place, New York, NY 10029

Email: stephen.ward@mssm.edu

REFERENCES

• 1 Wanless I R, Gryfe A. Nodular transformation of the liver in hereditary hemorrhagic telangiectasia.  Arch Pathol Lab Med. 1986;  110 331-335
  PubMedSearch in Google Scholar
• 2 Wanless I R, Albrecht S, Bilbao J et al.. Multiple focal nodular hyperplasia of the liver associated with vascular malformations of various organs and neoplasia of the brain: a new syndrome.  Mod Pathol. 1989;  2 456-462
  PubMedSearch in Google Scholar
• 3 Nguyen B N, Flejou J-F, Terris B et al.. Focal nodular hyperplasia of the liver: a comprehensive pathologic study of 305 lesions and recognition of new histologic forms.  Am J Surg Pathol. 1999;  23 1441-1463
  CrossrefPubMedSearch in Google Scholar
• 4 Bioulac-Sage P, Reboiussou S, Cunha A S et al.. Clinical, morphologic and molecular features defining so-called telangiectatic focal nodular hyperplasia of the liver.  Gastroenterology. 2005;  128 1211-1218
  CrossrefPubMedSearch in Google Scholar
• 5 Bioulac-Sage P, Rebouissou S, Thomas C et al.. Hepatocellular adenoma subtype classification using molecular markers and immunohistochemistry.  Hepatology. 2007;  46 740-748
  CrossrefPubMedSearch in Google Scholar
• 6 Paradis V, Champault A, Ronot M et al.. Telangiectatic adenoma: an entity associated with increased body mass index and inflammation.  Hepatology. 2007;  46 140-146
  CrossrefPubMedSearch in Google Scholar
• 7 Zucman-Rossi J, Benhamouche S, Godard C et al.. Differential effects of inactivated Axin 1 and activated beta-catenin mutations in human hepatocellular carcinomas.  Oncogene. 2007;  26 774-780
  CrossrefPubMedSearch in Google Scholar
• 8 Attal P, Vilgrain V, Brancatelli G et al.. Telangiectatic focal nodular hyperplasia: US, CT, and MR imaging findings with histopathologic correlation in 13 cases.  Radiology. 2003;  228 465-472
  CrossrefPubMedSearch in Google Scholar
• 9 Peterfy C G, Rosenthall L. Large telangiectatic focal nodular hyperplasia presenting with normal radionuclide studies: case report.  J Nucl Med. 1990;  31 2037-2039
  PubMedSearch in Google Scholar
• 10 Haber M, Rueben A, Oliveiro P et al.. Multiple focal nodular hyperplasia of the liver associated with hemihyperthrophy and vascular malformations.  Gastroenterology. 1995;  108 1256-1262
  PubMedSearch in Google Scholar
• 11 Guindi M. So called telangiectatic focal nodular hyperplasia: a newly recognized variant of hepatic adenoma.  Pathol Case Rev. 2007;  12 154-159
  PubMedSearch in Google Scholar
• 12 Bioulac-Sage P, Balabaud C, Bedossa P et al.. Pathological diagnosis of liver cell adenoma and focal nodular hyperplasia: Bordeaux update.  J Hepatol. 2007;  46 521-527
  CrossrefPubMedSearch in Google Scholar
• 13 Kim H-S, Kim Y A, Kim C J et al.. Telangiectatic focal nodular hyperplasia of the liver: a case detected at birth.  J Korean Med Sci. 2003;  18 746-750
  PubMedSearch in Google Scholar
• 14 Zucman-Rossi J, Jeannot E, Nhieu J T et al.. Genotype-phenotype correlation in hepatocellular adenoma: a new classification and relationship with HCC.  Hepatology. 2006;  43 515-524
  CrossrefPubMedSearch in Google Scholar
• 15 Yamagata K, Oda N, Kaisaki P J et al.. Mutations in the hepatocyte nuclear factor-1alpha gene in maturity-onset diabetes of the young (MODY3).  Nature. 1996;  384 458-460
  CrossrefPubMedSearch in Google Scholar
• 16 Bacq Y, Jacquemin E, Balabaud C et al.. Familial liver adenomatosis associated with hepatocytes nuclear factor 1alpha inactivation.  Gastroenterology. 2003;  125 1470-1475
  CrossrefPubMedSearch in Google Scholar
• 17 Reznik Y, Dao T, Coutant R et al.. Hepatocyte nuclear factor-1 alpha gene inactivation: cosegregation between liver adenomatosis and diabetes phenotypes in two maturity-onset diabetes of the young (MODY3) families.  J Clin Endocrinol Metab. 2004;  89 1476-1480
  CrossrefPubMedSearch in Google Scholar

Stephen C WardM.D. Ph.D. 

Department of Pathology, The Mount Sinai Medical Center

One Gustave L. Levy Place, New York, NY 10029

Email: stephen.ward@mssm.edu