Hemangioendothelioma

To the Editor. -Focal nodular hyperplasia (FNH) is a mass lesion composed of benign hepatocytes. Typically, a prominent branching artery is present within a central fibrous scar. Increased arterial flow is thought to be a possible cause of the hepatocellular hyperplasia.1 Most examples are idiopathic, occurring in a normal or nearly normal liver. Recent reports have described FNH and FNH-like lesions in a variety of different clinical and anatomic settings, including hypoplasia or agenesis of the portal vein,3 Budd-Chiari syndrome,'4 cirrhosis of various etiologies,5,6 hereditary hemorrhagic telangiectasia,7 multiple FNH syndrome,3 and adjacent to fibrolamellar carcinoma8-13 and hydatid cyst.14 This myriad of associations and the report of Bralet et al,15 which appeared in a recent issue of the ARCHIVES, offer some insight into the pathogenesis of FNH. This letter reviews this information, adds a new case, and proposes a revised hypothesis for the pathogenesis of FNH.

The patient Bralet et al described was a young woman treated with oral contraceptives who presented with a large epithelioid hemangioendothelioma in the left lobe and several metastatic deposits in the right lobe of her liver. There were 3 lesions of "FNH" in the right lobe and cells of epithelioid hemangioendothelioma in all 3 lesions. Two points should be mentioned.

1. It is not dear that the regions of hepatocellular hyperplasia were actually FNH. The authors do not describe enlarged central vessels with a branched hierarchy accompanied by ductular proliferation. The case has similarities to the multiple FNH syndrome,3 in that the nodules are multiple and there is a hemangioma elsewhere in the liver. However, the pathogenesis of the hyperplastic nodules is likely to be different in this case. The close proximity of neoplastic cells and hepatocellular hyperplasia suggests the neoplasm played a role in causing the hyperplasia. In the absence of more details, it might be better to consider these nodules as peritumoral hyperplasia, as described below.

2. The authors suggest that local obstruction of vessels (ie, ischemia) could account for the hyperplasia. This is in keeping with previous suggestions that atrophy appears to precede hyperplasia in nodular regenerative hyperplasia.16 However, parenchyma adjacent to primary and metastatic carcinomas usually shows atrophy rather than hyperplasia. 17 What conditions are required to generate an exception to the usual atrophic response?

A new case presented here offers additional clues (Figure 1). This patient had a solitary fibrolamellar carcinoma accompanied by a 14-mm-diameter FNH immediately adjacent to the carcinoma and 3 remote FNH lesions measuring 2, 2, and 11 mm in diameter. The carcinoma invaded many structures in the region of the largest FNH, including the portal and hepatic veins, lymphatics, and nerves. All 3 of the remote FNH lesions had central branched vessels and ductular proliferation in a fibrous matrix, and all were free of carcinoma cells. All 3 lesions had adjacent hepatic vein obliteration or stenosis, likely postthrombotic in origin. In one 2-mm FNH, an arteriovenous shunt was identified. Thus, local venous obstruction could have played a role in the development of the FNH response, as suggested by Lough et al18 for non-tumor-associated FNH. Organization of the thrombus may lead to formation of arteriovenous shunts that could augment angiogenesis in the supplying artery and its branches.

Berman described FNH adjacent to the fibrolamellar type of hepatocellular carcinoma in 3 of 12 cases.8 Since then, single case reports have documented hyperplastic or nodular lesions immediately adjacent to various focal lesions, including fibrolamellar carcinoma,9-13 hemangioma,1,19 and echinococcal cyst.14 In one case, a 5mm FNH lesion was noted remote from a large fibrolamellar carcinoma.20 These hyperplastic lesions have been illustrated in very few cases. Only 1 lesion has been demonstrated that grossly resembled FNH.14 One liver had a peripheral irregular zone of hyperplasia with ductular proliferation and radiating fibrous septa." One liver had a 1- to 2-cm band of peritumoral hepatocytes that resisted acetaminophen toxicity. In this band there was no fibrous septation; a few arteries were unaccompanied by ducts or portal veins.13 In none of these cases was arterial branching described.

The presence of remote FNH lesions suggests an additional stimulus operating at a distance, such as systemic elevation of tumor-derived growth factors or sex hormones. The angiogenic substances, vascular endothelial growth factor or basic fibroblast growth factor, have been documented in endothelial neoplasms, including epithelioid hemangioendothelioma, angiosarcoma, and hemangioma.21-24 Transforming growth factor-beta has been documented within fibrolamellar carcinomas.25 Focal nodular hyperplasia has a female predominance in most studies. There is evidence that estrogens may induce hepatic angiogenesis in the rat.26 Many patients with FNH have been exposed to oral contraceptives, including the patient with associated echinococcal cyst.14 The coincidence in some patients of multiple FNH with various vascular lesions and neoplasms, including vascular malformations, hemangioma, meningioma, astrocytoma, and vascular dysplasia, adds another dimension to the puzzle.3 Astrocytomas and meningiomas are responsive to female hormones,27,28 possibly through enhanced vascular endothelial growth factor production.29

Considering this body of information, it appears that FNH and peritumoral hyperplasia are nonspecific responses to local increased arterial perfusion. This unity is the basis for the hypothesis presented diagrammatically in Figure 2. In brief, increased arterial flow may be generated by anomalous arteries or angiogenesis. Local angiogenesis may be stimulated by local factors (eg, local venous thrombosis, postthrombotic arteriovenous shunts, and tumor production of angiogenic factors) and augmented by systemic factors (eg, oral contraceptives, female gender, and systemic elevation of tumor-associated growth factors). Mild angiogenesis may account for peritumoral hyperplasia. Marked angiogenesis may cause the FNH phenotype with arterial branching, ductular proliferation, and fibrosis. The fibrosis may be secondary to flow-related injury.30

References

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2. Wanless IR, Lentz JS, Roberts EA. Partial nodular transformation of liver in an adult with persistent ductus venosus. Arch Pathol Lab Med. 1985; 109:427.432.

3. Wanless IR, Albrecht S, Bilbao 1, 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.

4. Tanaka M, Wanless IR. Pathology of the liver in Budd-Chiari syndrome: portal vein thrombosis and the histogenesis of veno-centric cirrhosis, venoportal cirrhosis, and large regenerative nodules. Hepatology. 1998;27:488-496.

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14. Komisarof JA, Olthoff K, Siegelman ES, Lawton TJ, Furth EE. Focal nodular hyperplasia contiguous with an echinococcal cyst. Am J Gastroenterol. 1999. In press,

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20. Farhi DC, Shikes RH, Silverberg SG. Ultrastructure of fibrolamellar oncocytic hepatoma. Cancer. 1982;50:702-709.

21. Dirix LY, Vermeulen PB, Hubens G, et al. Serum basic fibroblast growth factor and vascular endothelial growth factor and tumour growth kinetics in advanced colorectal cancer. Ann Oncol. 1996;7: 843-848.

22. Bussolino F, Mantovani A, Persico G. Molecular mechanisms of blood vessel formation. Trends Biochem Sci. 1997;22:251-256.

23. Uchida K, Takahashi A, Miyao N, et al. juvenile hemangioma of the testis: analysis of expression of angiogenic factors. Urology. 1997;49:285286.

24. Zetter BR. Angiogenesis and tumor metastasis. Annu Rev Med. 1998;49:407-424.

25. Orsatti G, Hytiroglou P, Thung SN, Ishak KG, Paronetto F. Lamellar fibrosis in the fibrolamellar variant of hepatocellular carcinoma: a role for transforming growth factor beta. Liver. 1997;17:152-156.

26. Ishii K, Matama S, Shibata H, et al. Microcirculatory responses to estradiol benzoate in chronic liver damage induced by carbon tetrachloride in the rat. Gastroenterol(pn. 1984;19:419-423.

27. Koper JW, Lamberts SW. Meningiomas, epidermal growth factor and progesterone. Hum Reprod. 1994;9(suppl 1):190-194.

28. Moresco RM, Scheithauer BW, Lucignani G, et al.Oestrogen receptors in meningiomas: a correlative PET and immunohistochemical study. Nucl Med Commun. 1997;18:606-615.

29. Rizk B, Aboulghar M, Smitz J, Ron-El R. The role of vascular endothelial growth factor and interleukins in the pathogenesis of severe ovarian hyperstimulation syndrome. Hum Reprod Update. 1997; 3:255-266.

30. Wanless IR. Arterialization of the liver causes baro-injury in cirrhosis and focal nodular hyperplasia (FNH). Hepatology. 1999;30:571 A.

IAN R. WANLESS, MD

Department of Laboratory

Medicine and Pathobiology

Toronto General Hospital and

University of Toronto

Toronto, Ontario, M5G 2C4

Canada

Copyright College of American Pathologists Aug 2000
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