Epithelioid Hemangioendothelioma, Multiple Focal Nodular Hyperplasias, and Cavernous Hemangiomas of the Liver an Unusual Association

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Epithelioid Hemangioendothelioma, Multiple Focal Nodular Hyperplasias, and Cavernous Hemangiomas of the Liver An Unusual Association

Marie-Pierre Bralet, MD, PhD; Benoit Terris, MD; Vale´rie Vilgrain, MD, PhD; Laurence Bre´geaud; Georges Molas, MD; Miche`le Corbic, MD; Jacques Belghiti, MD, PhD; Jean-Franc¸ois Fle´jou, MD, PhD; Claude Degott, MD, PhD

● Malignant vascular neoplasms of the liver are uncom- dice, or gastrointestinal bleeding. She had taken oral contracep- mon. We report the case of a young woman who developed tives for 10 years. Abdominal examination revealed a tender ep- an epithelioid hemangioendothelioma of the liver associ- igastric mass. There was neither ascites nor lymphadenopathy. ated with multiple focal nodular hyperplasias and hepatic Laboratory data showed normal blood cell count, hemoglobin cavernous hemangiomas. Such an unusual association is rate, serum transaminase activities, and ␣-fetoprotein level. Se- rum ␥-glutamyl transpeptidase (2.5 times the normal value) and probably not fortuitous and could support the theory that alkaline phosphatase (1.5 times the normal value) activities were focal nodular hyperplasia is a reaction to an abnormal vas- mildly increased. Computed tomography and magnetic reso- cular supply rather than a true neoplasm. nance imaging of the abdomen revealed multiple hepatic nod- (Arch Pathol Lab Med. 1999;123:846–849) ules. Lesions of the left hepatic lobe were hypervascular on the computed tomographic scan and hyperintense and heteroge-

neous on the T2-weighted magnetic resonance image, suggesting ocal nodular hyperplasia (FNH) is a benign lesion of a ﬁbrous component. In addition, 2 small lesions of the left lobe the liver that occurs predominantly in young women F were strongly hyperintense on T2-weighted images as observed 1,2 and is asymptomatic in most cases. Histologically, it is in cavernous hemangiomas. In the right hepatic lobe, lesions were characterized by nodular hyperplasia of the hepatic pa- highly suggestive of FNH but atypical because of the presence

renchyma around a central stellate fibrous scar containing of multiple foci that were strongly hyperintense on T2-weighted abnormal vessels and numerous bile ductules.1,2 It has images. Thoracic computed tomographic scan showed 2 pulmo- been associated with various lesions, including hepatic he- nary nodules in the right inferior lobe. Preoperative liver biopsy mangioma, hepatocellular adenoma, fibrolamellar carci- specimens disclosed EHE in both lobes. Orthotopic liver trans- noma, vascular malformations of various organs, and neo- plantation was discussed but rejected because of pulmonary le- plasia of the brain.3–6 To the best of our knowledge, no sions suggesting a second and/or metastatic location of EHE. association of FNH and hepatic malignant vascular tumor Pulmonary nodules were surgically resected, and left hepatec- has been reported yet. Malignant vascular tumors of the tomy with additional resection of hepatic nodules from segments VI and VII was performed. The use of oral contraceptives was liver are rare and include angiosarcoma, Kaposi sarcoma, stopped. and epithelioid hemangioendothelioma (EHE). Epithelioid hemangioendothelioma is of intermediate-grade malig- PATHOLOGIC FINDINGS nancy and of relatively favorable prognosis compared with angiosarcoma.7–13 Tissues were fixed in 4% neutral-buffered formalin, em- We describe the association of a primary EHE of the bedded in paraffin, and routinely processed. Sections were liver with 3 nodules of FNH and 2 hepatic cavernous he- stained with hematoxylin-eosin, Masson trichrome, Perls mangiomas. Such an association constitutes an additional Prussian blue, Alcian blue, and periodic acid–Schiff with argument for the hypothesis that FNH is a hyperplastic and without prior diastase digestion. response of the liver parenchyma to the presence of pre- The left hepatectomy (Figure 1) measured 17 ϫ 11 ϫ 6 existing vascular abnormalities. cm and weighed 360 g. It contained a main mottled tumorous mass of 10 cm with indistinct borders. In addition, REPORT OF A CASE multiple, firm, white-red, ill-defined nodules ranging A previously healthy, 35-year-old woman was investigated be- from 0.1 to 1.0 cm in diameter were haphazardly scattered cause of recent abdominal pain without fever, weight loss, jaun- throughout the lobe. The intervening liver was soft and dark reddish-brown and contained 2 hemangiomas mea- Accepted for publication February 19, 1999. suring 2 and 1 cm, respectively. Histologically, the largest From the Departments of Pathology (Drs Bralet, Terris, Molas, Fle´jou, mass and the nodules showed the typical features of EHE and Degott and Ms Bre´geaud), Radiology (Dr Vilgrain), Hepatology (Dr (Figure 2). They were composed of small cords or nests Corbic), and Digestive Surgery (Dr Belghiti), Beaujon Hospital, Clichy, France. of dendritic-shaped cells and epithelioid cells with cyto- Reprints: Marie-Pierre Bralet, MD, PhD, De´partement de Pathologie, plasmic vacuoles that occasionally contained red blood Hoˆpital Henri Mondor, 51 Avenue du Marećhal de Lattre de Tassigny, cells. Ultrastructural examination confirmed that most tu- 94010 CRETEIL Cedex, France. mor cells resembled endothelial cells with intracellular lu- 846 Arch Pathol Lab Med—Vol 123, September 1999 Hemangioendothelioma, Hyperplasias, and Hemangiomas—Bralet et al Figure 1. Left hepatectomy. Most of the lobe is occupied by a ill-defined, mottled tumorous mass (arrowheads) corresponding to epithelioid hemangioendothelioma. Note a cavernous hemangioma (arrow). mina and occasional intracytoplasmic Weibel-Palade bod- Microscopic analysis showed typical features of FNH (Fig- ies. Immunohistochemical analysis performed on paraffin- ure 5). However, the macroscopically red foci disseminat- embedded tissue sections demonstrated a cytoplasmic ed throughout the 3 FNHs corresponded to areas of EHE. positivity of the EHE tumor cells with anti-CD31 antibody These malignant areas of varying size (from a few tumor (Immunotech, Marseille, France). Regressive changes char- cells to a true neoplastic nodule) were more or less well acterized by tumor cell atrophy and formation of a densely limited. They were either surrounded by the hyperplastic hyalinized stroma were observed in the central part of the hepatic parenchyma or located near or adjacent to a ra- tumor. By contrast, the periphery of the tumor showed diating fibrous septum containing abnormal vessels, pro- high cellularity with a centrifugal growth pattern to the liferating bile ductules, and inflammatory cells (Figure 6). adjacent liver. Intravascular growth was marked and con- No vascular invasion by EHE tumor cells of the large dys- sisted of irregularly distributed papillary projections of trophic vessels of FNH fibrous bands was noted. tumor cells into the lumen of central or portal veins (Fig- The 2 pulmonary nodules, 0.6 and 1 cm, corresponded ure 3). The intervening liver showed a normal lobular ar- to EHE. Alveolar lumina were filled with densely hyalin- chitecture, without portal fibrosis or hepatocyte necrosis ized fibrotic micronodules surrounded at the periphery by or inflammation. The 2 hemangiomas were of cavernous a few viable EHE tumor cells. type without infiltration by the EHE tumor cells. Resected specimens from the right hepatic lobe com- COMMENT prised one nodule from segment VII, which measured 7 In the present case, EHE affecting both liver and lung ϫ 6 ϫ 6 cm and weighed 130 g, and one from segment occurred in a young woman taking oral contraceptives. VI, which measured 8 ϫ 6 ϫ 6 cm and weighed 80 g. The This malignant vascular tumor was associated with mul- nodule from segment VII was firm, pale, and lobulated, tiple FNHs and hepatic cavernous hemangiomas. To date, with distinct borders but no encapsulation, and contained no definite etiopathogenic factor has been ascribed to a 1.2-cm central fibrous scar. This overall macroscopic as- EHE. A relationship with oral contraceptive use and vinyl pect was suggestive of FNH but several unusual red foci chloride exposition has been suggested.14,15 In contrast to ranging from 0.4 to 1.8 cm in diameter were disseminated Kaposi sarcoma, genome of herpesvirus 8 has not been throughout this main lesion (Figure 4). Segment VI com- detected in EHE tumor cells.16 New insights into tumor prised 2 independent lesions also suggestive of FNH, biology of EHE led speculation that EHE tumor cells may which measured 2 cm each and contained small red foci. derive from primitive ‘‘reticuloendothelial’’ cells that can Arch Pathol Lab Med—Vol 123, September 1999 Hemangioendothelioma, Hyperplasias, and Hemangiomas—Bralet et al 847 Figure 4. Hepatic nodule located in segment VII suggestive of focal nodular hyperplasia. This lobulated mass of 6 cm is well circumscribed and pale, with a central scar (arrow), but several foci of epithelioid hemangioendothelioma (arrowheads) are observed.

of multiple FNHs of the liver, vascular malformations of various organs, and neoplasia of the brain.6 In addition, Mathieu et al3 have shown that the association of hemangioma with FNH is frequent (23%) and not fortuitous and that prolonged administration of oral contraceptives Figure 2. Epithelioid hemangioendothelioma. Tumoral cells are em- might facilitate the recognition of this association. As stat- bedded in a fibrous stroma and show evidence of vascular differenti- ed by Wanless et al,21 morphologic observations support ation with large intracytoplasmic vacuoles containing blood red cells the theory that a vascular anomaly precedes the devel- (arrows) (hematoxylin-eosin, original magnification ϫ400). opment of FNH and that hepatocellular hyperplasia may Figure 3. Papillary projections of epithelioid hemangioendothelioma be a response to high sinusoidal pressure and/or in- cells into the lumen of a medium hepatic vein (hematoxylin-eosin, creased blood flow. original magnification ϫ200). A characteristic feature of EHE is the infiltration of si- nusoids and intrahepatic veins of all sizes with polypoid projections narrowing and obliterating their lumen.7,28 differentiate along endothelial and dendritic pathways Therefore, it is possible that because of the intravascular and that EHE lesions might represent a neoplastic analog tufted growth pattern of EHE, there is a decreased per- of wound healing.17 In hepatic EHE, the nontumoral liver fusion in EHE areas and consequently an increased blood is usually normal or shows mild nonspecific changes. flow to other areas of liver parenchyma. This nonuniform- However, cirrhosis of undetermined origin, cholestasis, ity of blood supply to various parts of liver parenchyma nodular regenerative hyperplasia, and even primary bili- could represent predisposing conditions to induce com- ary cirrhosis have occasionally been reported.7,18–20 To our pensatory regeneration of hepatic parenchyma and might knowledge, the association of a primary, diffuse EHE of explain the occurrence of FNH. Similarly, in a child with the liver with multiple FNHs and several cavernous he- sickle cell anemia who developed an FNH, Markowitz et mangiomas has never been reported. Although we cannot al29 suggested that the genesis of this lesion might pre- rule out such an association as coincidental, we believe sumably be attributed to the impairment of blood flow by that it is not fortuitous. sickle cells and the tendency for small vessel occlusions. It is now generally assumed that FNH represents an Moreover, as already suggested in a few cases of fibrola- abnormal adaptive response of liver parenchyma to local mellar carcinoma, the peritumoral zone of this type of hemodynamic disturbance.21,22 This assumption is sup- cancer resembles FNH, which then represents a hyper- ported by some evidence for the polyclonal nature of FNH plastic response of liver parenchyma to the high vascular- and by a similar immunohistochemical pattern observed ity of fibrolamellar carcinoma.5 In addition, the use of oral both in FNH and in normal liver, according to the com- contraceptives for a long period in the present patient position of extracellular matrix and cell adhesion mole- could favor the growth of FNHs and their detection.1–3 Al- cules.23–25 Both solitary and multiple forms of FNH have though a causal role of oral contraceptive use in the de- been described. However, patients with multiple FNHs velopment of FNH has never been demonstrated, several commonly have other lesions, often vascular in nature, lo- arguments suggest that these agents probably exert a tro- calized in the liver and other organs such as the brain,6,26,27 phic effect that leads to an increase in size and vascular- suggesting the existence of a distinct syndrome consisting ity.2 It should also be stated that mechanisms involving 848 Arch Pathol Lab Med—Vol 123, September 1999 Hemangioendothelioma, Hyperplasias, and Hemangiomas—Bralet et al 2. Knowles DM, Wolff M. Focal nodular hyperplasia of the liver: a clinicopathologic study and review of the literature. Hum Pathol. 1976;7:533–545. 3. Mathieu D, Zafrani ES, Anglade MC, Dhumeaux D. Association of focal nodular hyperplasia and hepatic hemangioma. Gastroenterology. 1989;97:154– 157. 4. Ndimbie OK, Goodman ZD, Chase RL, Ma CK, Lee MW. Hemangiomas with localized nodular proliferation of the liver: a suggestion on the pathogenesis of focal nodular hyperplasia. Am J Surg Pathol. 1990;14:142–150. 5. Saxena R, Humphreys S, Williams R, Portmann B. Nodular hyperplasia sur- rounding fibrolamellar carcinoma: a zone of arterialized parenchyma. Histopa- thology. 1994;25:275–278. 6. Wanless IR, 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. 7. Ishak KG, Sesterhenn I, Goodman ZD, Rabin L, Stromeyer W. Epithelioid hemangioendothelioma of the liver: a clinicopathologic and follow-up study of 32 cases. Hum Pathol. 1984;15:839–852. 8. Weiss SW, Enzinger FM. Epithelioid hemangioendothelioma: a vascular tumor often mistaken for a carcinoma. Cancer. 1982;50:970–981. 9. Laüffer JM, Zimmermann A, Kra¨henbu¨hl L, Triller J, Baer HU. Epithelioid hemangioendothelioma of the liver: a rare hepatic tumor. Cancer. 1996;78:2318– 2327. 10. Scoazec J-Y, Lamy P, Degott C, et al. Epithelioid hemangioendothelioma of the liver: diagnostic features and role of liver transplantation. Gastroenterology. 1988;94:1447–1453. 11. Van de Stadt J, Gelin M, Adler M, Lambilliotte JP. Epithelioid hemangioendothelioma and liver transplantation. Gastroenterology. 1989;96:275–276. 12. Radin DR, Craig JR, Colletti PM, Ralls PW, Halls JM. Hepatic epithelioid hemangioendothelioma. Radiology. 1988;169:145–148. 13. Ekfors TO, Joensuu K, Toivio I, Laurinen P, Pelttari L. Fatal epithelioid hae- mangioendothelioma presenting in the lung and liver. Virchows Arch A Pathol Anat. 1986;410:9–16. 14. Dean PJ, Haggitt RC, O’Hara CJ. Malignant epithelioid hemangioendothelioma of the liver in young women: relationship to oral contraceptive use. Am J Surg Pathol. 1985;10:695–704. 15. Gelin M, Van de Stadt J, Rickaert F, et al. Epithelioid hemangioendothelioma of the liver following contact with vinyl chloride: recurrence after orthotopic liver transplantation. J Hepatol. 1989;8:99–106. 16. Ishak KG, Bijwaard KE, Markhouf HR, Taubenberger JK, Lichy JH, Good- man ZD. Absence of human herpesvirus 8 DNA sequences in vascular tumors of the liver. Liver. 1998;18:124–127. 17. Demetris AJ, Minervini M, Raikow RB, Lee RG. Hepatic epithelioid hemangioendothelioma: biological questions based on pattern of recurrence in an allograft and tumor immunophenotype. Am J Surg Pathol. 1997;21:263–270. Figure 5. Microscopic appearance of the focal nodular hyperplasia of 18. Kelleher M, Iwatsuki S, Sheahan DG. Epithelioid hemangioendothelioma segment VII. The central dense fibrous septum contains dystrophic ves- of liver: clinicopathological correlation of 10 cases treated by orthotopic liver sels (arrowheads), marginal ductular proliferation, and inflammatory transplantation. Am J Surg Pathol. 1989;13:999–1008. cells infiltrate (hematoxylin-eosin, original magnification ϫ100). 19. Marino IR, Todo S, Tzakis AG, et al. Treatment of hepatic epithelioid hemangioendothelioma with liver transplantation. Cancer. 1988;62:2079–2084. Figure 6. Immunohistochemical detection of CD31. Labeling is pres- 20. Terada T, Nakanuma Y, Hoso M, Kono N, Watanabe K. Hepatic epithelioid ent in the endothelial cells lining abnormal vessels of focal nodular hemangioendothelioma in primary biliary cirrhosis. Gastroenterology. 1989;97: hyperplasia fibrous septa and in the epithelioid hemangioendothelioma 810–811. neoplastic cells (lower right) (original magnification ϫ100). 21. Wanless IR, Mawdsley C, Adams R. On the pathogenesis of focal nodular hyperplasia of the liver. Hepatology. 1985;5:1194–1200. 22. Wanless IR. Micronodular transformation (nodular regenerative hyperplasia) of the liver: a report of 64 cases among 2500 autopsies and a new classifi- the presence of nodules of EHE inside the FNHs are prob- cation of benign hepatocellular nodules. Hepatology. 1990;11:787–797. ably not certain. The FNHs could develop around and en- 23. Paradis V, Laurent A, Fle´jou J-F, Vidaud M, Bedossa P. Evidence for the polyclonal nature of focal nodular hyperplasia of the liver by the study of X- trap preexisting lesions of EHE. However, we cannot rule chromosome inactivation. Hepatology. 1997;26:891–895. out that EHE secondarily grew within an already formed 24. Scoazec J-Y, Fle´jou J-F, D’Errico A, et al. Focal nodular hyperplasia of the FNH, suggesting a propensity of EHE tumor cells to be liver: composition of the extracellular matrix and expression of cell-cell and cell- matrix adhesion molecules. Hum Pathol. 1995;26:1114–1125. attracted toward hypervascularized conditions such as 25. Nerlich A, Berndt R, Schleicher E. Differential basement membrane com- FNH. position in multiple epithelioid haemangioendotheliomas of liver and lung. His- In summary, we report the case of a young woman tak- topathology. 1991;18:303–307. ing oral contraceptives who developed primary EHE of 26. Haber M, Reuben A, Burrell M, Oliverio P, Salem RR, West AB. Multiple focal nodular hyperplasia of the liver associated with hemihypertrophy and vas- the liver associated with multiple FNHs and hepatic cav- cular malformations. Gastroenterology. 1995;108:1256–1262. ernous hemangiomas. We suggest that this association is 27. Portmann B, Stewart S, Higenbottam TW, Clayton PT, Lloyd JK, Williams not coincidental and that FNH could be secondary to ab- R. Nodular transformation of the liver associated with portal and pulmonary ar- terial hypertension. Gastroenterology. 1993;104:616–621. normal vascularization of the parenchymal liver because 28. Fukayama M, Nihei Z, Takizawa T, Kawaguchi K, Harada H, Koike M. of numerous vascular occlusion by EHE tumor cells. Malignant epithelioid hemangioendothelioma of the liver spreading through the hepatic veins. Virchows Arch A Pathol Anat. 1984;404:275–287. References 29. Markowitz RI, Harcke HT, Ritchie WG, Huff DS. Focal nodular hyperplasia 1. Ishak KG, Rabin L. Benign tumors of the liver. Med Clin North Am. 1975; of the liver in a child with sickle cell anemia. AJR Am J Roentgenol. 1980;134: 59:995–1013. 594–597.

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