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Epithelioid hemangioendothelioma (EH) is a rare vascular neoplasm that was first described by Weiss and Enzinger . The natural history and clinical course of EH is largely unknown given its rarity, but its malignant potential is thought to range between that of a benign hemangioma to a malignant angiosarcoma [Woodall et al. 2008; Mehrabi et al. 2006; Uchimura et al. 2001]. Primary disease can involve soft tissue and visceral organs to include heart, spleen, lung, bone, and lymph nodes [Woodall et al. 2008; Mehrabi et al. 2006]. Primary malignant hepatic epithelioid hemangioendothelioma (HEH) is an exceptionally rare tumor with a reported incidence of less than 0.1 per 100,000, with less than 440 published reports in the literature [Mehrabi et al. 2006]. The exact etiopathogenesis of HEH is unknown but possible etiologic factors have been described to include oral contraceptives, vinyl chloride, asbestos, hepatic trauma, viral hepatitis, primary biliary cirrhosis, and alcohol consumption [Mehrabi et al. 2006].
In contrast to the obscure and rare nature of HEH, ulcerative colitis (UC) is one of the major inflammatory bowel diseases (IBDs) with an incidence reported between 12 and 15 per 100,000 [Kildebo et al. 1990; Stonnington et al. 1987]. Although the etiopathogenesis for UC is not exactly defined, improved understanding of the immunopathogenesis of IBD has resulted in significant advances in the research and development of immunosuppressive and biologic agents [Jones and Loftus, 2007]. Currently, infliximab, a chimeric IgG1 monoclonal antibody to tumor necrosis factor-alpha (TNF-α), has demonstrated efficacy for the induction and maintenance of remission in moderate to severe UC [Rutgeerts et al. 2005]. As the utilization of infliximab for UC has increased, there has been increasing concern about its long-term safety given its immunosuppressive effects. Specifically, the increased risk of malignancy, in particular lymphoma, has been an area of controversy and debate [Biancone et al. 2007; Jones and Loftus, 2007; Reddy and Loftus, 2006].
To the best of the authors’ knowledge, HEH has never been reported to occur in the setting of UC, exposure to infliximab, or both. Here, we report the first case of HEH in the setting of chronic UC treated with infliximab.
A 28-year-old man with a history of UC presented to our clinic with incidental hepatic lesions found on CT during an evaluation for nephrolithiasis. Left-sided UC was diagnosed 5 years previously. Despite topical and oral mesalamine, his colitis remained active. Infliximab (5mg/kg) was started 2 years prior to presentation with the complete resolution of his symptoms. He received no concomitant immunomodulator therapy and infliximab was continued as monotherapy for maintenance every 8 weeks. One month prior to presentation, he developed left flank pain and urinary symptoms that were felt to secondary to nephrolithiasis. An outside CT was performed which demonstrated a calculus at the left ureterovesical junction. In addition, the CT revealed multiple low attenuation lesions throughout the liver with the largest measuring 3.2cm×2.6cm (Figure 1). Physical exam was unremarkable. Complete blood count, electrolyte panel, and liver function tests were unremarkable. Image directed liver biopsy confirmed HEH with positive immunohistochemical staining for CD31 and CD34 in neoplastic cells (Figure 2). Infliximab was stopped, and high-dose oral mesalamine with topical therapy for maintenance was initiated. Positron emission tomography (PET) confirmed intrahepatic but not extrahepatic disease, and increased radiotracer uptake was limited to three foci in the right hepatic lobe. Consultation with the Liver Transplant Clinic was obtained and transplantation was not recommended given that the lesions were felt amenable to surgical or ablative therapy, and based on the limited experience our center has had with transplantation for HEH, there has been almost universal recurrence. A right hepatectomy, cholecystectomy and subsegmental resection of segment 4B were performed. Postoperative pathology confirmed HEH with negative margins and pathology of the uninvolved portions of his liver were unremarkable. His postoperative course was uncomplicated and he is without evidence of recurrence at 6 months followup. His colitis remains in remission on oral and topical mesalamine.
HEH is a rare neoplasm of vascular origin whose etiopathogenesis is unknown and associations with other diseases are infrequent. UC is an IBD in which immunopathogenesis is thought to play a central role clinically and, consequently, has resulted in the development of novel and effective therapies including infliximab. Anti-TNF agents have been associated with an increased risk for lymphoma [Jones and Loftus, 2007; Rutgeerts et al. 2005]. However, this report is the first to describe HEH developing in a patient with UC on maintenance infliximab. Given the rarity of HEH, and possible association between infliximab and carcinogenesis, this case report is noteworthy.
Patients with primary malignant HEH have a female predominance, with a mean age of presentation of approximately 42 years [Mehrabi et al. 2006]. Although patients are often asymptomatic and masses are found incidentally, commonly reported symptoms include right upper quadrant abdominal pain, hepatomegaly, and weight loss [Mehrabi et al. 2006]. However, more ominous presentations with portal hypertension or hepatic failure have been described [Mehrabi et al. 2006]. The most common physical finding is hepatosplenomegaly [Garcia-Botella et al. 2006]. Possible associated exposures include oral contraceptive pills [Dean et al. 1985], vinyl chloride [Shin et al. 1991; Gelin et al. 1989], hepatic trauma [Banerjee and Rennison, 1992], viral hepatitis [Lauffer et al. 1996], and primary biliary cirrhosis [Terada et al. 1989]. However, given its obscurity and lack of prospective data, no definitive or causative factors are known.
HEH has no pathognomonic radiographic findings. Two forms of HEH have been described and likely represent different disease stage: a multifocal nodular infiltration in the liver is seen in the early stages and these lesions later grow in size and coalesce to form a diffuse pattern of infiltration [Radin et al. 1988]. Often these lesions are located peripherally and extend to the liver capsule [Miller et al. 1992]. Possible association of these peripheral lesions with capsular retraction appears to be an area of controversy [Miller et al. 1992; Furui et al. 1989].
Similarly, there are no definitive diagnostic laboratory tests for HEH. Non-specific laboratory abnormalities include increased alkaline phosphatase, γ-glutamyl transpeptidase, aspartate aminotransferase, alanine aminotransferase, and bilirubin [Mehrabi et al. 2006]. Tumor markers including α-fetoprotein, carcinoembryonic antigen and carbohydrate antigen 19-9 are commonly normal and used to exclude other potential malignancies [Mehrabi et al. 2006].
The gold standard for diagnosis remains histopathology from liver biopsy. The vascular nature of HEH is supported by the immunohistochemical evidence of endothelial differentiation with positive staining for markers to include factor VIII-related antigen, CD31, and CD34; all of which are positive in the vast majority of cases [Mehrabi et al. 2006]. The vascular nature of HEH may be significantly relevant in this patient with a history of both UC and infliximab therapy. As IBD involves cycles of inflammation with intestinal regeneration, the potential pathologic role of angiogenesis has been investigated recently [Scaldaferri et al. 2009; Koutroubakis et al. 2006]. Levels of vascular endothelial growth factor A (VEGF-A), a mediator of angiogenesis, in both plasma and intestine have been shown to be upregulated in patients with IBD [Scaldaferri et al. 2009]. Also increased expression of endothelial junction adhesion molecules, such as CD146 and CD31, in patients with IBD support the role of angiogenesis [Bardin et al. 2006]. These findings support the hypothesis that the patient’s underlying IBD, and not treatment with infliximab, may have contributed to the development of the HEH.
The counterhypothesis that infliximab itself had a central etiologic role seems less likely. TNF-α blockade appears to ameliorate endothelial dysfunction and downregulate mediators of angiogenesis such as VEGF [Cardillo et al. 2006; Macias et al. 2005]. Furthermore, infliximab reduces circulating VEGF levels and leads to an observed reduction in number of blood vessels in patients with rheumatoid arthritis [Maini and Feldmann, 2002]. Thus, if infliximab improves endothelial function and suppress angiogenesis and abnormal angiogenesis plays an important etiologic role in HEH, we hypothesized that IBD and not infliximab more likely contributed to the development of HEH in this patient. To explore this hypothesis, we reviewed the medical records of all subjects who have presented to our institution with pathology proven EH. A total of 30 subjects were identified and aside from the patient presented here, there were no other subjects found with a history of IBD. However, given the rarity of HEH, the lack of identifying other subjects with IBD does not dissuade us from our hypothesis.
Treatment strategies for HEH vary and there are no randomized prospective studies evaluating different therapeutic interventions. Management commonly involves liver resection, liver transplantation, chemotherapy, radiotherapy, or monitoring [Mehrabi et al. 2006]. Given the multifocal nature of HEH, liver resection is often precluded and liver transplantation appears to be quite efficacious [Hoti and Adam, 2008]. Furthermore, unlike other primary hepatic tumors, extrahepatic involvement of HEH does not appear to correlate with survival and should not preclude transplantation [Hoti and Adam, 2008]. In this case, the patient underwent right hepatectomy and wedge resection of segment 4B and transplantation was not pursued.
In summary, this is the first report of HEH complicating UC on maintenance therapy with infliximab. Although there is ongoing concern and controversy regarding the potential pathological role of infliximab initiating or propagating lymphoproliferative disorders, such potential seems remote for HEH. However, given the vascular nature of HEH, the role of angiogenesis in UC, and findings that infliximab improves endothelial function and suppresses angiogenesis, we hypothesize that the patient’s underlying IBD predisposed this patient to the development of HEH.