VOLUME 29 䡠 NUMBER 35 䡠 DECEMBER 10 2011 JOURNAL OF CLINICAL ONCOLOGY Chemoresponsive Liver Hemangioma in a Patient With a Metastatic Germ Cell Tumor Introduction Testicular germ cell tumors are the most common solid organ malignancy in young adult men. Approximately 25% of patients with disseminated cancer present with symptoms of regional or disseminated spread of disease. The presence of nonpulmonary visceral metastasis is an independent factor that places such patients into the higher risk groups with a predicted 5-year survival of 41% for nonseminoma and 67% for seminoma.1 Management of patients with nonpulmonary visceral metastases from nonseminoma includes fullschedule chemotherapy with bleomycin, etoposide, and cisplatin (BEP) for four courses and resection of any residual radiographic abnormality if technically feasible.2 Hepatic hemangiomas are the most common benign tumors of the liver.3 These tumors are generally asymptomatic, although they may present as a mass that is associated with vague abdominal pain, abdominal compartment syndrome, heart failure, hepatic failure, and even death.4 Although observation is recommended for small, asymptomatic hemangiomas, symptomatic and/or large hemangiomas (⬎ 4 cm) may require surgical intervention.3 Liver metastases and hemangiomas may be distinguished with imaging modalities, including magnetic resonance imaging (MRI), on the basis of lesion morphology and T2 measurements. However, overlap between these entities may occur, particularly when metastases are hypervascular.5 Case Report A healthy 39-year-old man presented with left testicular pain and swelling. The physical examination and ultrasound were suspicious for malignancy. Alpha-fetoprotein and human chorionic gonadotropin levels were 20.4 ng/mL and 2.1 mIU/mL, respectively. An orchiectomy was performed and pathology revealed a 3.5-cm mixed germ cell tumor (80% embryonal cell carcinoma and 20% seminoma) without lymphovascular invasion. An abdominal scan showed bulky paraaortic adenopathy and a right hepatic lesion with low intensity and peripheral enhancement (Figs 1A and 1B). After the orchiectomy, tumor markers remained elevated and the patient received primary chemotherapy. Although hepatic hemangioma was strongly suspected, the initial plan was to consider the patient as having International Germ Cell Consensus Classification good-risk nonseminoma, and restaging was planned during the third cycle of therapy to ensure that the paraortic mass was decreasing in size and that the presumed hemangioma remained unchanged. With BEP, the mildly elevated alpha-fetoprotein and human chorionic gonadotropin levels normalized rapidly, as expected. However, follow-up imaging studies that were performed 1 month after chemotherapy showed a decreased but still present retroperitoneal mass as well as a substantially shrunken liver lesion (Fig 2). e842 © 2011 by American Society of Clinical Oncology D I A G N O S I S I N O N C O L O G Y A B Fig 1. With these unexpected findings, the decision was made to proceed with postchemotherapy retroperitoneal lymph node dissection along with intraoperative evaluation of the liver abnormality. If the shrinking liver lesion was proven to be related to the metastatic germ cell tumor, additional postoperative chemotherapy would be considered. A right nerve–sparing bilateral template retroperitoneal lymph node dissection was performed with an intraoperative core liver biopsy. Retroperitoneal pathology was necrosis/fibrosis and a liver biopsy showed masses of blood vessels that were atypical and/or irregular in arrangement and size, findings that favored hepatic hemangioma (Fig 3). Journal of Clinical Oncology, Vol 29, No 35 (December 10), 2011: pp e842-e844 Downloaded from jco.ascopubs.org on September 9, 2014. For personal use only. No other uses without permission. Copyright © 2011 American Society of Clinical Oncology. All rights reserved. Diagnosis in Oncology Fig 2. Discussion This patient case presented unique challenges in terms of initial diagnostics and ongoing clinical decision making. From a clinical viewpoint, the chance that the hepatic lesion represented metastatic dissemination to the liver was low. There was no evidence of other distant dissemination, and the level of tumor marker elevation was also low. However, if this liver lesion did represent metastatic disease, there would have been a substantially different prognosis and treatment plan. Thus, a reassessment was planned after three cycles of therapy to allow for adjustment of the treatment plan if necessary. Surprisingly, the liver lesion decreased substantially; this raised the possibility that this unusual lesion did indeed represent atypical metastases. Hepatic hemangioma is the most common benign liver tumor and the second most common cause of liver mass after metastases, with an incidence of 0.4% to 7.3% in autopsies and 1.7% on routine abdominal ultrasound. It is confirmed in more than 90% of patients by a computed tomography (CT) scan or MRI.3 Histologically, hemangiomas are composed of large endothelium-lined vascular spaces that are separated by fibrous septa of varying thicknesses. The pathogenesis of cavernous hemangioma remains unclear, but vascular endothelial growth factor (VEGF) is recognized as an essential regulator of normal and abnormal angiogenesis.6 Liver metastases may mimic the appearance of hemangiomas on a variety of commonly employed imaging techniques. On CT, hemangiomas are usually hypoattenuating compared with the adjacent parenchyma. However, they may be iso- or hyperattenuating, especially in patients with steatosis.7 The feature of globular enhancement has been found to be 88% sensitive and 84% to 100% specific for differentiating hemangiomas from hypervascular metastases.8 On MRI, similar signal intensity on T2weighted images has been described for metastases and hemangiomas.5 Although there are some pathognomonic features for hepatic hemangiomas on imaging studies, Giuliante et al9 showed that the diagnosis of hepatic hemangioma remained dubious in nearly 10% of patients using three different imaging modalities (including ultrasound, CT, MRI, scintigraphy, and angiography). Different therapeutic approaches have been proposed for liver hemangiomas, including observation, embolization, hepatic artery ligation, and surgical resection.10 Bevacizumab is a recombinant monoclonal antibody against VEGF and has been shown to be effective in the treatment of cavernous hemangioma in case reports.6 Neonatal hemangiomatosis that includes the liver has been treated successfully with cyclophosphamide.11 Also, parotid hemangiomas during infancy have been successfully treated with low-dose bleomycin and dexamethasone.12 To the best of our knowledge, there are no reports of a hepatic hemangioma that responded to systemic chemotherapy in a patient with testis cancer. Hashimoto et al13 described a histologically confirmed hepatic hemangioma in a patient with an ovarian yolk sac tumor that decreased in size after BEP chemotherapy. The authors suggested that development of the hemangioma might be a result of estrogen.13 Surgery and chemotherapy led to suppressed ovarian function, which resulted in a diminished estrogen level and secondary decrease in hemangioma size. Although there are some conflicting data in the literature with respect to the role of estrogen in the pathogenesis of hepatic hemangioma,3,14 estrogen might promote angiogenesis activity and VEGF expression in vascular smooth muscle cells.15 Hormonal levels were not recorded for our patient. Another hypothesis is that the decreased size of the hemangioma in our patient could have been a result of the chemotherapy, perhaps through antiangiogenic mechanisms.16 In conclusion, there is no definitive consensus with respect to an approach to differentiate hepatic hemangioma from metastasis in a patient with malignancy. Our patient case demonstrates that in addition to a lack of definitive imaging criteria, a chemotherapy-induced response of hemangioma can mimic a chemotherapy response of metastatic disease, making these two entities difficult to distinguish on clinical grounds. Hooman Djaladat Norris Comprehensive Cancer Center, Institute of Urology, University of Southern California, Los Angeles, CA Craig R. Nichols Fig 3. www.jco.org British Columbia Cancer Agency, Vancouver, British Columbia, Canada; Multi-Disciplinary Testicular Cancer Clinic, Virginia Mason Medical Center, Seattle, WA © 2011 by American Society of Clinical Oncology Downloaded from jco.ascopubs.org on September 9, 2014. For personal use only. No other uses without permission. Copyright © 2011 American Society of Clinical Oncology. All rights reserved. e843 Djaladat, Nichols, and Daneshmand Siamak Daneshmand Norris Comprehensive Cancer Center, Institute of Urology, University of Southern California, Los Angeles, CA AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. REFERENCES 1. Copson E, McKendrick J, Hennessey N, et al: Liver metastases in germ cell cancer: Defining a role for surgery after chemotherapy. BJU Int 94:552-558, 2004 2. You YN, Leibovitch BC, Que FG: Hepatic metastasectomy for testicular germ cell tumors: Is it worth it? J Gastrointest Surg 13:595-601, 2009 3. Conter RL, Longmire WP Jr: Recurrent hepatic hemangiomas: Possible association with estrogen therapy. Ann Surg 207:115-119, 1988 4. Christison-Lagay ER, Burrows PE, Alomari A, et al: Hepatic hemangiomas: Subtype classification and development of a clinical practice algorithm and registry. J Pediatr Surg 42:62-67, 2007; discussion 67-8 5. Semelka RC, Worawattanakul S, Noone TC, et al: Chemotherapy-treated liver metastases mimicking hemangiomas on MR images. Abdom Imaging 24:378-382, 1999 6. Mahajan D, Miller C, Hirose K, et al: Incidental reduction in the size of liver hemangioma following use of VEGF inhibitor bevacizumab. J Hepatol 49:867870, 2008 7. Heiken JP: Distinguishing benign from malignant liver tumours. Cancer Imaging 7:S1-S14, 2007 (Spec No A) 8. Leslie DF, Johnson CD, Johnson CM, et al: Distinction between cavernous hemangiomas of the liver and hepatic metastases on CT: Value of contrast enhancement patterns. AJR Am J Roentgenol 164:625-629, 1995 9. Giuliante F, Ardito F, Vellone M, et al: Reappraisal of surgical indications and approach for liver hemangioma: Single-center experience on 74 patients. Am J Surg 201:741-748, 2010 10. Akamatsu N, Sugawara Y, Komagome M, et al: Giant liver hemangioma resected by trisectorectomy after efficient volume reduction by transcatheter arterial embolization: A case report. J Med Case Reports 4:283, 2010 11. Vlahovic A, Simic R, Djokic D, et al: Diffuse neonatal hemangiomatosis treatment with cyclophosphamide: A case report. J Pediatr Hematol Oncol 31:858-860, 2009 12. Yang Y, Sun M, Cheng X, et al: Bleomycin A5 plus dexamethasone for control of growth in infantile parotid hemangiomas. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 108:62-69, 2009 13. Hashimoto M, Sugawara M, Ishiyama K, et al: Reduction in the size of a hepatic haemangioma after chemotherapy. Liver Int 28:1043-1044, 2008 14. Gemer O, Moscovici O, Ben-Horin CL, et al: Oral contraceptives and liver hemangioma: A case-control study. Acta Obstet Gynecol Scand 83:1199-1201, 2004 15. El-Hashemite N, Walker V, Kwiatkowski DJ: Estrogen enhances whereas tamoxifen retards development of Tsc mouse liver hemangioma: A tumor related to renal angiomyolipoma and pulmonary lymphangioleiomyomatosis. Cancer Res 65:2474-2481, 2005 16. Zeng Q, Li Y, Chen Y, et al: Gigantic cavernous hemangioma of the liver treated by intra-arterial embolization with pingyangmycin-lipiodol emulsion: A multi-center study. Cardiovasc Intervent Radiol 27:481-485, 2004 DOI: 10.1200/JCO.2011.38.1434; published online ahead of print at www.jco.org on November 7, 2011 ■ ■ ■ e844 © 2011 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY Downloaded from jco.ascopubs.org on September 9, 2014. For personal use only. No other uses without permission. Copyright © 2011 American Society of Clinical Oncology. All rights reserved.