Successful Multimodal Treatment for Aggressive Metastatic and Recurrent Fibrolamellar Hepatocellular Carcinoma in a Child Arzu Okur, MD,* Eylem Pınar Eser, MD,w Gu ¨ldal Yilmaz, MD,w Aydın Dalgic¸, MD,z U ¨ mit O ¨ zgu ¨r Akdemir, MD,y Aynur Og ˘uz, MD,* Ceyda Karadeniz, MD,* Gu ¨len Akyol, MD,w Billur Demirog ˘ullari, MD,8 O ¨ znur Boyunag ˘a, MD,z and Faruk Gu ¨c¸lu ¨ Pınarlı, MD* Summary: Fibrolamellar variant of hepatocellular carcinoma (FLHCC) does not have a favorable prognosis than conventional HCC, and there is no difference regarding the response to che- motherapy and the degree of surgical resectability. FLHCC com- monly recurs after complete surgical resection, and there is a high rate of lymph node metastases. Herein, we report a 12-year-old girl with metastatic FLHCC with multiple recurrences aggressively treated with surgery, chemotherapy, and antiangiogenic agents. She is in complete remission after 4 years and 2 months after the diagnosis of metastatic FLHCC. The standard treatment of FLHCC is excision of the primary tumor and its metastases. Chemotherapy for FLHCC is controversial, and it has been sug- gested that cytoreductive chemotherapy was ineffective and adju- vant chemotherapy did not improve survival. Our patient with multiple recurrences was successfully treated with surgery, first-line chemotherapy with cisplatin and doxorubicin, second-line chemo- therapy with 5-fluorouracil/interferon-a combination, and adjuvant antiangiogenic agents like cyclophosphamide and thali- domide. As FLHCC patients have no underlying liver disease, they can tolerate higher doses of chemotherapy compared with con- ventional HCC patients. We support the use of repeated aggressive surgery with adjuvant chemotherapy and antiangiogenic therapy, which provided complete remission in our patient with metastatic and recurrent FLHCC. Key Words: fibrolamellar hepatocellular carcinoma, surgery, che- motherapy, antiangiogenic therapy, 5-fluorouracil, interferon-a (J Pediatr Hematol Oncol 2014;36:e328–e332) T he fibrolamellar variant of hepatocellular carcinoma (FLHCC), described originally in 1956 by Edmondson, 1 comprises about 13% to 22% of all hepatocellular carci- nomas in children and young adults. FLHCC has been considered as a rare and unique variant that differs from other forms of HCC with its biological, pathologic, clinical, as well as molecular characteristics. 2,3 In contrast to earlier reports, FLHCC does not have a favorable prognosis than classic HCC as there is no difference regarding the response to chemotherapy and the degree of surgical resectability. 4–7 Further, FLHCC commonly recurs after complete surgical resection, and there is a high rate of lymph node metastases compared with conventional HCC. 8 Herein, we report a case of FLHCC with multiple recurrences aggressively treated with surgery, chemotherapy, and antiangiogenic agents. CASE REPORT A 12-year-old girl was admitted to hospital with a weight loss of 5 kg in last 3 months, intermittent constipation, and fatigue. Physical examination revealed an enlarged liver of 4 cm and 6 cm in the midclavicular line and below the xiphoid process, respectively. Laboratory investigations were significant for a C-reactive protein level of 74.3 mg/dL, erythrocyte sedimentation rate of 85 mm/h, and hemoglobin level of 9.5 g/dL, with normal aspartate amino- transferase, alanine aminotransferase, prothrombin time, activated partial thromboplastin time, a-fetoprotein, and b-human chorionic gonadotropin. Hepatitis B surface antigen was negative and Anti- HBs was 177 IU/mL. Abdominal ultrasound and computed tomography (CT) showed mass lesions of 57  50 50 mm, 58  58  62 mm, and 60  56 mm in the fifth to sixth segments, adjacent to caudate lobe, and in the fourth segment of the liver, respectively, along with a 32 32  48 mm para-aortic lymphadenopathy. Thorax CT was normal. An 18F-FDG-PET CT scan showed enhanced metabolic activity in the mass lesions of the liver (SUVmax = 6.7) and in the para-aortic lymph nodes (SUV- max = 8.3) (Figs. 1A, B). Histopathologic examination of the tumor tissue obtained by USG-guided trucut biopsy from the liver mass revealed a tumoral lesion composed of wide trabeculas, which are made up of tumor cells with large eosinophilic granular cyto- plasms and atypical hyperchromatic nuclei and characterized with fibrous irregular lamellar stromal areas. The patient was diagnosed as hepatocellular neoplasia (compatible with FLHCC) and treated with 4 cycles of chemotherapy with cisplatin and doxorubicin as it was not possible to resect multiple primary tumors in the liver. There was a subsequent regression of the mass lesions in the liver after chemotherapy but the para-aortic lymph nodes continued to increase in size. Therefore, the patient underwent partial hepatic resection and intra-abdominal lymph node excision. Macroscopi- cally, lobulated tumoral liver mass measuring 6 cm in its greatest dimension had a cut surface of grayish-white fibrous texture in central portion and orange-tan color at the periphery. Microscopic examination of the resection material revealed almost the same histopathologic features as the needle biopsy (Figs. 2A–C). Therefore, diagnosis of pure FLHCC was determined. Surgical margins were free of tumor. There was no cirrhotic change in nontumoral liver parenchyme. Moreover, a metastatic lymph node was detected at the portal hilus of the liver (Fig. 2D). Postoperative 18F-FDG-PET CT scan was completely nor- mal and she has received adjuvant antiangiogenic treatment with cyclophosphamide and thalidomide for 6 months. However, a mass lesion adjacent to right liver lobe and surrounding multiple lymph nodes were detected during a routine follow-up after 21 months of surgery. A second operation consisting of the removal of a tumor of 70  60 mm extending from the first resection area of the liver to Received for publication September 10, 2013; accepted January 30, 2014. From the Departments of *Pediatric Oncology; wPathology; zSurgery; yNuclear Medicine; 8Pediatric Surgery; and zRadiology, Gazi University Medical Faculty, Bes ¸evler, Ankara, Turkey. The authors declare no conflict of interest. Reprints: Faruk Gu¨c ¸lu¨ Pınarlı, MD, Department of Pediatric Oncol- ogy, Gazi University Medical Faculty, Bes ¸evler, Ankara 06500, Turkey (e-mail: fgpinarli@gazi.edu.tr). Copyright r 2014 by Lippincott Williams & Wilkins CLINICAL AND LABORATORY OBSERVATIONS e328 | www.jpho-online.com J Pediatr Hematol Oncol  Volume 36, Number 5, July 2014