Bone Marrow Transplantation (2010) 45, 1357–1359 & 2010 Macmillan Publishers Limited All rights reserved 0268-3369/10
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LETTER TO THE EDITOR
Focal nodular hyperplasia in pediatric allogeneic hematopoietic cell transplant: case series
Bone Marrow Transplantation (2010) 45, 1357–1359; doi:10.1038/bmt.2009.336; published online 8 February 2010 Focal nodular hyperplasia (FNH) is an uncommon benign hepatic tumor. In the general population it is difficult to quantify the incidence; however, it is estimated to account for 8% of all primary liver tumors1 and 0.02% of pediatric liver tumors.2 FNH is often found incidentally, although some patients may present with vague abdominal complaints. It is rarely reported in children. The etiology is not clearly understood. It is speculated that it develops as a hyperplastic response to a pre-existing arterial malformation. Diagnosis based on radiographic findings can be difficult and needle biopsy may be necessary to confirm the diagnosis.1 It is unclear whether patients who have received chemotherapy and TBI as conditioning for hematopoietic SCT (HSCT) are at increased risk for the development of FNH. However, it is important for clinicians caring for these patients to be aware of this entity, as HSCT patients are at risk for hepatic complications. The following case series describes three pediatric patients post HSCT patients with FNH.
Case 1 A 20-year-old female patient had been diagnosed with ALL at 3 years of age. She was treated on the Pediatric Oncology Group (POG) protocol 8699. She relapsed 3 years after the completion of therapy, was re-induced with chemotherapy and achieved a second remission. She underwent an allogeneic HSCT with a seven of eight HLA-matched unrelated donor. Conditioning consisted of cytarabine (18 gm/m2), CY (2.7 gm/m2) and TBI to a total dose of 1400 cGy with partial shielding to the lungs, the liver and the kidneys. GVHD prophylaxis was with partial T-cell depletion of the BM graft with Ab/C0 and CYA, as previously described by Casper et al.3 She had no evidence of sinusoidal obstruction syndrome post HSCT. She had stage 1 acute skin GVHD and chronic mild, limited skin GVHD, which resolved completely. Fourteen years after HSCT she presented with abdominal distention, which began 5 months before her clinic visit. Her medications included chlordiazepoxide, clidinium bromide, calcium, fiber, multi-vitamin and oral contraceptives. She had an abdominal computed tomography (CT) and magnetic resonance imaging (MRI) of her liver, which showed a 4 cm 5 cm mass in her left lobe, with a central scar and a nodular lesion surrounding the scar. A second lesion
was found in the right lobe, which enhanced with contrast on both the CT and MRI. A small liver cyst and small lesion in the right lobe consistent with a hemangioma were also seen. Owing to her history of malignancy and risk of secondary neoplasm, an open liver biopsy was performed. Pathology confirmed the diagnosis of FNH, multi focal. Owing to continued abdominal pain and the inflammatory response noted, complete resection of these lesions by a formal left lateral segmentectomy was performed. The patient tolerated these procedures without complications and made a full recovery. She remains off oral contraception because of the possible association between FNH and oral contraceptions. She had a follow-up MRI of her liver 6 months post-op, which was normal without focal abnormality.
Case 2 An 11-year-old male was diagnosed with hemophagocytic lymphohistiocytosis at the age of 4 years. He was treated with chemotherapy according to the Histiocyte Society Protocol (HLH-94) and subsequently relapsed. He was re-induced with chemotherapy and had an allogeneic HSCT with an eight of eight HLA-matched unrelated donor. Conditioning consisted of cytarabine, CY and TBI as described above, with partial shielding to the lungs, the liver and the kidney. GVHD prophylaxis was with partial T-cell depletion of the graft by Ab/C0 and CYA as previously described by Casper et al.3 Post transplant, he developed stage 2 acute GVHD of the gut and skin, and chronic mild limited skin GVHD which resolved. He had no evidence of sinusoidal obstruction syndrome. Seven years after BMT he had an abdominal CT secondary to trauma. He had complained of occasional right upper quadrant pain present for several months before the trauma. Physical examination was normal. Abdominal CT revealed a 3.3 3.3 cm lobulated lesion with a central focus on low attenuation and questionable radiating septa in the anterior segment of the right hepatic lobe. A laproscopic-guided biopsy was performed and several core biopsies were taken. The pathology was consistent with FNH. The patient tolerated the procedure without complications. He is 18 months post procedure and has no changes in his liver lesions.
Case 3 A 7 1/2-year-old female was diagnosed with AML at the age of 10 months. She received chemotherapy according to
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the Children’s Cancer Group protocol 2891. She relapsed in her central nervous system without marrow involvement 6 months after diagnosis. She attained a second CR and underwent a haploidentical BMT as described by Talano et al.4 Conditioning consisted of cytarabine, CY and TBI 1200 cGy and an additional 900 cGy to her brain. Her PBSC product underwent CD34 selection with CD3-cell depletion by the Isolex machine. She received no immune suppression post HSCT. During her transplant course she had no evidence of sinusoidal obstruction syndrome or acute/chronic GVHD. She had adenovirus viremia, which was successfully treated with cidofovir. She did not have adenovirus hepatitis. She presented to the BMT clinic 5 years post HSCT with transaminitis (AST98, ALT119) and hyperlipedemia (triglycerides 1762). Physical examination was normal. She has a history of three juvenile polyps and chronic constipation. A liver ultrasound revealed multiple hypoechoic lesions in the liver. An abdominal CT revealed many hypodense, enhancing nodules throughout the liver. A liver biopsy was performed and a diagnosis of FNH was made. She is at present 1-year post biopsy and asymptomatic. FNH is an uncommon finding in children in general and rarely reported as a complication of HSCT.2,5–10 It can occur at all ages but it is typically found in women during their reproductive years. 8 The incidence of FNH as a complication of allogeneic HSCT is unknown. Sudour et al.2 retrospectively evaluated HSCT patients who underwent liver MRI for the evaluation of hemochromatosis. In their cohort of 58 patients under the age of 18 years, 17 patients were found to have FNH (35%). There are a few further reports of children developing FNH after treatment for solid tumors.6,10,12 There are characteristic radiological findings of FNH seen on both CT and MRI. On contrast-enhanced CT, findings typically demonstrate a diffuse homogenous hyperdense appearance. The homogenous bright enhancement reflects the presence of a central scar and is the most characteristic CT finding with FNH.13 MRI, which is superior to CT for evaluation of FNH, and does not expose the child to ionizing radiation, should include dynamic Gadolinium-enhanced scanning. Characteristic findings on dynamic MRI scanning include a hypointense signal on T1 and hyperintense signal on the T2-weighted sequences on the non-contrast portion of the study. There is typically hypervascularity on the arterial images followed by slight hyper or isointensity on the portal venous phase. The central scar will typically demonstrate decreased signal on the arterial phase and slight enhancement on the portal venous phase.10,13,14 Although all MRI features may not be seen, the presence of some of these characteristics should strongly suggest a diagnosis of FNH. The pathophysiology of FNH is poorly understood. Some speculate that it may be a reaction to a local vascular abnormality or may be induced by vascular injury. Bouyn et al. (2003)6 evaluated pediatric patients with a previous history of malignancy who developed FNH post treatment. They speculated that FNH may be a consequence of vascular disease or injury sustained Bone Marrow Transplantation
to the vascular endothelium secondary to chemotherapy and/or radiation. Treatment recommendations are conservative because of the benign nature of the disease. If a diagnosis can be made confidently radiologically, biopsy may not be necessary and serial radiological evaluation may be adequate.1 In cases of tumor enlargement, questionable radiological findings or symptoms, further intervention including biopsy and/or resection may be indicated.1,2,10,11 The relationship between FNH and previous chemotherapy, radiation and HSCT is unclear. It does appear that pediatric survivors of HSCT may be at increased risk for the development of FNH. Although not well understood, HSCT patients may be at higher risk for the development of FNH secondary to vascular damage initiated by chemotherapy, radiation, venoocclusive disease, GVHD and other medications.2 FNH should be considered in the differential diagnosis of HSCT patients who present with liver lesions. These lesions often mimic metastatic disease or secondary neoplasms and radiological studies may not definitively differentiate between a benign and malignant process. Radiological testing should include the use of Gadolinium-enhanced MRI as characteristic radiological findings are described, which may lead to the diagnosis without the need for further intervention and will decrease the radiation exposure in these young patients. Biopsy should be considered for patients with uncharacteristic radiological findings. The risk of malignant transformation is thought to be low. However, because of the increased risk of secondary cancers after HSCT, long-term monitoring should be considered.
Conflict of interest The authors declare no conflict of interest.
Acknowledgements We would like to thank the entire Blood and Marrow transplant team for their continued care and support of HSCT patients post transplant. We would also like to thank the Midwest Athletes Against Cancer (MACC) Fund for support of this work.
L Anderson, D Gregg, D Margolis, J Casper and J Talano Division of Pediatric Blood and Marrow Transplant, Division of Pediatric Radiology, Medical College of Wisconsin, Children’s Hospital of Wisconsin, Milwaukee, WI, USA E-mail:
[email protected]
References 1 Somech R, Brazowski E, Kesller A, Weiss B, Getin E, Lerner A et al. Focal nodular hyperplasia in children. J Pediatr Gastroenterol Nutr 2001; 32: 480–483. 2 Sudour H, Mainard L, Baumann C, Clement L, Salmon A, Bordigoni P. Focal nodular hyperplasia of the liver following hematopoietic SCT. Bone Marrow Transplant 2009; 43: 127–132. 3 Casper J, Camitta B, Truitt R, Baxter-Lowe LA, Bunin N, Lawton C et al. Unrelated bone marrow donor transplants for
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children with leukemia or myelodysplasia. Blood 1995; 85: 2354–2363. Talano J, Keever-Taylor C, Eapen M, Casper J, Margolis D. Haploidentical family donor transplants in children using high doses of positively selected CD34+ cells with low CD3+ cells: an initial report of the Milwaukee experience. American Society of Hematology Annual Meeting Abstract 2003. Bonney GK, Gomez D, Al-Mukhtar A, Toogood GJ, Lodge JP, Prasad R. Indication for treatment and long-term outcome of focal nodular hyperplasia. HPB (Oxford) 2007; 9: 368–372. Icher- De Bouyn C, Leclere J, Raimondo G, Le Pointe HD, Couanet D, Valteau-Couanet D et al. Hepatic focal nodular hyperplasia in children previously treated for a solid tumor. Incidence, risk factors, and outcome. Cancer 2003; 97: 3107–3113. Joyner Jr BL, Levin TL, Goyal RK, Newman B. Focal nodular hyperplasia of the liver: a sequela of tumor therapy. Pediatr Radiol 2005; 35: 1234–1239. La Vecchia C, Tavani A. Female hormones and benign liver tumours. Dig Liver Dis 2006; 38: 535–536.
9 Pezzullo L, Muretto P, De Rosa G, Picardi M, Lucania A, Rotoli B. Liver nodular regenerative hyperplasia after bone marrow transplant. Haematologica 2000; 85: 669–670. 10 Junewick J, Mitchell D. Focal nodular hyperplasia in oncology patients. Pediatr Radiol 2006; 36: 464. 11 Yany Y, Fu S, Li A, Zhou W, Pan Z, Cui L et al. Management and surgical treatment for focal nodular hyperplasia in children. Pediatr Surg Int 2008; 24: 699–703. 12 Citak EC, Karadeniz C, Oguz A, Boyunaga O, Ekinci O, Okur V. Nodular regenerative hyperpasia and focal nodular hyperplasia of the liver mimicking hepatic metastasis in children with solid tumors and a review of literature. Pediatr Hematol Oncol 2007; 24: 281–289. 13 Blonski W, Reddy KR. Evaluation of nonmalignant liver masses. Curr Gastroenterol Rep 2006; 8: 38–45. 14 Mortele KJ, Praet M, Van Vlierberghe H, de Hemptinne B, Zou K, Ros PR. Focal nodular hyperplasia of the liver: detection and characterization with plain and dynamicenhanced MRI. Abdom Imaging 2002; 27: 700–707.
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