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Focal nodular hyperplasia of the liver in longterm survivors of neuroblastoma
European Journal of Radiology 74 (2010) e1–e5
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European Journal of Radiology journal homepage: www.elsevier.com/locate/ejrad
Focal nodular hyperplasia of the liver in longterm survivors of neuroblastoma How much diagnostic imaging is necessary? Gabriele Benz-Bohm a,∗ , Barbara Hero c,3 , Axel Gossmann b,2 , Thorsten Simon c,3 , Friederike Körber a,1 , Frank Berthold c,3 a
Division of Pediatric Radiology, A. Gossmann (formerly), Department of Radiology, University of Cologne, Kerpenerstr. 62, 50924 Köln, Germany Department of Radiology, Cologne City Hospitals, Ostmerheimer Strasse 200, 51109 Köln, Germany c Department of Pediatrics, Division of Pediatric Oncology and Hematology, University of Cologne, Kerpenerstr. 62, 50924 Köln, Germany b
a r t i c l e
i n f o
Article history: Received 5 November 2008 Accepted 5 March 2009 Keywords: Focal nodular hyperplasia Children Neuroblastoma Diagnostic imaging
a b s t r a c t Objectives: Focal nodular hyperplasia of the liver is a tumor-like lesion, uncommon in children, but it has recently been more frequently observed in children treated for malignant diseases, especially neuroblastoma. The aetiology is unclear, the pathogenesis remains controversial. Focal nodular hyperplasia of the liver is suspected to be a sequela of tumor therapy. Methods: Besides the clinical data we evaluated the imaging modalities needed to diagnose focal nodular hyperplasia of the liver in children with neuroblastoma who have been followed in our institution for more than 5 years. Results: Out of 60 children six developed focal nodular hyperplasia at a median time of 10.5 years after diagnosis of neuroblastoma and 9.4 years after the end of treatment. The diagnosis of focal nodular hyperplasia was based on imaging criteria which are variable in ultrasonography and specific in MRI. Only one child underwent surgical biopsies to rule out liver metastases. Conclusions: Longterm survivors of neuroblastoma are at risk of developing focal nodular hyperplasia, especially if they underwent toxic chemotherapy and/or radiotherapy to the liver during initial treatment. The recommended diagnostic imaging tools are ultrasonography for detecting liver lesions and MRI for confirming and characterizing these lesions as focal nodular hyperplasia. © 2009 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Focal nodular hyperplasia (FNH) of the liver is a tumor-like lesion with an unclear aetiology, mostly found in an otherwise normal liver. It is composed of normal hepatocytes, supplied by large arteries and surrounded by a fibrous stroma with biliary ductules, thus forming a stellate “scar” [1]. FNH is uncommon in children [2]: the annual incidence of FNH has been reported as approximately 2.25 per million children [3]. Reports of pediatric cases have been limited to individual cases and retrospective analyses [2,4]. However in the last few years, an increased frequency in children after treatment of malignant diseases has been reported, especially in longterm sur-
∗ Corresponding author at: Birresbornerstr. 40, 50935 Köln, Germany. Tel.: +49 221 433358. E-mail addresses: [email protected] (G. Benz-Bohm), [email protected] (B. Hero), [email protected] (A. Gossmann), [email protected] (T. Simon), [email protected] (F. Körber), [email protected] (F. Berthold). 1 Tel.: +49 221 4784228; fax: +49 221 4783347. 2 Tel.: +49 221 89073285; fax: +49 221 89073248. 3 Tel.: +49 221 4784380; fax: +49 221 4784689. 0720-048X/$ – see front matter © 2009 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ejrad.2009.03.011
vivors of neuroblastoma (NB) [3,5–7]. Therefore, besides the clinical data, the purpose of this study was to evaluate the imaging modalities needed to diagnose FNH of the liver in children with NB who had follow-up investigations of 5 years or longer. 2. Materials and methods We analysed retrospectively the clinical and radiological data of children with NB who had been followed in our institution for 5 years or more, then focused on imaging modalities to diagnose FNH of the liver. Between 01/1990 and 12/2007, 149 NB-patients were seen in our hospital. Of those, 46 patients died within 5 years after diagnosis, 43 patients were followed for less than 5 years in our hospital and 60 patients for more than 5 years. Follow-up investigations, dependent on risk and time, were performed according to the recommendations of the German cooperative NB trials which have been approved by the ethical committee of the University of Cologne. Ultrasonography (US) of the abdomen was scheduled every 6 weeks in the first year after treatment, every 3 months from the second to the fifth year and twice a year until 10 years. If the primary tumor was located in the chest,
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Fig. 1. Sonograms of FNH: hyperechoic (a, patient1), isoechoic (b, patient 2), hypoechoic (c, patient 3).
X-ray was used instead of US in intervals of 3 months or longer. Additional MRI was recommended at least every 3 months in the first year after treatment, every 6–12 months in the second to the fifth year and if US or X-ray demonstrated abnormal, insufficient or equivocal results. US was performed and evaluated by two experienced pediatric radiologists on Acuson Sequoia (Siemens Medical Solutions USA, Inc.) with vector, curved-array and linear transducers and frequencies between 7.5 and 3.5 MHz. If liver lesions, suggesting FNH, were found, MRI of the liver was performed on whole body 1.5 T scanners (Achieva or Gyroscan ACS-NT, Philips Medicine Systems, Best, The Netherlands) using the following protocol:
• Axial and coronal T2w respiratory-triggered ultra turbo spin-echo (UTSE) • Axial T1w breath hold gradient-echo sequence (GRE) • Dynamic images of the liver were acquired prior to and then 30, 60, 120, 240, and 480 s following rapid bolus injection of gadopentetate dimeglumine (0.1 mmol Gd/kg body weight, MagnevistTM , Bayer Schering Pharma, Berlin, Germany) followed by a flush of sterile saline solution • T1w GRE imaging was repeated 5 min after Gd-DTPA administration.
Two experienced radiologists, one a pediatric radiologist, evaluated the MRI findings according to well-known criteria [8].
3. Results 60 patients, 31 male and 29 female, were followed in our hospital for 5 years or longer with a median follow-up time of 9.7 years (range 5–24 years) after diagnosis. Six of them, three girls, one female young adult and two boys, developed FNH 6 to 19.9 years (median 10.5 years) after the diagnosis of NB and 4.1–12.9 years (median 9.4 years) after the end of treatment for NB (Table 1). At the diagnosis of FNH, all six patients were asymptomatic, had normal liver function tests and normal tumormarker levels (catecholamine metabolites, neuron-specific enolase). Of the six patients with FNH, 45 abdominal US and 21 MRI of the liver were evaluated. FNH was detected during routine US-examination in all patients, confirmed and characterized by the typical findings in MRI. In all patients, two or more lesions were found: two had two, three had three and one had four. The solitary nodules were well delineated, homogenous and had diameters of one to four cm. US: The lesions were hyperechoic in 2, isoechoic in 2, or hypoechoic in 2. A central scar was not seen (Fig. 1).
Fig. 2. Plain and dynamic-enhanced MRI of FNH (patient 4): hypointensity on T1w; strong enhancement except for the central scar 30 s post contrast and a complete wash out 1 min post contrast.
G. Benz-Bohm et al. / European Journal of Radiology 74 (2010) e1–e5
Fig. 3. Histological tissue section, HE × 25, patient 4: peripheral nodular part of FNH, well circumscribed, but nonencapsulated, irregulary distributed portal fields. Courtesy of M. Ortmann, MD, Department of Pathology, University of Cologne.
MRI: On imaging with T1w sequences the lesions were slightly hypointens in 5, or isointens in 1, with T2w sequences slightly hyperintens in 5, or isointens in 1. In the dynamic series after injection of contrast material, there was a rapid and strong enhancement during the early arterial phase, except for the central scar, and a complete wash out thereafter in all patients (Fig. 2). The central scar was detected in three out of six patients. After the diagnosis of FNH, the patients had follow-up examinations for 0.56–4.6 years, median 3 years. In one patient, the lesions progressed in number and size. In addition, dynamic-enhanced MRI showed a more rapid and stronger enhancement during the early arterial phase. Surgical biopsies were performed to rule out liver metastases. FNH was verified histologically (Fig. 3). In the other five patients the imaging findings of FNH did not change during follow-up, either in US or in MRI. The six patients developing FNH had been diagnosed with stage 3 or 4 NB according to the International Neuroblastoma Staging System (INSS, 1993). The age at diagnosis ranged from 4 months to 5.6 years (for details see Table 1). Only one boy had liver metastases at initial diagnosis (patient 5). The patients were treated with intensive polychemotherapy cycles according to the German cooperative NB trials NB82, NB90 and NB97 (Table 1) [9]. Induction therapy consisted of six or more cycles in five patients and was followed by further treatment modalities in three (maintenance therapy in 2, megatherapy with autologous stem- cell rescue in 1, consolidation therapy with antiGD2-antibody ch 14.18 in 2). In one patient however, chemotherapy was limited to four cycles of induction therapy (patient 6). Melphalan was given to two children, either during megatherapy or low dose maintenance therapy. None of our patients received busulfan. Two children received radiotherapy with abdominal radiation field, where parts of the liver were involved (radiation dose varied from 25–30 Gy).
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Two patients experienced relapses: one was treated with intensive second line therapy including polychemotherapy with various regimes and ch 14.18 antibody treatment (patient 2), the other with MIBG-therapy of 3.7 GBq, local cervical radiation and immunomodulatory therapies (patient 3). Of the 54 patients who did not develop FNH, 33 were treated with intensive polychemotherapy, 24 received six or more cycles. Seven patients underwent megatherapy, 10 received oral maintenance therapy, and 11 anti-GD2-antibody therapy. Melphalan was given to 10 patients including all seven patients with megatherapy and three patients with oral maintenance therapy. Six patients received radiotherapy with abdominal radiation field, one MIBGtherapy. In none of the patients, with or without FNH, were vascular complications or venoocclusive disease (VOD) observed during therapy. The young adult (patient 2) used oral contraceptives (OC) prior to the development of FNH. All patients with FNH are alive and did not develop NBrecurrence after the diagnosis of FNH. 4. Discussion Of 60 patients in longterm follow-up after treatment of NB, six were diagnosed with FNH. The incidence seems to be increasing [7]: 10% (6/60) of our patients in follow-up more than 5 years and 15% (6/39) of those treated with chemotherapy developed FNH. At the diagnosis of FNH our patients were asymptomatic as reported for most children with FNH [2–4]. Although we saw four female and two male patients (Table 1), our number of patients is too small to confirm the previously reported female predominance [3]. Contrary to the literature [3] all our patients had two or more lesions with diameters from one to four cm, which is in the range reported in the literature (generally under 5 cm with variation from less than 1 cm to more than 20 cm [2,10]). The liver lesions were detected during routine follow-up with US. This is the method of choice to detect lesions of the liver, especially in children and young adults. But with this technique it is not possible to provide a specific and confident characterization of the lesions because of the variable echogenicity [3,5,11], which we observed in our patients as well: in 2 the lesions were hyperechoic, in 2 isoechoic and in 2 hypoechoic (Fig. 1). A central scar was not seen. As liver metastases are not uncommon in NB patients, focal liver lesions, detected by US, need to be further characterized by MRI. Typical findings for FNH in plain and dynamic-enhanced MRI include: • A well-delineated, homogenous, round lesion • Isointens or slightly hypo- or hyperintens signals on T1w and T2w images • In the dynamic series after contrast material, a rapid and strong enhancement during the early arterial phase except for the central scar and a complete wash out after
Table 1 Children treated for NB who developed FNH. Patients
Age at NBdiagnosis (years)
Gender
Primary tumor
Initial stage INSS
Initial treatment according to trial
Interval between NB- and FNHdiagnosis (years)
Interval between end of NBtherapy and FNHdiagnosis (years)
1 2 3 4 5 6
1.2 2.3 1.0 1.6 5.6 0.4
M F F F M F
Abdomen Abdomen/thorax Thorax Abdomen Abdomen Abdomen
3 3 4 4 4 3
NB90 NB82 NB97 NB90 NB97 NB90 Median
9.4 19.9 6.0 11.6 8.9 13.2 10.5
8.8 11.8 4.1 10.0 7.3 12.9 9.4
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• The central scar typically hypointens on T1w and hyperintens on T2w images, decreased signal intensity on the arterial phase and enhancement on the portal venous phase [8]. When several of these typical findings are present simultaneously, diagnosis of FNH is strongly suggested. As our patients showed at least three out of these findings, we diagnosed FNH by MRI (Fig. 2). However in one child we used histological verification as the lesions progressed in number and size and showed a more rapid and stronger enhancement during the early arteriel phase in dynamic-enhanced MRI. FNH was verified (Fig. 3). Although a typical finding of FNH, the central scar is not always detected by MRI in the FNH lesions [8]. We saw the central scar in three of six patients by MRI. The central scar was not detected by US. Atypical MRI findings such as heterogeneity, poor delineation, pseudocapsulelike rim, atypical intensity of the lesion or the scar in T1w or T2w sequences should suggest different diagnosis, especially in combination and a biopsy should be performed. Most metastases have no central scar. A solitary hypervascular lesion may simulate a metastasis [12]. A metastasis in the area of a FNH of the liver in a young woman with Ewing’s sarcoma of the left lower ribs was reported [13]. A fibrolamellar carcinoma may have a central scar but with low signal intensity on T2w images [14]. Hepatic adenoma is a benign lesion without central scar [3]. Nodular regenerative hyperplasia is a multi-acinar regenerative nodular lesion, rare in children. These lesions are hyperechoic on US, hypodense with no significant enhancement and no central scar on CT. MRI findings are variable and non-specific [15]. Further imaging methods may be helpful to support the diagnosis of FNH, but not all of them are suitable for the use in children. Color Doppler sonography is useful for additional information about intranodular and perinodular blood flow distribution [11], but was not used regularly. The contrast-enhanced power Doppler sonography for characterization of FNH is not normally used in children [6,16]. As CT is not superior to MRI [17], it should be avoided in children and young adults, because of the radiation dose. Dynamicenhanced MRI with liver-specific delayed images (3 h) to improve the diagnostic efficacy are not suitable for children because of the long investigation time [18]. Finally, the use of liver-specific contrast agent is not permitted for children [19]. The pathogenesis of FNH remains controversial. It is mostly suggested that FNH is a hyperplastic response of the liver parenchyma to the presence of a pre-existing vascular malformation. Another hypothesis: FNH is induced by vascular injury such as thrombosis, intimal hyperplasia, high sinusoidal pressure or increased flow [2,3,10,20]. Icher-De Bouyn et al. [3] reported NB to be most often associated with FNH and suggest that the development of FNH may be linked to the type of therapy not to the type of malignancy. They discussed the cytoreductive agents busulfan and melphalan as the most hepatotoxic drugs, especially as risk factor for VOD. In our patients with FNH no child received busulfan, only two children melphalan and no child had VOD or other vascular complications. In addition, the combination of radiotherapy with chemotherapy may be important for the development of FNH [3,20]. Radiotherapy of parts of the liver was applied to two of six children with FNH, one received melphalan in low dose during maintenance therapy. MIBG-therapy of 3.7 GBq was applied to one child with FNH. In one of our patients with FNH, chemotherapy for NB was limited to four cycles induction therapy. This patient experienced none of the risk factors mentioned above, but chemotherapy was started at the very young age of 4 months. Altogether, three patients with FNH were treated with chemotherapy below 18 months of age
(Table 1). Thus, very young age may be an additional risk factor for FNH. However, even experiencing risk factors does not necessarily lead to the development of FNH, as suggested by our 33 NB patients who did not develop FNH. In contrast, in the report of Icher-De Bouyn et al. [3] three out of 14 patients with FNH had no risk factors for FNH, as was the case with three of our six patients. One of six patients used OC before the development of FNH. The possibility of OC as a risk factor for FNH was discussed for a long time. The study of Mathieu et al. demonstrated the independence of the development of FNH from OC use [21]. 5. Conclusions Longterm survivors of neuroblastoma are at risk of developing FNH, especially if they experienced risk factors during initial treatment. The incidence is higher than suggested. In the absence of any other signs of tumor-relapse and in the presence of typical imaging patterns for FNH in MRI, close imaging follow-up examinations appear to be sufficient to rule out liver metastases. These include US and possibly plain and dynamic-enhanced MRI as the diagnostic imaging. More invasive procedures should be reserved for equivocal findings. Conflict of interest None. References [1] International Working Party. Terminology of nodular hepatocellular lesions. Hepatology 1995; 22:983–93. [2] Stocker JT, Kamal GI. Focal nodular hyperplasia of the liver: a study of 21 pediatric cases. Cancer 1981;48:336–45. [3] Icher-De Bouyn C, Leclere J, Raimondo G, et al. Hepatic focal nodular hyperplasia in children previously treated for a solid tumor: incidence, risk factors, and outcome. Cancer 2003;97:3107–13. [4] Freidl T, Lackner H, Huber J, Sovinz P, Moser A. Focal nodular hyperplasia in children following treatment of hemato-oncologic diseases. Klin Pädiatr 2008;220:384–7. [5] Brisse H, Servois V, Bouche B, et al. Hepatic regenerating nodules: a mimic of recurrent cancer in children. Pediatr Radiol 2000;30:386–93. [6] Joyner Jr BL, Levin TL, Goyal RK, Newman B. Focal nodular hyperplasia of the liver: a sequela of tumor therapy. Pediatr Radiol 2005;35:1234–9. [7] Sudour H, Mainard L, Baumann C, Clement L, Salmon A, Bordigoni P. Focal nodular hyperplasia of the liver following hematopoietic SCT. Bone Marrow Transplant 2008:1–6. [8] Mortelé 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 dynamic-enhanced MRI. Abdom Imaging 2002;27:700–7. [9] Berthold F, Hero B, Kremens B, et al. Long-term results and risk profiles of patients in five consecutive trials (1979-1997) with stage 4 neuroblastoma over 1 year of age. Cancer Lett 2003;197:11–7. [10] Wanless IR, Mawdsley C, Adams R. On the pathogenesis of focal nodular hyperplasia of the liver. Hepatology 1985;5:1194–200. [11] Cheon J-E, Kim WS, Kim I-O, Jang J-J, Seo JK, Yeon KM. Radiological features of focal nodular hyperplasia of the liver in children. Pediatr Radiol 1998;28:878–83. [12] Mahfouz AE, Hamm B, Taupitz M, Wolf KJ. Hypervascular liver lesions: differentiation of focal nodular hyperplasia from malignant tumors with dynamic gadolinium-enhanced MR imaging. Radiology 1993;186:133–8. [13] Hagay ZJ, Zirkin HJ, Moses M, Khodadadi J. Ewing’s sarcoma metastatic to focal nodular hyperplasia of liver. J Surg Oncol 1986;32:100–5. [14] Hamrick-Turner JE, Shipkey FH, Cranston PE. Fibrolamellar hepatocellular carcinoma: MR appearance mimicking focal nodular hyperplasia. J Comput Assist Tomogr 1994;18:301–4. [15] Trenschel GM, Schubert A, Dries V, Benz-Bohm G. Nodular regenerative hyperplasia of the liver: case report of a 13-year-old girl and review of the literature. Pediatr Radiol 2000;30:64–8. [16] Ungermann L, Eliás P, Zizka J, Ryska P, Klzo L. Focal nodular hyperplasia: spoke-weel arterial pattern and other signs on dynamic contrast-enhanced ultrasonography. Eur J Radiol 2007;63:290–4. [17] Carlson SK, Johnson CD, Bender CE, Welch TJ. CT of focal nodular hyperplasia of the liver. Am J Roentgenol 2000;174:705–12. [18] Grazioli L, Morana G, Federle MP, et al. Focal nodular hyperplasia: morphologic and functional information from MR imaging with gadobenate dimeglumine. Radiology 2001;221:731–9.
G. Benz-Bohm et al. / European Journal of Radiology 74 (2010) e1–e5 [19] Marin D, Iannaccone R, Laghi A, et al. Focal nodular hyperplasia: intraindividual comparison of dynamic gadobenate dimeglumine- and ferucarbotranenhanced Magnetic Resonance Imaging. J Magn Reson Imaging 2007;25: 775–82.
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[20] Fajardo LF, Colby TV. Pathogenesis of veno-occlusive liver disease after irradiation. Arch Pathol Lab Med 1980;104:584–8. [21] Mathieu D, Kobeiter H, Maison P, et al. Oral contraceptive use and focal nodular hyperplasia of the liver. Gastroenterol 2000;118:560–4.
Contents lists available at ScienceDirect
European Journal of Radiology journal homepage: www.elsevier.com/locate/ejrad
Focal nodular hyperplasia of the liver in longterm survivors of neuroblastoma How much diagnostic imaging is necessary? Gabriele Benz-Bohm a,∗ , Barbara Hero c,3 , Axel Gossmann b,2 , Thorsten Simon c,3 , Friederike Körber a,1 , Frank Berthold c,3 a
Division of Pediatric Radiology, A. Gossmann (formerly), Department of Radiology, University of Cologne, Kerpenerstr. 62, 50924 Köln, Germany Department of Radiology, Cologne City Hospitals, Ostmerheimer Strasse 200, 51109 Köln, Germany c Department of Pediatrics, Division of Pediatric Oncology and Hematology, University of Cologne, Kerpenerstr. 62, 50924 Köln, Germany b
a r t i c l e
i n f o
Article history: Received 5 November 2008 Accepted 5 March 2009 Keywords: Focal nodular hyperplasia Children Neuroblastoma Diagnostic imaging
a b s t r a c t Objectives: Focal nodular hyperplasia of the liver is a tumor-like lesion, uncommon in children, but it has recently been more frequently observed in children treated for malignant diseases, especially neuroblastoma. The aetiology is unclear, the pathogenesis remains controversial. Focal nodular hyperplasia of the liver is suspected to be a sequela of tumor therapy. Methods: Besides the clinical data we evaluated the imaging modalities needed to diagnose focal nodular hyperplasia of the liver in children with neuroblastoma who have been followed in our institution for more than 5 years. Results: Out of 60 children six developed focal nodular hyperplasia at a median time of 10.5 years after diagnosis of neuroblastoma and 9.4 years after the end of treatment. The diagnosis of focal nodular hyperplasia was based on imaging criteria which are variable in ultrasonography and specific in MRI. Only one child underwent surgical biopsies to rule out liver metastases. Conclusions: Longterm survivors of neuroblastoma are at risk of developing focal nodular hyperplasia, especially if they underwent toxic chemotherapy and/or radiotherapy to the liver during initial treatment. The recommended diagnostic imaging tools are ultrasonography for detecting liver lesions and MRI for confirming and characterizing these lesions as focal nodular hyperplasia. © 2009 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Focal nodular hyperplasia (FNH) of the liver is a tumor-like lesion with an unclear aetiology, mostly found in an otherwise normal liver. It is composed of normal hepatocytes, supplied by large arteries and surrounded by a fibrous stroma with biliary ductules, thus forming a stellate “scar” [1]. FNH is uncommon in children [2]: the annual incidence of FNH has been reported as approximately 2.25 per million children [3]. Reports of pediatric cases have been limited to individual cases and retrospective analyses [2,4]. However in the last few years, an increased frequency in children after treatment of malignant diseases has been reported, especially in longterm sur-
∗ Corresponding author at: Birresbornerstr. 40, 50935 Köln, Germany. Tel.: +49 221 433358. E-mail addresses: [email protected] (G. Benz-Bohm), [email protected] (B. Hero), [email protected] (A. Gossmann), [email protected] (T. Simon), [email protected] (F. Körber), [email protected] (F. Berthold). 1 Tel.: +49 221 4784228; fax: +49 221 4783347. 2 Tel.: +49 221 89073285; fax: +49 221 89073248. 3 Tel.: +49 221 4784380; fax: +49 221 4784689. 0720-048X/$ – see front matter © 2009 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ejrad.2009.03.011
vivors of neuroblastoma (NB) [3,5–7]. Therefore, besides the clinical data, the purpose of this study was to evaluate the imaging modalities needed to diagnose FNH of the liver in children with NB who had follow-up investigations of 5 years or longer. 2. Materials and methods We analysed retrospectively the clinical and radiological data of children with NB who had been followed in our institution for 5 years or more, then focused on imaging modalities to diagnose FNH of the liver. Between 01/1990 and 12/2007, 149 NB-patients were seen in our hospital. Of those, 46 patients died within 5 years after diagnosis, 43 patients were followed for less than 5 years in our hospital and 60 patients for more than 5 years. Follow-up investigations, dependent on risk and time, were performed according to the recommendations of the German cooperative NB trials which have been approved by the ethical committee of the University of Cologne. Ultrasonography (US) of the abdomen was scheduled every 6 weeks in the first year after treatment, every 3 months from the second to the fifth year and twice a year until 10 years. If the primary tumor was located in the chest,
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G. Benz-Bohm et al. / European Journal of Radiology 74 (2010) e1–e5
Fig. 1. Sonograms of FNH: hyperechoic (a, patient1), isoechoic (b, patient 2), hypoechoic (c, patient 3).
X-ray was used instead of US in intervals of 3 months or longer. Additional MRI was recommended at least every 3 months in the first year after treatment, every 6–12 months in the second to the fifth year and if US or X-ray demonstrated abnormal, insufficient or equivocal results. US was performed and evaluated by two experienced pediatric radiologists on Acuson Sequoia (Siemens Medical Solutions USA, Inc.) with vector, curved-array and linear transducers and frequencies between 7.5 and 3.5 MHz. If liver lesions, suggesting FNH, were found, MRI of the liver was performed on whole body 1.5 T scanners (Achieva or Gyroscan ACS-NT, Philips Medicine Systems, Best, The Netherlands) using the following protocol:
• Axial and coronal T2w respiratory-triggered ultra turbo spin-echo (UTSE) • Axial T1w breath hold gradient-echo sequence (GRE) • Dynamic images of the liver were acquired prior to and then 30, 60, 120, 240, and 480 s following rapid bolus injection of gadopentetate dimeglumine (0.1 mmol Gd/kg body weight, MagnevistTM , Bayer Schering Pharma, Berlin, Germany) followed by a flush of sterile saline solution • T1w GRE imaging was repeated 5 min after Gd-DTPA administration.
Two experienced radiologists, one a pediatric radiologist, evaluated the MRI findings according to well-known criteria [8].
3. Results 60 patients, 31 male and 29 female, were followed in our hospital for 5 years or longer with a median follow-up time of 9.7 years (range 5–24 years) after diagnosis. Six of them, three girls, one female young adult and two boys, developed FNH 6 to 19.9 years (median 10.5 years) after the diagnosis of NB and 4.1–12.9 years (median 9.4 years) after the end of treatment for NB (Table 1). At the diagnosis of FNH, all six patients were asymptomatic, had normal liver function tests and normal tumormarker levels (catecholamine metabolites, neuron-specific enolase). Of the six patients with FNH, 45 abdominal US and 21 MRI of the liver were evaluated. FNH was detected during routine US-examination in all patients, confirmed and characterized by the typical findings in MRI. In all patients, two or more lesions were found: two had two, three had three and one had four. The solitary nodules were well delineated, homogenous and had diameters of one to four cm. US: The lesions were hyperechoic in 2, isoechoic in 2, or hypoechoic in 2. A central scar was not seen (Fig. 1).
Fig. 2. Plain and dynamic-enhanced MRI of FNH (patient 4): hypointensity on T1w; strong enhancement except for the central scar 30 s post contrast and a complete wash out 1 min post contrast.
G. Benz-Bohm et al. / European Journal of Radiology 74 (2010) e1–e5
Fig. 3. Histological tissue section, HE × 25, patient 4: peripheral nodular part of FNH, well circumscribed, but nonencapsulated, irregulary distributed portal fields. Courtesy of M. Ortmann, MD, Department of Pathology, University of Cologne.
MRI: On imaging with T1w sequences the lesions were slightly hypointens in 5, or isointens in 1, with T2w sequences slightly hyperintens in 5, or isointens in 1. In the dynamic series after injection of contrast material, there was a rapid and strong enhancement during the early arterial phase, except for the central scar, and a complete wash out thereafter in all patients (Fig. 2). The central scar was detected in three out of six patients. After the diagnosis of FNH, the patients had follow-up examinations for 0.56–4.6 years, median 3 years. In one patient, the lesions progressed in number and size. In addition, dynamic-enhanced MRI showed a more rapid and stronger enhancement during the early arterial phase. Surgical biopsies were performed to rule out liver metastases. FNH was verified histologically (Fig. 3). In the other five patients the imaging findings of FNH did not change during follow-up, either in US or in MRI. The six patients developing FNH had been diagnosed with stage 3 or 4 NB according to the International Neuroblastoma Staging System (INSS, 1993). The age at diagnosis ranged from 4 months to 5.6 years (for details see Table 1). Only one boy had liver metastases at initial diagnosis (patient 5). The patients were treated with intensive polychemotherapy cycles according to the German cooperative NB trials NB82, NB90 and NB97 (Table 1) [9]. Induction therapy consisted of six or more cycles in five patients and was followed by further treatment modalities in three (maintenance therapy in 2, megatherapy with autologous stem- cell rescue in 1, consolidation therapy with antiGD2-antibody ch 14.18 in 2). In one patient however, chemotherapy was limited to four cycles of induction therapy (patient 6). Melphalan was given to two children, either during megatherapy or low dose maintenance therapy. None of our patients received busulfan. Two children received radiotherapy with abdominal radiation field, where parts of the liver were involved (radiation dose varied from 25–30 Gy).
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Two patients experienced relapses: one was treated with intensive second line therapy including polychemotherapy with various regimes and ch 14.18 antibody treatment (patient 2), the other with MIBG-therapy of 3.7 GBq, local cervical radiation and immunomodulatory therapies (patient 3). Of the 54 patients who did not develop FNH, 33 were treated with intensive polychemotherapy, 24 received six or more cycles. Seven patients underwent megatherapy, 10 received oral maintenance therapy, and 11 anti-GD2-antibody therapy. Melphalan was given to 10 patients including all seven patients with megatherapy and three patients with oral maintenance therapy. Six patients received radiotherapy with abdominal radiation field, one MIBGtherapy. In none of the patients, with or without FNH, were vascular complications or venoocclusive disease (VOD) observed during therapy. The young adult (patient 2) used oral contraceptives (OC) prior to the development of FNH. All patients with FNH are alive and did not develop NBrecurrence after the diagnosis of FNH. 4. Discussion Of 60 patients in longterm follow-up after treatment of NB, six were diagnosed with FNH. The incidence seems to be increasing [7]: 10% (6/60) of our patients in follow-up more than 5 years and 15% (6/39) of those treated with chemotherapy developed FNH. At the diagnosis of FNH our patients were asymptomatic as reported for most children with FNH [2–4]. Although we saw four female and two male patients (Table 1), our number of patients is too small to confirm the previously reported female predominance [3]. Contrary to the literature [3] all our patients had two or more lesions with diameters from one to four cm, which is in the range reported in the literature (generally under 5 cm with variation from less than 1 cm to more than 20 cm [2,10]). The liver lesions were detected during routine follow-up with US. This is the method of choice to detect lesions of the liver, especially in children and young adults. But with this technique it is not possible to provide a specific and confident characterization of the lesions because of the variable echogenicity [3,5,11], which we observed in our patients as well: in 2 the lesions were hyperechoic, in 2 isoechoic and in 2 hypoechoic (Fig. 1). A central scar was not seen. As liver metastases are not uncommon in NB patients, focal liver lesions, detected by US, need to be further characterized by MRI. Typical findings for FNH in plain and dynamic-enhanced MRI include: • A well-delineated, homogenous, round lesion • Isointens or slightly hypo- or hyperintens signals on T1w and T2w images • In the dynamic series after contrast material, a rapid and strong enhancement during the early arterial phase except for the central scar and a complete wash out after
Table 1 Children treated for NB who developed FNH. Patients
Age at NBdiagnosis (years)
Gender
Primary tumor
Initial stage INSS
Initial treatment according to trial
Interval between NB- and FNHdiagnosis (years)
Interval between end of NBtherapy and FNHdiagnosis (years)
1 2 3 4 5 6
1.2 2.3 1.0 1.6 5.6 0.4
M F F F M F
Abdomen Abdomen/thorax Thorax Abdomen Abdomen Abdomen
3 3 4 4 4 3
NB90 NB82 NB97 NB90 NB97 NB90 Median
9.4 19.9 6.0 11.6 8.9 13.2 10.5
8.8 11.8 4.1 10.0 7.3 12.9 9.4
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• The central scar typically hypointens on T1w and hyperintens on T2w images, decreased signal intensity on the arterial phase and enhancement on the portal venous phase [8]. When several of these typical findings are present simultaneously, diagnosis of FNH is strongly suggested. As our patients showed at least three out of these findings, we diagnosed FNH by MRI (Fig. 2). However in one child we used histological verification as the lesions progressed in number and size and showed a more rapid and stronger enhancement during the early arteriel phase in dynamic-enhanced MRI. FNH was verified (Fig. 3). Although a typical finding of FNH, the central scar is not always detected by MRI in the FNH lesions [8]. We saw the central scar in three of six patients by MRI. The central scar was not detected by US. Atypical MRI findings such as heterogeneity, poor delineation, pseudocapsulelike rim, atypical intensity of the lesion or the scar in T1w or T2w sequences should suggest different diagnosis, especially in combination and a biopsy should be performed. Most metastases have no central scar. A solitary hypervascular lesion may simulate a metastasis [12]. A metastasis in the area of a FNH of the liver in a young woman with Ewing’s sarcoma of the left lower ribs was reported [13]. A fibrolamellar carcinoma may have a central scar but with low signal intensity on T2w images [14]. Hepatic adenoma is a benign lesion without central scar [3]. Nodular regenerative hyperplasia is a multi-acinar regenerative nodular lesion, rare in children. These lesions are hyperechoic on US, hypodense with no significant enhancement and no central scar on CT. MRI findings are variable and non-specific [15]. Further imaging methods may be helpful to support the diagnosis of FNH, but not all of them are suitable for the use in children. Color Doppler sonography is useful for additional information about intranodular and perinodular blood flow distribution [11], but was not used regularly. The contrast-enhanced power Doppler sonography for characterization of FNH is not normally used in children [6,16]. As CT is not superior to MRI [17], it should be avoided in children and young adults, because of the radiation dose. Dynamicenhanced MRI with liver-specific delayed images (3 h) to improve the diagnostic efficacy are not suitable for children because of the long investigation time [18]. Finally, the use of liver-specific contrast agent is not permitted for children [19]. The pathogenesis of FNH remains controversial. It is mostly suggested that FNH is a hyperplastic response of the liver parenchyma to the presence of a pre-existing vascular malformation. Another hypothesis: FNH is induced by vascular injury such as thrombosis, intimal hyperplasia, high sinusoidal pressure or increased flow [2,3,10,20]. Icher-De Bouyn et al. [3] reported NB to be most often associated with FNH and suggest that the development of FNH may be linked to the type of therapy not to the type of malignancy. They discussed the cytoreductive agents busulfan and melphalan as the most hepatotoxic drugs, especially as risk factor for VOD. In our patients with FNH no child received busulfan, only two children melphalan and no child had VOD or other vascular complications. In addition, the combination of radiotherapy with chemotherapy may be important for the development of FNH [3,20]. Radiotherapy of parts of the liver was applied to two of six children with FNH, one received melphalan in low dose during maintenance therapy. MIBG-therapy of 3.7 GBq was applied to one child with FNH. In one of our patients with FNH, chemotherapy for NB was limited to four cycles induction therapy. This patient experienced none of the risk factors mentioned above, but chemotherapy was started at the very young age of 4 months. Altogether, three patients with FNH were treated with chemotherapy below 18 months of age
(Table 1). Thus, very young age may be an additional risk factor for FNH. However, even experiencing risk factors does not necessarily lead to the development of FNH, as suggested by our 33 NB patients who did not develop FNH. In contrast, in the report of Icher-De Bouyn et al. [3] three out of 14 patients with FNH had no risk factors for FNH, as was the case with three of our six patients. One of six patients used OC before the development of FNH. The possibility of OC as a risk factor for FNH was discussed for a long time. The study of Mathieu et al. demonstrated the independence of the development of FNH from OC use [21]. 5. Conclusions Longterm survivors of neuroblastoma are at risk of developing FNH, especially if they experienced risk factors during initial treatment. The incidence is higher than suggested. In the absence of any other signs of tumor-relapse and in the presence of typical imaging patterns for FNH in MRI, close imaging follow-up examinations appear to be sufficient to rule out liver metastases. These include US and possibly plain and dynamic-enhanced MRI as the diagnostic imaging. More invasive procedures should be reserved for equivocal findings. Conflict of interest None. References [1] International Working Party. Terminology of nodular hepatocellular lesions. Hepatology 1995; 22:983–93. [2] Stocker JT, Kamal GI. Focal nodular hyperplasia of the liver: a study of 21 pediatric cases. Cancer 1981;48:336–45. [3] Icher-De Bouyn C, Leclere J, Raimondo G, et al. Hepatic focal nodular hyperplasia in children previously treated for a solid tumor: incidence, risk factors, and outcome. Cancer 2003;97:3107–13. [4] Freidl T, Lackner H, Huber J, Sovinz P, Moser A. Focal nodular hyperplasia in children following treatment of hemato-oncologic diseases. Klin Pädiatr 2008;220:384–7. [5] Brisse H, Servois V, Bouche B, et al. Hepatic regenerating nodules: a mimic of recurrent cancer in children. Pediatr Radiol 2000;30:386–93. [6] Joyner Jr BL, Levin TL, Goyal RK, Newman B. Focal nodular hyperplasia of the liver: a sequela of tumor therapy. Pediatr Radiol 2005;35:1234–9. [7] Sudour H, Mainard L, Baumann C, Clement L, Salmon A, Bordigoni P. Focal nodular hyperplasia of the liver following hematopoietic SCT. Bone Marrow Transplant 2008:1–6. [8] Mortelé 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 dynamic-enhanced MRI. Abdom Imaging 2002;27:700–7. [9] Berthold F, Hero B, Kremens B, et al. Long-term results and risk profiles of patients in five consecutive trials (1979-1997) with stage 4 neuroblastoma over 1 year of age. Cancer Lett 2003;197:11–7. [10] Wanless IR, Mawdsley C, Adams R. On the pathogenesis of focal nodular hyperplasia of the liver. Hepatology 1985;5:1194–200. [11] Cheon J-E, Kim WS, Kim I-O, Jang J-J, Seo JK, Yeon KM. Radiological features of focal nodular hyperplasia of the liver in children. Pediatr Radiol 1998;28:878–83. [12] Mahfouz AE, Hamm B, Taupitz M, Wolf KJ. Hypervascular liver lesions: differentiation of focal nodular hyperplasia from malignant tumors with dynamic gadolinium-enhanced MR imaging. Radiology 1993;186:133–8. [13] Hagay ZJ, Zirkin HJ, Moses M, Khodadadi J. Ewing’s sarcoma metastatic to focal nodular hyperplasia of liver. J Surg Oncol 1986;32:100–5. [14] Hamrick-Turner JE, Shipkey FH, Cranston PE. Fibrolamellar hepatocellular carcinoma: MR appearance mimicking focal nodular hyperplasia. J Comput Assist Tomogr 1994;18:301–4. [15] Trenschel GM, Schubert A, Dries V, Benz-Bohm G. Nodular regenerative hyperplasia of the liver: case report of a 13-year-old girl and review of the literature. Pediatr Radiol 2000;30:64–8. [16] Ungermann L, Eliás P, Zizka J, Ryska P, Klzo L. Focal nodular hyperplasia: spoke-weel arterial pattern and other signs on dynamic contrast-enhanced ultrasonography. Eur J Radiol 2007;63:290–4. [17] Carlson SK, Johnson CD, Bender CE, Welch TJ. CT of focal nodular hyperplasia of the liver. Am J Roentgenol 2000;174:705–12. [18] Grazioli L, Morana G, Federle MP, et al. Focal nodular hyperplasia: morphologic and functional information from MR imaging with gadobenate dimeglumine. Radiology 2001;221:731–9.
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[20] Fajardo LF, Colby TV. Pathogenesis of veno-occlusive liver disease after irradiation. Arch Pathol Lab Med 1980;104:584–8. [21] Mathieu D, Kobeiter H, Maison P, et al. Oral contraceptive use and focal nodular hyperplasia of the liver. Gastroenterol 2000;118:560–4.