The discovery of hepatic nodules in the follow-up of children treated for malignancies suggests recurrence of the disease and raises a diagnostic dilemma. For this reason, a differential diagnosis between benign focal liver lesions related to the treatment and malignant lesions is often difficult, but necessary. Benign hepatic lesions are rare entities in childhood but some of them have been reported more frequently in children with a history of malignancy after cancer treatment (1,2). An increased prevalence of focal nodular hyperplasia (FNH) has been reported in children after chemoradiation therapy (1–4) especially after hematopoietic stem cell transplantation (HSCT) (5–7). Nodular regenerative hyperplasia (NRH) has also been reported as a rare sequela of antineoplastic therapy (8–11). Other benign liver lesions such as hepatocellular adenoma and hemangioma have been etiologically associated with the use of medications intensively used in pediatric oncology, such as steroids and oral contraceptives (11–15).
Conceptually, all of these regenerative hepatic lesions are different entities but their pathogeneses may be similar in nature (16–18). Some reports have suggested that circulatory disturbances underlie FNH, NRH, and other benign nodular lesions (16,18–20). The vascular injury induced by the chemoradiation therapy may lead to the development of benign regenerative lesions (2,5,16), but the precise mechanisms by which circulatory disturbances could cause these lesions have not been elucidated. We retrospectively evaluated and analyzed the series of benign nodular hepatic lesions that occurred in children treated for cancer in our institution in a period of 11 years. Clinical and radiological findings of hepatic lesions are extensively described and a risk factor analysis of the factors associated with the onset of these lesions has been conducted.
We conducted a retrospective analysis of cases of benign nodular hepatic lesions that were diagnosed in patients who had been treated for a malignant neoplasm in our clinic between 1995 and 2006. A total of 564 abdominal ultrasound (US) examinations administered to 236 patients (110 female and 126 male patients) were considered. All the patients had an ultrasonography evaluation of the liver performed before starting the treatment and none had revealed nodules. The available radiological characterization of the nodular lesions that was performed in addition to US, including contrast-enhanced ultrasonography (CEUS), magnetic resonance imaging (MRI) and/or computed tomography (CT) scan, and positron emission tomography (PET), has been reported. In particular, 7 patients diagnosed as having a nodular hepatic lesion at abdominal US had received a CEUS evaluation, 12 an abdominal CT scan, 8 MRI, and 3 PET. To define a lesion compatible with FNH at US evaluation the following criteria were used: a well-circumscribed homogeneous lesion with variable echogenicity and central arterial vessel with spoke wheel appearance (1) with a color Doppler US pattern showing a typical color flow mapping and a spoke-wheel distribution of arterial branches, stemming from the central artery within the scar (21). Arterial signals can be identified both within and on the border of the mass, showing high peak flow and low (<0.71) resistance index (21). At CEUS evaluation: a lesion with central spoke wheel–shaped enhancement during early arterial phase that becomes homogeneous during late arterial phase, homogeneous enhancement similar to that of the liver parenchyma during portal venous and late phases (1,21). Data about clinical presentation, laboratory serological analyses of liver function, and previous treatment history were collected of patients who had been diagnosed as having nodular hepatic lesions.
In the risk factor analysis, the following risk factor possibly associated with the development of benign hepatic lesions after treatment have been evaluated: age at the time of antineoplastic treatment, sex, type of disease (hematological vs solid tumor), HSCT, abdominal radiation (including total body irradiation pre-HSCT), occurrence of veno-occlusive disease, and the use of oral contraceptive. A logistic regression model was used for univariate and multivariate analyses (22). Statistical analysis was performed using the R 2.14.1 software package.
Fourteen diagnoses of benign nodular hepatic lesions have been found: 10 were FNH and 4 hemangiomas. Neither adenomas nor NRH has been found. Six male and 8 female patients with nodular benign nodular lesions had received the treatment with antineoplastic therapy at a median age of 7.7 years (range 1.2–15.6 years). The median age at diagnosis of the hepatic lesion was 15.7 years (range 10.3–26.2 years). The median interval between the diagnosis of malignancy and the discovery of the benign hepatic lesion was 6.7 years (2.4–11.6). Each one of the patients showed negative hepatitis B virus and hepatitis C virus serology results and none of the patients had abnormal liver function test results, except 1 with a mild increase of transaminases (Table 1). None of the 14 patients presented clinical or laboratory signs of disease progression at the time of discovery of the lesion. All of the patients were asymptomatic except 1 case with positive anamnesis for recurrent abdominal pain. A physical examination did not reveal any pathological diagnostic findings. No other peculiar laboratory findings were observed.
The US features of FNH revealed multiple hypoechoic liver nodules located in both hepatic lobes in 9 patients, whereas 1 case presented a single liver lesion. The median nodule size was 14.8 mm (range 6–60). Color Doppler US showed signals of vascularization both in the central and in the peripheral zone (coin-like figuration), with Doppler spectral traces characterized by high frequency (3 kHz) and low systodiastolic variation (low resistive index) (21). SonoVue-enhanced US has been applied in 4 of 10 cases: liver lesions during the arterial phase looked like hypervascular masses and the portal venous phase lesions showed an enhancement equal to the liver. The evaluation of FNH by CT scan showed a diffuse, homogeneous hypodense lesion. Contrast-enhanced CT images confirmed the hypervascularity of FNH on the arterial phase and the sustained enhancement of the lesions on the portal venous phase. A central scar has been demonstrated with CT in 4 of 10 cases. The MRI of FNH showed a hypointense signal on T1-weighted images and a hyperintense signal on T2-weighted images. A gadolinium-enhanced MRI revealed a hyperintensity of the liver nodules on the arterial phase and a sustained enhancement on the portal venous phase. A PET evaluation was performed in 3 of 10 of FNH, and it showed hypercaptation of the C-acetate and a normal captation of 2-fluoro-2-deoxy-D-glucose in the liver lesions. A liver biopsy was conducted in 2 patients and revealed the regenerative benign nature of the nodules, characterized by an abnormal nodular architecture surrounded by fibrous septa, vessel malformation, and cholangiolar proliferation, confirming the diagnosis of FNH. The median follow-up time of the observation after the FNH diagnosis was 3.8 years (range 2.3–7.2 years), consisting in an abdominal US performed every 3 to 6 months. No malignant transformation was observed and the number of nodules only increased mildly in 2 patients (from 4 to 6 and from 3 to 5, respectively, cases 3 and 4), whereas size and radiologic characteristics of the nodules remained the same.
The 4 hemangiomas diagnosed presented a single homogeneous hyperechoic mass with well-defined margins. No vascular signal was detected by color Doppler. CEUS was performed in 3 of 4 cases showing a peripheral globular enhancement progressing toward the center of the nodule in the arterial and portal phases and persistent enhancement in the late phase. The MRI revealed a hypointense lesion on T1-weighted images and hyperintense on T2-weighted images. The unenhanced CT showed a hypoattenuating lesion with a progressive centripetal enhancement similar to CEUS after intravenous administration of contrast material. The median follow-up time of observation after the hemangioma diagnosis was 3.75 years (range 1.3–9.2 years), consisting in an abdominal US performed every year. No malignant transformation was found.
In the risk factor analysis, the univariate model showed the following factors as significantly associated with the development of a benign hepatic lesion: HSCT as part of the antineoplastic treatment (P = 0.007), abdominal radiation (P = 0.02), and the use of oral contraceptives (P = 0.03) (Table 2). Only for FNH, HSCT and abdominal radiation confirmed their significant association in univariate analysis (P = 0.02 and P = 0.01, respectively), whereas the use of oral contraceptives was not confirmed (P = 0.24). For hemangioma, the only variables significantly associated with the onset have been the use of oral contraceptives (P = 0.04) and the female sex (P = 0.01). In the multivariate Cox regression analysis (Table 2), only the HSCT has resulted significantly associated with a higher probability of developing a benign nodular lesion (P = 0.01).
The finding of 1 or multiple nodular lesions in the liver during the follow-up of a patient treated for malignancy in infancy always raises many diagnostic doubts and perplexities. In these kinds of patients, first we need to exclude metastases and the recurrence of the disease in the diagnostic process of hepatic lesions. To do this, a correct diagnostic investigation has to be conducted and possible risk factors have to be taken into account. We have retrospectively evaluated our diagnoses of nodular hepatic lesions in children previously treated for cancer with the aim to make the physicians aware of the possible consequences of anticancer therapy and to help them in the difficult process of differential diagnosis and management.
The median age of our patients at the time of the diagnosis of benign nodular hepatic lesion is 15.7 years. The median interval between the diagnosis of malignancy and the discovery of the benign hepatic lesion was 6.7 years. In particular for FNH (median time of diagnosis 16.5 years after a median time off-therapy of 8.3 years), the data appear to be comparable with the data of the 2 largest series of pediatric FNH after anticancer therapy (2,7). Bouyn et al (2) reported a series of 14 FNH in the same setting of patients where the median age of diagnosis was 12.5 years and the median interval between treatment and discovery of FNH was 8.5 years. In a setting of exclusively transplanted children, Sudour et al (7) reported 17 cases of FNH in patients of a median age of 12.1 years with a median time after HSCT of 6.4 years. The delay between the treatment and occurrence of FNH must be interpreted with caution because of the retrospective nature of the major studies on this topic. Anyway, the concordance of most of the data allows us to assume that the median time of onset of this lesion after treatment is at least >2 years. Some authors have speculated that FNH may occur earlier when liver vascular injury is significant (7). A greater degree of hepatic damage can be represented by a higher cumulative treatment burden, as for relapsed disease, or by the presence of HSCT during the treatment history of high-risk diseases.
No cases of NRH or adenomas have been detected in our series. NRH occurred in 22.5% of a series of 103 patients following HSCT (11), but other investigators have seen much lower prevalence (7,15). Instead, we have found 4 cases of hemangiomas that were not detected before the antineoplastic treatment. To our knowledge, no cases of hemangioma related to the antineoplastic treatment have been reported in literature whereas they are typically reported in female young adults with history of oral contraceptive therapy (12). The use of oral contraceptives is indicated in the treatment of young women with premature ovarian failure caused by antineoplastic treatment (14,15). Maybe our findings have to be interpreted considering that all of the patients with hemangiomas were girls with a median age of 18.3 years, half of which were receiving oral contraceptive therapy. Moreover, in our risk factor analysis, the only variables linked to the development of hemangiomas have been the female sex and the use of oral contraceptive (P = 0.01 and P = 0.04, respectively).
In accordance with the other series reported in the literature (2,7,8), our diagnoses of nodular hepatic lesions during the posttreatment follow-up period have been casual without any particular clinical or laboratory symptoms/signs of suspicion. The pathogenesis of benign hepatic regenerating lesions following treatment with chemotherapy, radiation therapy, and HSCT remains controversial. The theory of the treatment-induced vascular injury is one of the most accredited ones (2,5) and these lesions could represent different outcomes of a similar circulatory disorder (16). Anyway, the exact underlying pathological mechanism is far from being elucidated but could be important for a physician to be aware of which patients are at major risk of developing these lesions after treatment. In our risk factor analysis, even if abdominal radiotherapy and the use of oral contraceptives seem to be significant in an univariate model, the only independent risk factor associated with the development of a benign hepatic lesion, especially FNH, has been the HSCT. These data are consistent with the data reported by Sudor et al (7) and support what we previously suspected in a recent article describing FNH after HSCT (5). Some variables peculiarly linked to the HSCT procedure such as the use of high dosage of alkylating agents, the occurrence of venous occlusive diseases, and hepatic graft-versus-host diseases may better explain this risk (5).
As confirmed in our series, these benign nodular hepatic lesions generally do not change their size and characteristics in time. To our knowledge, no malignant transformation has been reported to date. Anyway, a correct follow-up management is recommended especially in the first 2 to 3 years after the discovery. Once diagnosed with maximal certainty, a conservative “wait-and-see” strategy is recommended. In conclusion, the detection of hepatic nodules in the follow-up program of children previously treated for cancer is not always associated with the recurrence of the disease. Physicians treating off-therapy children, especially children who have undergone HSCT, must know that the treatment received in infancy could have caused benign regenerative hepatic lesions. The physician must keep in mind the risk factors that are possibly associated with the occurrence of a benign nodular hepatic lesion. Differential diagnoses of malignant hepatic lesions or metastases are possible using correctly the improved imaging techniques and avoiding an invasive procedure such as a percutaneous biopsy. After a secure diagnosis is made, only a close imaging follow-up is recommended.
1. Chung EM, Cube R, Lewis RB, et al. From the archives of the AFIP: pediatric liver masses: radiologic-pathologic correlation part 1. Benign tumors. Radiographics
2. Bouyn CI, Leclere J, Raimondo G, et al. Hepatic focal nodular hyperplasia in children previously treated for a solid tumor. Incidence, risk factors, and outcome. Cancer
3. Joyner BL Jr, Levin TL, Goyal RK, et al. Focal nodular hyperplasia of the liver: a sequela of tumor therapy. Pediatr Radiol
4. Freidl T, Lackner H, Huber J, et al. Focal nodular hyperplasia in children following treatment of hemato-oncologic diseases. Klin Padiatr
5. Masetti R, Biagi C, Kleinschmidt K, et al. Focal nodular hyperplasia of the liver after intensive treatment for pediatric cancer: is hematopoietic stem cell transplantation a risk factor? Eur J Pediatr
6. Anderson L, Gregg D, Margolis D, et al. Focal nodular hyperplasia in pediatric allogeneic hematopoietic cell transplant: case series. Bone Marrow Transplant
7. Sudour H, Mainard L, Baumann C, et al. Focal nodular hyperplasia of the liver following hematopoietic SCT. Bone Marrow Transplant
8. Citak EC, Karadeniz C, Oguz A, et al. Nodular regenerative hyperplasia and focal nodular hyperplasia of the liver mimicking hepatic metastasis in children with solid tumors and a review of literature. Pediatr Hematol Oncol
9. Brisse H, Servois V, Bouche B, et al. Hepatic regenerating nodules: a mimic of recurrent cancer in children. Pediatr Radiol
10. Luks FI, Yazbeck S, Brandt ML, et al. Benign liver tumors in children: a 25-year experience. J Pediatr Surg
11. Snover DC, Weisdorf S, Bloomer J, et al. Nodular regenerative hyperplasia of the liver following bone marrow transplantation. Hepatology
12. Giannitrapani L, Soresi M, La Spada E, et al. Sex hormones and risk of liver tumor. Ann N Y Acad Sci
13. Inaba H, Pui CH. Glucocorticoid use in acute lymphoblastic leukaemia. Lancet Oncol
14. Armstrong GT, Chow EJ, Sklar CA. Alterations in pubertal timing following therapy for childhood malignancies. Endocr Dev
15. Gelbaya T, Vitthala S, Nardo L, et al. Optimizing hormone therapy for future reproductive performance in women with premature ovarian failure. Gynecol Endocrinol
16. Shulman HM, Fisher LB, Schoch HG, et al. Veno-occlusive of the liver after marrow transplantation: histological correlates of clinical signs and symptoms. Hepatology
17. Kondo F. Benign nodular hepatocellular lesions caused by abnormal hepatic circulation: etiological analysis and introduction of a new concept. J Gastroenterol Hepatol
18. Di Carlo I, Urrico GS, Ursino V, et al. Simultaneous occurrence of adenoma, focal nodular hyperplasia, and hemangioma of the liver: are they derived from a common origin? J Gastroenterol Hepatol
19. Kondo F. Focal nodular hyperplasia of the liver: controversy over etiology. J Gastroenterol Hepatol
20. Kondo F, Nagao T, Sato T, et al. Etiological analysis of focal nodular hyperplasia of the liver, with emphasis on similar abnormal vasculatures to nodular regenerative hyperplasia and idiopathic portal hypertension. Pathol Res Pract
21. Gaiani S, Casali A, Serra C, et al. Assessment of vascular patterns of small liver mass lesions: value and limitation of the different Doppler ultrasound modalities. Am J Gastroenterol
22. Hosmer DW Jr, Lemeshow S. Applied Logistic Regression. 2nd edNew York:Wiley; 2000.