CASE REPORT
Multiple malignant and benign lesions in the liver in a child with adrenocortical carcinoma
Ina Sorge · Uta Bierbach . Rainer Finke · Wolfgang Hirsch
Received: 18 July 2007 /Revised: 6 October 2007 /Accepted: 5 November 2007/Published online: 7 February 2008 C Springer-Verlag 2008
Abstract We report 4-year-old girl who was diagnosed with adrenocortical carcinoma when she was 2 years old. At the time of diagnosis there were no metastases, but 6 months later multiple liver metastases appeared. Follow- ing intensive chemotherapy the metastases resolved com- pletely. Multifocal lesions were detected in the liver by US 16 months later. Their morphology on US and MRI differed from the previous metastases. Histopathological examina- tion confirmed focal nodular hyperplasia. We discuss the origin and the uncommon appearance of multifocal nodular hyperplasia in hormone-active tumours such as adrenocor- tical carcinoma in children.
Keywords Adrenocortical carcinoma · Focal nodular hyperplasia · Liver metastases · Children
Introduction
Adrenocortical carcinoma is a very rare malignant tumour in children. The prognosis highly depends on the tumour stage and declines substantially when metastases occur. On finding multifocal liver lesions in patients with a malig-
I. Sorge () . W. Hirsch ☒ Department of Paediatric Radiology, University of Leipzig, Liebigstrasse 20a, 04103 Leipzig, Germany e-mail: Ina.Sorge@medizin.uni-leipzig.de
U. Bierbach Department of Paediatrics, University of Leipzig, Leipzig, Germany
R. Finke Department of Paediatric Surgery, University of Halle, Halle, Germany
nancy known to produce liver metastases, spread of the tumour has to be assumed. This is not always the case, especially when the tumour or its therapy is hormone- active, as is shown by the very rare case reported here of multiple focal nodular hyperplasia (FNH) occurring as a side effect of the tumour therapy.
Case report
A 2-year-old girl presented because of enlargement of the clitoris and pubic hair growth. A large tumour was palpable in the left upper abdomen. US and MRI demonstrated a heterogeneous 9×9×6-cm tumour with necrotic areas in the left adrenal region. Laboratory tests showed plasma testosterone at 100 times the normal level. Histological examination of the completely removed tumour revealed it to be adrenocortical carcinoma. There was no infiltration of the renal capsule and the local lymph nodes were unaffected. Imaging did not demonstrate metastatic disease and so chemotherapy was not recommended. During the following weeks the patient was well. Clinical, laboratory, and radiological tests were performed regularly because of the poor prognosis of this disease.
Six months after diagnosis, multiple hypoechoic hepatic lesions up to 10 mm in size were identified on US (Fig. 1). These were confirmed by MRI and were hyperintense on T2-weighted (T2-W) images (Fig. 2) and hypointense on T1-weighted (T1-W) images (Fig. 3). They showed delayed enhancement following administration of gadolinium con- trast agent (Fig. 4). Laboratory tests showed a distinct increase in plasma testosterone to 10 times the normal level, as well as an increase in serum DHEA-sulphate (a testosterone precursor) to 140 times the normal level. Metastatic disease was confirmed histologically.
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The patient underwent chemotherapy according to the GPOH-MET 97 recommendations (vincristine, ifosfamide, Adriamycin, carboplatin, and etoposide). In addition, she was started on long-term therapy with mitotane (a cytostatic drug that selectively acts on the adrenal cortex). During therapy, laboratory findings normalized. US and MRI documented complete disappearance of the metastases. During the following 15 months all clinical, laboratory, and radiological tests, which were performed monthly, remained normal with no evidence of relapse or metastases.
Several hepatic lesions were again demonstrated by US 22 months after tumour diagnosis and 16 months after the occurrence of metastases. They were slightly hyperechoic (Fig. 1), 3-6 mm in size, and did not show increased flow on colour imaging. These lesions differed from the previous metastases that had been hypoechoic. Extensive laboratory investigations were undertaken, but all findings were normal
including plasma testosterone, serum DHEA-sulphate, and urinary corticosteroids. The patient was asymptomatic and new metastatic disease was thought unlikely. On repeat US the lesions had increased slightly in size and number.
About 8 weeks later, MRI demonstrated a total of 13 hepatic lesions, 5-11 mm in size. They were slightly hyperintense on T2-W images (Fig. 2) and hypointense on T1-W images (Fig. 3), and showed early, moderate enhancement. On a late dynamic series the signal of the lesions was almost the same as that of the surrounding normal liver (Fig. 4). Thus the MRI characteristics of these lesions also differed from the metastases seen previously. Despite these findings and normal repeat hormone tests, histological assessment was considered necessary because of the high prognostic importance of potential new metastases. Histological examination of three lesions in the left lobe demonstrated FNH.
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Discussion
Adrenocortical carcinoma is a very rare malignant tumour with a poor prognosis. In Germany it occurs in 1-2 patients per 1 million population each year. Only 10% of the patients are younger than 10 years of age [1]. One-third of patients show metastases at the time of diagnosis; most of the others develop metastases during the course of the disease even if the tumour is apparently completely removed [1]. Metastases are mainly seen in local lymph nodes, but also in the liver, lung, and rarely in bones. The prognosis is poor. In stage 1 and 2 disease the 5-year survival is approximately 60% and in stage 3 disease it is approximately 40%, while patients with stage 4 disease live for only approximately 12 months [3]. Detection or exclusion of metastases has prognostic importance; new relapse after therapy for the metastases seems to be fatal.
When multifocal hepatic lesions are found in a patient with a malignancy that is known to metastasize to the liver, the first assumption is metastatic disease. Our case suggests
that FNH is an important differential diagnosis, especially in those with hormonally active tumours and aggressive chemotherapy. FNH is very uncommon in early childhood, but its incidence in children seems to be much higher after treatment of malignant tumours. Bouyn et al. [2] described 14 patients who were treated with chemotherapy for a malignant tumour in childhood and then developed FNH of the liver after 4-21 years. In one-third of the patients FNH was multifocal. Joyner et al. [3] reported three children who developed FNH, one after treatment of acute lymphoblastic leukaemia and one after treatment of neuroblastoma. The lesions appeared after 3, 8 and 9 years, respectively. Kumagai et al. [4] reported a 21-month-old girl with nephroblastoma and a latency of only 10 months from the beginning of chemotherapy until the occurrence of FNH.
In our patient, a causal relationship between chemotherapy of the adrenocortical carcinoma and occurrence of FNH is also assumed. The special features of our patient are the consecutive occurrence of initially malignant and later benign focal hepatic lesions, the short latency of only 16 months from
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beginning of chemotherapy until the development of FNH, and the rapid and simultaneous development of 13 FNH lesions within a period of 4 weeks. In the patients of Bouyn et al. [2] the highest number of lesions was six.
The aetiology of FNH is not yet fully ascertained. For a long time, it was assumed that later regenerative growth of an embryonic vascular malformation could result in a focal or multifocal tumour [5]. Hormonal contraceptives have been considered as growth-stimulating factors. Some authors [2-4, 6, 7] consider that injury to the vascular endothelium and subsequent localized circulatory distur- bances might lead to hepatocyte proliferation and thus the development of FNH. Kumagai et al. [4] found arterial and portal thrombi histologically and recanalization in the nodule, leading them to suggest that thrombosis of the hepatic artery or portal vein could be the cause of hepatic necrosis and that reperfusion following arterial recanaliza- tion results in nodule formation. This is supported by the possibility that some chemotherapeutic agents cause throm- boembolic complications and the development of venooc- clusive disease. Our patient was treated with intensive chemotherapy including vincristine, ifosfamide, Adriamy- cin, carboplatin, and etoposide.
Histologically, liver tissue with focal sclerosis and expanded portal fields, but no thrombosis, was found in our patient. Kondo [5] has reported that an area of the liver becomes atrophic after portal blood flow is interrupted or reduced. Recanalization of thromboses alone may not explain nodule formation since blood flow within a recanalized artery is lower than normal. We assume that growth stimuli are additionally required.
Because she suffered from a hormonally active tumour, our patient was commenced an antiadrenal therapy with mitotane in addition to conventional chemotherapy. This therapy leads to complete blockage of hormone release from the adrenal cortex. Mitotane is a highly toxic agent. It reversibly increases the blood level of hormone-binding proteins. This mechanism may involve oestrogen excess leading to feminization phenomena [8]. Assuming that hormonal contraceptives might stimulate the growth of FNH, a similar effect of antiandrogenic therapy may occur if appropriate conditions exist. Thus the combination of two stimulating factors-
chemotherapy and antiandrogenic therapy-could explain the rapid development of multifocal FNH in our patient.
Imaging findings of FNH are varied. On US, FNH is mostly hypoechoic. Bouyn et al. [2] found hyperechoic FNH lesions similar to those in our patient in only 1 of their 14 patients. We could not identify the typical central scar of FNH in our patient on US or MRI. We assume this was because of the small size of the lesions. Because of its hypervascularity, FNH usually shows rapid and marked contrast enhancement. In our patient there was early but only moderate enhancement on T1-W MR images. In the late dynamic series the signal of the lesions was almost the same as that of the surrounding liver tissue.
Multifocal liver lesions in a child with a malignant tumour are generally suspicious for metastases. However, it is important to be aware of the higher incidence of (frequently multifocal) FNH due to therapy of that tumour. If the imaging findings are typical, and clinical as well as nonclinical parameters correlate, biopsy may be unneces- sary. However, in a patient with atypical findings, histo- logical confirmation is still required.
References
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