Date Published: February 28, 2019
Publisher: Public Library of Science
Author(s): Nassim Fard, Heinz-Peter Schlemmer, Friedhelm Raue, Björn Jobke, Giorgio Treglia.
Liver metastases from neuroendocrine tumors in multiple endocrine neoplasia syndrome are common (75%) and significantly impairs the prognosis. Characterisation of liver lesions in these patients is challenging, as liver metastases are difficult to differentiate from benign liver lesions such as haemangioma.
In this study we aimed to characterize the radiological findings of hepatic metastases in MEN patients. The findings of contrast-enhanced CT were considered for the main diagnosis. We retrospectively evaluated 25 patients with MEN-syndrome (10 MEN1/ 15 MEN2) including 11 men and 14 women between 28–62 years of age.
Liver metastases (48%, 12/25) and hemangioma (40%, 10/25) were the most common liver lesions among our patients. The most common primary tumors in our MEN1 and MEN2 patients with liver metastases were of pancreatic neuroendocrine tumor (70%, 7/10) und medullary thyroid carcinoma (100%, 15/15) origin, respectively. CT-characteristics were grouped into three main categories, depending on contrast dynamics. The majority of hepatic metastases (75%, 14/25) are presented as multiple lesions with a slow growth in an average 5 years of follow-up-period. We were able to find a common CT pattern and categorise these for each MEN-syndrome. Hepatic metastases in MEN1 presented commonly a blurred arterial enhancement with a low portal venous enhancement and less frequently a prominent enhancement in the arterial phase, which mimics the classical haemangioma. In MEN2 the liver metastases exhibited disseminated mixed hyper- and hypo-enhanced lesions in CT-scans. Moreover, lesion calcifications are pathognomonic in MEN2. The main limitation of this study is the missing histopathological confirmation in the majority of cases.
In this retrospective imaging study, we were able to categorise and find a common CT pattern for hepatic lesions in patients with MEN-syndrome. In order to differentiate these lesions sufficiently, a combination of a 3-phasic CT-scan with US is required. Other liver specific imaging modalities (MRI, CEUS, SMS-PET/CT) should complement the diagnosis in individual cases.
Multiple endocrine neoplasia syndromes (MEN-syndrome) are rare complex heredity cancer syndromes (incidence rate in MEN1: 2–20/100,000 and MEN2: 1/350,000 ) with variable endocrine manifestation. Distant metastases in medullary thyroid carcinoma (MTC) occur in approximately 20% of the cases . Liver is a common site for distant metastases in both type of MEN-syndromes and it causes significant increases in morbidity and mortality rate [4–6]. Liver metastases (LM) are found in about 46%-93% of the patients with neuroendocrine tumors (NETs), including those with MEN1 . Distance metastasis of MTC depends on tumor stage and calcitonin (Ctn) level. Liver metastases are observed in 13% of MTC with a serum Ctn level more than 400pg/ml . These lesions are generally hypervascular and exhibit variable atypical imaging appearances, therefore, the differentiation between LM and other vascular hepatic lesions, especially hemangioma, is challenging [8–10]. State-of-the art 68Ga-DOTA-somatostatin analogue-PET/CT improves specificity in detecting the metastases of NET, especially in liver and lymph nodes; nevertheless this imaging technique is not yet a routine protocol for every follow-up in patients with long-term stable disease in Germany. The indications for new treatments (such as systematic therapy with tyrosine kinase inhibitors) are based on RECIST criteria, which cannot be accurately applied to PET. Moreover, its value in MTC is still disputable, for one due to missing correlations between PET positive findings (sensitivity) and calcitonin levels [11–14].
We retrospectively searched our databases for all cases with MEN-syndrome (type 1 or 2), who received radiological assessment from 2004–2014. The initial research yielded 43 patients. All cases were referred from a single specialised local endocrinological partner institution (FAR) and investigated at the DKFZ.
Twenty-five consecutive cases of genetically proven MEN-syndrome were evaluated in our study including 10 patients with MEN1 and 15 patients with MEN2. The mean age of all patients including 11 (44%) men and 14 (56%) women was 40 years (SD ±12). Moreover, the mean average follow-up-period of all cases was about 5±3 years (range: 6 months-12 years). In 40% of all cases multiple hepatic lesions (≥3 lesions) were observed (MEN1: 5/10 vs. MEN2: 9/15 patients), whereas only 16% had a solitary lesion (MEN1: 5/10 vs. MEN2: 6/15 patients).
MEN1- and MEN2-syndromes may include benign (parathyroid, pituitary) or malignant tumors, which can be secretory or non-secretory, but both syndromes are defined by the presence of NET in two or more different hormonal tissues .
Metastatic liver lesions in MEN patients are mostly multiple and very slow-growing thus very difficult to characterise in a prospective manner. In this cohort, we categorised our CT-findings in order to provide an index for diagnosing metastatic lesions in liver. LM in patients MEN1 commonly appear with a blurred arterial enhancement with a rapid wash-out in PVP. In MEN2 patients the LM were associated with high levels of Ctn and CEA and exhibited a disseminated mixed appearance including hyper- and hypo-enhanced lesions in CT scans. Lesional calcifications in MEN2 were pathognomonic. With US, a hyperechogenic pattern was the main feature in both syndrome types. There are less common findings in both syndromes, which mimic the classical haemangioma as well as other liver metastases. The essential key for differentiating LM in MEN syndrome from other focal hepatic lesions is a combined radiological examination including US, observation of contrast-behaviour in 3-phasic CT-scan as well as monitoring tumor markers. Furthermore, other liver specific and disease imaging modalities (MRI, CEUS, 68Ga-DOTA-somatostatin analogue-PET/CT) can complement the diagnosis in individual cases.