Evaluation of radiological prognostic factors of hepatic metastases in patients with non-functional pancreatic neuroendocrine tumors

https://doi.org/10.1016/j.ejrad.2013.06.017Get rights and content

Abstract

Purpose

There are different therapeutic options in non-functional well to moderately differentiated (G1 and G2) pancreatic neuroendocrine tumors (pNET) with unresectable hepatic metastases including systemic chemotherapy and novel molecular targeted therapies. Treatment with somatostatin analogs (SSA) as antiproliferative agents is optional. At initial diagnosis watchful waiting until tumor progression is a well-established approach. Goal of this study was to evaluate imaging features as potential prognostic factors predicting early tumor progression in order to select patients that might benefit from an earlier initiation of medical treatment.

Patients and methods

In 44 patients we correlated tumor grade, chromogranin A (CgA) levels, treatment with SSA and imaging features of hepatic metastases on contrast-enhanced multiphase CT and MR imaging with time to tumor progression (TTP) according to RECIST 1.0.

Results

In the total patient cohort none of the tested imaging features was found to be a statistically significant prognostic factor for TTP. Since treatment with SSA was associated with an increased TTP we also analyzed a subgroup of 30 patients not treated with SSA. In this subgroup of patients hypoenhancement of hepatic metastases during early contrast phases was found to be a negative prognostic factor for early tumor progression within 12 months (p = 0.039). The other evaluated parameters including hepatic tumor load, number of metastases, and presence of regressive morphological changes did not reveal significant results.

Conclusion

Hypovascularization of liver metastases from G1 and G2 pNET reflected by hypoenhancement during the early contrast phases seems to be associated with early tumor progression. In patients with hypoenhancing metastases repeated biopsy for reassessment of grading of these metastases, and early initiation of therapy should be considered.

Introduction

Neuroendocrine neoplasms (NEN) are a rare and heterogeneous group of malignancies that can arise from neuroendcrine cells of various locations in mostly the gastrointestinal tract, pancreas, and lung. Poorly differentiated NEN (G3) are referred to as neuroendocrine carcinomas (NEC) whilst well to moderately differentiated tumors (G1 and G2) are referred to as neuroendocrine tumors (NET) [1]. They can cause symptoms due to mass effects and due to hormonal secretion. The pancreas is amongst the more common sites of primary tumors with an annual incidence of about 0.32/100,000 [2]. Many patients present with metastatic disease at time of initial diagnosis and the presence of hepatic metastases is a negative prognostic factor [2], [3], [4].

Treatment recommendations depend mainly on tumor differentiation and extent of disease as well as on functional activity. In non-functional well to moderately differentiated (G1 and G2) pancreatic neuroendocrine tumors (pNET) surgical resection of hepatic metastases and primary tumor with curative intent is recommended where feasible. Since pNET have a variable natural course watchful waiting is a well established approach if metastases are unresectable, especially in G1 pNET. Somatostatin analogs (SSA) are considered optional in non-functional tumors. They were found to have disease stabilizing effects [5], [6], [7] but data from a placebo controlled trial in pNET are still pending (CLARINET study). It remains unclear if an early initiation of such treatment leads to an improved overall prognosis. Systemic chemotherapy should be initiated upon tumor progression [4]. As it is unpredictable whether a newly diagnosed patient will experience progressive disease (PD) in short term or remain stable, close surveillance by means of imaging is obligatory. Predictors of the individual course of the disease would be desirable in order to identify patients who might profit from early treatment initiation or intensification.

Goal of this study was to evaluate imaging features as potential prognostic factors predicting early tumor progression within twelve months in patients newly diagnosed with non-functional G1 and G2 pNET metastasized to the liver.

Section snippets

Total patient cohort

From the institutional database we identified patients who were newly diagnosed with hepatic metastases of non-functional G1 and G2 pNET between 2001 and 2011 and who had received no prior antiproliferative treatment other than SSA. Further inclusion criteria were the availability of CT or MR imaging with at least arterial and venous contrast phase performed at the initial time of diagnosis of hepatic metastases as well as close follow-up imaging valid for analysis according to the response

Patients and treatment

Forty-four patients newly diagnosed with hepatic metastases of non-functional pNET and without prior antiproliferative treatment other than SSA were included in this study. Twenty-three patients were female. The age range was 30–80 years. In 34 patients hepatic metastases were present at the initial time of diagnosis of the pNET. Ten patients had metachronous hepatic metastases occurring after 4.5 years on average (range, 0.6–7.3 years). Twenty-nine patients had lymphatic metastases, 10

Discussion

In this retrospective study of patients with non-functional G1 and G2 pNET with unresectable hepatic metastases, treatment with SSA was found to be associated with a prolonged TTP. Our study was not designed to analyze the effectiveness of treatment with SSA and therefore no treatment recommendations can be deduced from these results. However, this finding is consistent with previous studies describing mild antiproliferative effects of SSA in well differentiated NET leading to disease

Conclusion

In conclusion we found that in treatment-naive patients with non-functional pNET and unresectable hepatic metastases hypoenhancement of the metastases during early contrast phases is a negative prognostic factor for early tumor progression. Enhancement is probably associated with tumor vascularization and differentiation. The finding of hypoenhancement might encourage considering repeated biopsy of metastases, especially if histology is not recent or taken from the primary tumor. In addition

Disclosures

T.D. has acted as a speaker for Novartis. B.W. and M.P. have acted as speakers and advisers for Novartis. Both have received research funding by Novartis. The other authors have no conflicts of interest to disclose.

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      Like the primary lesions, nodal metastases are also typically hypervascular and more conspicuous on arterial phase. Liver metastases are also typically hypervascular in arterial phase; lesions with hypoenhancement in all phases suggest a poor prognosis.39 MR imaging is a more sensitive modality compared with CT scans for the detection of NET liver metastases.

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      Typically, disease recurrence, progression, or deficits in therapeutic efficacy are defined using an amalgamation of anatomic/morphologic and functional imaging interpolated with alterations in symptomatology and perturbations in biomarkers. Anatomic imaging using the Response Evaluation Criteria in Solid Tumors (RECIST) has well-documented limitations that include suboptimal reproducibility, insensitivity in the interpretation of disease responsiveness to targeted therapies, and relatively low discriminant indices in the identification of metastatic disease.18–20 Functional imaging with somatostatin receptor–based strategies, for example, 68Ga–somatostatin analog (SSA) PET/CT, has considerable value21 but limited spatial resolution (several millimeters for PET scanners), and partial volume effects constrain the ability to delineate small lesions.

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      The pathologic grade of NETs is defined by their mitotic index and Ki67 index. Our experience suggests that G1/G2 NETs are characterized by predominantly peripheral enhancement in the late arterial phase, while loss of this pattern indicates dedifferentiation and is seen in higher-grade NETs [21]. Our results show that the IR protocol (ASIR 40%) results in a 37.6% dose reduction without degrading diagnostic confidence in comparison to the standard full-dose scan via filtered back projection (FBP), which is consistent with reports in the literature [10,22–24].

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      Radiological Response Evaluation Criteria In Solid Tumors v1.1 (RECIST) criteria are insensitive for measuring treatment responses in these often “indolent” lesions.24 Response to therapies is rarely associated with early measurable (detectable) changes in tumor size and represents a substantial limitation in GEP-NEN management.25,26 The recognition of somatostatin receptors as key regulators of NEN function provided an effective therapeutic strategy in terms of secretory inhibition, symptomatic control, and quality of life improvement.27

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    1

    These authors contributed equally to this work.

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