- Top of page
- MATERIALS AND METHODS
- FUNDING SUPPORT
- CONFLICT OF INTEREST DISCLOSURES
In the current study, we retrospectively studied the relations of outcomes to clinical characteristics as well as histopathologic characteristics based on the 2010 WHO classification, including SSTR-2a scores, in 79 patients who had PNETs diagnosed histopathologically from 1988 through 2012. Univariate analysis demonstrated that a pancreatic tumor that measured ≥20 mm in greatest dimension, stage IV disease according to the TNM staging system as proposed by the AJCC/UICC, vascular invasion, NEC according to the 2010 WHO classification, and an SSTR-2a score of 0 were associated significantly with poor outcomes. On multivariate analysis, NEC and an SSTR-2a score of 0 were each independently related to poor outcomes.
Corleto et al reported the impact of the presence or absence of SSTR-2a gene expression on the outcomes of PNETs in 33 patients with well differentiated gastroenteropancreatic endocrine carcinomas. To our knowledge, however, no previous study has reported the clinicopathologic characteristics and outcomes from a large series of patients with confirmed diagnoses of primary PNETs. Somatostatin is a cyclic peptide that investigators incidentally discovered could potently inhibit growth hormone secretion from the pituitary gland. Somatostatin receptors are classified into 5 subtypes, and SSTR-2 is subclassified into 2 variants according to the presence or absence of splicing: SSTR-2a and SSTR-2b.[10, 11] SSTR-2a has been implicated in the inhibition of endocrine hormone secretion, the suppression of growth factor-induced cell cycle progression, and the induction of apoptosis.[11-13] Octreotide, a drug that binds with high affinity to SSTR-2a, was developed to take advantage of these effects. Recent studies have demonstrated the therapeutic usefulness of octreotide in patients with unresectable, well differentiated PNETs.[2, 3, 14]
In our study, SSTR-2a was positive in significantly higher proportions of NETG1 and NETG2 than in NEC. With regard to correlation between SSTR-2a expression and Ki-67 labeling index, SSTR-2a expression reportedly was significantly lower in tumors with a Ki-67 labeling index ≥2% or higher than in those with a Ki-67 labeling index <2%. Conversely, some investigators have observed no difference in the expression levels of somatostatin receptor subtypes between NET and NEC.[1, 15] Thus, these findings remain controversial. In the current study, an SSTR-2a score of 0 was a significant independent predictor of a poor outcome. This observation may be attributed to the finding that some patients with NEC, which carries an extremely poor prognosis, were positive for SSTR-2a. Moreover, SSTR-2a was negative in 10 of the 54 patients with NETG1 or NETG2, including 3 patients who died. Consequently, our study demonstrated that NEC and an SSTR-2a score of 0 were each independent prognostic factors. Corleto et al reported that tumors with a Ki-67 labeling index <2% that were positive for both SSTR-2 and SSTR-5 were associated with significantly better outcomes than tumors with a Ki-67 labeling index ≥2% that were negative for both SSTR-2 and SSTR-5. When groups of tumors were compared according to the presence or absence of SSTR expression, tumors that were positive for SSTR-2 and SSTR-5 were associated with slightly (but not significantly) better outcomes than those that were negative for SSTR-2 and SSTR-5. This may be attributed to the observation that approximately 50% of the patients in the study by Corleto et al had primary NETs in organs other than the pancreas and that well differentiated endocrine carcinomas were studied. Although an SSTR-2a score of 0 was an independent predictor of poor outcomes in our study, the hazard ratio was about 8 times higher in patients with NEC. To confirm our finding that negativity for SSTR-2 is strongly related to poor outcomes in patients with PNETs, further studies in larger numbers of patients are required.
Our results reconfirmed the usefulness of the TNM staging system and the 2010 WHO classification. Stage IV disease according to the TNM classification was not an independent poor prognostic factor on multivariate regression analysis, probably because stage IV disease was significantly more common among patients with NEC than among those with NETG1 or NETG2 (P < .01; Fisher exact test) and because considerable numbers of long-term survivors were included among the patients with stage IV disease who had NETG1 or NETG2. With regard to the 2010 WHO classification, however, NEC was associated significantly with poorer outcomes than other carcinomas, but outcomes did not differ significantly between NETG1 and NETG2. Recently, Hamilton et al reported that classifying NETG1, NETG2, and NEC on the basis of Ki-67 labeling indexes of <5%, 5% to 9%, or ≥9%, instead of the currently used WHO recommendation of <2%, 2% to 20%, or >20%, correlated more strongly with outcomes in patients with PNETs, suggesting that reassessment of staging criteria is warranted. Another problem is that the 2010 WHO classification does not clearly include vascular invasion, which is an extremely important biologic characteristic of tumor cells. In our study, vascular invasion was related significantly to poor outcomes. Further studies of larger numbers of patients should be performed to confirm this finding.
Ito et al recently reported the results from a large epidemiologic study of PNETs in Japan. Both the annual prevalence and the annual incidence of PNETs were higher in Japan than in Western countries. This finding may be attributed to excellent health check-up programs in Japan, particularly the routine use of abdominal ultrasonography on a trial basis and easy access to advanced imaging examinations (eg, endoscopic ultrasonography, computed tomography, and magnetic resonance imaging). This medical environment is enabled by the National Health Insurance system in Japan. In our study, 42% of the 79 patients were asymptomatic. One of the characteristics of our hospital is that few patients have functional tumors or tumors associated with MEN-1. This is attributed to the observation that patients with functional tumors and classic hormone-related symptoms do not present at our hospital, because there is no department of endocrinology. The resection rate in our study was 75%, which was lower than that in the study by Ito et al. This lower resection rate suggests that many of our patients had nonfunctional tumors with a risk of metastasis and that most functional tumors were insulinomas, which have a low risk of metastasis.
In patients with PNETs, the main treatment goal is total surgical resection and control of tumor growth. At the time of diagnosis, about 20% of patients already have metastases to other organs. In addition to surgical resection to reduce tumor volume and local treatment, such as radiofrequency ablation and transcatheter arterial chemoembolization, medical therapy also plays an important role in the management of PNETs. With recent advances in molecular biology, high expression levels of multiple growth factors and their receptors have been demonstrated in NETs. Clinical trials of molecular-targeted agents that inhibit the proliferative activities of these factors and receptors have been conducted.[18, 19] Representative molecular-targeted agents include sunitinib, a tyrosine kinase inhibitor, and everolimus, a mammalian target of rapamycin (mTOR) inhibitor. Both of these inhibitors have produced good outcomes, suggesting that many patients with well differentiated PNETs would benefit from treatment. However, a regimen for NEC remains to be established, and outcomes remain extremely poor. Currently, combination chemotherapy, including a platinum compound, is used to treat NEC, similar to small cell lung cancer, which has similar pathologic and clinical features. Unfortunately, satisfactory results have not been obtained.[20, 21] In our study, SSTR-2a was positive in an appreciable proportion of patients with NEC and was associated with extremely poor outcomes. Therefore, future studies should investigate whether patients who have SSTR-2a-positive NEC are sensitive to somatostatin analogues.
Our study had several important limitations. It was a retrospective clinical trial of a relatively small group of patients with PNET who were treated at a single hospital. There were extreme imbalances between the number of patients with NEC versus those with NETG1 or NETG2, as well as between the number of patients with an SSTR 2A of score 0 versus those with scores from 1 to 3. Because our study period was approximately 24 years, therapy evolved considerably, and patients who received treatment in the early part of the study did not receive somatostatin analogues or molecular-targeted agents, which are now widely used to treat well differentiated tumors, NETG1, and NETG2. Such differences in treatment most likely had an appreciable impact on patient outcomes. Ideally, a large, multicenter, prospective study should be performed within a well defined period. Another limitation was that we used immunostaining to evaluate SSTR-2a expression. Evaluation of SSTR-2a mRNA expression would have been more quantitative, objective, and ideal. However, the results of immunohistochemical analysis are considered adequate. Evaluation of SSTR expression by indium-111 pentetreotide scintigraphy (octeroscan) would have been desirable, but this technique is not widely used as an examination in Japan, because it is not covered by the Japanese National Health Insurance system. Therefore, we did not use octreoscan imaging.
In our study, not only NEC but also an SSTR-2a score of 0 was a significant independent predictor of poor outcomes, suggesting that the evaluation of SSTR-2a may be useful for selecting treatment regimens and predicting outcomes in the future. Because a considerable proportion of patients with NEC have SSTR-2a–positive tumors, further analyses of the usefulness of somatostatin analogues are warranted in patients with these tumors.