Annals of Oncology Advance Access originally published online on January 21, 2008
Annals of Oncology 2008 19(5):903-908; doi:10.1093/annonc/mdm552
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gastrointestinal tumors |
Prognostic factors at diagnosis and value of WHO classification in a mono-institutional series of 180 non-functioning pancreatic endocrine tumours
1 Department of Surgical and Gastroenterological Sciences
2 Department of Medicine and Public Health
3 Department of Pathology, University of Verona, Verona
4 Department of Digestive and Liver Disease, II School of Medicine, University ‘La Sapienza’, Rome, Italy
* Correspondence to: Dr M. Falconi, Chirurgia Generale B, Dipartimento di Scienze Chirurgiche e Gastroenterologiche, Policlinico ‘GB Rossi’, P.le LA Scuro 10, 37134 Verona, Italy. Tel: +39-045-8124553; Fax: +39-045-8201294; E-mail: massimo.falconi{at}univr.it
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Abstract |
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Background: Non-functioning pancreatic endocrine tumours (NF-PETs) are an aggressive gastroenteropancreatic neoplasm. The present study assessed survival, value of World Health Organisation (WHO) classification and prognostic utility of clinicopathological parameters at diagnosis.
Patients and methods: From 1990 to 2004, 180 patients with NF-PETs were entered in a prospective database, and predictors of prognosis were tested in uni- and multivariate models.
Results: There were 25 (14%) benign lesions, 38 (21%) neoplasms of uncertain behaviour, 100 well-differentiated carcinomas (56%) and 17 poorly differentiated carcinomas (9%). Radical resection was possible in 93 cases (51.6%). Overall 5-, 10- and 15-year survival rates were 67%, 49.3% and 32.8%, respectively, and were significantly higher in radically resected patients (93%, 80.8% and 65.2%, respectively; P < 0.00001). By multivariate analysis, poor differentiation [hazard ratio (HR) 7.3; P = 0.0001], nodal metastases (HR 3.05; P = 0.02), liver metastases (HR 3.29; P = 0.003), Ki-67 >5% (HR 2.5; P = 0.012) and weight loss (HR 3.06; P = 0.001) were significantly associated with mortality.
Conclusion: This study confirms the good long-term survival of patients with NF-PETs and the prognostic value of WHO classification, liver metastases, poor differentiation, Ki-67, nodal metastases and weight loss. These latter two parameters have a prognostic value similar to that of liver metastases and Ki-67.
Key words: pancreatic endocrine tumours, pancreatic neoplasm, pancreatic surgery, prognostic factors, survival
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introduction |
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TopAbstractintroductionpatients and methodsresultsdiscussionfundingAcknowledgementsReferences |
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Pancreatic endocrine tumours (PETs) are clinically defined as functioning (F-PET) or non-functioning pancreatic endocrine tumour (NF-PET) depending on the presence of symptoms due to hormonal hypersecretion. According to the World Health Organisation (WHO) classification, the vast majority of both F-PET and NF-PET are classified as well-differentiated endocrine neoplasms that may be either benign or malignant [1]. The latter are characterised by the presence of invasion and/or metastases. It is widely recognised that NF-PET represents the most aggressive subset among gastroenteropancreatic endocrine tumours [2–8].
During the last few years, the proportion of patients with NF-PET diagnosed has progressively increased and represent up to one-half of clinically observed PETs [1]. In high-volume centres, the proportion of NF-PETs may reach 80% of cases [3, 9, 10]. In spite of this, limited data are available on prognostic factors and long-term survival of NF-PET as only a few studies have addressed these issues in well-characterised clinical series [11–15]. Most studies have investigated single prognostic parameters in heterogeneous series of patients with endocrine tumours originating from different anatomical sites and were composed of both functioning and non-functioning neoplasms with various histological subtypes [2, 3, 16, 17]. Moreover, the clinical validation of the WHO classification in a large series of NF-PET is still lacking [5].
The present study was carried out on a series of 180 sporadic NF-PET observed at a single institution in order to assess: (i) long-term survival, (ii) the value of WHO classification and (iii) the prognostic utility of clinical and pathological parameters at diagnosis.
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patients and methods |
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TopAbstractintroductionpatients and methodsresultsdiscussionfundingAcknowledgementsReferences |
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From 1990 to 2004, all consecutive patients suffering from sporadic NF-PET observed in our institution were entered in a prospective database. A non-functioning tumour was defined by the lack of any clinical syndrome due to excess hormonal secretion, independently of laboratory data [18]. All patients with MEN 1 syndrome (n = 5) or von Hippel–Lindau disease (n = 2) diagnosed by family history and with a confirmed genetic mutation were excluded from the study. Patients with tumours arising from the papilla of Vater (n = 8), bile duct (n = 1) or the duodenum (n = 2) were also excluded.
All patients underwent a routine medical evaluation that included clinical, laboratory and imaging assessments. From 1998, standard laboratory analysis included chromogranin A (evaluated by IRMA SCHERING-CIS®, normal value (n.v.) <98 ng/ml), neuron-specific enolase (NSE, n.v. <12.5 ng/ml) and CA 19.9 (n.v. <25 U/ml). Tumour staging was carried out by conventional imaging procedures including ultrasonography, computed tomography and/or magnetic resonance imaging. From 1998, all patients also underwent somatostatin receptor scintigraphy (Octreoscan®) as part of their routine work-up (n = 107).
Follow-up was updated yearly or at shorter intervals as deemed necessary, and the last follow-up was in 2006.
pathological assessment
Diagnosis of PET was on the basis of conventional histological and immunohistochemical examinations (chromogranin A, synaptophysin and NSE) of surgical or biopsy specimens. All cases were reviewed and classified according to the criteria of the WHO [1] based on the WHO 2004 classification. The WHO classification for PETs divides well-differentiated endocrine neoplasms from carcinomas on the basis of gross local invasion and/or the presence of metastases. Well-differentiated endocrine tumours were further divided into those with benign or uncertain behaviour on the basis of size (<2 or 
2 cm), number of mitoses/high power field or percentage of Ki-67-positive cells (cut-off value 
2 or >2%) and the presence or absence of angio- and/or perineural invasion. High-grade neoplasms with overt malignant behaviour were classified as poorly differentiated endocrine carcinomas [1].
treatment strategy
Whenever possible, radical resection was accomplished, also resecting nearby organs (stomach, colon, kidney and adrenal gland), vessels or liver metastases. If radical resection was not achievable due to local infiltration, palliative surgical bypasses (gastric and/or biliary) were carried out in the presence of obstructive symptoms. In the presence of unresectable liver metastasis, debulking or palliative procedures were carried out only when the primary tumour or at least 90% of liver tumour burden was resectable.
Antitumoural treatment has changed over the years, but up-to-date guidelines have been generally followed as detailed elsewhere [19]. Advanced poorly differentiated carcinomas underwent chemotherapy on the basis of cisplatin plus etoposide. Patients suffering from well-differentiated carcinomas with Octreoscan®-positive disease underwent therapy with somatostatin analogues following diagnosis. Whenever the residual or/and recurrent disease was limited to the liver, ablative therapies were considered such as radiofrequency ablation and trans-arterial chemoembolisation, as previously reported [19, 20]. In well-differentiated carcinoma with diffuse, Octreoscan®-negative disease, systemic chemotherapy with streptozotocin, 5-fluorouracil (5-FU) or doxorubicin were adopted.
When progression occurred, defined according to previously described WHO criteria [21], second and third lines of therapy, commonly on the basis of chemotherapy with streptozotocin, 5-FU or doxorubicin, were adopted. From 2003, in Octreoscan® strongly positive carcinomas, second line therapy was on the basis ofpeptide receptor radionuclide therapy (PRRT). This latter was considered as first line starting from 2003 in high-burden carcinomas with positive scintigraphy. For well-differentiated carcinomas, adjuvant treatment was never carried out.
statistical analysis
Clinical (sex, age, clinical symptoms at diagnosis and laboratory data), pathological (size, nodal or liver involvement, Ki-67 value and WHO classification) and surgical/oncological variables were analysed. Distributions of continuous variables are reported as median and interquartile range (IQR) (25th and 75th percentiles). Categorical variables are presented as numbers and percentages.
Comparison between the two groups (alive or disease-related deaths) was carried out using a Student's t-test, or a Mann–Whitney U test, for continuous variables. Qualitative data were compared with a chi-square test with Yates' correction and a Fisher's exact test when necessary. The main outcome was survival after diagnosis. Follow-up time, in survival analysis, was limited to 180 months. Survival data were analysed using the Kaplan–Meier function and log-rank test. A Cox proportional hazards model was used to evaluate significant 15-year mortality predictors. All P values were two sided and considered significant when <0.05.
For analysis of prognostic factors, resection and antitumoural therapies were excluded since they were related to both the extent of disease and degree of differentiation.
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results |
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study population
One hundred and eighty patients, 92 males (51.1%) and 88 females (48.9%), entered the study. At diagnosis, the median age was 58 years (IQR 49–66 years). The presence of abdominal pain was present in 94 (52.2%) patients, weight loss in 60 (33.7%), while an incidental diagnosis was reported in 55 cases (30.5%). Other presenting symptoms were anorexia in 28 patients (15.6%), jaundice or intestinal symptoms in 23 (12.8%), abdominal mass in 13 (7.3%), vomiting in 14 (7.8%) and bleeding in six (3.4%) patients. A previous benign or malignant neoplasm was diagnosed in 28 patients (prostate in five cases, breast in four, colon in three, bladder, ovarian, thyroid in two and other sites in 10 cases). In 50% of patients with a previous neoplasm, diagnosis of NF-PET was incidental.
The tumour was located in the head of the pancreas in 88 (48.9%) patients and in the body–tail in 92 cases (51.1%). At diagnosis, the median size of the primary tumour was 30 mm (IQR 20–54 mm). Eighty-seven patients had no metastases at diagnosis, while 34 (18.8%) showed nodal and 59 had (32.7%) extranodal metastases. Among the latter patients, the disease was extrahepatic in four cases (two bone, one breast and one lung). The proportion of patients with liver and/or nodal metastases did not change before and after the routine introduction of Octreoscan®.
According to WHO classification, there were 25 benign tumours (14%), 38 neoplasms with uncertain behaviour (21%), 100 well-differentiated carcinomas (56%) and 17 poorly differentiated carcinomas (9%).
treatments
One hundred and forty-eight (82.2%) patients underwent surgery; radical resection was achieved in 93 cases (51.6%), which was achieved by extending the resection to the liver in two patients, the colon in two, the stomach in one and the kidney in another case. Major vascular resections were carried out in eight patients. In addition, 19 (10.5%) patients had resection of the primary tumour as debulking. Considering the entire patient population, there were 45 distal pancreatectomies, 39 pancreaticoduodenectomies and 28 parenchyma-sparing resections (14 enucleations and 14 middle-pancreatectomies).
A surgical bypass was carried out in 20 patients (biliary in six, digestive in five, both in eight and in one patient pancreatic derivation). In 16 cases, the intervention was limited to laparotomy/laparoscopy. In the surgical series, only one patient (0.5%) died, which was due to a pulmonary embolism after explorative laparotomy.
First-line medical treatment at diagnosis or recurrence was generally on the basis of somatostatin analogues, which were administered in 73 of 98 (74.4%) patients who underwent medical therapy. In 13 cases, it was associated with chemotherapy and in seven cases with interferon. Systemic chemotherapy alone was carried out in 18 patients. In 14 patients, unresectable liver metastases were treated by ablative therapies, 12 of which in association with somatostatin analogues. Furthermore, seven patients received PRRT analogues.
None of the benign endocrine tumours were submitted to antitumoural treatment, although it was carried out in 100% of poorly differentiated carcinomas, 80% of well-differentiated carcinomas and 5% of neoplasms with uncertain behaviour. Moreover, none of the tumours judged as unresectable at diagnosis became resectable following chemotherapy.
survival analysis
The median follow-up period was 43.1 months (range 0.4–196). Overall median survival was 116.4 months [95% confidence interval (CI) 65.2–164.7] with a 5-, 10- and 15-year survival rate of 67%, 49.3% and 32.8%, respectively, following diagnosis. One hundred and six (58.8%) patients were still alive at the end of follow-up.
No differences in survival were observed between the 68 unresected patients (5-year survival 37.3%; 10-year survival 17.4%; median 30.4 months; 95% CI 16.4–44.4) and those undergoing palliative resection (n = 19) (5-year survival 47%, 10-year survival not reached; median 57.8 months; 95% CI 6.7–108.9) (P = 0.81). For the 93 radically resected patients, the median survival was not reached (P < 0.00001) and the 5-, 10-, and 15-year survival rates increased to 93%, 80.8% and 65.2%, respectively. The Kaplan–Meier survival curves are shown in Figure 1.
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Statistically significant survival rates (P < 0.00001) were observed between patients with residual disease submitted to further antitumoural treatment (5-year survival 40.6%, 10-year survival 13.6%; median 60.8 months; 95% CI 44.4–77.1) and those that were not (5-year survival 89.5%, 10-year survival 78%; median 149.8 months; 95% CI 136.1–163.6).
In the 34 patients with nodal involvement (N1) but no liver metastases (M0), the 5-year survival rate was 49.4% (median 58.9 months, 95% CI 29.5–88.3), while in the 59 patients with liver metastases (Nx, M1) was 40% (median 39.5 months; 95% CI 11.3–67.7) (P = 0.1). The Kaplan–Meier survival curves according to these parameters are shown in Figure 2. No statistical significant differences were observed in the survival analysis before and after the routine use of Octreoscan®.
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All the 25 patients with benign neoplasms are still alive and free of disease at the time of writing. Two patients with uncertain behaviour neoplasms died. These included one patient submitted to pancreaticoduodenectomy with 15 negative lymph nodes, but angioinvasion, and another that was not submitted to radical resection due to intraoperative haemorrhage (both observed in the first 5 years of the present series). All the 17 patients with poorly differentiated carcinoma died within 3.5 years (median 11.8 months, 95% CI 5.5–18.1 months). The median survival in the 100 patients with well-differentiated carcinomas was 69.3 months (95% CI 51.6–87) with 3-, 5- and 10-year survival rates of 66.8%, 55.6% and 28.8%, respectively. Figure 3 shows the survival curves according to the WHO classification.
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predictors of mortality at diagnosis
Table 1 summarises the univariate analyses of death (comparison of death rates at 15 years) and survival determinants (comparison of cumulative survival rates). The presence of other neoplasms in previous medical history showed an apparent correlation at univariate analysis, but due to the low number of cases was excluded from multivariate analysis (n = 28, 16.3%). As for laboratory parameters, there were no correlations with chromogranin A (P = 0.26). Significant association between 15-year mortality was found with abnormal values of CA 19.9 and NSE (CA 19.9 P = 0.0017 and NSE P = 0.0023, respectively). Sex, age, site, family history for any cancer and diabetes were not associated with survival.
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In multivariate analysis, the following parameters were significantly associated with disease-related mortality: poor differentiation [hazard ratio (HR) 7.3; 95% CI 3.13–17.05; P = 0.0001], nodal metastases (HR 3.05; 95% CI 1.92–7.04; P = 0.02), liver metastases (HR 3.29; 95% CI 1.5–7.20; P = 0.003), Ki-67 >5% (HR 2.50; 95% CI 1.22–5.09; P = 0.012) and weight loss (HR 3.06; 95% CI 1.58–5.9; P = 0.001) (Table 2). Size with a HR of 1.01 (95% CI 0.99–1.01) was not significant (P = 1.152). Likewise pain was not confirmed as a significant predictor in multivariate analysis.
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discussion |
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TopAbstractintroductionpatients and methodsresultsdiscussionfundingAcknowledgementsReferences |
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Our study analysed 180 patients with sporadic NF-PET observed in the same centre during a 14-year period. In this series of cases, the median overall disease-related survival was 9.7 years, thus confirming the generally long-term survival of NF-PET. The WHO classification also provided a good estimation of prognosis as shown by Kaplan–Meier survival curves. Moreover, between the clinical and pathological factors recorded at diagnosis, multivariate analysis selected five parameters that showed prognostic value: weight loss, nodal metastases, liver metastases, poor differentiation and a Ki-67 >5%. The novel findings of our study include the demonstration that nodal metastasis and weight loss are independent prognostic factors and, importantly, that they have a prognostic significance similar to liver metastasis and Ki-67. In fact, all the aforementioned four parameters are associated with a similar high risk of death.
The 5-year survival rate of 67% observed in our series is similar to that reported in other NF-PET series, which ranges from 50% to 65% [11–15] (Table 3). Only one study reported a 43% survival rate, but this lower rate can be explained by the different characteristics of the population under study [14]. In fact, it was composed mostly of patients with metastatic (61.3%) and unresectable disease (72.8%), which is nearly twice that in the present study (32.7% and 48.4%, respectively). The WHO classification efficiently discriminated among tumours with different clinical behaviour. All patients with benign neoplasms are alive, while 2 of 38 neoplasms with uncertain behaviour died of disease; the median survival of well-differentiated carcinomas was 69.3 months, while it was 11.8 months for poorly differentiated cancers.
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Regarding the different clinicopathological factors selected by univariate analysis, including e.g. pain and tumour size, only five were selected by multivariate analysis as independent factors correlating with survival: nodal metastases, liver metastases, poor differentiation, Ki-67 and weight loss. The presence of distant metastases and nodal involvement have been already reported as unfavourable factors in NF-PET patients but, as for nodal metastases, only using univariate analysis [2, 15, 16]. The independent value of both liver and nodal metastases in NF-PET has been assessed for the first time in the present study. Interestingly, both parameters are associated with a risk of death that is three times higher. This increased risk of liver metastases is lower than the HR of 8.3 reported by Madeira et al. [2], but with a 5-year survival rate of 40%. It could be argued that, since the observation period is quite long, major changes in the diagnosis of PET have occurred during the observation period, especially for the use of Octreoscan®. For example, the classification of tumours may have been different before and after Octreoscan was routinely employed, and some metastases may have been missed at diagnosis. In this latter regard, however, no differences were found in survival in this large cohort before and after the introduction of Octreoscan®. Poor differentiation of the neoplasm was the most significant determinant of survival, with a HR of 7.3. All patients with poorly differentiated carcinomas died within 3.5 years after diagnosis (median 11.8 months) and only 23.5% were resectable at diagnosis. While this result may appear more favourable than those previously reported, this dismal survival widely justifies the fact that WHO classification considers these tumours as a separate group [2, 22–24].
The present study also confirms the prognostic value of the proliferative index, evaluated by Ki-67. Other studies already reported the value of this parameter in NF-PET with a different cut-off value of >2% [22] or 5% [24, 25]. In our study, between all tested cut-off values, i.e. 2%, 5% and 10%, only tumours with a Ki-67 >5% have unfavourable prognosis in both univariate and multivariate analyses. With regards to clinical parameters, only weight loss correlated with the presence of more aggressive disease.
An additional advantage of our study resides in the fact that all the clinical and pathological parameters were recorded at the time of diagnosis and that we did not include treatments in the analysis of possible prognostic factors. In fact, while it is obvious that radical surgery is the only chance for cure at present, with a 5-year survival rate of 93%, it is also obvious that the surgical choice is the direct result of the stage of the disease at diagnosis. Similarly, antitumoural therapies were excluded from the analysis as they are chosen according to both the extent and degree of differentiation of the disease [19]. This is only feasible in a mono-institutional series in which a homogeneous treatment strategy is ensured. Notably, all published series that considered resection and medical therapies identified these factors as significant at multivariate analysis [2, 3, 14, 16, 17].
In conclusion, our study indicates that the evaluation of nodal metastasis and weight loss should be included along with liver metastasis, Ki-67 index and degree of differentiation in the prognostic assessment of NF-PET at diagnosis. These parameters contribute to the formation of an accurate prognostic assessment, which is of paramount importance for therapeutic decision making.
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funding |
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TopAbstractintroductionpatients and methodsresultsdiscussionfundingAcknowledgementsReferences |
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Fondazione CaRiVerona; European Community FPVI MolDiagPaCa; Ministero Università e Ricerca e Ministero Salute; Associazione Italiana Ricerca Cancro; Fondazione Giorgio Zanotto.
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Acknowledgements |
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TopAbstractintroductionpatients and methodsresultsdiscussionfundingAcknowledgementsReferences |
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The authors report no conflicts of interest.
Received for publication August 27, 2007. Revision received November 2, 2007. Accepted for publication November 5, 2007.
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References |
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