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Journal of Clinical Oncology, Vol 25, No 35 (December 10), 2007: pp. 5609-5615 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.12.9809 Determining Prognosis in Patients With Pancreatic Endocrine Neoplasms: Can the WHO Classification System Be Simplified?
From the Departments of Surgery, Pathology, and Epidemiology/Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY Address reprint requests to Peter J. Allen, MD, Department of Surgery, Memorial Sloan-Kettering Cancer Center, Howard 1223, 1275 York Ave, New York, NY 10021; e-mail: allenp{at}mskcc.org
Purpose The WHO classification for well-differentiated pancreatic endocrine neoplasms (PENs) incorporates both stage and grade. This study compares the prognostic value of a simplified staging and grading system with the WHO system in a large single-institution study.
Patients and Methods A prospective database (1982 to 2005) identified 183 patients who underwent operative treatment for PENs. Tumors were staged (< 2 cm primary,
Results Median age of the 183 patients was 56 years, and 53% were women. Median follow-up time was 44 months (range, 1 to 226 months). Classification identified 28 patients (15%) with WHO 1.1 disease, 74 (41%) with 1.2 disease, and 81 (44%) with 2.0 disease. Classification by stage identified 35 patients (19%) with tumors less than 2 cm, 96 (52%) with tumors Conclusion Accurate prognostic information can be obtained by combining tumor size and metastases with simple grading information based on necrosis and mitotic rate.
Pancreatic endocrine neoplasms (PENs) are a group of uncommon tumors that exhibit a broad spectrum of biologic aggressiveness. The incidence of PENs in the United States is estimated to be four cases per million individuals per year, with 5-year survival rates between 44% and 71%.1-3 Factors predictive of outcome have been difficult to establish because of the uncommon nature of these neoplasms. Some have reported that functional tumors, defined by the symptoms produced from the excess hormone secreted, have a better prognosis than nonfunctional tumors.4 However, the differences in outcome between functional and nonfunctional PENs may be secondary to the presumed earlier presentation of functional tumors (especially insulinomas, which are the most prevalent), rather than an inherent difference in biologic aggressiveness.5 Multiple studies have attempted to develop staging and grading systems to better define prognosis.1,4,5 These studies have often defined benign or malignant PENs based on stage-related criteria such as tumor size and the presence of nodal or distant metastases.1,4 Phan et al,4 in a report of 125 patients with PENs, defined malignant PENs as those with nodal or distant metastases at the time of surgery or the development of such metastases during follow-up. Other reports, including one from our own institution, have suggested that tumor grade is also a valuable prognostic tool for patients with PENs.5 Grade has been applied to pulmonary endocrine tumors as well as PENs and is based on histopathologic criteria such as the mitotic rate and the presence of necrosis.6 The current WHO classification system uses both stage-related criteria (size and presence of metastases) and grade-related criteria (mitotic rate, perineural invasion, angioinvasion, and Ki-67 proliferative index) to predict outcome. Because this approach includes the majority of well-accepted pathologic prognostic factors, it has been presumed to be more accurate in predicting outcome, but its clinical application is cumbersome. The multiple grading parameters may make it difficult to reliably reproduce this system between pathologists and institutions. By combining both stage-related and grade-related parameters, the WHO system does not allow separate prognostic evaluation within a given group (eg, for metastatic PENs).
The primary aim of this study was to evaluate the separate prognostic accuracy of tumor stage and tumor grade in a large group of patients with PEN treated at a single institution. Tumor stage was based on the schema put forth by WHO (< 2 cm primary,
Review of Memorial Sloan-Kettering Cancer Center's (MSKCC) pancreatic database (1982 to 2005) identified 183 patients who had undergone resection of a primary well-differentiated PEN. PENs measuring less than 0.5 cm in diameter (microadenomas) and tumors with more than 10 mitoses per 10 high-powered fields (HPF) and widespread necrosis (poorly differentiated endocrine carcinomas) were excluded. Patients who underwent resection before 1998 (n = 69) have been previously reported in the study by Hochwald et al.5 The study was approved by MSKCC's Internal Review Board. There are no conflicts of interest. Clinicopathologic variables were confirmed by chart review. Patient factors included sex, age, and symptoms at presentation. Treatment-related factors included the date and type of operation, operative blood loss, and length of stay. Disease-related factors included the date and location of recurrence, treatment of recurrence, and survival as measured to the time of last follow-up or death. Patient status at last follow-up was documented as no evidence of disease, alive with disease, dead of disease, dead of other cause, or postoperative death, which was defined as death within 30 days of surgery. Histopathology was reviewed by two pathologists (L.H.T. and D.S.K.). All patients had hematoxylin and eosin slides available for review, and some had immunohistochemical stains previously performed. Pathologic information recorded included the tumor diameter, operative margin (positive or negative), presence of vascular or perineural invasion, presence of tumor necrosis, and number of mitoses/50 HPF. Nodal status was also recorded, as well as the presence or absence of any distant metastatic disease at presentation.
Tumors were categorized by the WHO criteria, by stage, and by grade. The current WHO classification system includes well-differentiated tumors with benign behavior (1.1: contained to the pancreas, no angioinvasion or perineural invasion, < 2 cm, < two mitoses/10 HPF, and < 2% Ki-67) or uncertain behavior (1.2: contained to the pancreas, angioinvasion or perineural invasion,
Tumors were individually staged and graded using our simplified schema. Stage was determined by the size of the tumor (< 2 cm or Clinicopathologic variables were assessed for their association with recurrence and survival. Patients not rendered free of gross disease (distant metastases) at the time of resection were not included in recurrence-free survival (RFS) estimates. RFS and disease-specific survival (DSS) were calculated using the Kaplan-Meier method, and comparisons were made using the log-rank test. Significance was defined as P < .05. The strength of the three prognostic systems (WHO, stage, and grade) was then assessed using the concordance index (CI).7,8 CI is a probability that ranges between 0 and 1. A CI of 0.5 is what you would achieve by pure chance (coin flip), whereas 1.0 signifies perfect discrimination between the two tests. This type of analysis has been used in the validation of disease-specific nomograms.
Between 1982 and 2005, 183 patients with PENs were treated at MSKCC. Patient, tumor, and treatment-related data are listed in Table 1. The median age at presentation was 56 years, and 53% of the patients (n = 98) were women. The treatment of the primary tumor involved pancreatic resection in 88% of the patients (n = 164) and enucleation in 12% of the patients (n = 22). Peripancreatic lymph nodes were pathologically assessed in 70% of pancreatic resection specimens (n = 117) compared with only 18% (n = 22) when enucleation was performed. Lymph nodes were not identified in 37 (83%) of 43 patients who underwent spleen-preserving distal pancreatectomy. For patients without identifiable metastatic disease who had pathologic nodal assessment (n = 107), the size of the primary tumor was not associated with the presence of nodal metastases (mean diameter: 4.8 cm for N0 v 4.7 cm for N1; P = .96), and five (26%) of 19 patients with tumors  2 cm had positive nodes.
Functional tumors were present in 29% of patients (n = 53), with more than half being insulinomas (n = 29). These patients presented with smaller tumors that were less likely to have nodal metastases or perineural or lymphovascular invasion (Table 2). There was no difference between these groups with respect to the average number of mitoses, presence of necrosis, or DSS.
Median length of follow-up in this study was 44 months (range, 1 to 226 months). Median DSS time and 5-year DSS rate for all patients in this study were 120 months and 87%, respectively. WHO classification, stage, and grade were the only patient, tumor, or treatment-related variables associated with RFS and DSS (Table 3).
Recurrence was documented in 30 (18%) of 166 patients who were initially rendered free of gross disease. Median time to first recurrence was 32 months. The most common site of first recurrence was in the liver (22 of 30 patients; 72%). Other sites of initial recurrence included the retroperitoneal lymph nodes (n = 6), bone (n = 2), ovary (n = 1), and stomach (n = 1). Treatment of the initial recurrence included hepatic artery embolization in 10 patients, hepatic resection in five patients, and systemic treatment (cytotoxic chemotherapy and/or octreotide) in eight patients. Median postrecurrence survival time was 32 months. Classification of tumors by the WHO system identified 28 patients (14%) with WHO 1.1 disease, 74 patients (41%) with 1.2 disease, and 81 patients (44%) with 2.0 disease. Within the group of 81 patients with WHO 2.0 disease, 35 patients presented with nodal metastases, seven patients presented with distant metastases, 10 patients presented with both distant and nodal metastases, and 29 patients presented with extrapancreatic extension without identifiable regional or distant disease. Within the group of WHO 2.0 patients, DSS was different between those who had metastatic disease (nodal or distant) and those who were classified as WHO 2.0 based on extrapancreatic extension alone (5-year DSS rate, 90% v 65%, respectively; P = .05). The WHO classification system was associated with both RFS and DSS (Figs 1A and 1B). Within the group of patients who presented with 1.1 and 1.2 disease, however, the RFS and DSS were similar (5-year RFS: 100% for 1.1 v 92% for 1.2; P = .14; 5-year DSS: 100% for 1.1 v 98% for 1.2; P = .23).
Stratification of patients by stage identified 35 patients (19%) with tumors less than 2 cm without evidence of metastatic disease, 96 patients (52%) with tumors  2 cm without metastases, and 52 patients (29%) with nodal or distant metastatic disease. The 29 patients within the WHO 2.0 group because of extrapancreatic extension but without metastatic disease were downstaged into the 2 cm group. These patients had larger tumors than other 2 cm stage patients without extrapancreatic extension (mean tumor size, 7.2 v 4.9 cm, respectively; P = .003). Stage also had prognostic value with respect to both the risk of recurrence and death from disease (Figs 1C and 1D). Stage at presentation was also associated with recurrence and survival in the group of patients who presented with nonmetastatic disease (5-year RFS rate: 100% for < 2 cm v 78% for 2 cm; P = .02; 5-year DSS rate: 100% for < 2 cm v 88% for 2 cm; P = .02). Tumor grade could be determined in 98% of patients (n = 180), with a median of 1 mitosis/50 HPF (range, 0 to 36 mitoses/HPF) and necrosis in 19 patients (16%). Using our grading system, 102 patients (56%) had low-grade tumors, and 78 patients (42%) had intermediate-grade tumors. Only two patients had documented necrosis and less than 2 mitoses/HPF. Patients with intermediate-grade tumors had significantly higher rates of recurrence and significantly decreased DSS (Fig 1E).
Tumor grade and stage were associated. Earlier stage tumors were more likely to be low grade (< 2 cm, 83%; The strength of these prognostic systems was then assessed by the CI. The CI of the WHO system was 0.72. The CI of the staging system alone was 0.71. The CI of grade alone was 0.66. When staging and grading were combined, the CI was 0.76. The DSS probabilities for this combined grading and staging system are presented in Table 4.
This study describes the presentation, treatment, and outcome of a large group of patients who underwent operative treatment for a PEN at a single institution. WHO classification, tumor stage, and tumor grade were associated with survival. The prognostic accuracy of tumor stage alone was equivalent to that of the WHO classification system (CI, 0.71 v 0.72, respectively). The most accurate measurement of prognosis in this group of patients was obtained when the simplified staging and grading criteria were combined. Given the relatively slowly progressive nature of this disease and general inability to cure patients who suffer recurrence, examination of the RFS provides an important method to assess prognostic variables. Overall RFS and DSS results of this study were similar to other smaller series reported in the literature (Table 5). Overall survival results were inversely proportional to the percentage of patients with metastatic disease. Studies of patients with predominantly node-negative nonmetastatic disease have reported 5-year survival rates of approximately 80% compared with 43% to 44% when the greatest percentage of patients presented with synchronous nodal/distant metastases.9,10
Functional tumors have been thought to have a better prognosis because they are often identified at an earlier stage.4 Although the 5-year DSS was not statistically different between patients with functional and nonfunctional tumors (88% v 84%, respectively), functional tumors presented as smaller tumors that were less likely to have spread to regional lymph nodes. Grade-related variables of mitotic rate and necrosis were not different between functional and nonfunctional tumors. These findings support the hypothesis that reported differences in the outcome between patients with functional and nonfunctional tumors are more likely related to earlier identification of disease rather than any inherent difference in tumor biology. This seems to be particularly true for insulinomas (the most prevalent type of functional PEN), which are exquisitely symptomatic and are generally detected when they measure less than 2 cm.
Appropriate treatment of patients with localized PENs consists of surgical resection or enucleation. Patients undergoing enucleation are highly selected (often with lesions Many different prognostic criteria have been reported for patients with PENs.4,5 Potentially important prognostic criteria include the presence of a functional tumor, stage-related criteria such as tumor size and the presence of metastases, and grade-related criteria such as mitotic rate, presence of necrosis, vascular invasion, perineural invasion, positive immunohistochemical staining for CK19, and an elevated labeling index with Ki-67.5,6,14 In a study from the Massachusetts General Hospital of 101 patients with PENs, mitotic rate, vascular invasion, perineural invasion, necrosis, and CK19 staining were all associated with DSS.12 CK19 emerged as the only predictor of survival on multivariate analysis; however, CK19 staining was strongly associated with the presence of necrosis (P = .006). The choice of mitotic rate and necrosis in the current study was made because of the previously identified prognostic value of these two factors, the ability to determine these factors by routine histologic analysis, the relative ease of measurement and reproducibility of these factors. The European Neuroendocrine Society consensus statement suggests a combination of staging (TNM) and grading (mitoses and Ki-67) to predict tumor behavior.14 Our system, although similar, uses simpler staging criteria, eliminates the need for immunohistochemical staining, and uses the presence of necrosis as one of the two grade-related parameters. Also, our system uses a much lower mitotic rate cut point (2 mitoses/50 HPF v 2 mitoses/10 HPF) to separate low- from intermediate-grade PENs, and the data presented in the current study help confirm the lower cut point established in prior work from our group. In the current study, the WHO system was associated with survival; however, no difference in recurrence or survival was observed between patients in the WHO benign (1.1) and uncertain (1.2) groups. These findings are similar to the findings in a recent Austrian study in which 100 patients with PEN were classified using the WHO classification system and had identical 5-year survival rates in the benign (1.1) and uncertain (1.2) categories (100%), whereas patients with low-grade malignant tumors (2.0) experienced a 5-year survival rate of 52%.15 Because of the lack of difference in outcome between the WHO benign and uncertain groups, the clinical utility of the WHO uncertain group was thought to be limited.
Patients within the uncertain group must have tumors confined to the pancreas without gross local invasion, an imprecisely defined parameter. This results in patients with large, nonmetastatic tumors being classified into the WHO subgroup with the worst prognosis (2.0). When patients were categorized according to stage alone, an intermediate group was identified ( Patients with low-grade tumors had excellent long-term outcomes (Table 4). Patients with low-grade (n = 15) or intermediate-grade (n = 37) tumors and either nodal or distant metastases (n = 15) experienced an estimated 5-year survival rate of 93%. Patients with intermediate-grade tumors with either nodal or distant metastases (n = 37) experienced an estimated 5-year survival rate of 58%. This difference in outcome was also seen in patients without evidence of metastatic disease and highlights the prognostic importance of tumor grade in patients with PENs. To further compare our simplified staging and grading system with the WHO classification system, we evaluated the CI of each. A CI of 0.72 was generated when the WHO classification system was applied to our data set. The CI was 0.76 when our simplified staging and grading systems were combined and applied to the same subset of patients. A CI of 0.76 implies that there is a 76% chance that the patient who experienced recurrence or died as a result of disease first had the higher stage or grade of disease. Although not perfect, this represents an encouraging level of predictive accuracy. This can be put into perspective when compared to other predictive models such as the Gail Model15 for breast cancer, which has a CI of 0.58. In summary, the current data further document excellent long-term outcome for patients undergoing resection or enucleation for nonmetastatic PENs. These data suggest that regional nodal status is not associated with tumor size and, therefore, nodal assessment should be routinely performed. In the current study, the WHO classification system, stage, and grade were associated with recurrence and survival. However, the current study suggests that the three-tiered WHO system results in two groups of patients (benign behavior and uncertain behavior) with excellent and similar prognoses. Our simplified staging and grading system was able to accurately stratify patients for recurrence and survival and had a higher CI than the WHO system. This system should be considered as an alternative and simpler, and therefore possibly more reproducible, prognostic system for patients with PENs that allows for prognostic subcategorization of patients within each stage group.
The author(s) indicated no potential conflicts of interest.
Conception and design: Cristina R. Ferrone, Laura H. Tang, James Tomlinson, Steven N. Hochwald, Murray F. Brennan, David S. Klimstra, Peter J. Allen Financial support: Murray F. Brennan Administrative support: Cristina R. Ferrone Provision of study materials or patients: Murray F. Brennan Collection and assembly of data: Cristina R. Ferrone, Laura H. Tang, James Tomlinson Data analysis and interpretation: Cristina R. Ferrone, Laura H. Tang, James Tomlinson, Mithat Gonen, David S. Klimstra, Peter J. Allen Manuscript writing: Cristina R. Ferrone, David S. Klimstra, Peter J. Allen Final approval of manuscript: Cristina R. Ferrone, Murray F. Brennan, David S. Klimstra, Peter J. Allen
Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Modlin IM, Sandor A: An analysis of 8305 cases of carcinoid tumors. Cancer 79:813-829, 1997[CrossRef][Medline] 2. Kulke M: Advances in the treatment of neuroendocrine tumors. Curr Treat Options Oncol 6:397-409, 2005[CrossRef][Medline] 3. Oberg K, Eriksson B: Medical treatment of neuroendocrine gut and pancreatic tumors. Acta Oncol 28:425-431, 1989[Medline] 4. Phan GQ, Yeo CJ, Hruban RH, et al: Surgical experience with pancreatic and peripancreatic neuroendocrine tumors: Review of 125 patients. J Gastrointest Surg 2:472-482, 1998[Medline] 5. Hochwald SN, Zee S, Conlon KC, et al: Prognostic factors in pancreatic endocrine neoplasms: An analysis of 136 cases with a proposal for low-grade and intermediate-grade groups. J Clin Oncol 20:2633-2642, 2002 6. Travis WD, Rush W, Flieder DB, et al: Survival analysis of 200 pulmonary neuroendocrine tumors with clarification of criteria for atypical carcinoid and its separation from typical carcinoid. Am J Surg Pathol 22:934-944, 1998[CrossRef][Medline] 7. Harrell FE Jr, Califf RM, Pryor DB, et al: Evaluating the yield of medical tests. JAMA 247:2543-2546, 1982 8. Gonen M, Heller G: Concordance probability and discriminatory power in proportional hazards regression. Biometrika 92:965-970, 2005 9. Kent RB 3rd, van Heerden JA, Weiland LH: Nonfunctioning islet cell tumors. Ann Surg 193:185-190, 1981[Medline] 10. Solorzano CC, Lee JE, Pisters PW, et al: Nonfunctioning islet cell carcinoma of the pancreas: Survival results in a contemporary series of 163 patients. Surgery 130:1078-1085, 2001[CrossRef][Medline] 11. Sarmiento JM, Farnell MB, Que FG, et al: Pancreaticoduodenectomy for islet cell tumors of the head of the pancreas: Long-term survival analysis. World J Surg 26:1267-1271, 2002[CrossRef][Medline] 11. Norton JA, Kivlen M, Li M, et al: Morbidity and mortality of aggressive resection in patients with advanced neuroendocrine tumors. Arch Surg 138:859-866, 2003 12. Deshpande V, Fernandez-del Castillo C, Muzikansky A, et al: Cytokeratin 19 is a powerful predictor of survival in pancreatic endocrine tumors. Am J Surg Pathol 28:1145-1153, 2004[CrossRef][Medline] 13. Jarufe NP, Coldham C, Orug T, et al: Neuroendocrine tumours of the pancreas: Predictors of survival after surgical treatment. Dig Surg 22:157-162, 2005[CrossRef][Medline] 14. Rindi G, Kloppel G, Alhman H, et al: TNM staging of foregut (neuro)endocrine tumors: A consensus proposal including a grading system. Virchows Arch 449:395-401, 2006[CrossRef][Medline] 15. Schindl M, Kaczirek K, Kaserer K, et al: Is the new classification of neuroendocrine pancreatic tumors of clinical help? World J Surg 24:1312-1318, 2000[CrossRef][Medline] Submitted June 10, 2007; accepted September 12, 2007.
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
