- Email: [email protected]
Clinical presentation and outcome of nonfunctional pancreatic neuroendocrine tumors in a modern cohort
The American Journal of Surgery (2015) 210, 1192-1196
Southwestern Surgical Congress
Clinical presentation and outcome of nonfunctional pancreatic neuroendocrine tumors in a modern cohort Duncan C. Watleya, Quan P. Ly, M.D.a,c, Geoffrey Talmon, M.D.b,c, Chandrakanth Are, M.D.a,c, Aaron R. Sasson, M.D.a,c,* a
Department of Surgery, Division of Surgical Oncology and bDepartment of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE; cFred and Pamela Buffet Cancer Center, Omaha, NE
KEYWORDS: Pancreatic tumor; Nonfunctional pancreatic tumors; Incidental tumors; Incidental nonfunctional pancreatic tumor; Neuroendocrine tumor; Nonfunctional neuroendocrine tumor
Abstract BACKGROUND: The natural history of nonfunctional pancreatic neuroendocrine tumors (NFPNETs) is largely unstudied due to its rarity. The primary goal of this study was to characterize clinical features and outcomes of incidental NF-PNETs. METHODS: An institutional review board–approved retrospective study of patients with NF-PNET evaluated by the Surgical Oncology of University of Nebraska Medical Center was performed. Patients were evaluated with dedicated pancreatic and liver imaging using multiphasic computed tomographic scan and dedicated magnetic resonance imaging protocols. RESULTS: Forty-six patients (male, 47.8%) were evaluated, and 35 ultimately resected. Of these, 16 tumors were discovered incidentally. The median age was 62 and 59 years in incidental and symptomatically discovered, respectively. Incidental median size was 2.4 cm vs 6 cm in the symptomatic group, with a P value of .037. The presence of lymphatic and liver metastases was 10% and 25% incidental and 45% and 67% for those with symptoms (lymphatic involvement, P 5 .05; liver metastases P 5 .07). Median overall survival was 45 and 76 months (P 5 .03). CONCLUSIONS: Incidentally discovered NF-PNETs represent a malignancy with more questions than answers. Our series indicates that these cancers are more indolent than previously believed. Ó 2015 Elsevier Inc. All rights reserved.
Pancreatic neuroendocrine tumors (PNETs) are rare neoplastic masses of islet cell origin, classically divided into tumors presenting with symptoms of hormonal excess (functional) and those without syndromic symptoms (nonfunctional). These tumors represent a small proportion The authors declare no conflict of interest. * Corresponding author. Tel.: 11-631-444-8086; fax: 631-444-7871. E-mail address: [email protected] Manuscript received April 11, 2015; revised manuscript August 3, 2015 0002-9610/$ - see front matter Ó 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjsurg.2015.08.012
of all pancreatic masses, with recent epidemiologic studies demonstrating an incidence of 1 to 5/million/year and accounting for 3% of pancreatic cancers.1–4 Relative instance of the 2 categories have changed in the last 3 decades. Before the ubiquitous use of computed tomography (CT), functional tumors represented the more common subtype, with nonfunctional pancreatic neuroendocrine tumors (NF-PNETs) accounting for one third of all PNETs.5 The NF-PNETs that were found during this period presented at late stage with symptoms of either mass effect or metastatic disease. With increased use of abdominal imaging, incidence of
D.C. Watley et al. Table 1
Pancreatic neuroendocrine tumor
1193
Demographics and clinical data of total population
Patient characteristics Age Median Range Sex, % Male Female Location Head Body/tail Size, cm Median Range Nodal status Node positive Synchronous liver metastases Positive metastases
n 5 46 59 23–84 48 52 15 (33%) 31 (67%) 4.85 .05–19 11 (37%) 24 (52%)
NF-PNETs has increased, and the subtype, now, represents 50% to 75% of all PNETs diagnosed.6 As many as 50% of these tumors are identified on imaging for an unrelated problem and are asymptomatic at diagnosis.6–8 Treatment for such incidental masses is generally surgical with few studies reporting malignant potential in 60% to 90% of NF-PNETs.9 However, because to the rarity of diagnosis, the clinical history of incidentally discovered tumors is largely unknown. The primary goal of this study is to characterize NF-PNETs of both incidental and symptomatic discovery in terms of clinical, pathologic, and surgical features; as well as to identify trends in the presentation of symptomatic tumors.
Methods Patients undergoing surgical evaluation for pancreatic mass by the surgical oncology service at the University of Nebraska Medical Center (UNMC) from January 1, 2002, to December 31, 2013 were identified through a pre-existing database, and retrospectively recruited pancreatic cancers of neuroendocrine origin based on pathologic examination and no clinical evidence of hormonal excess at presentation were selected. Patients with genetic syndromes, such as multiple endocrine neoplasia or von Hippel-Lindau, as well Table 2
as mixed adenoneuroendocrine carcinoma were excluded. The patients underwent evaluation at UNMC with a highresolution pancreatic protocol CT scan or magnetic resonance imaging of the pancreas and liver. Pathologic analysis was performed on either surgical or biopsy specimens, and histopathologic findings were characterized according to the World Health Organization classification scheme for PNETs.10 Data points were retrieved through institutional record and social security index review, and included demographics, presenting symptoms, tumor size and location, extent of metastasis, pathology, disease progression, and overall survival. The cohort of patients was divided into 2 groups: NF-PNETs discovered on imaging in the absence of jaundice or abdominal complaints or during surgical intervention for an unrelated problem (incidental tumors) and NF-PNETs that presented with any of the following: jaundice, pancreatitis, abdominal pain, or unexplained weight loss (symptomatic tumors). The 2 groups were compared using chi-square analysis. Patients with symptomatic tumors were also segregated based on tumor location, head, and body and/or tail. Rates of presenting symptoms listed previously were compared between the 2 groups using chi-square analysis. Overall survival was calculated as the time in months from diagnosis with tissue biopsy to date of death. Survival curves were calculated by the method of Kaplan and Meier.11 Histologically, poorly differentiated tumors were included for all analysis excluding survival. This study was approved by the Institutional Review Board (IRB) at the UNMC.
Results During the study period, 46 patients were evaluated, and 35 ultimately received surgical resection (Table 1). Of the total population, 16 tumors were discovered incidentally. When compared with symptomatic patients, there was no difference in age (62 years vs 59 years in symptomatic), sex (63% male vs 40% male), or surgical resection rate (73% vs 81%; Table 2). Surgical pathology data points differed between the 2 groups. Incidental tumors were more commonly found in the body of the pancreas, ([head 5 4, body 5 16] vs [head 5 11, body 5 19], P 5 .42), but the difference was not statistically significant.
Operative resection and tumor examination
Patient characteristics
Incidental
Symptomatic
P value
n Tumor size (cm) Age, median, (y) Location Head Body/tail Resection of the primary tumor Positive nodes (resected patients) Liver metastases
16 2.4 57
30 6 64
.04 .57
4 12 13 1 4
(25%) (75%) (81%) (10%) (25%)
11 19 22 10 12
(37%) (63%) (73%) (45%) (55%)
d .42 .55 .05 .07
1194
The American Journal of Surgery, Vol 210, No 6, December 2015 Table 3 patients
Histopathologic Differenaon 14
Number of Paents
12 10 8 6 4 2 0 well
mod incidental
poor
well
mod
Patient characteristics
Head
Body/tail
P value
N Sex (M/F), % Age (range) Tumor size (cm) Presenting symptoms, % Jaundice Abdominal pain Weight loss
11 36 59 (23–84) 3.2
19 42 59 (30–84) 8.5
d .75 .56 ,.05
36 64 67
13 74 59
.10 .56 .70
poor
symptomac
Figure 1 Histopathologic differentiation segregated by 2010 WHO guidelines for NF-PNETs. WHO 5 World Health Organization.
Incidentally found tumors were statistically smaller (2.4 cm vs 6 cm, P 5 .037). Lymphatic involvement (10% vs 45% in symptomatic, P 5 .05) and liver metastasis (25% vs 55%, P 5 .07) were both different. Histopathologic grading was available for 14 of the 16 incidental tumors and 22 of the 30 symptomatic patients. There was no difference between the 2 groups, Fig. 1. Median overall survival was 45 months (median events not reached in 10 out of 30) in symptomatic and 76 months (median events not reached in 13 out of 16) in incidental patients, respectively (P 5 .03), Fig. 2. Symptomatic patients with tumors in the head had higher instance of jaundice (36% vs 13% in body and/or tail, P 5 .10) and weight loss (67% vs 59%, P 5 .70), but less instance of abdominal pain (64% vs 74%, P 5 .56) (Table 3). Insufficient data were found for comparison of rates of pancreatitis with only 13 out of 19 results for tumors of body and/or tail.
Conclusions Incidentally discovered NF-PNETs have represented a quandary in surgical oncology decision-making for
Figure 2
Clinical presentation in symptomatically presenting
Kaplan-Meier survival curve.
decades. Many reports reveal relatively high likelihood of tumor progression and metastasis, but truly unknown incidence of disease makes this a difficult determination for fear of subjecting patients with benign pathology to complications of surgery. Current epidemiologic evidence demonstrates a yearly incidence of 1 to 5cases/million, which is discordant with autopsy studies showing incidence as high as 1.5%.1–4,12 This incongruity is also evident in the increased discovery of incidental NF-PNETs with increased use of CT imaging for abdominal pathology. In our patient population, we found that incidental tumors comprised 35% of NF-PNETs evaluated. These patients did remarkably well in comparison to symptomatically presenting in terms of size, lymph node involvement, liver metastasis, and overall survival. Significantly, striking was the difference in overall survival, 45 months vs 76 with only 3 of the 16 incidental patients succumbing to their disease during the study period. A recent report described a similar patient population with remarkably similar lymph node and liver metastasis rate at the time of surgery.13 However, the survival data were significantly different. In their series, incidentally discovered NF-PNETs had a 49.8% and 16.6%, respectively, 5- and 10-year survival rate. Our series represented a 5-year survival of 62.5%. Only 3 of the 16 incidental patients in our series have made it to the 10-year survival mark, thus little comparison can be made for long-term survival differences between the 2 series. One difference that could contribute to the survival difference between the 2 series is our more contemporary design. Our series was composed of patients collected exclusively when multiaxial dedicated CT and magnetic resonance imaging protocols were standardized for our institution beginning in 2002. This may have allowed us to capture smaller masses and assess for extrapancreatic disease, especially liver metastasis, in a more reliable way. In conclusion, incidentally discovered NF-PNETs represent a malignancy with more questions than answers in terms of management. Our series indicates that these cancers are more indolent than previously believed, but because of the retrospective nature of design, further investigation with clinical trials comparing surgical and nonsurgical management should be investigated.
D.C. Watley et al.
Pancreatic neuroendocrine tumor
References 1. Fesinmeyer MD, Austin MA, Li CL, et al. Differences in survival by histologic type of pancreatic cancer. Cancer Epidemiol Biomarkers Prev 2005;14:1766. 2. Yao JC, Hassan M, Phan A, et al. One hundered years after ‘‘carcinoid’’. Epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. J Clin Oncol 2008; 26:3063. 3. Kloppel G, Perren A, Heit PU. The gastroenteropancreatic neuroendocrine cell system and its tumors: the WHO classification. Ann N Y Acad Sci 2004;1014:13. 4. Oberg K. Pancreatic endocrine tumors. Semin Oncol 2010;37: 594–618. 5. Metz DC, Jensen RT. Gastrointestinal neuroendocrine tumors: pancreatic endocrine tumors. Gastroenterology 2008;135:1469–92. 6. Klimstra DS, Modlin IR, Coppola D, et al. The pathologic classification of neuroendocrine tumors: a review of nomenclature, grading, and staging systems. Pancreas 2010;39:707. 7. 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 2002;20:2633. 8. Zerbi A, Falconi M, Rindi G, et al. Clinicopathological features of pancreatic endocrine tumors: a prospective multicenter study in Italy of 297 sporadic cases. Am J Gastroenterol 2010;105:1421. 9. Ito T, Igarashi H, Jensen R. Pancreatic neuroendocrine tumors: clinical features, diagnosis and medical treatment: advances. Best Pract Res Clin Gastroenterol 2012;26:737–53. 10. Rindi G, Arnold R, Bosman FT, et al. Nomenclature and classification of neuroendocrine neoplasms of the digestive system. In: Bosman TF, Carneiro F, Hruban RH, et al., eds. WHO Classification of Tumours of the Digestive System. 4th ed. Lyon: International Agency for Research on cancer (IARC); 2010. p. 13. 11. Kaplan E, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958;53:457–81. 12. Grimelius L, Hultguist GT, Stenkvist B. Cytological differentiation of asymptomatic pancreatic islet cell tumours in autopsy material. Virchows Arch A Pathol Anat Histol 1975;365:275–88. 13. Haynes A, Deshpande V, Ingkakul T, et al. Implications of incidentally discovered nonfunctioning pancreatic endocrine tumors short-term and long-term patient outcomes. Arch Surg 2011;146:534–8.
Discussion Discussant Dr. Brian Eastridge (San Antonio, TX): This study is a retrospective review of an 11-year experience at the Buffett Cancer Center of the diagnosis and management of these nonfunctional pancreatic neuroendocrine tumors. During that period, they had 46 tumors, 30 of which were symptomatic and 16 incidental. You just heard about the survival of those 2 subgroups. With that being said, again, with this small number of patients, I think one of the most striking questions I had is, how did you get the definition of incidental? How were those patients found? Was it for workup of other neoplastic disease? Was it an incidentaloma found on some other medical evaluation?
1195 Because many of these patients were older, was the survival attributable to tumor mortality in the end? In the incidentally found tumors, you said 13 of the 16 were ultimately resected. What made the other 3 nonresectable? Was it evidence of advanced metastatic disease or some other medical comorbidity? I think probably the most important point is, how do we practically use this information, particularly with those patients that had incidental findings? It sounds like they were found almost by chance. Dr. Duncan C. Watley: The 1st question was, how did we find them? Basically, how did we find incidental tumors? Several of the patients actually were being worked up for hematuria, but otherwise they were commonly found based on trauma imaging I saw. We had several patients with abdominal trauma, car accidents, that sort of thing. None of our patients were being evaluated for other neoplastic disease. Dr. Brian Eastridge (San Antonio, TX): It’s striking that you mention that because I’m a trauma surgeon. Frequently, we find these incidentalomas. We don’t know what to do with them other than refer them to the appropriate specialist. The 2nd question was about, was your survival actually cancer related, your ultimate cancer survival? Why were the incidentals that you couldn’t resect unresectable? Dr. Duncan C. Watley: The 2nd question, I don’t actually have the statistics right in front of me, but those symptomatic patients, the 20 out of 30 that have succumbed to their disease were because of metastatic disease. They either progressed to liver failure because of liver metastasis or distant metastatic disease. The 3rd question, I can’t really speak to that. I’m not quite sure. I’m sorry about that. There was quite a difference between the 2 groups. I think what’s going to be really interesting for our group is to continue following them and to see what was done in the long-term because these incidental masses did progress. They did have liver metastasis down the road. I want to see, in our additional studies from here on out, what treatment was given to these patients, and did they respond just dramatically to this treatment for these liver metastases? I think that will be the interesting point of the study. Dr. Richard Zorn (Tallahassee, FL): How many of those 16 were grossly malignant? Dr. Duncan C. Watley: I think it was roughly 60%. We had KI-67s that were maybe 30, 40%. Dr. Richard Zorn (Tallahassee, FL): So, out of the incidental just ‘‘by the way’’ lesions, 40% were completely benign? Dr. Robert Sticca (Grand Forks, ND): I have 1 question. The current National Comprehensive Cancer Network guidelines for incidental pancreatic neuroendocrine tumors would suggest that for tumors less than 1 cm they may be
1196
The American Journal of Surgery, Vol 210, No 6, December 2015
observed. What’s your strategy in your institution for less than 1-cm tumors? Dr. Duncan C. Watley: We do observe those with serial imaging. Dr. Robert Sticca (Grand Forks, ND): Were any of these people in that category? Is that why maybe those 3 were not resected?
Dr. Duncan C. Watley: No. I am not certain about that. We did have one .05-cm mass that was resected. Speaking to my senior author about this, he said they were having lots of problems with chronic pancreatitis, and it was a surgery because of that rather than the mass. That would be the only response I have to that question.
Southwestern Surgical Congress
Clinical presentation and outcome of nonfunctional pancreatic neuroendocrine tumors in a modern cohort Duncan C. Watleya, Quan P. Ly, M.D.a,c, Geoffrey Talmon, M.D.b,c, Chandrakanth Are, M.D.a,c, Aaron R. Sasson, M.D.a,c,* a
Department of Surgery, Division of Surgical Oncology and bDepartment of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE; cFred and Pamela Buffet Cancer Center, Omaha, NE
KEYWORDS: Pancreatic tumor; Nonfunctional pancreatic tumors; Incidental tumors; Incidental nonfunctional pancreatic tumor; Neuroendocrine tumor; Nonfunctional neuroendocrine tumor
Abstract BACKGROUND: The natural history of nonfunctional pancreatic neuroendocrine tumors (NFPNETs) is largely unstudied due to its rarity. The primary goal of this study was to characterize clinical features and outcomes of incidental NF-PNETs. METHODS: An institutional review board–approved retrospective study of patients with NF-PNET evaluated by the Surgical Oncology of University of Nebraska Medical Center was performed. Patients were evaluated with dedicated pancreatic and liver imaging using multiphasic computed tomographic scan and dedicated magnetic resonance imaging protocols. RESULTS: Forty-six patients (male, 47.8%) were evaluated, and 35 ultimately resected. Of these, 16 tumors were discovered incidentally. The median age was 62 and 59 years in incidental and symptomatically discovered, respectively. Incidental median size was 2.4 cm vs 6 cm in the symptomatic group, with a P value of .037. The presence of lymphatic and liver metastases was 10% and 25% incidental and 45% and 67% for those with symptoms (lymphatic involvement, P 5 .05; liver metastases P 5 .07). Median overall survival was 45 and 76 months (P 5 .03). CONCLUSIONS: Incidentally discovered NF-PNETs represent a malignancy with more questions than answers. Our series indicates that these cancers are more indolent than previously believed. Ó 2015 Elsevier Inc. All rights reserved.
Pancreatic neuroendocrine tumors (PNETs) are rare neoplastic masses of islet cell origin, classically divided into tumors presenting with symptoms of hormonal excess (functional) and those without syndromic symptoms (nonfunctional). These tumors represent a small proportion The authors declare no conflict of interest. * Corresponding author. Tel.: 11-631-444-8086; fax: 631-444-7871. E-mail address: [email protected] Manuscript received April 11, 2015; revised manuscript August 3, 2015 0002-9610/$ - see front matter Ó 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjsurg.2015.08.012
of all pancreatic masses, with recent epidemiologic studies demonstrating an incidence of 1 to 5/million/year and accounting for 3% of pancreatic cancers.1–4 Relative instance of the 2 categories have changed in the last 3 decades. Before the ubiquitous use of computed tomography (CT), functional tumors represented the more common subtype, with nonfunctional pancreatic neuroendocrine tumors (NF-PNETs) accounting for one third of all PNETs.5 The NF-PNETs that were found during this period presented at late stage with symptoms of either mass effect or metastatic disease. With increased use of abdominal imaging, incidence of
D.C. Watley et al. Table 1
Pancreatic neuroendocrine tumor
1193
Demographics and clinical data of total population
Patient characteristics Age Median Range Sex, % Male Female Location Head Body/tail Size, cm Median Range Nodal status Node positive Synchronous liver metastases Positive metastases
n 5 46 59 23–84 48 52 15 (33%) 31 (67%) 4.85 .05–19 11 (37%) 24 (52%)
NF-PNETs has increased, and the subtype, now, represents 50% to 75% of all PNETs diagnosed.6 As many as 50% of these tumors are identified on imaging for an unrelated problem and are asymptomatic at diagnosis.6–8 Treatment for such incidental masses is generally surgical with few studies reporting malignant potential in 60% to 90% of NF-PNETs.9 However, because to the rarity of diagnosis, the clinical history of incidentally discovered tumors is largely unknown. The primary goal of this study is to characterize NF-PNETs of both incidental and symptomatic discovery in terms of clinical, pathologic, and surgical features; as well as to identify trends in the presentation of symptomatic tumors.
Methods Patients undergoing surgical evaluation for pancreatic mass by the surgical oncology service at the University of Nebraska Medical Center (UNMC) from January 1, 2002, to December 31, 2013 were identified through a pre-existing database, and retrospectively recruited pancreatic cancers of neuroendocrine origin based on pathologic examination and no clinical evidence of hormonal excess at presentation were selected. Patients with genetic syndromes, such as multiple endocrine neoplasia or von Hippel-Lindau, as well Table 2
as mixed adenoneuroendocrine carcinoma were excluded. The patients underwent evaluation at UNMC with a highresolution pancreatic protocol CT scan or magnetic resonance imaging of the pancreas and liver. Pathologic analysis was performed on either surgical or biopsy specimens, and histopathologic findings were characterized according to the World Health Organization classification scheme for PNETs.10 Data points were retrieved through institutional record and social security index review, and included demographics, presenting symptoms, tumor size and location, extent of metastasis, pathology, disease progression, and overall survival. The cohort of patients was divided into 2 groups: NF-PNETs discovered on imaging in the absence of jaundice or abdominal complaints or during surgical intervention for an unrelated problem (incidental tumors) and NF-PNETs that presented with any of the following: jaundice, pancreatitis, abdominal pain, or unexplained weight loss (symptomatic tumors). The 2 groups were compared using chi-square analysis. Patients with symptomatic tumors were also segregated based on tumor location, head, and body and/or tail. Rates of presenting symptoms listed previously were compared between the 2 groups using chi-square analysis. Overall survival was calculated as the time in months from diagnosis with tissue biopsy to date of death. Survival curves were calculated by the method of Kaplan and Meier.11 Histologically, poorly differentiated tumors were included for all analysis excluding survival. This study was approved by the Institutional Review Board (IRB) at the UNMC.
Results During the study period, 46 patients were evaluated, and 35 ultimately received surgical resection (Table 1). Of the total population, 16 tumors were discovered incidentally. When compared with symptomatic patients, there was no difference in age (62 years vs 59 years in symptomatic), sex (63% male vs 40% male), or surgical resection rate (73% vs 81%; Table 2). Surgical pathology data points differed between the 2 groups. Incidental tumors were more commonly found in the body of the pancreas, ([head 5 4, body 5 16] vs [head 5 11, body 5 19], P 5 .42), but the difference was not statistically significant.
Operative resection and tumor examination
Patient characteristics
Incidental
Symptomatic
P value
n Tumor size (cm) Age, median, (y) Location Head Body/tail Resection of the primary tumor Positive nodes (resected patients) Liver metastases
16 2.4 57
30 6 64
.04 .57
4 12 13 1 4
(25%) (75%) (81%) (10%) (25%)
11 19 22 10 12
(37%) (63%) (73%) (45%) (55%)
d .42 .55 .05 .07
1194
The American Journal of Surgery, Vol 210, No 6, December 2015 Table 3 patients
Histopathologic Differenaon 14
Number of Paents
12 10 8 6 4 2 0 well
mod incidental
poor
well
mod
Patient characteristics
Head
Body/tail
P value
N Sex (M/F), % Age (range) Tumor size (cm) Presenting symptoms, % Jaundice Abdominal pain Weight loss
11 36 59 (23–84) 3.2
19 42 59 (30–84) 8.5
d .75 .56 ,.05
36 64 67
13 74 59
.10 .56 .70
poor
symptomac
Figure 1 Histopathologic differentiation segregated by 2010 WHO guidelines for NF-PNETs. WHO 5 World Health Organization.
Incidentally found tumors were statistically smaller (2.4 cm vs 6 cm, P 5 .037). Lymphatic involvement (10% vs 45% in symptomatic, P 5 .05) and liver metastasis (25% vs 55%, P 5 .07) were both different. Histopathologic grading was available for 14 of the 16 incidental tumors and 22 of the 30 symptomatic patients. There was no difference between the 2 groups, Fig. 1. Median overall survival was 45 months (median events not reached in 10 out of 30) in symptomatic and 76 months (median events not reached in 13 out of 16) in incidental patients, respectively (P 5 .03), Fig. 2. Symptomatic patients with tumors in the head had higher instance of jaundice (36% vs 13% in body and/or tail, P 5 .10) and weight loss (67% vs 59%, P 5 .70), but less instance of abdominal pain (64% vs 74%, P 5 .56) (Table 3). Insufficient data were found for comparison of rates of pancreatitis with only 13 out of 19 results for tumors of body and/or tail.
Conclusions Incidentally discovered NF-PNETs have represented a quandary in surgical oncology decision-making for
Figure 2
Clinical presentation in symptomatically presenting
Kaplan-Meier survival curve.
decades. Many reports reveal relatively high likelihood of tumor progression and metastasis, but truly unknown incidence of disease makes this a difficult determination for fear of subjecting patients with benign pathology to complications of surgery. Current epidemiologic evidence demonstrates a yearly incidence of 1 to 5cases/million, which is discordant with autopsy studies showing incidence as high as 1.5%.1–4,12 This incongruity is also evident in the increased discovery of incidental NF-PNETs with increased use of CT imaging for abdominal pathology. In our patient population, we found that incidental tumors comprised 35% of NF-PNETs evaluated. These patients did remarkably well in comparison to symptomatically presenting in terms of size, lymph node involvement, liver metastasis, and overall survival. Significantly, striking was the difference in overall survival, 45 months vs 76 with only 3 of the 16 incidental patients succumbing to their disease during the study period. A recent report described a similar patient population with remarkably similar lymph node and liver metastasis rate at the time of surgery.13 However, the survival data were significantly different. In their series, incidentally discovered NF-PNETs had a 49.8% and 16.6%, respectively, 5- and 10-year survival rate. Our series represented a 5-year survival of 62.5%. Only 3 of the 16 incidental patients in our series have made it to the 10-year survival mark, thus little comparison can be made for long-term survival differences between the 2 series. One difference that could contribute to the survival difference between the 2 series is our more contemporary design. Our series was composed of patients collected exclusively when multiaxial dedicated CT and magnetic resonance imaging protocols were standardized for our institution beginning in 2002. This may have allowed us to capture smaller masses and assess for extrapancreatic disease, especially liver metastasis, in a more reliable way. In conclusion, incidentally discovered NF-PNETs represent a malignancy with more questions than answers in terms of management. Our series indicates that these cancers are more indolent than previously believed, but because of the retrospective nature of design, further investigation with clinical trials comparing surgical and nonsurgical management should be investigated.
D.C. Watley et al.
Pancreatic neuroendocrine tumor
References 1. Fesinmeyer MD, Austin MA, Li CL, et al. Differences in survival by histologic type of pancreatic cancer. Cancer Epidemiol Biomarkers Prev 2005;14:1766. 2. Yao JC, Hassan M, Phan A, et al. One hundered years after ‘‘carcinoid’’. Epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. J Clin Oncol 2008; 26:3063. 3. Kloppel G, Perren A, Heit PU. The gastroenteropancreatic neuroendocrine cell system and its tumors: the WHO classification. Ann N Y Acad Sci 2004;1014:13. 4. Oberg K. Pancreatic endocrine tumors. Semin Oncol 2010;37: 594–618. 5. Metz DC, Jensen RT. Gastrointestinal neuroendocrine tumors: pancreatic endocrine tumors. Gastroenterology 2008;135:1469–92. 6. Klimstra DS, Modlin IR, Coppola D, et al. The pathologic classification of neuroendocrine tumors: a review of nomenclature, grading, and staging systems. Pancreas 2010;39:707. 7. 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 2002;20:2633. 8. Zerbi A, Falconi M, Rindi G, et al. Clinicopathological features of pancreatic endocrine tumors: a prospective multicenter study in Italy of 297 sporadic cases. Am J Gastroenterol 2010;105:1421. 9. Ito T, Igarashi H, Jensen R. Pancreatic neuroendocrine tumors: clinical features, diagnosis and medical treatment: advances. Best Pract Res Clin Gastroenterol 2012;26:737–53. 10. Rindi G, Arnold R, Bosman FT, et al. Nomenclature and classification of neuroendocrine neoplasms of the digestive system. In: Bosman TF, Carneiro F, Hruban RH, et al., eds. WHO Classification of Tumours of the Digestive System. 4th ed. Lyon: International Agency for Research on cancer (IARC); 2010. p. 13. 11. Kaplan E, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958;53:457–81. 12. Grimelius L, Hultguist GT, Stenkvist B. Cytological differentiation of asymptomatic pancreatic islet cell tumours in autopsy material. Virchows Arch A Pathol Anat Histol 1975;365:275–88. 13. Haynes A, Deshpande V, Ingkakul T, et al. Implications of incidentally discovered nonfunctioning pancreatic endocrine tumors short-term and long-term patient outcomes. Arch Surg 2011;146:534–8.
Discussion Discussant Dr. Brian Eastridge (San Antonio, TX): This study is a retrospective review of an 11-year experience at the Buffett Cancer Center of the diagnosis and management of these nonfunctional pancreatic neuroendocrine tumors. During that period, they had 46 tumors, 30 of which were symptomatic and 16 incidental. You just heard about the survival of those 2 subgroups. With that being said, again, with this small number of patients, I think one of the most striking questions I had is, how did you get the definition of incidental? How were those patients found? Was it for workup of other neoplastic disease? Was it an incidentaloma found on some other medical evaluation?
1195 Because many of these patients were older, was the survival attributable to tumor mortality in the end? In the incidentally found tumors, you said 13 of the 16 were ultimately resected. What made the other 3 nonresectable? Was it evidence of advanced metastatic disease or some other medical comorbidity? I think probably the most important point is, how do we practically use this information, particularly with those patients that had incidental findings? It sounds like they were found almost by chance. Dr. Duncan C. Watley: The 1st question was, how did we find them? Basically, how did we find incidental tumors? Several of the patients actually were being worked up for hematuria, but otherwise they were commonly found based on trauma imaging I saw. We had several patients with abdominal trauma, car accidents, that sort of thing. None of our patients were being evaluated for other neoplastic disease. Dr. Brian Eastridge (San Antonio, TX): It’s striking that you mention that because I’m a trauma surgeon. Frequently, we find these incidentalomas. We don’t know what to do with them other than refer them to the appropriate specialist. The 2nd question was about, was your survival actually cancer related, your ultimate cancer survival? Why were the incidentals that you couldn’t resect unresectable? Dr. Duncan C. Watley: The 2nd question, I don’t actually have the statistics right in front of me, but those symptomatic patients, the 20 out of 30 that have succumbed to their disease were because of metastatic disease. They either progressed to liver failure because of liver metastasis or distant metastatic disease. The 3rd question, I can’t really speak to that. I’m not quite sure. I’m sorry about that. There was quite a difference between the 2 groups. I think what’s going to be really interesting for our group is to continue following them and to see what was done in the long-term because these incidental masses did progress. They did have liver metastasis down the road. I want to see, in our additional studies from here on out, what treatment was given to these patients, and did they respond just dramatically to this treatment for these liver metastases? I think that will be the interesting point of the study. Dr. Richard Zorn (Tallahassee, FL): How many of those 16 were grossly malignant? Dr. Duncan C. Watley: I think it was roughly 60%. We had KI-67s that were maybe 30, 40%. Dr. Richard Zorn (Tallahassee, FL): So, out of the incidental just ‘‘by the way’’ lesions, 40% were completely benign? Dr. Robert Sticca (Grand Forks, ND): I have 1 question. The current National Comprehensive Cancer Network guidelines for incidental pancreatic neuroendocrine tumors would suggest that for tumors less than 1 cm they may be
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observed. What’s your strategy in your institution for less than 1-cm tumors? Dr. Duncan C. Watley: We do observe those with serial imaging. Dr. Robert Sticca (Grand Forks, ND): Were any of these people in that category? Is that why maybe those 3 were not resected?
Dr. Duncan C. Watley: No. I am not certain about that. We did have one .05-cm mass that was resected. Speaking to my senior author about this, he said they were having lots of problems with chronic pancreatitis, and it was a surgery because of that rather than the mass. That would be the only response I have to that question.