Imaging Pearls ❯ Pancreas ❯ Neuroendocrine Tumors (PNET)
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- “Among the 5579 patients with localized pNETs ≤2 cm during 2015 and 2020, 2027 underwent observation (36.3%) whereas 3552 underwent resection (63.7%). On multivariable analysis female sex, further distance traveled, tumor size 1.01cm-2 cm, and pancreas body/tail tumors were associated with surgery whereas increasing age, later year of diagnosis, and treatment at an academic program were associated with observation.”
Trends in the Use of Observation for Small Nonfunctional Pancreatic Neuroendocrine Tumors.
Ruff SM, Dillhoff M, Tsai S, Pawlik TM, Sukrithan V, Konda B, Cloyd JM.
JAMA Surg. 2024 Aug 21: - “These findings highlight a growing nationwide trend in the initial nonoperative management of small NF-pNETs. As most patients with small NF-pNETs still undergo resection despite its associated morbidity and unclear survival advantage, research should focus on whether barriers exist to adopting active surveillance in specific patient populations. Further research on the long-term efficacy of active surveillance, cost effectiveness strategies, and further refining patient-related risk factors other than tumor size will ultimately guide the evidence based and personalized management of small NF-pNETs.”
Trends in the Use of Observation for Small Nonfunctional Pancreatic Neuroendocrine Tumors.
Ruff SM, Dillhoff M, Tsai S, Pawlik TM, Sukrithan V, Konda B, Cloyd JM.
JAMA Surg. 2024 Aug 21: - Background. PanNETs are a rare group of pancreatic tumors that display heterogeneous histopathological and clinical behavior. Nodal disease has been established as one of the strongest predictors of patient outcomes in PanNETs. Lack of accurate preoperative assessment of nodal disease is a major limitation in the management of these patients, in particular those with small (< 2 cm) low-grade tumors. The aim of the study was to evaluate the ability of radiomic features (RF) to preoperatively predict the presence of nodal disease in pancreatic neuroendocrine tumors (PanNETs).
Preoperative Prediction of Lymph Node Metastases in Nonfunctional Pancreatic Neuroendocrine Tumors Using a Combined CT Radiomics-Clinical Model.
Ahmed TM, Zhu Z, Yasrab M, Blanco A, Kawamoto S, He J, Fishman EK, Chu L, Javed AA
Ann Surg Oncol. 2024 Aug 23. doi: 10.1245/s10434-024-16064-4. Epub ahead of print - Results. Of the 320 patients included in the study, 92 (28.8%) had nodal disease based on histopathological assessment of the surgical specimen. A radiomic signature based on ten selected RF was developed. Clinicopathological characteristics predictive of nodal disease included tumor grade and size. Upon internal validation the combined radiomics and clinical feature model demonstrated adequate performance (AUC 0.80) in identifying nodal disease. The modelmaccurately identified nodal disease in 85% of patients with small tumors (< 2 cm).
Conclusions. Non-invasive preoperative assessment of nodal disease using RF and clinicopathological characteristics is feasible.
Preoperative Prediction of Lymph Node Metastases in Nonfunctional Pancreatic Neuroendocrine Tumors Using a Combined CT Radiomics-Clinical Model.
Ahmed TM, Zhu Z, Yasrab M, Blanco A, Kawamoto S, He J, Fishman EK, Chu L, Javed AA
Ann Surg Oncol. 2024 Aug 23. doi: 10.1245/s10434-024-16064-4. Epub ahead of print - ”In conclusion, this study presents a novel tool on the basis of RFs and clinical factors for accurate prediction of nodal disease in NF-PanNETs. Furthermore, we demonstrated that addition of RFs to clinical factors can make this model more robust and accurate. Further validation of this model is required to assess its performance in external cohorts. If validated, this tool could allow for non-invasive serial assessment of nodal disease in patients with well differentiated nonfunctioning PanNETs to tailor management plans and provide precise therapy on the basis of each patient’s disease biology.”
Preoperative Prediction of Lymph Node Metastases in Nonfunctional Pancreatic Neuroendocrine Tumors Using a Combined CT Radiomics-Clinical Model.
Ahmed TM, Zhu Z, Yasrab M, Blanco A, Kawamoto S, He J, Fishman EK, Chu L, Javed AA
Ann Surg Oncol. 2024 Aug 23. doi: 10.1245/s10434-024-16064-4. Epub ahead of print 
- Purpose: The purpose of this study was to develop a radiomics-based algorithm to identify small pancreatic neuroendocrine tumors(PanNETs) on CT and evaluate its robustness across manual and automated segmentations, exploring the feasibility of automated screening.
Conclusion: Radiomics features identify small PanNETs, with stable performance when extracted using automated segmentations. These models demonstrate high sensitivity, complementing the high specificity of radiologists, and could serve as opportunistic screeners.
Radiomics machine learning algorithm facilitates detection of small pancreatic neuroendocrine tumors on CT.
Lopez-Ramirez F, Soleimani S, Azadi JR, Sheth S, Kawamoto S, Javed AA, Tixier F, Hruban RH, Fishman EK, Chu LC.
Diagn Interv Imaging. 2024 Sep 14:S2211-5684(24)00172-4. doi: 10.1016/j.diii.2024.08.003. Epub ahead of print. PMID: 39278763 . - Results:A total of 135 patients with 142 PanNETs,and135 healthy controls were included.There were 168 women and 102 men,with a mean age of 55.4 +/-11.6(standard deviation) years(range:20−85years). Median PanNET size was 1.3cm (Q1,1.0;Q3,1.5;range:0.5−1.9).The arterial phase Light GBM model achieved the best performance in the test set,with 90% sensitivity (95% confidence interval[CI]:80−98),76% specificity (95%CI:62−88)and an AUC of 0.87 (95% CI:0.79−0.94).Using features from the automated segmentations,this model achieved an AUC of 0.86(95%CI:0.79−0.93). In comparison, the radiologists achieved a mean 50% sensitivity and 100% specificity using arterial phase CT images.
Radiomics machine learning algorithm facilitates detection of small pancreatic neuroendocrine tumors on CT.
Lopez-Ramirez F, Soleimani S, Azadi JR, Sheth S, Kawamoto S, Javed AA, Tixier F, Hruban RH, Fishman EK, Chu LC.
Diagn Interv Imaging. 2024 Sep 14:S2211-5684(24)00172-4. doi: 10.1016/j.diii.2024.08.003. Epub ahead of print. 
Radiomics machine learning algorithm facilitates detection of small pancreatic neuroendocrine tumors on CT.
Lopez-Ramirez F, Soleimani S, Azadi JR, Sheth S, Kawamoto S, Javed AA, Tixier F, Hruban RH, Fishman EK, Chu LC.
Diagn Interv Imaging. 2024 Sep 14:S2211-5684(24)00172-4. doi: 10.1016/j.diii.2024.08.003. Epub ahead of print.
Radiomics machine learning algorithm facilitates detection of small pancreatic neuroendocrine tumors on CT.
Lopez-Ramirez F, Soleimani S, Azadi JR, Sheth S, Kawamoto S, Javed AA, Tixier F, Hruban RH, Fishman EK, Chu LC.
Diagn Interv Imaging. 2024 Sep 14:S2211-5684(24)00172-4. doi: 10.1016/j.diii.2024.08.003. Epub ahead of print.
Radiomics machine learning algorithm facilitates detection of small pancreatic neuroendocrine tumors on CT.
Lopez-Ramirez F, Soleimani S, Azadi JR, Sheth S, Kawamoto S, Javed AA, Tixier F, Hruban RH, Fishman EK, Chu LC.
Diagn Interv Imaging. 2024 Sep 14:S2211-5684(24)00172-4. doi: 10.1016/j.diii.2024.08.003. Epub ahead of print.- “In conclusion, this study demonstrates the feasibility of radiomics-based tools, with features extracted from manual and automatic pancreas segmentations, to detect small PanNETs with higher sensitivity than two experienced radiologists.These preliminary results suggest that radiomics could potentially serve as a second reader or opportunist screener for detection of low-stage disease and ultimately impact clinical care.”
Radiomics machine learning algorithm facilitates detection of small pancreatic neuroendocrine tumors on CT.
Lopez-Ramirez F, Soleimani S, Azadi JR, Sheth S, Kawamoto S, Javed AA, Tixier F, Hruban RH, Fishman EK, Chu LC.
Diagn Interv Imaging. 2024 Sep 14:S2211-5684(24)00172-4. doi: 10.1016/j.diii.2024.08.003. Epub ahead of print.
- “PNETs constitute up to 3% of clinically detected pancreatic tumors. Differentiating PNET from IPAS on CT is challenging as both may appear as well-circumscribed arterial phase enhancing lesions. Cinematic rendering is a 3D postprocessing technology that uses an advanced global lighting mode to generate photorealistic images. The precision with which cinematic rendering simulates intricate interactions of light passing through imaged volumes yields superb surface detail and textural perception.”
Cinematic Rendering for Differentiation of Pancreatic Neuroendocrine Tumor From Intrapancreatic Accessory Spleen.
Ahmed TM, Fishman EK.
AJR Am J Roentgenol. 2024 Mar;222(3):e2430862.
- “PNETs constitute up to 3% of clinically detected pancreatic tumors. Differentiating PNET from IPAS on CT is challenging as both may appear as well-circumscribed arterial phase enhancing lesions. Cinematic rendering is a 3D postprocessing technology that uses an advanced global lighting mode to generate photorealistic images. The precision with which cinematic rendering simulates intricate interactions of light passing through imaged volumes yields superb surface detail and textural perception.”
Cinematic Rendering for Differentiation of Pancreatic Neuroendocrine Tumor From Intrapancreatic Accessory Spleen.
Ahmed TM, Fishman EK.
AJR Am J Roentgenol. 2024 Mar;222(3):e2430862.
- “Pancreatic neuroendocrine tumours (PNETs) are a rare subset of pancreatic tumours that have historically comprised up to 3% of all clinically detected pancreatic tumours. In recent decades, however, advancements in imaging have led to an increased incidental detection rate of PNETs and imaging has played an increasingly central role in the initial diagnostics and surgical planning of these tumours. Cinematic rendering (CR) is a 3D post-processing technique that generates highly photorealistic images through more realistically modelling the path of photons through the imaged volume. This allows for more comprehensive visualization, description, and interpretation of anatomical structures. In this 2-part review article, we present the first description of the various CR appearances of PNETs in the reported literature while providing commentary on the unique clinical opportunities afforded by the adjunctive utilization of CR in the workup of these rare tumours.”
Cinematic Rendering of Pancreatic Neuroendocrine Tumours: Opportunities for Clinical Implementation: Part 1: Tumour Detection and Characterization
Ahmed TM, Fishman EK, Chu LC.
Can Assoc Radiol J. 2024 Mar 20:8465371241239035. Epub ahead of print. PMID: 38509705. - At CT, PNETs typically appear as well circumscribed avidly enhancing masses that may arise from any portion of the pancreas. Enhancement patterns for small PNETs are usually uniform, and some may present with a characteristic rim enhancement that can help clue in the diagnosis. The degree and homogeneity of lesion enhancement is correlated with tumour grade, and among larger PNETs, which predominantly consist of non-hyperfunctioning variants, the presence of cystic degeneration, intralesional necrosis and calcification can result in an inhomogeneous pattern of enhancement. PNETs are classically best visualized in the arterial phase. While smaller PNETs can be particularly difficult to see on venous or delayed images, a small proportion of PNETs may atypically be better visualized on portal venous phase imaging.
Cinematic Rendering of Pancreatic Neuroendocrine Tumours: Opportunities for Clinical Implementation: Part 1: Tumour Detection and Characterization
Ahmed TM, Fishman EK, Chu LC.
Can Assoc Radiol J. 2024 Mar 20:8465371241239035. Epub ahead of print. PMID: 38509705. - Differential diagnoses of PNETs consist of pancreatic metastases, most often from renal cell carcinoma, solid variant serous cystadenoma, peripancreatic gastrointestinal stromal tumour, and intrapancreatic accessory spleen.5 In rarer cases of hypovascular PNETs, differentiation from adenocarcinoma is essential and carries significant implications for management.
Cinematic Rendering of Pancreatic Neuroendocrine Tumours: Opportunities for Clinical Implementation: Part 1: Tumour Detection and Characterization
Ahmed TM, Fishman EK, Chu LC.
Can Assoc Radiol J. 2024 Mar 20:8465371241239035. Epub ahead of print. PMID: 38509705. - “Cinematic rendering may allow for the detection of the presence of tumour in cases where subtle textural changes due to inherent differences between normal and abnormal tissue are present, but a defined mass is not yet visible. Through this, CR can potentially facilitate early disease detection and help differentiate PNETs from normal pancreatic parenchyma. CR can similarly assist in differentiating PNETs from intrapancreatic accessory spleens through accentuating textural differences that may not be appreciable at non-cinematic imaging . Display configurations of CR may also be manipulated to conceal uninvolved pancreatic parenchyma, allowing for isolated visualization of PNETs. This can make tumours remarkably conspicuous as well as highlight the spatial relationship of the tumour with extra-pancreatic anatomy.”
Cinematic Rendering of Pancreatic Neuroendocrine Tumours: Opportunities for Clinical Implementation: Part 1: Tumour Detection and Characterization
Ahmed TM, Fishman EK, Chu LC.
Can Assoc Radiol J. 2024 Mar 20:8465371241239035. Epub ahead of print. PMID: 38509705. - “While PNETs are typically solid tumours, the presence of cystic internal components is not uncommon, with up to 10% of PNETs being purely cystic. Cystic components in PNETs are most often encountered among larger PNETs that undergo cystic degeneration or necrosis. Rarely, small PNETs with cystic change are also encountered and can pose diagnostic challenges. Purely cystic PNETs generally exhibit more indolent behaviour and carry more favourable prognoses, which has also led to the rise of conflicting opinions regarding the value of resection in these cases.”
Cinematic Rendering of Pancreatic Neuroendocrine Tumours: Opportunities for Clinical Implementation: Part 1: Tumour Detection and Characterization
Ahmed TM, Fishman EK, Chu LC.
Can Assoc Radiol J. 2024 Mar 20:8465371241239035. Epub ahead of print. PMID: 38509705. - “Purely cystic PNETs generally exhibit more indolent behaviour and carry more favourable prognoses, which has also led to the rise of conflicting opinions regarding the value of resection in these cases.19 Simultaneously however, cystic PNET can be misdiagnosed as a potentially malignant cystic lesion (ie, mucinous cystic neoplasm, intraductal papillary neoplasm) that ought to be resected, or a benign cystic lesion (ie, serous cystadenoma) for which surgery is not indicated, which can lead to suboptimal patient outcomes. Radiological characterization of the internal architecture of these tumours is therefore particularly important due to the wide range of potential implications upon management.”
Cinematic Rendering of Pancreatic Neuroendocrine Tumours: Opportunities for Clinical Implementation: Part 1: Tumour Detection and Characterization
Ahmed TM, Fishman EK, Chu LC.
Can Assoc Radiol J. 2024 Mar 20:8465371241239035. Epub ahead of print. PMID: 38509705.. - “Cinematic rendering is uniquely suited to visualization of these cases through its ability to greatly improve depth perception. Improved depth perception, in conjunction with dynamic textural visualization of CR may allow for optimal characterization of the internal architecture of cystic components. This can result in superior visualization of fine internal septations and mural nodularity within these lesions that may help in differentiating them from other cystic pancreatic lesions. In particular, the presence of an avidly enhancing hypervascular rim, owing to the rich blood supply of PNETs, is known to be a highly suggestive radiologic feature of cystic PNETs. Improved characterization of the cystic mural interface using CR may be especially advantageous in appreciating this key finding.”
Cinematic Rendering of Pancreatic Neuroendocrine Tumours: Opportunities for Clinical Implementation: Part 1: Tumour Detection and Characterization
Ahmed TM, Fishman EK, Chu LC.
Can Assoc Radiol J. 2024 Mar 20:8465371241239035. Epub ahead of print. PMID: 38509705. 
- “Precise evaluation of the presence and extent of vascular invasion is essential in determining the resectability of PNETs and to plan for possible vascular reconstruction. Though CT is considered to have excellent sensitivity in identifying major vessel involvement, prior studies have found that 25% to 50% of patients with PNETs who are radiologically determined to have vascular invasion, are confirmed to have true vascular invasion at the time of surgery. On the more concerning flipside of this, it is similarly possible that patients with softer radiological signs of vascular invasion may be denied surgery due to perceived vascular involvement in the absence of true involvement. In these equivocal cases, vascular abutment may be misinterpreted as vascular encasement and vice versa. CR may alleviate the diagnostic burden in these cases by generating exquisitely detailed vascular maps that allow radiologists to visualize the tumour-vessel interface with increased confidence. Through this, it may be possible to differentiate vascular stretching, abutment, and compression from true vessel invasion. Radiological assessment of vascular involvement in PNETs is also uniquely nuanced as PNETs may not traditionally encase vessels but instead tend to invade and expand venous vasculature.”
Cinematic Rendering of Pancreatic Neuroendocrine Tumours: Opportunities for Clinical Implementation: Part 2: Preoperative Planning and Evaluation of Metastatic Disease.
Ahmed TM, Fishman EK, Chu LC.
Can Assoc Radiol J. 2024 Mar 20:8465371241239035. Epub ahead of print. PMID: 38509705. - “Unlike PDAC, the presence of hepatic metastases in PNETs does not preclude surgical resection, and potentially curative resection of the primary tumour and metastatic hepatic implants is still possible in up to 25% of patients.14 Timely radiological identification of hepatic metastases and subsequent deliberation of their resectability is therefore critical to the management of metastatic PNETs. Using CR, rendering parameters can be modified to either highlight the characteristically hypervascular metastases but may also be adjusted to optimize visualization in cases of atypical hypovascular-appearing metastases. Display settings can also be further modified to render the background hepatic parenchyma translucent to further accentuate any hepatic metastases. Once lesions are identified, the enhanced depth perception of CR can also help differentiate them from benign liver lesions through improving visualization of their internal architecture. “
Cinematic Rendering of Pancreatic Neuroendocrine Tumours: Opportunities for Clinical Implementation: Part 2: Preoperative Planning and Evaluation of Metastatic Disease.
Ahmed TM, Fishman EK, Chu LC.
Can Assoc Radiol J. 2024 Mar 20:8465371241239035. Epub ahead of print. PMID: 38509705. - “CR augmentation also has the potential to go beyond optimizing disease detection and classification and may also impact surgical planning. This is achieved through the generation of photorealistic images that essentially serve as personalized anatomic models for the operating team. Anecdotally, pancreatic surgeons at our institution have found these reconstructions helpful for preoperative planning and in improving intraoperative situational awareness. This is particularly relevant in cases of laparoscopic surgery, where real-time intraoperative visualization is restricted.”
Cinematic Rendering of Pancreatic Neuroendocrine Tumours: Opportunities for Clinical Implementation: Part 2: Preoperative Planning and Evaluation of Metastatic Disease.
Ahmed TM, Fishman EK, Chu LC.
Can Assoc Radiol J. 2024 Mar 20:8465371241239035. Epub ahead of print. PMID: 38509705. - “While CR has shown promise in enhancing the diagnostics and surgical planning of PNETs in our institution, there remain certain limitations that hinder broader adoption. One significant constraint revolves around the specialized expertise required to generate CR images. Optimization of CR images is crucial to accurately represent the anatomy and pathology of interest. This task demands the dedicated training of radiologists who need to customize the display settings for each specific pathology. Using incorrect parameters can impede visualization and may result in incorrect diagnoses. This is compounded by the shadowing effects generated by the CR global lighting model which if not duly accounted for may potentially obscure visualization of significant pathology. As CR becomes more widely adopted, this aspect of CR is anticipated to become more standardized and perhaps even automated.”
Cinematic Rendering of Pancreatic Neuroendocrine Tumours: Opportunities for Clinical Implementation: Part 2: Preoperative Planning and Evaluation of Metastatic Disease.
Ahmed TM, Fishman EK, Chu LC.
Can Assoc Radiol J. 2024 Mar 20:8465371241239035. Epub ahead of print. PMID: 38509705. - “CR holds promising potential for enhancing the diagnostics and surgical planning of PNETs. Part 2 of this pictorial review highlights the utility of CR in vascular mapping, preoperative planning, and evaluation of metastatic disease of PNETs. In the words of Dr. O’Brien, cinematic rendering, though still in its infancy, is an exciting technique; future studies investigating implementation of CR into clinical practice have potential to add great value to our practice.”
Cinematic Rendering of Pancreatic Neuroendocrine Tumours: Opportunities for Clinical Implementation: Part 2: Preoperative Planning and Evaluation of Metastatic Disease.
Ahmed TM, Fishman EK, Chu LC.
Can Assoc Radiol J. 2024 Mar 20:8465371241239035. Epub ahead of print. PMID: 38509705.
- “Pancreatic neuroendocrine neoplasms (PaNENs) represent a unique class of neoplasm that are distinct from the more common pancreatic adenocarcinoma in histology, management, and prognosis. PaNENs are relatively rare, making up just 3–5% of all pancreatic cancers with an incidence of 2.5–5 per 100,000 globally and 0.48 per 100,000 population annually in the USA. During 2000–2016, the incidence of PaNEN significantly rose from 0.27 to 1.06 per 100,000 persons with an average annual percentage change of 9.4 . There is some speculation that the increased incidence may be partly related to widespread increase in the use of cross-sectional diagnostic imaging [namely computed tomography (CT) and magnetic resonance imaging (MRI)] during that period.”
Pancreatic neuroendocrine neoplasms: a 2022 update for radiologists
Samuel J. Galgano et al.
Abdominal Radiology (2022) 47:3962–3970 - “The proliferative index and/or the number of mitoses/2mm2 [7]. The PaNENs with a Ki-67 index of less than 3% and/or a mitotic count of less than 2 mitoses/2 mm2 are defined as low grade or grade1 (G1) tumors. Intermediate grade or grade 2 (G2) tumors have a Ki-67 index between 3 and 20% or a mitotic count between 2 and 20 mitoses/2 mm2, while high grade or grade 3 (G3) tumors have a Ki-67 index of greater than 20% or a mitotic count of greater than 20 mitoses/2 mm2. Critically, the 2017 WHO criteria separated these well-differentiated G3 PaNENs from poorly differentiated G3 neuroendocrine carcinoma based on tumor cell morphology.”
Pancreatic neuroendocrine neoplasms: a 2022 update for radiologists
Samuel J. Galgano et al.
Abdominal Radiology (2022) 47:3962–3970 - "PaNENs are complex, heterogeneous tumors and range in behavior from indolent lesions to aggressive lesions with potential to metastasize. Thus, knowledge of PaNEN pathology is essential to direct imaging and treatment decisions. Use of cross-sectional imaging with multiphasic CT or MRI and functional imaging utilizing several PET tracers provides comprehensive staging information and allows for accurate non-invasive evaluation of metastatic disease. Understanding both NCCN and NANETS guidelines is helpful in understanding the management and follow-up of patients with PaNENs and helps to bridge the gap between radiologists and treating clinicians.”
Pancreatic neuroendocrine neoplasms: a 2022 update for radiologists
Samuel J. Galgano et al.
Abdominal Radiology (2022) 47:3962–3970
- “Von Hippel–Lindau (VHL) disease is a rare autosomal dominantly inherited familial syndrome with an incidence of 2–3 cases per 100,000 population . Approximately 65–75% of patients with VHL as a component of multi-visceral tumors have some form of pancreatic lesions (cystic and solid tumors) .The incidence of pancreatic lesions among the VHL population varies considerably among different kindred. An incidence rate of 37% in Hawaiian VHL kindred was reported compared with 0% in Newfoundland VHL kindred. The pancreatic lesions can be benign or malignant, can produce symptoms due to the mass effect or hormonal activity, can present as recurrent multifocal lesions, or be associated with lesions involving several organs simultaneously. Thus, it is of paramount importance to understand the management of various pancreatic manifestations of VHL.”
Pancreatic manifestations in von Hippel–Lindau disease: A case report
Subhashini Ayloo, Michele Molinari
International Journal of Surgery Case Reports 21 (2016) 70–72 - “Patients with VHL disease are found to have retinal angiomas, renal cell carcinomas, pheochromocytomas, CNS hemangioblastomas, tumors of the inner ear and epididymis, cystic lesions of the ovaries, and cystic and endocrine tumors of the pancreas. The clinical diagnostic criteria, as proposed in 1964 by Melmon and Rosen for VHL disease, are as follows: (i) greater than one CNS hemangioblastoma; (ii) CNS hemangioblastoma in combination with visceral manifestation of VHL disease; and (iii) any manifestation and a known family history of VHL disease.”
Pancreatic manifestations in von Hippel–Lindau disease: A case report
Subhashini Ayloo, Michele Molinari
International Journal of Surgery Case Reports 21 (2016) 70–72 - “Pancreatic neuroendocrine tumors (pNETs) are found in 5–17% of VHL disease patients [8]. Often of islet cell tumor origin and often found in women (66%) at a median age of 38 years, 17–25% of pNETs have metastasized at the time of diagnosis. On the other hand, most cystic manifestations of VHL disease are benign, but differentiation of these lesions from premalignant cystic lesions, such as intraductal papillary mucinous neoplasms or mucinous cystadenomas is mandatory. Because renal cell carcinoma is one of the components of VHL disease, metastatic lesions to the pancreas should also be considered in the differential diagnosis.”
Pancreatic manifestations in von Hippel–Lindau disease: A case report
Subhashini Ayloo, Michele Molinari
International Journal of Surgery Case Reports 21 (2016) 70–72 - Pancreatic Lesions in VHL
- IPMN
- Serous cystadenoma
- PNET
- Metastatic RCC to pancreas
- Multiple Endocrine Neoplasia 1
- In 1953, Paul Wermer first described a familial syndrome of primary hyperparathyroidism (PHPT), pituitary adenoma, and pancreatic neuroendocrine tumor (pNET), which was termed “Wermer syndrome”. This combination of hormone-secreting tumors was later distinguished as MEN 1, which carries autosomal-dominant penetrance with a gene locus on chromosome 11. - “Approximately 90% of MEN-associated pNETs are nonfunctional. Biochemical derangements of functional primary tumors depend on the histologic subtype. The most common functional pNETs are insulinomas and gastrinomas, followed by VIPomas, glucagonomas, and somatostatinomas. Biochemical derangement can also result from primary tumor or metastatic disease exerting mass effect on adjacent structures, such as elevated bilirubin level from obstruction of the extrahepatic biliary ducts or acute pancreatitis with elevated lipase value secondary to compression of the main pancreatic duct.”
Multimodality Imaging Review of Multiple Endocrine Neoplasia
Ali A et al.
AJR 2021; 217:245–256 
- Multiple Endocrine Neoplasia 2
- MEN 2 is a less common variant of familial hormonal tumors characterized by the presence of medullary thyroid carcinoma (MTC), pheochromocytoma, and parathyroid adenoma. This condition was first reported by John Sipple in 1953 and was termed “Sipple syndrome”. This syndrome is caused by a genetic defect of the RET protooncogene on chromosome 10. MEN 2 is further divided into two variants: MEN 2A and the less common variant MEN 2B. MEN 2A is composed of MTC, pheochromocytoma, and parathyroid adenoma. MEN 2B is similar to MEN 2A but without parathyroid adenoma and has the added features of marfanoid habitus and multiple ganglioneuromas. These features are important to obtain from the referring clinician because it is difficult to detect these features on imaging. - Multiple Endocrine Neoplasia 4
- Recently, a new variation of MEN syndrome was described in a subset of MEN mutation–negative patients with MEN 1–like features. This variant was termed “MEN 4”; MEN 4 is caused by a separate gene mutation of tumor suppressor gene CDKN1B. Only 19 confirmed cases of MEN 4 have been reported in the literature. Given the small subset of MEN 4 cases, definitive conclusions are difficult to draw regarding the clinical course of this disease. However, the most common phenotype of MEN 4 is PHPT and pituitary adenoma.
- “Although typically solid and hyperenhancing, pancreatic neuroendocrine tumors can be mixed cystic and solid and, rarely, almost entirely cystic with a thick hyperenhancing rim or mural nodularity. These tumors can be multifocal, and, although they usually are sporadic, they can be associated with neurofibromatosis 1, multiple endocrine neoplasia type 1, or VHL disease. There is a relatively high degree of metastatic disease, either to lymph nodes or liver.”
Incidental Pancreatic Cysts on Cross-Sectional Imaging
Shannon M. Navarro et al.
Radiol Clin N Am 59 (2021) 617–629
- “The incidence of pancreatic neuroendocrine tumors (PNETs) has risen more than 6-fold over the last several decades, likely because of widespread use of advanced imaging studies for abdominal complaints. A subject of ongoing controversy is how to best manage small (<2 cm), incidentally discovered PNETs. Although most PNETs behave in an indolent fashion, some lesions will manifest more aggressive behavior. Surgical proce- dures play a pivotal role in the management of these tumors, as they represent the only curative treatment. Although most surgeons would advocate for resection of all functional PNETs (those causing a syndrome), recommendations to resect or observe asymptomatic or nonfunctional (NF) PNETs 2 cm or smaller vary based on data from different studies. This Viewpoint highlights the issues surrounding management strategies for patients with small NF-PNETs.”
Surgery vs Observation for Patients With Small Pancreatic Neuroendocrine Tumors
Aziz H, Howe JR, Pawlik TM
JAMA Surgery May 2021 Volume 156, Number 5 - "The European Neuroendocrine Tumor Society and the National Comprehensive Cancer Network guidelines suggest that observation is a reasonable option for pa- tients with PNETs 2 cm or smaller. The North American Neuroendocrine Tumor Society guidelines state that ob- servation is appropriate for NF-PNETs smaller than 1 cm, but management of 1- to 2-cm lesions should be individualized based on age, comorbidities, growth, grade, extent of the surgical procedure needed, and patient preference.”
Surgery vs Observation for Patients With Small Pancreatic Neuroendocrine Tumors
Aziz H, Howe JR, Pawlik TM
JAMA Surgery May 2021 Volume 156, Number 5 - “Dong et al analyzed 989 patients who underwent curative-intent resection for NF-PNETs. Of 328 patients with tumors 2 cm or smaller who underwent resection and nodal dissection, 12.8% had lymph node metastasis, which conferred a 3-fold increased risk of tumor recurrence. Of note, patients with tumors measuring 1.5 to 2 cm had a significantly higher incidence of lymph node metastasis (17.9% vs 8.7%), higher Ki-67, and a greater risk of recurrence (8.0% vs 4.5%) compared with patients with PNETs 1.5 cm or smaller. Therefore, the authors suggested that patients with NF-PNETs measuring 1.5 to 2 cm should be strongly considered for surgical resection.”
Surgery vs Observation for Patients With Small Pancreatic Neuroendocrine Tumors
Aziz H, Howe JR, Pawlik TM
JAMA Surgery May 2021 Volume 156, Number 5 - “Observation may also be preferred because pancreatic resec- tion continues to be associated with a risk of substantial morbidity as well as the potential for exocrine and endocrine insufficiency. A common cause of postoperative morbidity is postoperative pancreatic fistula, and severe postoperative complications occurred in 30% to 45% of patients who underwent surgery for small PNETs.6 Although mortality has improved over time for pancreatic resection, 30-day mortality in national databases still ranges from 4% to 8%. With these complication and mortality rates in mind, and because patients under surveillance rarely die of disease or develop distant metastasis, an initial approach of observation appears to be a safe option for many patients with NF-PNETS 2 cm or smaller.”
Surgery vs Observation for Patients With Small Pancreatic Neuroendocrine Tumors
Aziz H, Howe JR, Pawlik TM
JAMA Surgery May 2021 Volume 156, Number 5 - “For the time being, patients with tumors smaller than 1 cm can be safely observed, while those with 1- to 2-cm NF-PNETs are best served by individualized care based on factors set forth in the North American Neuroendocrine Tumor Society guidelines.”
Surgery vs Observation for Patients With Small Pancreatic Neuroendocrine Tumors
Aziz H, Howe JR, Pawlik TM
JAMA Surgery May 2021 Volume 156, Number 5
- “Most neuroendocrine tumors with or without cystic changes (> 90%) are sporadic and 10% are associated with genetic syndromes, such as MEN type 1, von Hippel–Lindau disease, neurofibromatosis type 1, and tuberous sclerosis. The most common pancreatic neoplasms in MEN1 are gastrinoma and insulinoma.”
Pearls and pitfalls of imaging features of pancreatic cystic lesions: a case‑based approach with imaging–pathologic correlation
Kumi Ozaki et al.
Japanese Journal of Radiology https://doi.org/10.1007/s11604-020-01032-1
- ”The octreoscan is 70%-95% sensitive for detecting PNETs with somatostatin receptors. However, not all PNETs have somatostatin receptors; therefore, a negative octreotide scan does not rule out PNETs. In addition, lymphocytes can also display somatostatin receptors on their surface and cause uptake of the radiolabeled analog creating a false positive. One of the two IPAS patients in our series had a false positive octreotide scan; this displays the challenges that persist in diagnosing incidental pancreatic lesions.”
Pancreatic Incidentalomas: A Management Algorithm for Identifying Ectopic Spleens
Baugh KA et al.
J Surg Res. 2019 Apr;236:144-152 - “Diagnosis of incidental distal pancreatic solid lesions like IPAS creates significant difficulty for pancreas surgeons. Our algorithm provides needed structure to the work up. Although this is designed to rule out IPAS, this algorithm can be used as a starting point for the work up of any incidentally found pancreatic mass. In the past, the work up of incidentally found lesions led to the development of useful guidelines in the adrenal gland. Therefore, establishment of protocols like the one proposed for pancreatic lesions may aid in the development of future guidelines for the pancreas.”
Pancreatic Incidentalomas: A Management Algorithm for Identifying Ectopic Spleens
Baugh KA et al.
J Surg Res. 2019 Apr;236:144-152 - “Work up of an incidental pancreatic solid lesion remains a challenge, especially for the diagnosis of IPAS. Successful diagnosis will require a strong index of suspicion, a multi- disciplinary approach, and the use of the proposed algorithm. In time, this may aid clinicians in the distinction between benign IPAS, which requires no further action and a lesion requiring resection.”
Pancreatic Incidentalomas: A Management Algorithm for Identifying Ectopic Spleens
Baugh KA et al.
J Surg Res. 2019 Apr;236:144-152
- Purpose: To assess qualitative and quantitative imaging features on enhanced CT that may differentiate pancreatic neuroendocrine tumors (PNETs) from pancreatic renal cell carcinoma (RCC) metastases.
Conclusions: Compared to pancreatic RCC metastases, PNETs are larger, more frequently solitary, contain calcification, show MPD dilation, and are subjectively and quantitatively more heterogeneous tumors.
Differentiation of pancreatic neuroendocrine tumors from pancreas renal cell carcinoma metastases on CT using qualitative and quantitative features
van der Pol CB et al.
Abdominal Radiology 2019 (in press) - “PNETs were larger than RCC metastases (37 ± 23 mm vs. 26 ± 21 mm, P = 0.038), more frequently solitary (P < 0.001), subjectively more heterogeneous (P = 0.033/0.144, R1/R2), and associated with calcification (P = 0.002/0.004) and MPD dilation (P = 0.025/0.006). Agreement for subjective features was moderate-to-almost perfect (K = 0.4879–0.9481). Quantitative texture analysis showed higher entropy in PNETs (6.32 ± 0.49 versus 5.96 ± 0.53; P = 0.004) with no difference in other features studied (P > 0.05). Entropy had ROC area under the curve for diagnosis of PNET of 0.77 ± 0.06, with optimal sensitivity/specificity of 71.4/79.1%.”
Differentiation of pancreatic neuroendocrine tumors from pancreas renal cell carcinoma metastases on CT using qualitative and quantitative features
van der Pol CB et al.
Abdominal Radiology 2019 (in press) - “Renal cell carcinoma (RCC) is among the most common primary malignancies that metastasize to the pancreas and typically appears as a hypervascular pancreatic mass on CT or MRI [. RCC metastases can resemble primary pancreatic neuroendocrine tumors (PNETs), which are also commonly hypervascular masses.”
Differentiation of pancreatic neuroendocrine tumors from pancreas renal cell carcinoma metastases on CT using qualitative and quantitative features
van der Pol CB et al.
Abdominal Radiology 2019 (in press) - “First-order texture features were extracted by histogram analysis, specifically; Kurtosis (a measure of histogram flatness), Skewness (a measure of histogram asymmetry), and Entropy (a measure of histogram irregularity) as described previously. Manual contouring of tumors was independently repeated in 17% of patients (10/60) for 17 tumors by a second fellowship-trained abdominal radiologist (NS), to assess reproducibility of segmentation.”
Differentiation of pancreatic neuroendocrine tumors from pancreas renal cell carcinoma metastases on CT using qualitative and quantitative features
van der Pol CB et al.
Abdominal Radiology 2019 (in press) - “With respect to texture analysis features studied, entropy was significantly higher in PNETs compared to RCC metastases (6.32 ± 0.49 vs. 5.96 ± 0.53, P = 0.004) with a trend towards higher levels of kurtosis and skewness, although the difference in the latter two features did not reach statistical significance between groups (P = 0.067 and 0.099, respectively).”
Differentiation of pancreatic neuroendocrine tumors from pancreas renal cell carcinoma metastases on CT using qualitative and quantitative features
van der Pol CB et al.
Abdominal Radiology 2019 (in press) - “The presence of tumor calcification and main pancreatic duct dilation were specific features for PNETs, whereas pancreatic RCC metastases tended to be smaller and were more frequently multiple. PNETs appeared subjectively and quantitatively more heterogeneous using texture analysis. Our results suggest that enhanced CT imaging features may accurately differentiate between PNET and pancreatic RCC metastases which may potentially obviate the need for histological sampling in select cases.”
Differentiation of pancreatic neuroendocrine tumors from pancreas renal cell carcinoma metastases on CT using qualitative and quantitative features
van der Pol CB et al.
Abdominal Radiology 2019 (in press) 
Differentiation of pancreatic neuroendocrine tumors from pancreas renal cell carcinoma metastases on CT using qualitative and quantitative features
van der Pol CB et al.
Abdominal Radiology 2019 (in press)- “PNETs often appear as solid hypervascular neoplasms on arterial or occasionally portal venous phase imaging. Prior work suggests that approximately 22% of PNETs contain calcification, similar to our study. Although MPD dilation is more commonly seen secondary to pancreatic adenocarcinoma rather than PNETs, a minority of PNETs have been found to cause MPD dilation, which may be due to mass effect from the tumor itself or from fibrotic stricture formation secondary to serotonin or related metabolites released by the tumor. In our study, we found that up to one-quarter of PNETs had associated MPD dilation, whereas this finding was not present for any pancreatic RCC metastases.”
Differentiation of pancreatic neuroendocrine tumors from pancreas renal cell carcinoma metastases on CT using qualitative and quantitative features
van der Pol CB et al.
Abdominal Radiology2019 (in press) - In conclusion, our study demonstrates that subjective imaging features and quantitative texture analysis may differentiate PNET from pancreatic RCC metastases. Tumor calcification, solitary masses, and MPD dilation were specific features for PNET but lacked sensitivity, whereas the quantitative texture analysis feature entropy improved sensitivity for diagnosis with moderate overall accuracy.”
Differentiation of pancreatic neuroendocrine tumors from pancreas renal cell carcinoma metastases on CT using qualitative and quantitative features
van der Pol CB et al.
Abdominal Radiology2019 (in press) - Our results suggest that imaging features at enhanced CT may accurately differentiate between pancreatic RCC metastases and PNET and could potentially obviate the need for his- tological confirmation, especially to confirm the presence of metastatic disease in patients with a history of RCC, although will require confirmation in larger sample sizes.
Differentiation of pancreatic neuroendocrine tumors from pancreas renal cell carcinoma metastases on CT using qualitative and quantitative features
van der Pol CB et al.
Abdominal Radiology2019 (in press)
- “Pancreatic NETs originate from the islet cells of Langerhans and are divided into low-, intermediate-, and high-grade according to the World Health Organization classification. High-grade NETs more frequently show vascular invasion, lymph node metastasis, and diffusion restriction compared with low-grade; therefore, high- grade NETs can mimic PDAC on images. However, high-grade NETs usually do not show pancreatic duct dilatation. In addition, they occasionally accompany tumor thrombus, which can be helpful in the differential diagnosis of high-grade NETs from PDAC. Liver metastases from NETs frequently reveal findings of hypervascularity and intralesional hemorrhage, in contrast to those from PDAC, which reveal hypovascularity.”
Pancreas Ductal Adenocarcinoma and its Mimics: Review of Cross- sectional Imaging Findings for Differential Diagnosis.
Kim, SS, et al.
Journal of the Belgian Society of Radiology. 2018; 102(1): 71, 1–8. - “SPTs are uncommon neoplasms with low malignancy potential, occurring predominantly in young women. Calcification, cystic change, and internal hemorrhage due to weak vascular channels are characteristic features of SPT. However, small (≤3 cm) SPTs show different imaging findings from larger ones, primarily a homogeneous nature. Small SPTs show a pure solid consistency, well-defined margin, and diffusion restriction on magnetic resonance (MR) imaging. After contrast infusion, small SPTs reveal an early heterogenous nature, followed by a progressive enhancement pattern.”
Pancreas Ductal Adenocarcinoma and its Mimics: Review of Cross- sectional Imaging Findings for Differential Diagnosis.
Kim, SS, et al.
Journal of the Belgian Society of Radiology. 2018; 102(1): 71, 1–8.
- VIPomas are rare tumors with an incidence of 0.05% to 2.0% and can occur both in children and adults. In adults, they occur most commonly between the ages of 30 to 50 years and are mostly intra-pancreatic (95%). A small proportion of tumors secreting VIP have been reported as colorectal cancer, lung cancer, pheochromocytoma, neurofibroma, and ganglioneuroblastoma. Majority of VIPomas occur as isolated tumors, but in about 5% of patients, they are part of the multiple endocrine neoplasia type 1 (MEN1) syndromes. More than 50% of VIPomas have metastasized by the time of diagnosis.
- Excessive secretion of VIP from the tumor has multiple effects on different organ systems, with its primary effects being on the GI system. VIP is a neurotransmitter belonging to the secretin- glucagon family and consists of 28 amino acids. It is a potent stimulator of intestinal cyclic adenosine monophosphate (cAMP) production and inhibitor of gastric acid secretion. It promotes vasodilation, glycogenolysis, lipolysis, and bone resorption. Effects secondary to these actions of VIP include huge secretion of water and electrolytes from the GI epithelial cells, hypokalemia, facial flushing, decreased gastric acidity, elevated blood glucose, and hypercalcemia.
- Diagnosis of VIPoma is made in patients with secretory diarrhea usually greater than 3.0 liters per day with a serum VIP level around 250 to 500 pg/ml (reference range is less than 190 pg/ml). Secretory diarrhea has a low fecal osmotic gap of less than 50 mOsm/kg. It is important to repeat levels of VIP to confirm diagnosis since levels may not be elevated between episodes of watery diarrhea. It is also imperative to determine VIP levels when the patient is symptomatic, as the VIPoma may only secrete VIP intermittently. Hence, a normal level may be a false negative. Among children suspected with VIPoma, catecholamine levels should also need to be measured. Levels of pancreatic polypeptide are elevated in tumors originating from the pancreas.
- “Multidetector computed tomography now offers a powerful tool for the evaluation, diagnosis, and risk stratification of pancreatic cystic neoplasms. Improvements in image quality and spatial reso- lution, as well as sophisticated 3-D reconstruction techniques, allow exquisite assessment of the internal architecture of these lesions that not only may allow the radiologist to provide a specific diagnosis but also to assess features that might predict the risk of malignancy.”
Multidetector Computed Tomography in the Evaluation of Cystic Tumors of the Pancreas Siva P. Raman, Elliot K. Fishman (in) Cystic Tumors of the Pancreas: Diagnosis and Treatment Marco Del Chiaro, StephanL.Haas, RichardD.Schulick Editors © Springer International Publishing Switzerland 2016 - “Cystic neuroendocrine tumors almost always demonstrate the presence of either a peripheral “rind” of hypervascular enhancing solid tissue or, alternatively, hyperenhancing mural nodularity along the margins of the cyst. This diagnosis is one of the primary reasons for the inclusion of arterial phase images in the evaluation of a suspected pancreatic cystic neoplasm, as both the solid rim and mural nodularity associated with these lesions are almost always most conspicuous on the arterial phase and may be more difficult to appreciate on venous phase imaging.”
Multidetector Computed Tomography in the Evaluation of Cystic Tumors of the Pancreas Siva P. Raman, Elliot K. Fishman (in) Cystic Tumors of the Pancreas: Diagnosis and Treatment Marco Del Chiaro, StephanL.Haas, RichardD.Schulick Editors © Springer International Publishing Switzerland 2016 - “Unfortunately, given that the hypervascular components may be less conspicuous on the venous phase, these lesions are not infre- quently incorrectly diagnosed as IPMN when only a venous phase is acquired. In addition, the presence of other signs of metastatic dis- semination can also be a strong clue to the correct diagnosis, including hyperenhancing liver or lymph node metastases.”
Multidetector Computed Tomography in the Evaluation of Cystic Tumors of the Pancreas Siva P. Raman, Elliot K. Fishman (in) Cystic Tumors of the Pancreas: Diagnosis and Treatment Marco Del Chiaro, StephanL.Haas, RichardD.Schulick Editors © Springer International Publishing Switzerland 2016
- “Thirty-three patients suspected of having a functioning tumor of the pancreas were studied with computed tomography (CT); 25 had angiographic studies also. Thirty-one cases were confirmed surgically; the other two were lost at follow-up and were excluded from the series. Of the 31 patients, 21 had insulinomas, five had Zollinger-Ellison syndrome, and five had assorted apudomas. CT was positive in 71% of the cases and negative in 29%; 22.6% of the studies were false negative and 6.4% were true negative. There were no false positives. Of the 21 patients with insulinomas, only one had false-negative CT and angiographic studies, caused by diffuse microadenomatosis. In one patient, two separate lesions of the pancreas were seen and identified correctly on both CT and angiography. All identified lesions smaller than 2 cm were seen only because of a hyperdensity on the enhanced CT scan. Lesions larger than 2 cm were identified either because their size distorted the pancreatic contour or because of their vascularity. The importance of proper CT technique using fast scanners and repeated bolus injections of contrast medium is stressed.”
CT of functioning tumors of the pancreas. Rossi P et al. AJR Am J Roentgenol. 1985 Jan;144(1):57-60. - “Thirty-three patients suspected of having a functioning tumor of the pancreas were studied with computed tomography (CT); 25 had angiographic studies also. Thirty-one cases were confirmed surgically; the other two were lost at follow-up and were excluded from the series. Of the 31 patients, 21 had insulinomas, five had Zollinger-Ellison syndrome, and five had assorted apudomas. CT was positive in 71% of the cases and negative in 29%; 22.6% of the studies were false negative and 6.4% were true negative.”
CT of functioning tumors of the pancreas. Rossi P et al. AJR Am J Roentgenol. 1985 Jan;144(1):57-60. - “Thirty-three patients suspected of having a functioning tumor of the pancreas were studied with computed tomography (CT); 25 had angiographic studies also. Thirty-one cases were confirmed surgically; the other two were lost at follow-up and were excluded from the series. Of the 31 patients, 21 had insulinomas, five had Zollinger-Ellison syndrome, and five had assorted apudomas. CT was positive in 71% of the cases and negative in 29%; 22.6% of the studies were false negative and 6.4% were true negative.”
CT of functioning tumors of the pancreas. Rossi P et al. AJR Am J Roentgenol. 1985 Jan;144(1):57-60. - Pancreatic neuroendocrine tumors (PNETs): Facts
- 1% to 2% of all pancreatic neoplasms
- Functioning vs non-functioning tumors
- Local invasiveness of tumors will vary
- May be syndrome related (MEN 1)
- Surgery is usually treatment of choice - Pancreatic neuroendocrine tumors (PNETs): Presentation
- Functioning tumors produce a range of hormones including;
insulin (hypoglycemia)
gastrin
glucagon
vasoactive intestinal peptide (VIP)
somatostatin - Pancreatic neuroendocrine tumors (PNETs): Detection
- Computed Tomography (CT)
- Magnetic Resonance Imaging (MRI)
- Ultrasound
- EUS (endoscopic ultrasound)
- Catheter Angiography
- Nuclear Medicine Studies - Pancreatic neuroendocrine tumors (PNETs): CT
- Incidental finding as 70% of lesion are non-functioning
- Frequency of detection of incidental PNET is based on protocol design including phase(s) of acquisition, multiphase acquisition, contrast injection rate and timing - Surgical Management: Options
- All tumors greater than 2 cm should be resected, typically with formal anatomic resection (pancreaticoduodenectomy, distal pancreatectomy) including negative margins and regional lymph nodes.
- Evidence suggests incidental tumors less than 1 cm can be followed with surveillance. - Surgical Management: Options
- Some studies with short-term follow-up suggest that all nonfunctioning PNET less than 2 cm might be followed with surveillance, with resection for growth.
- Pancreatic enucleation is most appropriate for small PNETs; lymph node resection should be considered for tumors 1 to 2 cm in size. - Surgical Management: Options
MEN1 is associated with small, multifocal tumors, most of which have a low risk of progression. Surgery is reserved for tumors greater than 1 to 2 cm in size.
Surgical Management of Pancreatic Neuroendocrine Tumors Thomas E. Clancy Hematology/Oncology Clinics of North America Volume 30, Issue 1, February 2016, Pages 103–118 - “The World Health Organization classifies neuroendocrine tumors into different grades based on histologic characteristics. Well-differentiated tumors include low-grade (G1) tumors with a low mitotic count and Ki-67 proliferative index of less than 3% as well as intermediate-grade (G2) tumors with mitotic counts of 2 to 20 per high-power field (HPF) and Ki-67 rate of 3% to 20%. Poorly differentiated tumors or high-grade (G3) tumors have mitotic rates more than 2 per 10 HPF and Ki-67 rate of greater than 20%. High-grade tumors, often referred to as neuroendocrine carcinomas, display more aggressive clinical behavior and unlike, well-differentiated tumors, are generally not candidates for surgical resection.”
Surgical Management of Pancreatic Neuroendocrine Tumors Thomas E. Clancy Hematology/Oncology Clinics of North America Volume 30, Issue 1, February 2016, Pages 103–118 - “Studies have demonstrated a direct relationship between tumor size and risk of metastases.56 With increased utilization and improved accuracy of cross-sectional imaging, an increasing number of incidental, small (<2.0 cm) PNETs are now identified. Given that only 6% of nonfunctional PNETs less than 2 cm in size will be metastatic at diagnosis, some suggests a conservative strategy; the optimal management of these more indolent neoplasms is debated.”
Surgical Management of Pancreatic Neuroendocrine Tumors Thomas E. Clancy Hematology/Oncology Clinics of North America Volume 30, Issue 1, February 2016, Pages 103–118 - Small diameter at diagnosis (<2 cm) is not an assurance of a benign behavior, and no size cut-off exists beyond which malignancy can be excluded safely. As a consequence, most institutions have recommended operative resection for all patients with NF-pNETs. However, pancreatic resections are associated with a risk of postoperative morbidity, mortality, and of long-term complications, even in high-volume centers. In this light, some authors proposed clinical surveillance rather than surgery for selected patients with small, incidentally discovered NF-pNET (i.e., older patients with comorbidities).
Incidental diagnosis as prognostic factor in different tumor stages of nonfunctioning pancreatic endocrine tumors Crippa S et al. Surgery Vol 155, Issue 1, January 2014, Pages 145–153 - “The absence of symptoms is not an assurance of benign behavior, even in small tumors. In a previous report we showed that only 6% of incidental NF-pNETs than 2 cm in size had malignancy, but no patient died of disease after a median follow-up of 47 months. A similar malignancy-rate (7.7%) in this subgroup of patients is reported by Haynes et al.”
Incidental diagnosis as prognostic factor in different tumor stages of nonfunctioning pancreatic endocrine tumors Crippa S et al. Surgery Vol 155, Issue 1, January 2014, Pages 145–153
- “Somatostatin-receptor scintigraphy
Similar to MRI, SRS is often used to localize PNETs when traditional cross-sectional imaging fails. SRS uses radiolabeled somatostatin analogues that bind to receptors expressed by the PNET.47 Hence, lesions with few somatostatin receptors, such as insulinomas, are often missed with this technique. The standard method of performing SRS is with injection of 111In-DTPA-octreotide (OctreoScan). SRS is particularly useful in assessing the burden of extrapancreatic metastatic disease, and also should be routinely performed to assess the somatostatin receptor status before treatment with somatostatin analogues. Overall, the sensitivity of SRS to detect gastrinomas, VIPomas, glucagonomas, and nonfunctioning PNETs ranges from 75% to 100%; however, for insulinomas, the sensitivity falls to 50% to 60%.”
Islet Cell Tumors of the Pancreas Sunil Amin, Michelle Kang Kim Gastroenterol Clin N Am 45 (2016) 83–100 - “Although 90% of PNETs occur sporadically, these tumors are also well-recognized features of 4 familial syndromes: multiple endocrine neoplasia type I (MEN1), von Hippel-Lindau syndrome (VHL), neurofibromatosis type 1 (NF1), and tuberous scle- rosis complex (TSC).7,8 Each of these syndromes is inherited in an autosomal domi- nant pattern, and the causative genes are MEN1, VHL, NF1, and TSC1/2, respectively.”
Islet Cell Tumors of the Pancreas Sunil Amin, Michelle Kang Kim Gastroenterol Clin N Am 45 (2016) 83–100 - “Von Hippel-Lindau Syndrome
Although pancreatic lesions are common in VHL, only 10% to 17% of patients with VHL develop PNETs. Furthermore, almost all VHL-associated PNETs are nonfunctioning. The mean age of diagnosis of PNETs is 29 to 38 years, and unlike MEN1, most of these lesions are solitary as opposed to multifocal.”
Islet Cell Tumors of the Pancreas Sunil Amin, Michelle Kang Kim Gastroenterol Clin N Am 45 (2016) 83–100 - “The clinical presentation of PNETs is frequently divided into 2 broad categories: functioning and nonfunctioning tumors. Functional tumors present with a defined clinical syndrome secondary to hormone hypersecretion. Functional PNETs included insulino- mas, gastrinomas, glucagonomas, VIPomas, and somatostatinomas. Nonfunctional tumors, which compromise 60% to 90% of all PNETs, do not present with symptoms related to hormone hypersecretion, although in some cases circulating hormone levels may be elevated nonetheless.”
Islet Cell Tumors of the Pancreas Sunil Amin, Michelle Kang Kim Gastroenterol Clin N Am 45 (2016) 83–100 - “The enhancement characteristics of a PNET on CT may also have prognostic value, as lesions that hypoenhance on CT scan tend to have worse overall survival than lesions that are isoenhancing or hyperenhancing (5-year survival 54% vs 89% vs 93%).”
Islet Cell Tumors of the Pancreas Sunil Amin, Michelle Kang Kim Gastroenterol Clin N Am 45 (2016) 83–100 - “MEN1 is characterized by PNETs in association with pituitary and parathyroid tumors. Almost all patients with MEN1 (>95%) will develop a PNET during their lifetime, although most of these will be nonfunctioning “micro-adenomas” (smaller than 0.5 cm) that are typically multifocal. Fewer than 15% of these nonfunctioning tumors will be large enough to be symptomatic.10 Functioning PNETs that are symptom- atic occur in between 20% and 70% of patients with MEN1, with approximately 55% of these patients presenting with Zollinger-Ellison (ZE) syndrome due to an underlying gastrinoma, and 20% presenting with symptoms from an insulinoma.”
Islet Cell Tumors of the Pancreas Sunil Amin, Michelle Kang Kim Gastroenterol Clin N Am 45 (2016) 83–100 - “Other functioning PNETs, such as VIPoma, glucagonoma, and somatostatinoma occur in fewer than 3% of patients with MEN1.12 The management of patients with MEN1 with PNETs is of particular significance, as PNETs are the leading cause (40%) of disease-specific mortality among patients with MEN1.13,14 Furthermore, the mean age of death among patients with MEN1 with PNETS is 55 years, which is lower than that of both the gen- eral population and patients with non-MEN1 PNETs.”
Islet Cell Tumors of the Pancreas Sunil Amin, Michelle Kang Kim Gastroenterol Clin N Am 45 (2016) 83–100
- “Once a diagnosis of Cystic Pancreatic Neuroendocrine Tumors (CPEN) has been established, the recommended treatment is surgical resection. Although some series suggest that CPENs have a lower Ki67 proliferative index and risk of carcinoma than solid PNETs, CPENs still harbor an 11% to 14% risk of malignancy and 8% to 14% risk of nodal or distant metastases, necessitating surgical resection as the only potential curative treatment.” Diagnosis and Management of Pancreatic Cystic Neoplasms Kim TS, Fernandez-del Castillo C Hematology/Oncology Clin North America Volume 29, Issue 4, August 2015, Pages 655–674
- What if the pancreatic mass is vascular?
• Vascular Pancreatic Mass: Differential Dx
• Neuroendocrine tumor (PNET)
• Metastases to the Pancreas
• Serous Cystadenoma (vascular border on arterial phase images) - Vascular Pancreatic Mass: Differential Dx
• Neuroendocrine tumor (PNET) are the most classic vascular lesions and range in size from 5mm to 20 cm
• Metastases to the Pancreas are usually from renal cell carcinoma but occur 10-15 years after the primary tumor has been resected.
• Pearl: if the patient has an absent kidney think metastatic renal cell carcinoma - Vascular Pancreatic Mass: Differential Dx
• Serous Cystadenoma (vascular border on arterial phase images) are rarely put in the vascular mass category but can have a vascular rim with stretching of the hepatic Artery or SMA. This is uncommon but can be a great mimicker of a PNET.
- “Incidental detection of pancreatic neuroendocrine tumors (PNETs) has substantially increased over the last decade due to widespread use of advanced imaging studies. Reliable initial imaging-based characterization is crucial for the differential diagnosis from other exocrine neoplasms and to determine the appropriate management plan.”
Aace/Ace disease state clinical review: pancreatic neuroendocrine incidentalomas. Herrera MF et al. Endocr Pract. 2015 May;21(5):546-53 - “It has been suggested that non-MEN related, nonfunctioning, and asymptomatic PNETs <2 cm with a Ki-67 index ≤2% carry a low risk of metastasis and may be observed in the absence of clinical or radiologic criteria of malignancy or progression, especially in older patients. However, because metastases may occur with long delay with smaller PNETS, physicians should consider patient age, lesion location, and the risks of operation, and patients not undergoing surgery need to be closely followed closely.”
Aace/Ace disease state clinical review: pancreatic neuroendocrine incidentalomas. Herrera MF et al. Endocr Pract. 2015 May;21(5):546-53 - “The natural history of pancreatic neuroendocrine tumors (panNETs) is extremely variable. One of the most controversial problems in diagnosis is the accurate prediction of the clinical behavior of these tumors. PanNETs that behave aggressively with a malignant course may have bland cytologic features, while some tumors with previously described "malignant" features may behave in a benign or indolent fashion.”
Pancreatic neuroendocrine tumors: accurate grading with Ki-67 index on fine-needle aspiration specimens using the WHO 2010/ENETS criteria. Farrell JM et al. Cancer Cytopathol. 2014 Oct;122(10):770-8. - “These results indicate that EUS-FNA cytology samples can be accurately graded based on the WHO Ki-67 labeling scheme. Thus, Ki-67 scoring in EUS-FNA cytology samples is an alternative approach for establishing the grade of panNETs. Accurate grading of panNETs is critical for predicting tumor biology, patient prognosis, and making informed decisions regarding patient management and treatment.”
Pancreatic neuroendocrine tumors: accurate grading with Ki-67 index on fine-needle aspiration specimens using the WHO 2010/ENETS criteria. Farrell JM et al. Cancer Cytopathol. 2014 Oct;122(10):770-8.
- “ The management of GEP-NETs has become complex, requiring a multidisciplinary approach. The World Health Organization classification of GEP-NETs has been revised; the U.S. Food and Drug Administration has approved molecular targeted agents (sunitinib,everolimus) for the treatment of pancreatic NETs; and the National Comprehensive Cancer Network clinical practice guidelines have been updated.”
Update on the Management of Gastroenteropancreatic Neuroendocrine Tumors with Emphasis on the Role of Imaging
Kim KW et al.
AJR 2013; 201:811-824 - “ Radiologists in collaboration with oncologists, surgeons and pathologists should adopt a multidisciplinary therapeutic approach that includes use of imaging and clinicopathologic data for optimize, focused care of patients with GEP-NETs.”
Update on the Management of Gastroenteropancreatic Neuroendocrine Tumors with Emphasis on the Role of Imaging
Kim KW et al.
AJR 2013; 201:811-824 - Pancreatic Neuroendocrine Tumors (NET)
- AKA “Islet cell tumors”
- Composed of well differentiated endocrine cells
- No longer categorized as “functioning” or “non-functioning”
- All NETs are hormonally active
- Now categorized as “syndromic” or “nonsyndromic” based on laboratory and clinical findings - Associations
- Von Hippel-Lindau Disease
- Retinal and CNS Hemangioblastomas
- Pheochromocytomas
- Serous Cystadenomas
- Pancreatic neuroendocrine tumors
- RCC
- Neurofibromatosis Type I
- Tuberous Sclerosis
- MEN Type I Syndrome
- Parathyroid hyperplasia or adenomas
- Neuroendocrine tumors of pancreas or duodenum
- Pituitary Adenomas - Syndromic NETs
- Clinically evident lesions due to hormone production and endocrinopathy
- Tend to present when smaller because of symptoms
- Often secrete multiple hormones, but the most secreted hormone establishes the syndrome
- Tend to be < 3 cm in size
- Insulinoma, Gastrinoma, Glucagonoma, VIPoma, Somatostatinoma - Syndromic NETs
- Two most common types:
- Insulinoma:
- Whipple triad: Fasting glucose < 50 mg/dl, symptomatic hypoglycemia, and symptom improvement after glucose
- 10% MEN-I, 10% malignant
- Tend to be small (< 2 cm)
- Gastrinoma:
- Most common NET in MEN-I
- Zollinger-Ellison Syndrome
- Peptic ulcer disease with ulcers in unusual locations (i.e. post-bulbar)
- Often malignant (30% present with liver metastases)
- Often multiple and can be extrapancreatic (“gastrinoma triangle”) - Nonsyndromic NET
- Roughly 50% of all NETs
- Tend to be larger because of lack of symptoms when smaller
- Produce symptoms when larger due to mass effect, metastases, local invasion, etc.
- Average size of over 5 cm
- More likely to be cystic, necrotic, calcified, and aggressive in behavior - Imaging Appearance
- Very well circumscribed
- Avidly enhancing on the arterial phase, and typically vascular on the venous phase
- Can rarely be more conspicuous on the venous phase
- Rarely cystic or necrotic
- Cystic lesion with hypervascular rim
- Usually will not obstruct the pancreatic or biliary ducts
- Exceptions are large tumors and small lesions secreting serotonin (causes fibrotic stricturing of the ducts)
- No pancreatic atrophy
- Hypervascular lymph nodes - Mimics of Pancreatic NET
- Pancreatic Metastases (especially RCC)
- Acinar Cell Carcinoma
- Intrapancreatic Splenule
- Peripancreatic GIST
- Solid Serous Cystadenoma
- Pancreatic Hamartoma
- Peripancreatic Paraganglioma
- “ These data suggest that serotonin produced by pancreatic endocrine neoplasms may be associated with local fibrosis and stenosis of the pancreatic duct. Clinicians should be aware that small pancreatic endocrine neoplasms can produce pancreatic duct stenosis resulting in ductal dilatation and/or upstream pancreatic atrophy out of proportion to the size of the tumor.”
Pancreatic Duct Stenosis Secondary to Small Endocrine Neoplasms: A Manifestation of Serotonin Production?
Shi C et al.
Radiology 2010; 257:107-114 - “ Clinicians should be aware that small pancreatic endocrine neoplasms can produce upstream ductal dilatation and/or pancreatic atrophy out of proportion to the size of the tumor.”
Pancreatic Duct Stenosis Secondary to Small Endocrine Neoplasms: A Manifestation of Serotonin Production?
Shi C et al.
Radiology 2010; 257:107-114
- What is the correct management of an incidental PNET-
A. Conservative followup at 6 month intervals-
B. No followup needed
C. Immediate surgery with pancreatectomy
D. It depends on other findings - “ Approximately 50% of incidental NETs show uncertain or malignant behavior. Solid tumors 3 cm or larger are commonly nonbenign; however, about 30% of tumors smaller than that size cutoff can be malignant. Nonbenign tumors and those with invasive features on MDCT have a higher incidence of recurrence.”
Incidental Neuroendocrine Tumors of the Pancreas: MDCT Findings and Features of Malignancy
Gallotti A et al.
AJR 2013; 200:355-362 - “ Other MDCT features such as the presence of vascular invasion, MPD dilatation, or peripancreatic lymph node enlargement are often associated with nonbenign tumors and show higher risk of recurrence.”
Incidental Neuroendocrine Tumors of the Pancreas: MDCT Findings and Features of Malignancy
Gallotti A et al.
AJR 2013; 200:355-362 - Neuroendocrine Tumors of the Pancreas: Facts
- 75% of cases are sporadic, 25% of cases occur as part of genetic syndromes
- Common age of occurrence is 5th-7th decade
- Non-functioning tumors now make up 60-80% of lesions detected
- Neuroendocrine tumors have malignant potential but biologic aggressiveness and metastasizing risk is variable
- Surgery remains the treatment of choice - Neuroendocrine Tumors of the Pancreas: CT Findings
- Lesions may be solid, cystic of mixed in appearance
- Peripheral or central calcification may occur and these lesions are more likely malignant
- Vascular invasion is consistent with malignant NET
- extra-pancreatic findings include vascular liver metastases, peri-portal adenopathy, and vascular invasion - “Cystic pancreas NETs are not rare and should be included in the differential diagnosis of a cystic pancreatic mass particularly if the cystic mass is associated with peripheral contrast enhancement. A minority of cystic pancreatic NETs can present with no peripheral enhancement.”
Pancreatic Neuroendocrine Tumor With Cystlike Changes: Evaluation with MDCT
Kawamoto S, Johnson PT, Shi C, Singhi AD, Hruban RH, Wolfgang CL, Edil BH, Fishman EK
AJR 2013; 200:W283-W290 - “Peripheral contrst enhancement greater than normal pancreatic parenchyma was observed in 11 of 13 (85%) predominantly cystic tumors including one case of equivocal peripheral enhancement.”
Pancreatic Neuroendocrine Tumor With Cystlike Changes: Evaluation with MDCT
Kawamoto S, Johnson PT, Shi C, Singhi AD, Hruban RH, Wolfgang CL, Edil BH, Fishman EK
AJR 2013; 200:W283-W290 - “ Nonfunctioning pancreatic NETs were reported to be more prevalent than functioning pancreatic NETs and accounted for approximately 85% of all pancreatic NETs.”
Pancreatic Neuroendocrine Tumor With Cystlike Changes: Evaluation with MDCT
Kawamoto S, Johnson PT, Shi C, Singhi AD, Hruban RH, Wolfgang CL, Edil BH, Fishman EK
AJR 2013; 200:W283-W290 - “ A dedicated CT protocol including arterial phase imaging is essential to detect peripheral contrast enhancement.”
Pancreatic Neuroendocrine Tumor With Cystlike Changes: Evaluation with MDCT
Kawamoto S, Johnson PT, Shi C, Singhi AD, Hruban RH, Wolfgang CL, Edil BH, Fishman EK
AJR 2013; 200:W283-W290 - Pancreatic Neuroendocrine Tumors: Associated Syndromes
- Multiple endocrine neoplasia 1 (MEN 1)
- Von Hippel Lindau (VHL) syndrome
- Neurofibromatosis type I
- “ The incidence of venous tumor thrombus detected by imaging was 33% in our study. This imaging finding was not accurately reported on the radiology report in 62% of the patients. In 18% of the patients with gross venous tumor thrombi, there was a significant alteration in the surgical plan. It is critical for the radiologist to be aware of the association of venous tumor thrombi in patients with nonfunctioning pancreatic neuroendocrine tumors and to report these findings.”
Venous Tumor Thrombus in Nonfunctional Pancreatic Neuroendocrine Tumors
Balachandran A et al.
AJR 2012; 199:602-606 - “ CT showed venous tumor thrombi in 29 of the 88 patients (33%). The CT finding was not accurately reported in 18 of the 29 patients (62%).”
Venous Tumor Thrombus in Nonfunctional Pancreatic Neuroendocrine Tumors
Balachandran A et al.
AJR 2012; 199:602-606