Pancreatic neuroendocrine tumors - Springer Link

Indian J Gastroenterol (January–February 2013) 32(1):3–17 DOI 10.1007/s12664-012-0257-2

REVIEW ARTICLE

Pancreatic neuroendocrine tumors Shailesh V. Shrikhande & Bhawna Sirohi & Mahesh Goel & Savio G. Barreto

Received: 15 March 2012 / Accepted: 4 September 2012 / Published online: 3 October 2012 # Indian Society of Gastroenterology 2012

Abstract Pancreatic neuroendocrine tumors (pancreatic NETs) are rare, low- to intermediate-grade neoplasms thought to arise from the pancreatic islets. Recent advances in pathology and our understanding of the biological behavior of this group of tumors has resulted in changes in their nomenclature and how we treat them. This review puts into perspective our current understanding of pancreatic NETs in terms of their incidence, pathology, and management. Keywords Chemoembolization . Glucagon . Insulin . Somatostatin

neuroendocrine tumors, or GEP NETs, reflects a greater appreciation of the origins, heterogeneity, and specific molecular signatures of such tumors [4]. As noted above, recent advances in pathology and our understanding of the biological behavior of this group of tumors have resulted in changes in their nomenclature and how we treat them. This review puts into perspective our current understanding of pancreatic NETs in terms of their incidence, pathology, and management.

Epidemiology Introduction Pancreatic neuroendocrine tumors (pancreatic NETs) are rare, low- to intermediate-grade neoplasms thought to arise from the pancreatic islets [1] and account for less than 5 % of pancreatic malignancies [2]. In 2004, Kloppel et al. [3] modified the existing WHO classification of neuroendocrine tumors of the gastrointestinal (GI) tract (including the pancreas) based on the localization of the tumors taking into account various morphological and biological criteria. This proposed classification addresses important aspects defining malignant potential according to morphological and histopathological criteria. The recent introduction of the term gastroenteropancreatic

S. V. Shrikhande (*) : M. Goel : S. G. Barreto Gastrointestinal and Hepato-Pancreato-Biliary Surgical Oncology, Tata Memorial Centre, Ernest Borges Marg, Parel, Mumbai 400 012, India e-mail: [email protected] B. Sirohi Medical and Hemato-Oncology, Artemis Health Sciences, Sector 51, Gurgaon 122 001, India

In 2008, a study from the Mayo Clinic reported the crude annual incidence of pancreatic NETs per 1,000,000 to be 1.8 in females and 2.6 in males. The study also found that the incidence of the tumors increased with advancing age [5]. In Hong Kong, the calculated annual incidence of clinically significant tumors was approximately 0.2 per 100,000 population with an autopsy incidence of 0.1 % [6]. These reports are not too dissimilar from the incidence of pancreatic NETs in Norway or the SEER database which has been estimated to be around 0.23 per 100,000 and 0.18 to 0.24 per 100,000, respectively [7]. Data from India [8, 9] has indicated that pancreatic NETs are not uncommon as a group as well as amongst pathological malignant lesions of the pancreas.

Pathology Pancreatic NETs arise from neuroendocrine cells of the pancreas. Numerous classifications exist in pancreatic NETs and this reflects the evolving knowledge of this complex and uncommon tumor type. Based on their differentiation, pancreatic NETs have traditionally been classified into well differentiated and poorly differentiated (which are malignant). The well differentiated

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NETs are then divided on the basis of production of hormones into functional, i.e. producing hormones such as insulin, gastrin, glucagon, somatostatin, ghrelin, pancreatic polypeptide (PP), vasoactive intestinal peptide (VIP), corticotropinreleasing hormone (CRH), calcitonin, growth hormonereleasing hormone (GHRH), neurotensin, adrenocorticotropic hormone (ACTH), growth hormone-releasing factor (GRF), parathyroid hormone-related peptide tumor, with their attendant syndromes, and non-functional tumors [10]. Pancreatic NETs are usually solitary, and multiple lesions should always raise the suspicion of associated syndromes such as multiple endocrine neoplasia/MEN (type 1) or Von Hippel Lindau syndrome [11]. Central to the diagnosis of pancreatic NETs is the appreciation of the classical pathological findings in well- and poorlydifferentiated lesions. On microscopy, well-differentiated neoplasms have characteristic organoid arrangements of uniform tumor cells, with nesting, trabecular, or gyriform patterns. The cells produce abundant neurosecretory granules which causes the strong and diffuse immunoexpression of NE markers such as chromogranin A (Cg A) and synaptophysin. Poorly differentiated NETs, on the other hand, are less likely to resemble non-neoplastic NE cells and have a more sheet-like or diffuse architecture, irregular nuclei, and less cytoplasmic granularity. Immunoexpression of NE markers, as a result, are more limited [12]. Grossly infiltrative growths greater than 2 cm, with evidence of angioinvasion, metastases and/or a high proliferative index indicate a poorer prognosis [11]. The World Health Organisation (WHO) has recently updated its classification of GEP-NE neoplasms as follows [13]: 1. Neuroendocrine tumor (NET) G1 (carcinoid) G2 2. Neuroendocrine carcinoma (NEC) G3 large cell or small cell type 3. Mixed adenoneuroendocrine carcinoma (MANEC) 4. Hyperplastic and preneoplastic lesions where, G indicates the Ki-67 activity (G120 %).

Staging There have been two staging systems proposed for pancreatic NETs in the last 5 years, viz. by the American Joint Committee on Cancer (AJCC) Staging and the International Union against Cancer (UICC) [14], and the European Neuroendocrine Tumor Society (ENETS) [15] (Table 1). While both systems may have been validated individually [16–18], there do appear to be significant discrepancies between them [19]. The differences may partly arise from the fact that the AJCC/ UICC have extended the use of their exocrine pancreas staging system to pancreatic NETs [19]. A result of this is varying definitions of T2 and T3. This could potentially affect the comparison of data from different studies [19].

Indian J Gastroenterol (January–February 2013) 32(1):3–17

Clinical features As mentioned above, pancreatic NETs may be functioning (produce hormones and their resultant syndromes), or nonfunctioning (no hormones produced and hence no associated symptom complexes). Non-functioning tumors are more common. Patients remain generally asymptomatic with the tumor generally being detected incidentally on imaging for unrelated symptoms. Symptoms, if they do arise, are usually the result of an enlarging tumor compressing surrounding structures. In tumors arising in the head or uncinate process of the pancreas, symptoms resulting from enlargement include jaundice or gastric outlet obstruction. Pain is uncommon and would reflect invasion of the celiac axis or liver metastases [1]. Patient with tumors to the left of the superior mesenteric vessel [1] generally present late with signs of weight loss, cachexia and back pain. Amongst the pancreatic NETs that do produce hormones, PPomas are generally asymptomatic except for occasional patients with watery diarrhea, diabetes mellitus, ulcer diathesis, or an erythematous pruritic rash [1]. To facilitate understanding and avoidance of repetition, the presentation, diagnosis and management of the two most common functioning tumors such as gastrinoma and insulinoma will be provided after the general description of pancreatic NETs. Symptom complexes arising from the rarer functioning pancreatic NETs include: 1) Glucagonoma – Patients with glucagon producing NETs may fit into one of three clinical types, viz glucagonoma with necrolytic migratory erythema (NME), glucagonoma with mild diabetes mellitus, or glucagonoma with multiple syndromes [20]. Rash in NME consists of erythema, papules, scabs and pigmental deposition in the regions of the inguinal canal, perineum, lower extremities, and buttocks. These eruptions are characterized by spontaneous remissions and exacerbations without identifiable precipitating factors [21, 22]. 2) Somatostatinoma - The most common presentation of such tumors is the somatostatinoma/inhibitory syndrome characterized by diabetes mellitus, diarrhea/steatorrhea, and cholelithiasis – a result of an inhibition of the other pancreatic hormones [23]. However, patients may also present with dyspepsia [24]. 3) VIPoma – Patients present with the WDHA syndrome – watery diarrhea (up to 20 bowel movements with a daily stool volume exceeding 3 l), hypokallemia and achlorhydria [25]. 4) Corticotropinoma – patients present with Cushing’s syndrome.


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Table 1 Comparison of the two current staging systems for pancreatic NETs [14, 15] AJCC/UICC

ENETS

Primary tumor (T) Primary tumor cannot be assessed No evidence of primary tumor Tumor limited to the pancreas; ≤ 2 cm Tumor limited to the pancreas; > 2 cm Tumor extends beyond the pancreas but without involvement of the celiac axis or the SMA Tumor involves the celiac axis or the SMA (unresectable primary tumor) Regional lymph nodes (N) Regional lymph nodes cannot be assessed No regional lymph nodal metastases Regional lymph nodal metastases Distant metastases (M) – No distant metastases Distant metastases T N M Tis N0 M0 T1 N0 M0 T2 T3 T1,2,3 T4 Any T

N0 N0 N1 Any N Any N

M0 M0 M0 M0 M1

TX T0 T1 T2 T3

Primary tumor cannot be assessed No e/o primary tumor Tumor limited to the pancreas; ≤2 cm Tumor limited to the pancreas; 2–4 cm Tumor limited to the pancreas; >4 cm, invading the duodenum or bile duct Tumor invading adjacent organs (stomach, colon, adrenal gland) or the wall of large vessels (celiac axis or the SMA)

T4

NX N0 N1

Regional lymph nodes cannot be assessed No regional lymph nodal metastases Regional lymph nodal metastases

MX M0 M1 Stage 0 IA

I

Distant metastases cannot be assessed No distant metastases Distant metastases T N T1 N0

M M0

IB IIA IIB III IV

IIA IIB IIIA IIIB IV

T2 T3 T4 Any T Any T

M0 M0 M0 M0 M1

N0 N0 N0 N1 Any N

SMA superior mesenteric artery

Diagnostic investigations Tumor markers Chromogranin A (CgA) CgA is useful in the diagnosis of pancreatic NETs and can be measured in the serum or plasma. Tissue immunohistochemistry for CgA is essential for the diagnosis of pancreatic NETs [26]. In pancreatic NETs, serum CgA levels have been found to be elevated in 100 % cases of gastrinomas and 70 % of non-functioning tumors [27]. Overall, though, it has been found to be expressed in 80 % to 90 % of pancreatic NETs [28]. CgA levels have been found to correlate well with the stage and extent of disease [29] such that levels higher than three times the upper normal limit at diagnosis indicating shorter survival [16]. However, the correlation with the grade of tumor is not straightforward with well differentiated tumors tending to express higher CgA levels as compared to poorly differentiated ones [30]. CgA levels have also been studied in patients on long-acting somatostatin analogs (SSA) [31]. It was found that in patients on long-acting SSA therapy, a decrease in CgA level by >30 % would enable the

identification of patients most likely to respond to chronic SSA treatment. To permit a valid interpretation of the CgA in case of patients on SSAs, serial measurement of CgA levels in these patients should be undertaken at the same interval following the injection owing to the ability of SSA to reduce CgA levels in blood. Similarly, the drop in CgA levels has been shown to be indicative of better survival in patients treated with other therapeutic agents [32, 33]. It is prudent to note though that benign conditions such as atrophic gastritis, acute pancreatitis, inflammatory bowel disease, etc. as well other malignancies such as colon, pancreatic, liver and breast cancer, may be associated with elevations in CgA levels in blood [26]. The most important clinical scenario is the patient on proton pump inhibitors (PPIs). High levels of CgA have been noted in these patients [34] which normalize within 2 weeks of ceasing the drug. The cause for the elevation has been attributed to suppression of gastric acid secretion leading to G-cell and enterochromaffin‐like (ECL) cell hyperplasia. Hence, in patients with suspected pancreatic NETs on PPIs, the drug should be ceased for 2 weeks prior to testing [34].

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Neuron-specific enolase It is less specific as compared to CgA in the diagnosis of pancreatic NETs [27]. It is a useful tissue marker [28]. Ki-67 Routine tissue staining for the proliferation marker, Ki-67, is recommended in all cases of pancreatic NETs [10] as it is essential for the accurate classification of the tumor [13–15].


al. [43] advised caution with the use of gadolinium as while the contrast agent failed to additionally detect any lesions not already demonstrated, it in fact caused a few lesions to become isointense to the rest of the pancreatic parenchyma. Owing to their high signal intensity on T2-weighted MRI, pancreatic NETs may be mistaken for cystic pancreatic tumors. In these cases, a ‘rim of enhancement’ with signal intensity different from the adjacent gland may help to identify the lesions as a pancreatic NET [45]. EUS and fine needle aspiration (EUS-FNA)

Other markers and tests In addition to the above markers, other markers, specific to the tumor suspected, may also be measured, viz. PP, VIP, pancreastatin, etc. All markers should preferably be measured in a fasting state [1]. In patients with NME, findings in support of the diagnosis include necrolysis of the upper one third of the epidermis with vacuolated keratinocytes, leading to focal or confluent necrosis [35]. Multiple biopsies may need to be taken [36]. It is essential to differentiate these from other conditions with similar histological findings, such as pellagra, zinc deficiency, and necrolytic acral erythema [22, 36]. Imaging - structural Contrast-enhanced, multi-detector computed tomography (MDCT) The use of arterial and portal venous phase contrast is highly recommended in the evaluation of suspected pancreatic NETs owing to their highly vascular nature. Pancreatic NETs appear either heterogeneously enhancing or homogeneously enhancing during the arterial and portal venous phases compared with the surrounding pancreatic parenchyma [37]. Pancreatic NETs do not distort the contour of the pancreas [38]. The ability to capture the vascular blush in small tumors is essential in the diagnosis of these lesions [38, 39]. Gouya et al. [40] reported a sensitivity of 94.4 % with thin-section dual-phase MDCT making it comparable to endoscopic ultrasound (EUS) in the detection of pancreatic NETs. Magnetic resonance imaging (MRI) Hayashi et al. [37] reported that MRI may be able to detect lesions previously undetected on CT. Islet cell tumors appear as hypointense on fat-suppressed T1- weighted sequences and hyperintense on fat-suppressed T2-weighted sequences [37, 41–43]. Bakir et al. [44] noted that whilst conventional MRI had a sensitivity of 91.6 % for detecting islet cell tumors, the additional performance of body diffusion-weighted MRI did not contribute further to the diagnostic capability except in patients with suspected or negative imaging findings. Owen et

EUS has repeatedly been shown to be useful as a diagnostic tool for pancreatic NETs with sensitivity as high as 95 % compared with MDCT (80 %) [46]. EUS-FNA has been reported to have an 87 % to 90 % sensitivity [47, 48] and 90.1 % diagnostic accuracy [49] for pancreatic NETs. The most helpful cytologic findings for the diagnosis of pancreatic NETs were a richly cellular sample with a monotonous, poorly cohesive population of small or medium-sized cells with granular chromatin (salt and pepper) and plasmacytoid morphology [50]. Ishikawa et al. [46] demonstrated that on mere imaging, heterogeneous ultrasonographic texture was the most significant factor for malignancy (OR053.33; 95 % CI, 10.79–263.58). Contrast-enhanced sonography has led to better diagnosis and characterization of liver and pancreas lesions. The contrast-enhanced sonography is significantly superior to B-mode sonography in the diagnosis of non-functioning PNETs with a correlation between enhancement pattern and the Ki67 index [51]. Imaging - functional Somatostatin receptor scintigraphy (SRS) 111

Indium-DTPA-octreotide/SRS is regarded as the gold standard in nuclear imaging for patients with pancreatic NETs [52] and hence routine performance of the SRS has been recommended [10] in addition to the use of CT and MRI. The sensitivity in detecting pancreatic NETs varies between 60 % and 90 % [52] but tends to be lower for insulinomas (20 % to 60 %). However, the future validity of the scan is questionable in the presence of newer and better nuclear imaging modalities [28]. This is indicated for all patients as the first staging modality and also with therapeutic intent if the scan is positive. 68

Ga-DOTA(0)-Phe(1)-Tyr(3)-octreotide (68Ga-DOTATOC) positron emission tomography computed tomography (PET-CT) Data on the use of this modality is sparse. Two recent cohort studies have compared the efficacy of this imaging modality


with MDCT and EUS. One study demonstrated an 87 % sensitivity of 68Ga-DOTATOC PET as compared to 96 % for EUS and 72 % for MDCT [53]. In the more recent cohort study of 20 patients, 68Ga-DOTATOC PET-CT has been shown to have 100 % sensitivity for the diagnosis of the primary tumor and metastatic disease in case of pancreatic NETs which was superior to MDCT and 18FDG-PET-CT [54]. 6-[F]fluoro-3,4dihydroxyphenylalanine (F-FDOPA) PET/CT (18F-FDOPA PET) using the catecholamine precursor 6-(fluoride-18) fluoro levodopa is also in use and is superior to SRS though in patients with suspected disease with negative tests previously, FDOPA PET did not add any additional information [55]. Traditionally, MDCT and MRI are the preliminary investigations performed for suspected lesions in the pancreas. Both these investigations afford a reasonable degree of sensitivity in the initial evaluation of pancreatic NETs and hence remain the recommended initial investigations. Further evaluation of suspicious lesions may then be carried out using EUS-FNA, which will permit histological confirmation of the diagnosis. Additionally, the use of EUS is absolutely indicated in patients with MEN 1 who are at risk for multifocal lesions [1]. 68Ga-DOTATOC PET-CT is certainly emerging as a very useful investigation although the benefit of this investigation at the current time may be limited due to the lack of its widespread availability.

Management Surgical While aggressive surgery is regarded as essential for pancreatic NETs [56–64], its actual impact in reducing local recurrence and metastasis has sometimes been questioned [65]. The heterogeneous nature and relative rarity of the disease has given rise to two dilemmas: firstly, single institution reports have identified conflicting factors influencing outcomes following resection of GEP-NETs [65] and secondly, the low numbers of patients amenable to surgical resection precludes the establishment of randomized clinical trials that might allow comparison of an aggressive surgical approach vs. nonsurgical or medical alternatives in patients with GEPNETs and hepatic metastases [66]. Despite these conflicting reports, surgery for localized, non-metastatic disease appears justified and essential especially when a complete resection (R0) can be achieved without additional morbidity to the patient. Rindi et al. proposed a management algorithm based on the histologic type, grade and stage of the tumor [15]. The various operations performed for pancreatic NETs include: 1) Pancreatoduodenectomy (PD) for lesions in the head and uncinate process the pancreas with/without venous resection (in advanced cases)

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2) Distal pancreatectomy for larger lesions in the body and tail of pancreas with/without spleen preservation 3) Pancreas-parenchyma sparing surgeries: a) Enculeation of solitary lesions have been performed in any portion of the pancreas so long as the lesion is benign and 15 mEq/hr along with an increase in serum gastrin levels >110–200 pg/mL following intravenous injection of recombinant secretin 0.4 μg/kg, will help confirm ZES in these patients. Other investigations that are useful include [103] serum CgA, SRS/Octreoscan in detecting primary (sensitivity up to 70 %) as well as metastatic lesions [104, 105], endoscopy [103, 105, 106] and EUS [1]. It is necessary to rule out or confirm the presence of MEN-1 [103], and antral H. pylori gastritis [103]. CT/MRI are necessary to determine resectability. The appropriate surgery would depend on the location of the tumor. Procedures may vary from enucleation for solitary lesions located away from the pancreatic duct to PPPD for larger lesions or multiple lesions in the head and uncinated process. Regional lymphadenectomy must be performed in all cases. In patients undergoing enucleation of the lesion, peripancreatic lymph nodes, lymph nodes adjacent to the hepatic artery and within the porta hepatis must be sampled. In patients in whom the lesion cannot identified in the pancreas, a duodenotomy must be performed to rule out duodenal gastrinomas (which are the most common [103]). In all patients, a careful examination of the “gastrinoma triangle” of Stabile (bounded by the junction of common and cystic ducts superiorly, the second and third portions of duodenum inferiorly and head and neck of pancreas medially) must be performed. Advanced/metastatic lesions should be managed by the afore-mentioned strategies. Insulinoma Owing to the production of insulin by the tumor, patients with functional insulinomas often present with the ‘Whipple’s triad” [107, 108] consisting of: attacks of nervous or gastrointestinal disturbances coming on in the fasting state, associated with hypoglycemia with blood sugar values below 50 mg%, and immediate relief of symptoms following the ingestion of glucose. The patients may present with blurred vision, confusion and abnormal behavior and progress to seizures and loss of consciousness if glucose is


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Table 3 Newer biological agents for the treatment of pancreatic NETs Agent

Mechanism

Response rates

Potential indications

Side effects

References

Interferon alpha

Antiproliferative and antitumor effects – ➣ Stimulation of T cells ➣ Induction of cell cycle arrest in G1 and G0 phases ➣ Inhibition of angiogenesis

Symptoms: 30 % −70 % Stable disease: 70 % Partial response: 11 %

As a second-line combination therapy with SST in patients with progressive disease when on SST monotherapy

Myalgias Fever and chills Depression Myelosuppression

[93, 94, 140, 153–157]

mTOR ➣ regulates cell growth, proliferation and metabolism of cells and involved in apoptotic cell death ➣ Upregulated in malignancies Patients with germ-line mutations of tuberous sclerosis complex 2 (endogenous inhibitor of mTOR) predisposed to developing Pancreatic NETs

RADIANT-3 results Median progressionfree survival Everolimus - 11.0 months Placebo - 4.6 months [HR: 0.35; 95 % CI 0.27 to 0.45; p