Gastrinomas and Non-functioning Pancreatic Endocrine Tumors in Multiple Endocrine Neoplasia Syndrome Type-1 (MEN-1)

doi:10.21203/rs.3.rs-2508035/v1

Download PDF

Short Report

Gastrinomas and Non-functioning Pancreatic Endocrine Tumors in Multiple Endocrine Neoplasia Syndrome Type-1 (MEN-1)

https://doi.org/10.21203/rs.3.rs-2508035/v1

This work is licensed under a CC BY 4.0 License

Journal Publication

published 26 Apr, 2023

Read the published version in Endocrine →

You are reading this latest preprint version

Purpose: Illustrate imaging findings of gastrinomas and non-functioning pancreatic endocrine tumors (NF-PNET) in a patient with multiple endocrine neoplasia type-1 (MEN-1) syndrome with a radiologic-pathologic correlation for both along with the results of a 13 yrs observational study.

Methods: A 48 yrs old male patient with MEN-1 and a Zollinger-Ellison syndrome was submitted to a duodeno-cephalopancreatectomy (DCP) extended to the pancreatic body to remove several gastrinomas shown by an endoscopic-ultrasonography as well as a large (> 2 cm) hypo-vascular pancreatic nodule shown by a contrast-enhanced multi-detector CT (CE-MDCT). Further conventional (CT/MR) and functional imaging (68Ga-PET-DOTA-TOC) studies were performed over the next 13 years.

Results: Up to 14 gastrin-positive NET-G1 (pT2,N1) as well as a single PNET-G2 (pT2,N0) were found at histo-pathology which also showed a NET-G1 in the uncinate process where CE-MDCT documented a 9 mm hyper-vascular nodule. A 7 mm pancreatic nodule with identical contrast-enhancement pattern was also shown at the level of the pancreatic tail which was left to preserve endocrine function. At this level, follow-up studies documented the occurence of a small (< 1 cm) hypo-vascular nodule which was metastatic at presentation and rapidly progressed under somastatin-analogs therapy whereas the hyper-vascular nodule remained stable over 13 years. Both the pancreatic lesion as well as the hepatic metastasis showed pathologic uptake of the radiotracer with a SUVmax of 6.3 and 29.5, respectively, allowing the patient to be scheduled for a Peptide Receptor Radionuclide Therapy performed with 29.6 GBq of 177Lu-Oxotreotide.

Conclusions: Contrast-enhancement patterns are correlated with both the histological grade as well as the biological behaviour of PNETS.

Multiple endocrine neoplasia type 1 (MEN-1) is a rare hereditary autosomal dominant syndrome due to frame-shift and non-sense mutations in the MEN-1 tumor suppressor gene localized on the long arm of chromosome 11 [1]. Also known as Wermer syndrome, it has a prevalence of 2–20/100.000 individuals who may develop multiple neoplastic lesions arising in the parathyroid (90–95%) as well as the pituitary glands (40–50%), the pancreatic islet cells (50–60%) and the duodenal wall (35–40%) [2].

While the most common clinical onset of patients affected by MEN-1 is due to primary hyperparathyroidism [3], duodeno-pancreatic endocrine tumors (DP-NETs) represent the main cause of cancer-related death which is most commonly due to non-functioning (NF) subtypes [4]. Indeed, these tend to have a more aggressive behavior compared to their sporadic counterparts with a malignant potential reported to be size-related with a cut-off value set at 2 cm [5–7]. Hence, active surveillance with either endoscopic ultrasonography (EUS), contrast-enhanced multi-detector-CT (MDCT) and/or Magnetic Resonance Imaging (MRI) is strongly recommended in patients with MEN-1 syndrome [8–10].

As far as contrast-enhanced MDCT is concerned, recent advances suggest that contrast-enhancement patterns of PNETs may be indeed predictive of tumor grading defined as the rate of expression of the proliferation index Ki-67 [11]. As most G1 (Ki-67 < 3%) tumors usually appear as hypervascular lesions, G2 (Ki-67 3–20%) or G3 (Ki-67 > 20%) tumors typically manifest as hypo-vascular lesions [12–14]. However, as PNETs in MEN-1 syndrome are usually multifocal [8–10], the co-existence of lesions with different contrast-enhancement patterns and different biological behavior may indeed occur in clinical practice.

Herein, we describe a case of 48 yrs old male with a genetic diagnosis of MEN-1 syndrome who had a clinical Zollinger-Ellison syndrome (ZES) due to duodenal gastrinomas shown by an EUS and confirmed by contrast-enhanced MDCT which also depicted loco-regional adenopathies and three other NF-PNETs with different contrast-enhancement patterns and biological behavior.

In 2009, a 48-year-old male affected by MEN-1 syndrome (frameshift mutation 317delC) was admitted to the Endocrinology and Metabolic Diseases Unit of our Institution with an history of relapsing peptic ulcers resistant to Proton Pump Inhibitors (PPIs) and high levels of gastrinemia (489 pg/ml). The patient had been previously submitted to a total para-thyroidectomy for primary hyperparathyroidism in 2005 and was under medical therapy with Cabergoline (0,5 mg pro die) for a prolattin-secreting pituitary adenoma.

The patient was first submitted to an EUS performed with a radial transducer (7.5–20 MHz, Olympus, GIF-UM130Q) which documented multiple hypo-echoic nodules (2–12 mm) within the duodenal wall (not shown) and then underwent a contrast-enhanced MDCT (Aquilion 64, Toshiba, Japan) which was performed according to a multiphasic protocol [8] after i.v. bolus (4 ml/sec) injection of 1.7 cc/Kg of a non ionic iodinated contrast media (370 mgI/ml). Arterial-phase imaging depicted multiple hypervascular sub-centimetric nodules at the level of both the pancreatic tail (Fig. 1a) as well as the uncinate process (Fig. 1c) along with an inhomogeneous and asymmetric thickening of the medial duodenal wall and a cluster of duodeno-pancreatic adenopathies which were both better depicted in the pancreatic phase (Fig. 1b). In addition, a large (30 x 26 mm) hypo-vascular nodule could also be appreciated in the dorsal aspect of the pancreatic body, much more conspicuous in the pancreatic phase (Fig. 1b) than in the arterial phase (Fig. 1a).

The patient was then submitted to a duodeno-cefalo-pancreatectomy (DCP) extended to the pancreatic body and the histopathological analysis revealed several (n = 14) gastrin-positive NET G1 tumors (Fig. 2a-b), the larger (pT2,N1) in the duodenal wall (Fig. 1b), a glucagon-positive NET G2 (pT2, N0) in the pancreatic body (Fig. 2c-d) and two well-differentiated G1 NETs in the pancreatic head (Fig. 1c) and in the pancreatic body (not shown). To preserve pancreatic endocrine function the pancreatic tail was not removed.

The patient started somatostatin analogs (SSA) therapy (Sandostatin LAR 30 mg/28 days → Lanreotide Autogel 120 mg/28 days) and follow-up contrast-enhanced MDCT examinations, performed bi-annually, showed the hypervascular nodule in the pancreatic tail to be stable in size (7–9 mm) over 6 years (Fig. 3a-c).

In 2017, however, an abdominal ultrasound depicted a hypoechoic lesion at the level of the V hepatic segment which was confirmed by a VIBE-T1-w Gadolinium-enhanced MR performed at 3 T (Somatom Trio, Siemens, Germany) and considered to be consistent with a liver metastasis (not shown) along with a small (9 mm) hypo-intense nodule at the level of the pancreatic tail (Fig. 3d) which had been prospectively overlooked at contrast-enhanced MDCT (Fig. 3c). Both the pancreatic lesion as well as the liver met showed focal uptake of the radiotracer at ⁶⁸Ga-DOTA-TOC PET/CT with a SUV_max of 6.3 and 29.5, respectively (not shown).

The patient was first shifted to high dose SSAs therapy (Lanreotide LAR 120 mg/14 days) and then submitted to a radio-frequency ablation (RFA) of the hepatic lesion in 2019 as shown by a contrast-enhanced MDCT follow-up study (Fig. 4a) which also documented progressive disease at the level of the pancreatic tail (Fig. 4b) with a SUV_max of 30 at ⁶⁸Ga-DOTA-TOC PET/CT (not shown).

The patient was therefore scheduled for a Peptide Receptor Radionuclide Therapy (PRRT) and received four cycles of ¹⁷⁷Lu-DOTATE 7.4 GBq (200 mCi) every 8 weeks between November 2020 and March 2021 with a cumulative dose of 29.6 GBq (800 mCi).

He is currently under clinical and instrumental follow-up with a last contrast-enhanced MDCT performed on May 2022 showing stable disease.

Although both functional as well as NF-PNET may occur in patients with MEN-1 syndrome [4], only the latter are considered the main cause of cancer-related mortality as a result of their malignant potential which has been reported to be size-dependent with a cut-off value set at 2 cm [5–7]. Active surveillance is strongly recommended in patients with MEN-1 and is usually accomplished by a combination of EUS with either contrast-enhanced CT and/or MR [8–10]. Dimension, however, is not the only feature that should be taken into account when evaluating either familial or sporadic PNET as recent studies have emphasized that contrast-enhancement patterns may indeed be predictive of their differentiation grade and biological behavior [12–14]. Indeed, an arterial-enhancement ratio < 1.1, reported as the ratio between the attenuation of the tumor and that of the surrounding parenchyma should be viewed with caution even in lesion smaller than 2 cm according to Belousova et al. [13]. In our patient, whereas the small hyper-vascular nodule depicted at the level of the pancreatic tail (Fig. 1b) had been stable over 10 years (Figs. 3–4) as a result of SSA therapy [15, 16], the nearby hypo-vascular lesion was metastatic at presentation despite being only 9 mm in its longest diameter (Fig. 3d). Even in the absence of a pathologic proof for both pancreatic lesions, we can reasonably argue that the hyper-vascular lesion was indeed a G1 NF-PNET as it showed the same attenuation pattern as the surgically removed nodule within the pancreatic head (Fig. 1) whereas the hypo-vascular nodule was likely a NF-PNET of an higher grade (G2/G3) as it showed a fairly low uptake (SUV_max 6.3) of the radiotracer at ⁶⁸Ga-DOTA-TOC PET/CT [17] and rapidly progressed under high dose SSA therapy (Fig. 4b).

As far as the hypo-vascular nodule depicted by contrast-enhanced MDCT at the level of the pancreatic body (Fig. 1b) is concerned, despite it only faintly immuno-stained for glucagon at histopathological analysis (Fig. 2d) it also has to be considered a NF-PNET. Indeed, this occurs quite often in patients with MEN-1 whereas true functioning glucagonomas are quite rare (< 3%) tumors and have a worse prognosis compared to gastrinomas [18]. However, the Ki-67 proliferation index (Fig. 2c) was consistent with its hypo-vascular appearance indicating a G2 PNET (Fig. 1b) [12–14].

As far as duodenal gastrinomas are concerned, contrast-enhanced MDCT clearly depicted the asymmetric and the inhomogeneous thickening of the medial duodenal wall which corresponded to the larger tumor found at histopathology (pT2) but failed to detect the multiple sub-mucosal nodules shown by EUS which is considered the gold standard as a result of its higher spatial and contrast resolution [8]. However, contrast-enhanced MDCT well depicted loco-regional adenopathies (Fig. 1b) which turned out to be true positive findings at histopathological analysis (pT2,N1).

Finally, this case arises a number of questions about the optimal surgical technique in patients with MEN-1 and PNETS [19, 20]. While there is a general consensus about surgical indications in NF-PNET > 2cm in view of their malignant potential [5–7], most surgeons favor a conservative approach to preserve endocrine function and offer the patient a better quality of life [19]. However, while such a conservative approach may be reasonable in patients undergoing a distal pancreatectomy, it can be considered debatable in those undergoing a DCP as this anecdotal case clearly shows. In retrospect, a total pancreatectomy would have spared the patient from a high grade NF-PNET possibly assuring him a better prognosis. Indeed, a prophylactic pancreatectomy should be considered a reasonable option in patients with MEN-1 due to both the improved surgical techniques as well as pharmacologic advances in insulin-replacement therapies [20].

In summary, we have herein reported a 13 years observational study in a patient with MEN-1 syndrome who developed both functioning as well as NF-PNET with different contrast-enhancement patterns and biological behaviours. As current guidelines on active surveillance in patients with MEN-1 are mainly focused on lesions’ diameters [7], this case shows that aside from dimension contrast-enhancement patterns of PNET should also be taken into account [12–14]. As far as the conservative surgical approach is concerned, this should be seriously reconsidered in patients with MEN-1 and much more so when a DCP is deemed necessary as in the present case [20].

Funding

The authors declare that no funds, grants, or other support were received during the preparation of this manuscript.

Competing interests

The authors have no relevant financial or non-financial interests to disclose.

Author contributions

Luigi Camera, MD: Conceptual design and manuscript draft

Francesca Boccadifuoco, MD: Data collection and literature search

Roberta Modica, MD, PhD: Referring physician

Luca Messerini, MD: Histo-pathological analysis

Antongiulio Faggiano, MD, PhD: Manuscript revision

Valeria Romeo, MD, PhD: MR study

Valeria Gauderi, MD, PhD: PPRT

Annamaria Colao, MD, PhD: Manuscipt revision

Simone Maurea, MD, PhD: Manuscript revision

Arturo Brunetti, MD: Manuscript editing

Ethics approval

This is an observational study. The Local Ethical Committee declared that no ethical approval is required.

Consent to participate and publish

A written informed consent was obtained by the patient for both.

Guo SS, Sawicki MP. Molecular and genetic mechanisms of tumorigenes in multiple endocrine neoplasia type-1. Mol Endocrinol 15, 1653-1664 (2001)
Effraimidis G, Knigge U, Rossing M, Oturai P, Rasmussen ÅK, Feldt-Rasmussen U. Multiple endocrine neoplasia type 1 (MEN-1) and neuroendocrine neoplasms (NENs). Semin Cancer Biol 79, 141-162 (2022)
Niederle B, Selberherr A, Bartsch DK, et al. Multiple Endocrine Neoplasia Type 1 and the Pancreas: Diagnosis and Treatment of Functioning and Non-Functioning Pancreatic and Duodenal Neuroendocrine Neoplasia within the MEN1 Syndrome - An International Consensus Statement. Neuroendocrinology 111, 609-630 (2021)
Thakker RV, Newey PJ, Walls GV, et al. Clinical practice guidelines for multiple endocrine neoplasia type 1 (MEN1). J Clin Endocrinol Metab 97, 2990-3011 (2012)
Doherty GM. Multiple endocrine neoplasia type 1: duodenopancreatic tumors. Surg Oncol 12, 135-143 (2003)
Kouvaraki MA, Shapiro SE, Cote GJ, et al. Management of pancreatic endocrine tumors in multiple endocrine neoplasia type 1. World J Surg 30, 643-653 (2006)
Falconi M, Eriksson B, Kaltsas G, et al. ENETS Consensus Guidelines Update for the Management of Patients with Functional Pancreatic Neuroendocrine Tumors and Non-Functional Pancreatic Neuroendocrine Tumors. Neuroendocrinology 103, 153-171 (2016)
Camera L, Paoletta S, Mollica C, et al. Screening of pancreaticoduodenal endocrine tumours in patients with MEN 1: multidetector-row computed tomography vs. endoscopic ultrasound. Radiol Med 116, 595-606 (2011)
Barbe C, Murat A, Dupas B, et al. Magnetic resonance imaging versus endoscopic ultrasonography for the detection of pancreatic tumors in multiple endocrine neoplasia type-1. Dig Liv Dis 44, 228-234 (2012)
Verde F, Galatola R, Romeo V, et al. Pancreatic Neuroendocrine Tumors in Patients with Multiple Endocrine Neoplasia Type 1: Diagnostic Value of Different MRI Sequences. Neuroendocrinology 111, 696-704 (2021)
Nagtegaal ID, Odze RD, Klimstra D, et al. The 2019 WHO classification of tumours of the digestive system. Histopathology 76, 182-188 (2020)
Cappelli C, Boggi U, Mazzeo S, et al. Contrast enhancement pattern on multidetector CT predicts malignancy in pancreatic endocrine tumours. Eur Radiol 25, 751-759 (2015)
Belousova E, Karmazanovsky G, Kriger A, et al. Contrast-enhanced MDCT in patients with pancreatic neuroendocrine tumours: correlation with histological findings and diagnostic performance in differentiation between tumour grades. Clin Radiol 72, 150-158 (2017)
Salahshour F, Mehrabinejad MM, Zare Dehnavi A, et al. Pancreatic neuroendocrine tumors (pNETs): the predictive value of MDCT characteristics in the differentiation of histopathological grades. Abdom Radiol 45, 3155-3162 (2020)
Ramundo V, Del Prete M, Marotta V, et al. Impact of long-acting octreotide in patients with early-stage MEN1-related duodeno-pancreatic neuroendocrine tumours. Clin Endocrinol 80, 850-855 (2014)
Faggiano A, Modica R, Lo Calzo F, et al. Lanreotide Therapy vs Active Surveillance in MEN1-Related Pancreatic Neuroendocrine Tumors < 2 Centimeters. J Clin Endocrinol Metab (2020) doi:10.1210/clinem/dgz007
Lastoria S, Marciello F, Faggiano A, et al. Role of ⁶⁸Ga-DOTATATE PET/CT in patients with multiple nedocrine neoplasia type 1 (MEN1). Endocrine (2016) doi:10.1007/s12020-015-0702y
Lévy-Bohbot N, Merle C, Goudet P, et al. Prevalence, characteristics and prognosis of MEN 1-associated glucagonomas, VIPomas, and somatostatinomas: study from the GTE (Groupe des Tumeurs Endocrines) registry. Gastroenterol Clin Biol 28, 1075-1081(2004)
Tonelli F, Fratini G, Nesi G, et al. Pancreatectomy in multiple endocrine neoplasia type-1 related gastrinomas and pancreatic endocrine neoplasia. Ann Surg 244, 61-70 (2006)
Casadei R, Ricci C, Taffurelli G, et al. Is total pancreatectomy as feasible, safe, efficacious and cost-effective as pancreaticoduodenectomy? A single center, prospective, observational study. J Gastrointest Surg (2016) doi 10.1007/s11605-016-3201-4

Download PDF

Journal Publication

published 26 Apr, 2023

Read the published version in Endocrine →

Editorial decision: Minor Revisions Needed
23 Mar, 2023
Reviewers agreed at journal
28 Jan, 2023
Reviewers invited by journal
28 Jan, 2023
Editor assigned by journal
24 Jan, 2023
First submitted to journal
23 Jan, 2023

You are reading this latest preprint version

Gastrinomas and Non-functioning Pancreatic Endocrine Tumors in Multiple Endocrine Neoplasia Syndrome Type-1 (MEN-1)

Status:

Journal Publication

Version 1

Abstract

Figures

Introduction

Case Report

Discussion

Declarations

References

Status:

Journal Publication

Version 1