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. 2022 Aug 13;6(10):bvac122. doi: 10.1210/jendso/bvac122

Metastatic Grade 3 Neuroendocrine Tumor in Multiple Endocrine Neoplasia Type 1 Expressing Somatostatin Receptors

Akua Graf 1, James Welch 2, Rashika Bansal 3, Adel Mandl 4, Vaishali I Parekh 5, Craig Cochran 6, Elliot Levy 7, Naris Nilubol 8, Dhaval Patel 9, Samira Sadowski 10, Smita Jha 11, Sunita K Agarwal 12, Corina Millo 13, Jenny E Blau 14, William F Simonds 15, Lee S Weinstein 16, Jaydira Del Rivero 17,✉
PMCID: PMC9469921  PMID: 36111275

Abstract

Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) may occur in 30% to 90% of patients with multiple endocrine neoplasia type 1 (MEN1). However, only 1% of GEP-NETs are grade 3 (G3). Given the rarity of these aggressive tumors, treatment of advanced G3 GEP-NETs in MEN1 is based on the treatment guidelines for sporadic GEP-NETs. We report a 43-year-old male with germline MEN1 followed at our institution, with clinical features including hyperparathyroidism, a nonfunctional pancreatic NET, and Zollinger–Ellison syndrome. On routine surveillance imaging at age 40, computed tomography/positron emission tomography imaging showed 2 arterially enhancing intraluminal masses on the medial aspect of the gastric wall. Anatomical imaging confirmed 2 enhancing masses within the pancreas and a rounded mass-like thickening along the lesser curvature of the stomach. The gastric mass was resected, and pathology reported a well-differentiated G3 NET with a Ki-67 >20%. The patient continued active surveillance. Eighteen months later cross-sectional imaging studies showed findings consistent with metastatic disease within the right hepatic lobe and bland embolization was done. On follow-up scans, including 68Ga-DOTATATE (68Ga-DOTA(0)-Tyr(3)-octreotate) imaging, interval increase in number and avidity of metastatic lesions were compatible with disease progression. Given a paucity of treatment recommendations for G3 tumors in MEN1, the patient was counseled based on standard NET treatment guidelines and recommended 177Lu-DOTATATE treatment. PRRT (peptide receptor radionuclide therapy) with 177Lu-DOTATATE (177Lu-tetraazacyclododecanetetraacetic acid-octreotide) is an important therapeutic modality for patients with somatostatin receptor–positive NETs. However, prospective studies are needed to understand the role of PRRT in G3 NETs.

Keywords: multiple endocrine neoplasia type 1 (MEN1), peptide receptor radionuclide therapy (PRRT), neuroendocrine tumor (NET), grade 3 (G3), gastroenteropancreatic (GEP)

Multiple endocrine neoplasia type 1 (MEN1) syndrome is an autosomal dominant disorder caused by loss-of-function germline mutations in the tumor suppressor gene MEN1 that encodes a 610 amino acid protein called menin [1]. MEN1 syndrome is characterized by the co-occurrence of primary hyperparathyroidism, duodenopancreatic neuroendocrine tumors (NETs), and pituitary adenomas, with less common NETs occurring in the adrenals, the lungs, or the gastric wall [1]. Some patients may also develop meningiomas, facial angiofibromas, collagenomas, and lipomas [2]. Most MEN1-related tumors show loss of heterozygosity at the MEN1 locus, chromosome 11q13, causing biallelic inactivation of the MEN1 gene with tumors developing following the 2-hit hypothesis [1].

Gastroenteropancreatic neuroendocrine tumors (GEPNETs) occur in 30% to 90% of patients with MEN1 [3]. However, only a few case reports of grade 3 (G3) GEP-NETs are reported in the literature. Additionally, the rarity of these tumors is confirmed from large longitudinal databases such as the Dutch registry where only ~1% of MEN1 GEP-NETs were classified as G3 [4].

NETs related to MEN1 are reported to have an increased rate of metastasis in those patients with tumors of an increased size; approximately 50% to 80% of patients have metastases at the time of diagnosis [5]. Metastatic disease is more prevalent in MEN1 syndrome than in patients with sporadic endocrine tumors [6, 7]. For example, metastases are present in up to 50% of patients with MEN1-associated insulinomas, whereas less than 10% of non-MEN1 insulinomas metastasize [7, 8]. While patients with MEN1 are living longer in recent years, they still have a shortened overall life expectancy with a mean age at death of 55 years [9]. Two-thirds of patients with MEN1 syndrome die from a MEN1-related cause, and in 40% to 45% of cases advanced pancreatic neuroendocrine tumors (pNETs) are considered the most common disease-related cause of death in patients with MEN1 [10]. When compared with the general population or nonaffected members in MEN1 families, MEN1 is linked to higher mortality with duodenopancreatic NETs (DP-NETs) and thymic NETs as the main cause (70%) of death [5]. To prevent progressive disease, follow-up examinations are mandatory for disease management. During follow-up, the most important prognostic factors for clinical decision making in MEN1-related GEP NETs are tumor size (larger tumor size is associated with a higher rate of metastasis and decreased overall survival), histologic grading (mitotic count/Ki-67 index), and annual growth rate [4, 11-16].

Given the rarity of these tumors and the paucity of data available, treatment for advanced GEP-NETs in MEN1 is based on the treatment guidelines for sporadic GEP-NETs and includes somatostatin agonists, targeted therapies, chemotherapy, and radiation [5]. With a lack of well-powered treatment studies in this population, important therapeutic guidance can be drawn from case reports demonstrating single-use efficacy of these agents. The FDA-approved PRRT (peptide receptor radionuclide therapy) with 177Lu-DOTATATE (177Lu-tetraazacyclododecanetetraacetic acid-octreotide) for GEP-NETs as an important therapy for SSTR (somatostatin receptor)-expressing NETs. Reported cases of MEN1 G3 NETs are, therefore, important to highlight for clinical practice. Here we report a case of a G3 NET in MEN1 widely positive on 68Ga-DOTATATE imaging making him eligible for 177Lu-DOTATATE treatment. This is a report of a case of G3 gastric NET arising in the context of MEN1 syndrome. After a first-line treatment with somatostatin analog, the patient has been treated with PRRT.

Case Presentation

A 43-year-old Caucasian male with a history of primary hyperparathyroidism, nonfunctional pNET, and Zollinger–Ellison syndrome had been followed at our institution for 23 years (Fig. 1). The patient’s maternal uncle was the index case and had been diagnosed with MEN1 previously. Consequently, our patient had genetic testing at age 23, which confirmed a heterozygous germline MEN1 mutation with a mutant allele at the c.306delC locus.

Figure 1.

Figure 1.

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MEN1 timeline of patient (by age).

The patient was lost to follow-up for 8 years but returned at age 32 for routine surveillance as part of our natural history study at our institution (NCT00001345). Computed tomography (CT) and magnetic resonance imaging (MRI) identified 2 subcentimeter enhancing masses within the pancreas on axial T1 imaging, and a rounded mass-like thickening was described along the lesser curvature of the stomach (Fig. 2). The gastric tumor size was 3.5 × 3 × 1.9 cm and multiple other smaller cluster nodules of 1.2 cm in aggregate were reported, gastrin levels were 435 pg/mL (normal <100 pg/mL). The gastric lesion was also positive on the 68Ga-DOTATATE positron emission tomography (PET) scan. A  68Ga-DOTATATE (PET) scan demonstrated an atypical intraluminal mass on the medial aspect of the gastric wall (Fig. 3A) and subsequently, an 18F-fluorodeoxyglucose (FDG)-PET showed no corresponding hypermetabolic lesion (Fig. 3D).

Figure 2.

Figure 2.

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MRI demonstrating a gastric neuroendocrine tumor.

Figure 3.

Figure 3.

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(A) Preoperative 68Ga-DOTATATE scan demonstrating an intraluminal mass on the gastric wall and small foci in the pancreas and duodenum. (B) and (C) 68Ga-DOTATATE at 12 and 24 months postoperatively, respectively, demonstrating progression of metastatic liver disease. (D and E) Negative 18FDG-PET scan prior to exploratory laparotomy and at progression of disease.

The patient subsequently underwent an exploratory laparotomy with resection of the gastric mass with anterior gastrotomy and lesser curvature lymphadenectomy. Pathology revealed a well-differentiated G3 NET with a Ki-67% positive level index of 42% (Fig. 4D) and no lymphovascular or perineural invasion was identified. Furthermore, analysis with c-MET immunohistochemistry (IHC) (Fig. 4A-4C) was positive. The c-MET gene encodes a receptor tyrosine kinase that is mutated, overexpressed, or amplified in various tumor types causing tumor development and progression by stimulating oncogenic signaling pathways. Polymerase chain reaction or fluorescence in situ hybridization to detect c-MET mRNA level or gene amplification was not performed. c-MET protein expression in sporadic pNETs and other tumors has suggested the use of c-MET inhibitors for the treatment of these tumors [17]. According to routine guidelines for G3 NETs, the tumor did not meet the criteria for platinum-based adjuvant chemotherapy based on its well-differentiated morphology.

Figure 4.

Figure 4.

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c-MET positivity by immunohistochemistry (IHC) at different magnifications: (A) 40×, (B) 100×, and (C) 400×. (D) Ki-67 positive tumor cells of 42% by IHC. (E) Sanger sequencing showing heterozygous germline MEN1 mutation and loss of heterozygosity in tumor DNA.

Follow-up surveillance imaging 18 months after surgery, using abdominal MRI and liver ultrasound, demonstrated findings consistent with metastatic disease in the right hepatic lobe. Three rounds of bland embolization were completed, and octreotide long-acting release was initiated (gastrin levels were 1334 pg/mL, 486 pg/mL, and 254 pg/mL prior to each bland embolization, and subsequently 137 pg/mL 5 months after the last embolization). Somatic mutation analysis through the next-generation sequencing assay for pan-cancer biomarkers (TruSight Oncology 500, Illumina) of the gastric NET showed the loss of heterozygosity at the MEN1 germline variant locus in the tumor tissue, which was confirmed by Sanger sequencing (Fig. 4E). No variants were identified in c-MET (included in the somatic sequencing panel). The additional variants of uncertain significance were found in ATM, E2F3, FAT1, FLCN, MAP3K4, and NRG1. Nine months after liver embolization, follow-up scans with abdominal CT, abdominal MRI, 68Ga-DOTATATE PET/CT, and 18F-FDG PET/CT imaging demonstrated an interval increase in number and avidity of metastatic lesions (40.09 SUV) and a new lytic lesion in the T4 vertebral body with 68Ga-DOTATATE avidity compatible with a new metastatic lesion and disease progression (Figs. 3B and 3C). No suspicious focal radiotracer uptake was noted in the bone marrow. As a result, PRRT with 177Lu-DOTATATE was recommended as a second-line treatment following somatostatin agonist therapy.

Discussion

The updated 2019 WHO classifications of digestive tumors separate well-differentiated grade G1, G2, G3 NETs from G3 neuroendocrine carcinomas (NECs) [18]. Due to histological challenges in classification between G3 well-differentiated NETs and G3 poorly differentiated NECs, the WHO recommends the use of immunohistochemical markers to distinguish between these 2 [19]. Thus, G3 NETs are classified by a high proliferation rate (Ki-67 index >20% and usually <55%; or >20 mitotic figures/2 mm2) [19]. The current treatment for G3 NETs is not standardized and treatment guidelines follow treatment algorithm for well-differentiated (G1, G2) NETs if Ki-67% <55% [20]. As for the nonfunctional pNETs, the size is important to determine the risk of metastasis. Small tumors (<2 cm) have a more indolent course, and many studies suggest these nonfunctional pNETs may be monitored safely through imaging. Further studies from Mayo Clinic support observation for small nonfunctional pNETs (<2 cm) since these neoplasms have an indolent growth [21]. In our case, the pNETs were reported to be <1 cm in size and unlikely to metastasize

First-line treatment for a localized G3 NET is typically surgery and, if appropriate, regional lymphadenectomy [20]. For metastatic or unresectable G3 NETs with a Ki-67 index <55%, the following treatment options (and their combinations) are recommended: somatostatin analogs such as lanreotide, PRRT with 177 Lu-DOTATATE if SSTR positivity exists. Targeted therapies such as mammalian target of rapamycin inhibitors or tyrosine kinases/receptors inhibitors, chemotherapy (temozolomide ± capecitabine), folinic acid + fluorouracil + oxaliplatin (FOLFOX), capecitabine (Xeloda®) + oxaliplatin (CAPEOX), immunotherapy with pembrolizumab, if high tumor mutational burden, and liver-directed therapies are recommended [3]. For G3 NETs or NECs with a Ki-67 >55%, cisplatin/carboplatin + etoposide are the recommended chemotherapeutic regimen [3]. Similarly, in MEN1-associated NETs, the aforementioned therapeutic options have proven to be beneficial [3]. However, treatment options for patients that provide improved progression-free survival over extended periods of time are limited [17]. Complicating the picture compared with sporadic NETs, MEN1-related NETs are multifocal tumors within multiple concurrent organs and often metastatic disease is challenging to definitively trace back to a single primary tumor [16].

Another, more personalized, treatment approach could result by gaining a deeper understanding of c-MET. Menin loss results in an upregulation of c-MET and is considered an actionable target for GEP-NETs [17]. Our patient’s tumor was thus tested for c-MET by IHC staining and was found to be positive. Previous reports have demonstrated a reciprocal relationship between menin loss and c-MET overexpression in both mouse and human pNETs, suggesting an oncogenic role of c-MET in MEN1-associated pNETs [17]. Furthermore, c-MET overexpression was demonstrated in sporadic nonfunctioning pNETs which correlated with poor prognosis [22]. As a tyrosine kinase receptor for the hepatocyte growth factor, c-MET tumor overexpression has been shown clinically to be associated with increased peritoneal and liver metastasis in gastric cancer patients and an overall poorer prognosis [17]. Further clinical trials of c-MET inhibition in GEP-NETs would help advance our understanding and potentially provide a precision medicine approach for advanced GEP-NETs.

Furthermore, PRRT with 177Lu-DOTATATE has been used to treat metastatic well-differentiated G1-G2 NETs [23]. 177Lu-DOTATATE therapy was approved in the United States in 2018 based on a randomized study of 177Lu-DOTATATE vs high dose octreotide for adult patients with SSTR-positive midgut NETs with a Ki-67 <20% [24-26].

The effectiveness of PRRT in G3 NET is not well characterized. A recent large retrospective multicenter study assessed the efficacy of PRRT in patients with GEP G3 NETs with SSTR positivity [23]. PRRT may be a treatment option for patients with progressive disease [23]. Similar to previous smaller studies (Thang et al [27] and Nicolini et al [28]), the results of Carlsen et al showed significant differences in patients with Ki-67 <55% vs Ki-67 ≥55% and found an OS of 31 vs 9 months, and PFS of 16 vs 6 months, respectively [23].

Generally, the likelihood of SSTR expression decreases in NETs with increasing tumor grade, while the opposite is true for fluorodeoxyglucose (FDG) uptake [29, 30]. Raj et al observed that in 70% of cases, G3 NETs seem to have a positive SSTR imaging uptake compared to 30% in NECs [31-35]. These studies emphasize that G3 NETs with SSTR positivity have shown promising response and disease control rates, as well as increases in PFS and OS with PRRT.

Conclusions

Here we report a case of a rare, rapidly progressive G3 gastric NET in a patient with MEN1 that was positive on 68Ga-DOTATATE scan. The patient was counseled based on standard NET treatment guidelines and recommended 177Lu-DOTATATE treatment. PRRT with 177Lu-DOTATATE is an important therapeutic modality for patients with NETs and should be considered in patients with MEN1 given the recognized data demonstrating improved disease control rates and increased progression-free and overall survival. Although G3 NETs in MEN1 are rare, prospective clinical studies would elucidate our understanding of the role of PRRT in G3 NETs in MEN1.

Acknowledgments

We would like to thank the physicians and nurses who played a role in taking care of this patient at the NIH Clinical Center.

Glossary

Abbreviations

CT

computed tomography

DP

duodenopancreatic

FDG

fluorodeoxyglucose

G3

grade 3

GEP

gastroenteropancreatic

IHC

immunohistochemistry

MEN1

multiple endocrine neoplasia type 1

MRI

magnetic resonance imaging

NEC

neuroendocrine carcinoma

NET

neuroendocrine tumor

PET

positron emission tomography

pNET

pancreatic neuroendocrine tumor

PRRT

peptide receptor radionuclide therapy

SSTR

somatostatin receptor

Contributor Information

Akua Graf, Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Health, Bethesda, MD 20892, USA.

James Welch, Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Health, Bethesda, MD 20892, USA.

Rashika Bansal, Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Health, Bethesda, MD 20892, USA.

Adel Mandl, Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Health, Bethesda, MD 20892, USA.

Vaishali I Parekh, Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Health, Bethesda, MD 20892, USA.

Craig Cochran, Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Health, Bethesda, MD 20892, USA.

Elliot Levy, Radiology and Imaging Sciences, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.

Naris Nilubol, Endocrine Surgery Section, Surgical Oncology Program, National Cancer Institute, Bethesda 20892, MD, USA.

Dhaval Patel, Endocrine Surgery Section, Surgical Oncology Program, National Cancer Institute, Bethesda 20892, MD, USA.

Samira Sadowski, Endocrine Surgery Section, Surgical Oncology Program, National Cancer Institute, Bethesda 20892, MD, USA.

Smita Jha, Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Health, Bethesda, MD 20892, USA.

Sunita K Agarwal, Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Health, Bethesda, MD 20892, USA.

Corina Millo, Radiology and Imaging Sciences, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.

Jenny E Blau, Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Health, Bethesda, MD 20892, USA.

William F Simonds, Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Health, Bethesda, MD 20892, USA.

Lee S Weinstein, Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Health, Bethesda, MD 20892, USA.

Jaydira Del Rivero, Email: jaydira.delrivero@nih.gov, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.

Funding

This study was funded by the National Institutes of Health intramural program (Grant number: 1ZIABC011789).

Author Contributions

A.G. prepared the initial draft of the manuscript and revised the manuscript. J.D.R. critically reviewed and revised the manuscript. J.W., R.B., A.M., V.P., C.C., E.L., N.N., D.P., S.S., S.J., S.A., J.B., W.S., and L.W. reviewed and revised the manuscript and provided input. All authors contributed to the article and approved the submitted version.

Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Disclosure Summary

The authors have nothing to disclose.

Data Availability

The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.

Ethics Statement

The studies involving human participants were reviewed and approved by National Institutes of Health. The patients/participants provided their written informed consent to participate in this study.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Data Availability Statement

The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.

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