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Open access

Nadine M Vaninetti, David B Clarke, Deborah A Zwicker, Churn-Ern Yip, Barna Tugwell, Steve Doucette, Chris Theriault, Khaled Aldahmani, and Syed Ali Imran

Purpose

Sellar masses may present either with clinical manifestations of mass effect/hormonal dysfunction (CMSM) or incidentally on imaging (pituitary incidentaloma (PI)). This novel population-based study compares these two entities.

Methods

Retrospective analysis of all patients within a provincial pituitary registry between January 2006 and June 2014.

Results

Nine hundred and three patients were included (681 CMSM, 222 PI). CMSM mainly presented with secondary hormone deficiencies (SHDs) or stalk compression (29.7%), whereas PIs were found in association with neurological complaints (34.2%) (P < 0.0001). PIs were more likely to be macroadenomas (70.7 vs 49.9%; P < 0.0001). The commonest pathologies among CMSM were prolactinomas (39.8%) and non-functioning adenomas (NFAs) (50%) in PI (P < 0.0001). SHDs were present in 41.3% CMSM and 31.1% PI patients (P < 0.0001) and visual field deficit in 24.2 and 29.3%, respectively (P = 0.16). CMSM were more likely to require surgery (62.9%) than PI (35.8%) (P < 0.0005). The commonest surgical indications were impaired vision and radiological evidence of optic nerve compression. Over a follow-up period of 5.7 years for CMSM and 5.0 years for PI, tumour growth/recurrence occurred in 7.8% of surgically treated CMSM and 2.6% without surgery and PI, 0 and 4.9%, respectively (P = 1.0). There were no significant differences in the risk of new-onset SHD in CMSM vs PI in those who underwent surgery (P = 0.7) and those who were followed without surgery (P = 0.58).

Conclusions

This novel study compares the long-term trends of PI with CMSM, highlighting the need for comprehensive baseline and long-term radiological and hormonal evaluations in both entities.

Open access

Erik Rösner, Daniel Kaemmerer, Elisa Neubauer, Jörg Sänger, and Amelie Lupp

Programmed death protein 1 (PD-1) and its ligand, PD-L1, have emerged as promising therapeutic targets for many types of cancer that overexpress PD-L1. However, data on PD-L1 expression levels in bronchopulmonary neuroendocrine neoplasms (BP-NEN) are limited and contradictory. In the present study, a total of 298 archived, formalin-fixed, paraffin-embedded BP-NEN samples from 97 patients diagnosed with typical carcinoid (TC), atypical carcinoid (AC), small cell lung cancer (SCLC), or large cell neuroendocrine carcinoma of the lung (LCNEC) were evaluated for PD-L1 expression by immunohistochemistry using the highly sensitive monoclonal anti-PD-L1 antibody 73-10. PD-L1 expression levels were semiquantitatively estimated by tumour grading. Of the 298 BP-NEN samples, 85% were positive for PD-L1 expression. PD-L1 immunostaining predominantly localized to the plasma membrane of both tumour cells and tumour-infiltrating immune cells. SCLC and LCNEC exhibited significantly higher PD-L1 expression levels than TC or AC. PD-L1 expression levels were also higher in patients with lymph node or distant metastases, in patients who smoked, and in patients who died during the follow-up period. Moreover, PD-L1 expression levels correlated positively with tumour grading, Ki-67 index and the expression of the chemokine receptor CXCR4 and negatively with the levels of somatostatin receptor 1 and chromogranin A. High tumour PD-L1 levels were associated with poor patient outcomes. In conclusion, PD-L1 expression is common in BP-NEN, increases with malignancy, and is associated with poor prognosis. Therefore, targeting the PD-1/PD-L1 axis could be a promising strategy for treating BP-NEN. PD-L1 may also represent a useful prognostic biomarker for this tumour entity.

Open access

K E Lines, R P Vas Nunes, M Frost, C J Yates, M Stevenson, and R V Thakker

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder characterised by occurrence of parathyroid tumours and neuroendocrine tumours (NETs) of the pancreatic islets and anterior pituitary. The MEN1 gene, encoding menin, is a tumour suppressor, but its precise role in initiating in vivo tumourigenesis remains to be elucidated. The availability of a temporally controlled conditional MEN1 mouse model would greatly facilitate the study of such early tumourigenic events, and overcome the limitations of other MEN1 knockout models, in which menin is lost from conception or tumour development occurs asynchronously. To generate a temporally controlled conditional mouse model, we crossbred mice with the MEN1 gene floxed by LoxP sites (Men1 L/L), and mice expressing tamoxifen-inducible Cre recombinase under the control of the rat insulin promoter (RIP2-CreER), to establish a pancreatic β-cell-specific NET model under temporal control (Men1 L/L/RIP2-CreER). Men1 L/L/RIP2-CreER mice aged ~3 months were given tamoxifen in the diet for 5 days, and pancreata harvested 2–2.5, 2.9–3.5 and 4.5–5.5 months later. Control mice did not express Cre and did not receive tamoxifen. Immunostaining of pancreata from tamoxifen-treated Men1 L/L/RIP2-CreER mice, compared to control mice, showed at all ages: loss of menin in all islets; increased islet area (>4.2-fold); increased proliferation of insulin immunostaining β-cells (>2.3-fold) and decreased proliferation of glucagon immunostaining α-cells (>1.7-fold). There were no gender and apoptotic or proliferation differences, and extra-pancreatic tumours were not detected. Thus, we have established a mouse model (Men1 L/L/RIP2-CreER) to study early events in the development of pancreatic β-cell NETs.

Open access

Benjamin G Challis, Andrew S Powlson, Ruth T Casey, Carla Pearson, Brian Y Lam, Marcella Ma, Deborah Pitfield, Giles S H Yeo, Edmund Godfrey, Heok K Cheow, V Krishna Chatterjee, Nicholas R Carroll, Ashley Shaw, John R Buscombe, and Helen L Simpson

Objective

In adults with hyperinsulinaemic hypoglycaemia (HH), in particular those with insulinoma, the optimal diagnostic and management strategies remain uncertain. Here, we sought to characterise the biochemical and radiological assessment, and clinical management of adults with HH at a tertiary centre over a thirteen-year period.

Design

Clinical, biochemical, radiological and histological data were reviewed from all confirmed cases of adult-onset hyperinsulinaemic hypoglycaemia at our centre between 2003 and 2016. In a subset of patients with stage I insulinoma, whole-exome sequencing of tumour DNA was performed.

Results

Twenty-nine patients were identified (27 insulinoma, including 6 subjects with metastatic disease; 1 pro-insulin/GLP-1 co-secreting tumour; 1 activating glucokinase mutation). In all cases, hypoglycaemia (glucose ≤2.2 mmol/L) was achieved within 48 h of a supervised fast. At fast termination, subjects with stage IV insulinoma had significantly higher insulin, C-peptide and pro-insulin compared to those with insulinoma staged I–IIIB. Preoperative localisation of insulinoma was most successfully achieved with EUS. In two patients with inoperable, metastatic insulinoma, peptide receptor radionuclide therapy (PRRT) with 177Lu-DOTATATE rapidly restored euglycaemia and lowered fasting insulin. Finally, in a subset of stage I insulinoma, whole-exome sequencing of tumour DNA identified the pathogenic Ying Yang-1 (YY1) somatic mutation (c.C1115G/p.T372R) in one tumour, with all tumours exhibiting a low somatic mutation burden.

Conclusion

Our study highlights, in particular, the utility of the 48-h fast in the diagnosis of insulinoma, EUS for tumour localisation and the value of PRRT therapy in the treatment of metastatic disease.

Open access

Ailsa Maria Main, Maria Rossing, Line Borgwardt, Birgitte Grønkær Toft, Åse Krogh Rasmussen, and Ulla Feldt-Rasmussen

Phaeochromocytomas and paragangliomas (PPGLs) are tumours of the adrenal medulla and extra-adrenal sympathetic nervous system which often secrete catecholamines. Variants of the SDHX (SDHA, -AF2, -B, -C, -D) genes are a frequent cause of familial PPGLs. In this study from a single tertiary centre, we aimed to characterise the genotype–phenotype associations in patients diagnosed with germline variants in SDHX genes. We also assessed whether systematic screening of family members resulted in earlier detection of tumours. The study cohort comprised all individuals (n = 59) diagnosed with a rare variant in SDHX during a 13-year period. Patient- and pathology records were checked for clinical characteristics and histopathological findings. We found distinct differences in the clinical and histopathological characteristics between genetic variants in SDHB. We identified two SDHB variants with distinct phenotypical patterns. Family screening for SDHB variants resulted in earlier detection of tumours in two families. Patients with SDHA, SDHC and SDHD variants also had malignant phenotypes, underlining the necessity for a broad genetic screening of the proband. Our study corroborates previous findings of poor prognostic markers and found that the genetic variants and clinical phenotype are linked and, therefore, useful in the decision of clinical follow-up. Regular tumour screening of carriers of pathogenic variants may lead to an earlier diagnosis and expected better prognosis. The development of a combined algorithm with clinical, genetic, morphological, and biochemical factors may be the future for improved clinical risk stratification, forming a basis for larger multi-centre follow up studies.

Open access

Nicola Tufton, Lucy Shapiro, Anju Sahdev, Ajith V Kumar, Lee Martin, William M Drake, Scott A Akker, and Helen L Storr

Objective

Phaeochromocytomas (PCC) and paragangliomas (PGL) are rare in children. A large proportion of these are now understood to be due to underlying germline mutations. Here we focus on succinate dehydrogenase subunit B (SDHB) gene mutation carriers as these tumours carry a high risk of malignant transformation. There remains no current consensus with respect to optimal surveillance for asymptomatic carriers and those in whom the presenting tumour has been resected.

Method

We undertook a retrospective analysis of longitudinal clinical data of all children and adolescents with SDHB mutations followed up in a single UK tertiary referral centre. This included index cases that pre-dated the introduction of surveillance screening and asymptomatic carriers identified through cascade genetic testing. We also conducted a literature review to inform a suggested surveillance protocol for children and adolescents harbouring SDHB mutations.

Results

Clinical outcomes of a total of 38 children are presented: 8 index cases and 30 mutation-positive asymptomatic carriers with 175 patient years of follow-up data. Three of the eight index cases developed metachronous disease and two developed metastatic disease. Of the 30 asymptomatic carriers, 3 were found to have PGLs on surveillance screening.

Conclusions

Surveillance screening was well tolerated in our paediatric cohort and asymptomatic paediatric subjects. Screening can identify tumours before they become secretory and/or symptomatic, thereby facilitating surgical resection and reducing the chance of distant spread. We propose a regular screening protocol commencing at age 5 years in this at-risk cohort of patients.

Open access

Ashley K Clift, Oskar Kornasiewicz, Panagiotis Drymousis, Omar Faiz, Harpreet S Wasan, James M Kinross, Thomas Cecil, and Andrea Frilling

Goblet cell carcinomas (GCC) are a rare, aggressive sub-type of appendiceal tumours with neuroendocrine features, and controversy exists with regards to therapeutic strategy. We undertook a retrospective review of GCC patients surgically treated at two tertiary referral centres. Clinical and histopathological data were extracted from a prospectively maintained database. Survival analyses utilised Kaplan–Meier methodology. Twenty-one patients were identified (9 females). Median age at diagnosis was 55 years (range 32–77). There were 3, 6 and 9 grade 1, 2 and 3 tumours, respectively. One, 10, 5 and 5 patients had stage I, II, III and IV disease at diagnosis, respectively. There were 8, 10 and 3 Tang class A, B and C tumours, respectively. Index operation was appendectomy (n = 12), right hemicolectomy (n = 6) or resections including appendix/right colon, omentum and the gynaecological system (n = 3). Eight patients underwent completion right hemicolectomy. Surgery for recurrence included small bowel resection (n = 2), debulking with peritonectomy and heated intraperitoneal chemotherapy, and hysterectomy and bilateral salpingo-oophorectomy (all n = 1). Median follow-up was 30 months (range 2.5–123). One-, 3- and 5-year OS was 79.4, 60 and 60%, respectively. Mean OS (1-, 3-, and 5-year OS) for Tang class A, B and C tumours were 73.1 months (85.7, 85.7, 51.4%), 83.7 months (all 66.7%) and 28.5 months (66.7, 66.7%, not reached), respectively. Chromogranin A/B and 68Ga-DOTATATE PET/CT were not useful in follow-up, but CEA, CA 19-9, CA 125 and 18F-FDG PET/CT identified tumour recurrence. GCC must be clearly discriminated from relatively indolent appendiceal neuroendocrine neoplasms. 18F-FDG PET/CT and CEA/CA19-9/CA 125 are useful in detecting recurrence of GCC.

Open access

Klaudia Zajkowska, Janusz Kopczyński, Stanisław Góźdź, and Aldona Kowalska

Noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) is a borderline thyroid tumour formerly known as noninvasive encapsulated follicular variant of papillary thyroid carcinoma. The prevalence of NIFTP is estimated at 4.4–9.1% of all papillary thyroid carcinomas worldwide; however, the rate of occurrence of NIFTP is eight times lower in Asian countries than in Western Europe and America. At the molecular level, NIFTP is characterised by the lack of BRAF V600E and BRAF V600E-like mutations or other high-risk mutations (TERT, TP53) and a high rate of RAS mutations, which is similar to other follicular-pattern thyroid tumours. The diagnosis of NIFTP can only be made after histological examination of the entire tumour removed during surgery and is based on strictly defined inclusion and exclusion criteria. Although the diagnosis is postoperative, the combination of certain findings of preoperative tests including ultrasonography, cytology, and molecular testing may raise suspicion of NIFTP. These tumours can be effectively treated by lobectomy, although total thyroidectomy remains an option for some patients. Radioactive iodine and thyroid stimulating hormone suppression therapy are not required. NIFTP has an extremely good prognosis, even when treated conservatively with lobectomy alone. Nevertheless, it cannot be considered as a benign lesion. The risk of adverse outcomes, including lymph node and distant metastases, is low but not negligible.

Open access

Ruth Therese Casey, Deborah Saunders, Benjamin George Challis, Deborah Pitfield, Heok Cheow, Ashley Shaw, and Helen Lisa Simpson

Context

Multiple endocrine neoplasia type 1 (MEN1) is a hereditary condition characterised by the predisposition to hyperplasia/tumours of endocrine glands. MEN1-related disease, moreover, malignancy related to MEN1, is increasingly responsible for death in up to two-thirds of patients. Although patients undergo radiological and biochemical surveillance, current recommendations for radiological monitoring are based on non-prospective data with little consensus or evidence demonstrating improved outcome from this approach. Here, we sought to determine whether cumulative radiation exposure as part of the recommended radiological screening programme posed a distinct risk in a cohort of patients with MEN1.

Patients and study design

A retrospective review of 43 patients with MEN1 attending our institution between 2007 and 2015 was performed. Demographic and clinical information including phenotype was obtained for all patients. We also obtained details regarding all radiological procedures performed as part of MEN1 surveillance or disease localisation. An estimated effective radiation dose (ED) for each individual patient was calculated.

Results

The mean ED for the total patient cohort was 121 mSv, and the estimated mean lifetime risk of cancer secondary to radiation exposure was 0.49%. Patients with malignant neuroendocrine tumours (NETS) had significantly higher ED levels compared to patients without metastatic disease (P < 0.0022).

Conclusions

In MEN1, radiological surveillance is associated with clinically significant exposure to ionising radiation. In patients with MEN1, multi-modality imaging strategies designed to minimise this exposure should be considered.

Open access

Linfei Yang, Xiao Yu, and Yongchao Yang

Although the upregulation of autotaxin (ATX) is associated with many solid tumours, its role in pancreatic neuroendocrine neoplasms (pNEN) has not been well elucidated. The expression of ATX in pNEN tissues and pNEN cell line BON1 was analysed by Western blot, PCR and immunocytochemistry upon exposure to interleukin-6 (IL-6). Additionally, pNEN cell line BON1 was transfected with siRNAs against ATX or signal transducer and activator of transcription 3 (STAT3) and assessed by in vitro invasion assays. The following results were obtained. The expression of ATX in pNEN tissues was significantly increased compared with that in normal pancreatic tissues. High ATX expression was strongly correlated with tumour grade, lymph node metastasis and tumour-node-metastasis stage. Furthermore, ATX downregulation notably inhibited the metastatic capacity of pNEN cells, whereas STAT3 knockdown was found to downregulate the expression of ATX. ATX expression was upregulated in BON1 cells upon stimulation with IL-6, and this was accompanied by activation/phosphorylation of STAT3. Western blot analysis of human pNEN tissue extracts confirmed increased ATX expression and STAT3 phosphorylation with elevated expression levels of IL-6. In conclusion, ATX is upregulated in pNEN and is correlated with the metastatic capacity of pNEN cells, potentially via interaction with STAT3 activation.