Carney complex: a curious case of a rare cancer syndrome caused by a novel pathogenic mutation in the PRKAR1A gene.

A 39-year-old woman was referred to the cancer genetics outpatient clinic for a clinical diagnosis of Carney complex (CNC) in her deceased brother. The patient had some characteristic clinical features such as periorbital lentigines and coarse facial features, suggestive of CNC; however, she did not meet major diagnostic criteria for CNC. Previous extensive investigations revealed a mild insulin-like growth factor 1 elevation, a stable left adrenal gland adenoma and a slightly enlarged pituitary gland. Single gene sequencing confirmed a novel pathogenic mutation in the PRKAR1A gene. This case, to our knowledge, is the first report of this mutation identified in a family of French-Canadian origin. This report broadens our understanding of the genotypic and phenotypic spectrum of this rare disease, while it highlights the value of a multidisciplinary approach in rare diseases, for genetic testing facilitated a timely diagnosis and enabled the initiation of early surveillance of CNC-related manifestations in our patient.

Significance of Crooke's Hyaline Change in Nontumorous Corticotrophs of Patients With Cushing Disease.

Background: Glucocorticoid excess in Cushing disease (CD) leads to negative feedback suppression, resulting in Crooke's hyaline change (CC) of nontumorous pituitary corticotrophs. We aimed to determine the predictive value of CC of nontumorous corticotrophs in CD. Methods: The retrospective chart review study included patients with clinical, biochemical, radiologic and outcome data and evaluable histopathology specimens from pituitary surgery for CD. The main outcome was remission of CD, defined by clinical features, biochemical testing, and corticosteroid dependency. Results: Of 144 CD patients, 60 (50 women, mean age 43.6±14) had clinical follow-up, biochemical data and histopathology specimens that included evaluable nontumorous adenohypophysis. Specimens from 50 patients (83.3%) demonstrated CC in nontumorous corticotrophs, and 10 (16.7%) had no CC (including 3 with corticotroph hyperplasia). One patient with CC was lost to follow-up and one without CC had equivocal outcome results. During a mean (SD) follow-up period of 74.9 months (61.0), recurrent or persistent disease was documented in 18 patients (31.0%), while 40 (69.0%) were in remission. In patients with CC, the remission rate was 73.5% (95% CI, 59.7%-83.7%) (36/49), whereas it was 44.4% (95% CI, 18.9%-73.3%) (4/9) in patients with no CC. The combination of serum cortisol >138 nmol/L within a week of surgery coupled with absence of nontumorous CC greatly improved the prediction of recurrent or persistent disease. Conclusions: CC of nontumorous corticotrophs was observed in 83% of patients with CD, and most patients with CC experienced remission. Absence of CC in nontumorous corticotrophs may serve as a predictor of reduced remission in patients with CD.

Preoperative prediction of non-invasive follicular thyroid neoplasm with papillary-like nuclear features: a Canadian single-Centre experience.

BACKGROUND: An international group of experts recommended reclassifying non-invasive follicular variant of papillary thyroid cancers (FVPTC) as 'non-invasive follicular thyroid neoplasm with papillary-like nuclear features' (NIFTP) in April 2016. The purpose of this study was to establish preoperative clinical, laboratory, ultrasonographic, and cytological variables, which can differentiate NIFTP from FVPTC. METHODS: We conducted a retrospective chart review of consecutive patients from a single institution evaluated between January 2012 and December 2017. 203 adult patients underwent lobectomy or total thyroidectomy for a FVPTC during that period. Each patient's medical chart was reviewed and information on pre-operative variables was recorded. An expert pathologist reviewed all surgical specimens and reclassified a subset of FVPTC as NIFTP according to the specific criteria. RESULTS: Overall, 44 patients were included in the NIFTP group and 159 in the non-NIFTP group. Mean age was 50.1 years in the NIFTP group and 50.7 in the non-NIFTP group. Most patients were female (86.4% (38/44) in the NIFTP group vs 79.8% (127/159) in the non-NIFTP group). More patients underwent lobectomy in the NIFTP group (50% (22/44) vs 16.4% (26/159) in the non-NIFTP group, p = < 0.0001). Less patients received radioactive iodine in the NIFTP group (31.8% (14/44) vs 52.2% (83/159) in the non-NIFTP group, p = 0.0177). Preoperative thyroglobulin levels were lower in NIFTP patients (Median 25.55 mcg/L +/- 67.8 vs 76.06 mcg/L +/- 119.8 in Non-NIFTP, p = 0.0104). NIFTP nodules were smaller (Mean size 22.97 mm +/- 12.3 vs 25.88 mm +/- 11.2 for non-NIFTP, p = 0.0448) and more often solid than non-NIFTP (93.2% (41/44) vs 74.8% (119/159) for non-NIFTP, p = 0.0067). 2017 ACR TIRADS nodule category of 1-4 on ultrasound had a negative predictive value and a sensitivity of 100% for NIFTP. ROC Curve Analysis demonstrated that a preoperative thyroglobulin level of 31.3 mcg/L had a sensitivity of 75% and a specificity of 62.5% to differentiate NIFTP from non-NIFTP cancers. CONCLUSION: Lower preoperative thyroglobulin levels, smaller nodule size, solid texture and 2017 ACR TIRADS Category of 1-4 are more strongly associated with NIFTP than FVPTC and can favour less invasive surgical options such as lobectomy.

Management of Small Bowel Neuroendocrine Tumors.

Several important landmark trials have reshaped the landscape of non-surgical management of small bowel neuroendocrine tumors over the last few years, with the confirmation of the antitumor effect of somatostatin analogue therapy in PROMID and CLARINET trials as well as the advent of therapies with significant potential such as mammalian target of rapamycin inhibitor (mTor) everolimus (RADIANT trials) and peptide receptor radionuclide therapy (PRRT) with 177-Lutetium (NETTER-1 trial). This narrative summarizes the recommended management strategies of small bowel neuroendocrine tumors. We review the main evidence behind each recommendation as well as compare and contrast four major guidelines, namely the 2016 Canadian Consensus guidelines, the 2017 North American Neuroendocrine Tumor Society guidelines, the 2018 National Comprehensive Cancer Network guidelines, and the 2016 European Neuroendocrine Tumor Society guidelines. Different clinical situations will be addressed, from loco-regional therapy to metastatic unresectable disease. Carcinoid syndrome, which is mostly managed by somatostatin analogue therapy and the serotonin antagonist telotristat etiprate for refractory diarrhea, as well as neuroendocrine carcinoma will be reviewed. However, several questions remain unanswered, such as the optimal management of neuroendocrine carcinomas or the effect of combining and sequencing of the aforementioned modalities where more randomized controlled trials are needed.

Co-occurrence of breast cancer and neuroendocrine tumours: New genetic insights beyond Multiple Endocrine Neoplasia syndromes.

OBJECTIVE: Age-standardized incidence of female breast cancer is 145.1 per 100000/year and 5.86 per 100000/year for neuroendocrine tumours (NET) in Canada. Evidence is scarce about gene variants that may predispose patients to develop both neoplasms. The objective of this study was to identify germline gene variants associated with this combination of tumours. DESIGN AND PATIENTS: A retrospective chart review (2007-2018) in a tertiary NET referral centre was completed. A series of 9 female patients with concurrent breast cancer and NET is presented. All patients underwent a 37 gene hereditary cancer next-generation sequencing panel. RESULTS: Mean age was 61.4 years (35-85) at breast cancer diagnosis and 63.4 years (51-89) at NET diagnosis. Four patients had a pancreatic, three had a small bowel and two had a lung NET. Two patients were known cases of MEN1, and one patient was found to harbour a pathogenic variant in MEN1 and a variant of unknown significance (VUS) in ATM. A second patient was found to harbour a pathogenic variant in APC. A third patient was found to carry a pathogenic variant in PALB2 as well as a VUS in FANCM, MLH1 and STK11. Another patient was found to harbour a VUS in MSH2. One patient was found to carry a pathogenic variant in NTHL1. CONCLUSION: The first cases of a PALB2, an APC and a NTHL1 pathogenic variants in patients with both breast cancer and NET were presented. NGS testing should be considered in specific patients with this combination of neoplasms, as certain germline variants beyond MEN1, have important implications for cancer surveillance.

Treatment Options for Pancreatic Neuroendocrine Tumors.

The management of pancreatic neuroendocrine tumors (PanNETs) involves classification into non-functional or functional PanNET, and as localized or metastatic PanNET. In addition, while most PanNETs are sporadic, these endocrine neoplasms can also be manifestations of genetic syndromes. All these factors may assist in forming a risk stratification system permitting a tailored management approach. Most PanNETs are classified as non-functional because they are not associated with clinical sequelae of hormone excess. They are characterized by non-specific symptoms, such as abdominal pain or weight loss, resulting from mass effect related to the pancreatic tumor or secondary to distant metastases. Accurate staging of the disease is essential for determining the appropriate approach to therapy. As cure is only potentially possible with surgical resection of the tumor, it is recommended to remove all localized and limited metastatic disease. However, many patients present with metastatic and/or advanced local disease. In such instances, the goal of therapy is to control tumor growth and/or decrease tumor burden, lengthen survival, and palliate local symptoms and those of hormone excess. This typically requires a multimodal approach, including surgery, liver-directed treatment, and systemic medical therapy.

The Clinicopathological Spectrum of Parathyroid Carcinoma.

Background: Parathyroid carcinoma is rare, representing <1% of primary hyperparathyroidism cases. Methods: Retrospective data of patients referred for evaluation of parathyroid disease between 2001 and 2018 were reviewed. The goal was to describe the clinical presentation, histopathologic characteristics, and treatment outcomes of parathyroid carcinoma. Results: We identified 8 cases of parathyroid carcinoma from the outpatient practice of a quaternary care Endocrine Oncology practice in Toronto, Canada. The clinical presentation was as follows: 5/8 cases (62.5%) of symptomatic hypercalcemia and 3/8 cases (37.5%) of a suspicious thyroid nodule. Hypercalcemia was evident in all 7 cases with pre-operative calcium measurements. Histopathologic features included: vascular invasion in 7/8 cases (87.5%) and immunohistochemical loss of either parafibromin, retinoblastoma, or p27 in all 8 cases. Additional treatment included: external beam radiotherapy in 5/8 cases (62.5%), chemotherapy for 2/8 patients (25%), and additional surgery for 3/8 patients (37.5%). Only 2 patients (25%) had long-term remission following surgical treatment, and the others had either persistent (3 patients) or recurrent disease (3 patients). Five patients developed metastatic disease, all involving lung. In one of two patients treated with Sorafenib there was evidence of regression of lung metastases. One patient died of disease progression. Conclusion: In this series of patients with parathyroid carcinoma largely presenting with symptomatic hypercalcemia and angioinvasive disease, only a minority achieved a durable remission. Lung was the most common site of distant metastasis. Surgery led to remission in two cases, but none of the six patients with persistent or recurrent disease ultimately achieved disease remission.