Intraductal Papillary Mucinous Carcinoma Versus Conventional Pancreatic Ductal Adenocarcinoma: A Comprehensive Review of Clinical-Pathological Features, Outcomes, and Molecular Insights

Intraductal papillary mucinous neoplasms (IPMN) are common and one of the main precursor lesions of pancreatic ductal adenocarcinoma (PDAC). PDAC derived from an IPMN is called intraductal papillary mucinous carcinoma (IPMC) and defines a subgroup of patients with ill-defined specificities. As compared to conventional PDAC, IPMCs have been associated to clinical particularities and favorable pathological features, as well as debated outcomes. However, IPMNs and IPMCs include distinct subtypes of precursor (gastric, pancreato-biliary, intestinal) and invasive (tubular, colloid) lesions, also associated to specific characteristics. Notably, consistent data have shown intestinal IPMNs and associated colloid carcinomas, defining the “intestinal pathway”, to be associated with less aggressive features. Genomic specificities have also been uncovered, such as mutations of the GNAS gene, and recent data provide more insights into the mechanisms involved in IPMCs carcinogenesis. This review synthetizes available data on clinical-pathological features and outcomes associated with IPMCs and their subtypes. We also describe known genomic hallmarks of these lesions and summarize the latest data about molecular processes involved in IPMNs initiation and progression to IPMCs. Finally, potential implications for clinical practice and future research strategies are discussed.

Frontal bone fibrous dysplasia in a 6-months-old boy: A distinctive entity

Fibrous Dysplasia (FD) is a non-malignant condition caused by post-zygotic, activating mutations of the GNAS gene that results in inhibition of the differentiation and proliferation of bone-forming stromal cells and leads to the replacement of normal bone and marrow by fibrous tissue and woven bone. The clinical behavior and progression of FD is variable. The management of this condition is difficult and in every case is strictly individualized. We report a case of frontal fibrous dysplasia in a 6month’s old boy who underwent a successfully resection of the lesion with an excellent cosmetic effect.

A novel GNAS mutation in pseudohypoparathyroidism type 1a in a Chinese man presented with recurrent seizure: a case report

Background Pseudohypoparathyroidism is a rare genetic disease characterized by hypocalcaemia and hyperphosphataemia due to the defect to the guanine nucleotide-binding protein alpha subunit (GNAS) gene. Patients with pseudoparathyroidism type 1a and 1c could manifest Albright’s hereditary osteodystrophy and multiple hormone resistance including gonadotropin and thyroid stimulating hormone. Case presentation Here we report a Chinese man who presented with fatigue, recurrent seizure and Albright’s hereditary osteodystrophy. His genetic study revealed a heterozygote mutation in the GNAS gene [NM_000516.4(GNAS): c2787_2788del (p.Val930AspfsTer12)]. After calcium and calcitriol supplement, his seizures achieved partially remission. Conclusions We report a case of PHP1a or 1c with a novel frameshift mutation in GNAS gene in a patient presenting with AHO, as well as TSH and partial gonadotropin resistance. This mutation in this case has not been reported in literature and adds to the spectrum of genetic mutations related to PHP.

K-RAS, B-RAF and GNAS Gene Status and Immunohistochemistry Analysis of Mucinous Neoplasm of Appendix

AIM Low grade appendiceal mucinous neoplasm (LAMN) and serrated lesions are sometimes hard to differentiate from morphology. We try to characterize them from the immunohistochemical and molecular perspective and to reflect the difference between them. METHODS 25 appendix neoplasm including 13 LAMNs, 12 serrated lesions were selected from January 2013 to December 2014. Immunohistochemical analyses for cytokeratin 20, MUC6, MUC5AC, MUC1, Ki-67, P53 and mismatch repair (MMR) proteins including MLH1, PMS-2, MSH-6, MSH-2 were performed. Microsatellite instability (MSI) status was also evaluated. Besides, we detect K-RAS, B-RAF and GNAS gene mutation status of these lesions. RESULTS Immunochemically, 83.3% serrated lesions showed scattered CK20 staining in the deep crypt, which was less so for LAMNs. As for mucin expression, MUC5AC had slightly higher positive rate in LAMNs and than in serrated lesions.MUC1 was significantly higher expressed in LAMNs than in serrated lesions. 46.1% LAMNs have P53 expression in deep crypt, while P53 was negative in the deep crypt of serrated lesions. 58.3% serrated lesions had deficient MMR protein expresion pattern compared to 23.1% of LAMNs. B-RAF mutation was detected in 3 cases, all were serrated lesions. K-ras and GNAS mutation was detected in both LAMNs and serrated lesions. CONCLUSION Immunohistochemical panel comprising markers such as CK20, MUC5AC, MUC1, Ki-67 and P53, with genotyping covering hotspots of the KRAS, BRAF and GNAS genes can help the differential diagnosis of low grade appendix neoplasm.

SAT-371 Severe Hypocalcemia Secondary to Pseudohypoparathyroidism

Introduction: Pseudohypoparathyroidism (PHP) is a rare disorder characterized by PTH resistance due to a mutation in the GNAS gene causing decreased cyclic AMP generation. The 5 subtypes of PHP include type 1a, 1b, 1c, 2, and pseudo-PHP with type 1a being the most common. Patients with PHP present with hypocalcemia, hyperphosphatemia, appropriately elevated PTH, and suppressed calcitriol levels. PHP type 1a patients have characteristic features including obesity, short stature, round facies, and shortened metacarpals. PHP patients should be evaluated for other endocrinopathies as mutations in the GNAS gene may result in resistance to other hormones like TSH, GHRH, and gonadotropins. Case Report: This patient is a 25 year old male who presented to clinic for evaluation of hypocalcemia. He denied any personal or family history of calcium disorders, thyroid disease, or parathyroid disease. He admitted to severe fatigue and muscle cramps for over one year leading to a car accident. He was sent to the emergency room and diagnosed with hypocalcemia requiring IV calcium gluconate. He was then seen by his family physician and was found to have elevated intact PTH and low 25-hydroxy vitamin D levels. He was placed on cholecalciferol 5000 international units (IU) daily, ergocalciferol 50,000 IU once weekly, calcium carbonate 500 mg (6 tablets daily), and referred to endocrinology. The physical exam was unremarkable. The laboratory values tested were an intact PTH of 645 pg/mL (10–65 pg/mL), ionized calcium of 4.2 mg/dL (4.6–5.08 mg/dL), magnesium of 2.1 mg/dL (1.5–2.3 mg/dL), 25-OH vitamin D of 31.7 ng/mL (20–100 ng/mL), and creatinine of 0.81 mg/dL (0.7–1.3 mg/dL) four months after starting the above mentioned calcium and vitamin D supplementation. Further testing revealed a phosphorus level of 4.8 mg/dL (2.3–4.7 mg/dL), calcitriol level of 55.8 pg/mL(19.9–79.3 pg/mL), TSH of 10.46 uIU/mL (0.4–4.2 uIU/mL) and free T4 of 1.5 ng/dL (0.8–1.7 ng/dL). His labs were consistent with PHP. Although unknown which PHP subtype, it is likely not type 1a as he lacks its characteristic phenotype. His abnormal thyroid function tests may be secondary to TSH resistance associated with the GNAS gene mutation. He was told to continue the current dose of calcium carbonate but to discontinue ergocalciferol and cholecalciferol. He was placed on calcitriol 0.5 mcg daily. He will have repeat levels of his ionized calcium, calcitriol, TSH, and free T4 in two weeks. If TSH is still above 10 uIU/mL, we will start levothyroxine replacement. Conclusion: Although a rare disorder, clinicians should have a high index of suspicion for PHP to prevent complications of hypocalcemia (tetany, arrhythmias, seizures) and metabolic bone disease from PTH resistance. References: Mantovani, G. Pseudohypoparathyroidism: Diagnosis and Treatment, The Journal of Clinical Endocrinology & Metabolism, Volume 96, Issue 10, 1 October 2011, Pages 3020–3030.