Objectives Introduction Materials and Methods ...

Patients with McCune-Albright syndrome have a broad spectrum of abnormalities in the gastrointestinal tract and pancreas Michaël

1, 2 Noë ,

1 Wood ,

2 Hackeng ,

2 Brosens ,

1 Debeljak ,

1 Yu ,

1 Suenaga ,

Laura D. Wenzel Lodewijk Feriyl Bhaijee, Marija Jun Masaya Aatur D. Singhi, Atif Zaheer, Alison Boyce, 1 1 1 1 Cembre Robinson, James R. Eshleman , Michael G. Goggins , Ralph H. Hruban , Michael T. Collins, Anne Marie Lennon, Elizabeth A. Montgomery 1

Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA 2 Department of Pathology, University Medical Center Utrecht, Utrecht, NL

Results

Introduction McCune-Albright Syndrome (MAS) is a rare sporadic syndrome, defined by a clinical spectrum of skeletal (fibrous dysplasia), endocrine (precocious puberty) and skin abnormalities (café au lait macules). The syndrome is caused by post-zygotic, activating mutations in the GNAS oncogene, leading to constitutional mosaicism for these alterations. The GNAS gene codes for the G protein-ɑ stimulatory subunit. Activating mutations in hot spot codon 201 cause ligand-independent signaling, elevated cAMP levels and activation of downstream signaling pathways. The same activating GNAS mutations are also found as alterations in a number of sporadic tumor types.

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Objectives To report thorough upper endoscopic examination of the gastrointestinal tract of seven patients with MAS, all selected for evaluation due to pancreatic cysts on magnetic resonance cholangiopancreatography (MRCP).

Materials and Methods As part of a screening protocol at the National Institutes of Health (NIH), patients with MAS were screened for pancreatic lesions using MRCP. All patients gave informed consent and the protocol was approved by the Institutional Review Board of the National Institute of Dental and Craniofacial Research. 7 patients with pancreatic cysts on MRCP were referred to the Johns Hopkins Hospital for endoscopic evaluation. At upper endoscopy, biopsies were taken from any visible lesions in the esophagus, stomach and duodenum. Endoscopic ultrasound (EUS) was performed and cyst fluid was sampled for pancreatic cysts >1.5cm. 2 patients with additional unusual lesions underwent resection of pancreatic and gastrointestinal lesions. DNA was extracted from the FFPE tissue of the biopsies or resections. The lesions were pyrosequenced for activating GNAS mutations in codon 201. Next-generation sequencing (NGS) and digital next-generation sequencing (digital NGS) on duodenal fluid samples was performed on the Ion Torrent PGM for the following genes: KRAS, GNAS, BRAF, PIK3CA, TP53, CDKN2A, SMAD4, RNF43, ARID1A, FBXW7, TGFBR2, and VHL.

A. Large gastric adenoma with high-grade dysplasia and multiple directions of differentiation; B. Intestinal differentiation in gastric adenoma; C. Gastric adenoma with high-grade dysplasia exhibiting irregularly fused glands, rounded nuclei with striking loss of nuclear polarity, and diffuse nuclear atypia; D. Areas of pyloric and oxyntic differentiation were prominent in the gastric adenoma; E. Nodular gastric heterotopia in the duodenum; F. No dysplasia is seen in the gastric-type epithelium. The presence of parietal cells suggests gastric heterotopia rather than gastric metaplasia

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proximal esophagus gastric heterotopia/metaplasia

incidence 4/7

GNAS mutated lesions 3/4

distal esophagus gastric heterotopia/metaplasia intestinal metaplasia

incidence 2/7 1/7

GNAS mutated lesions 1/2 wild-type

stomach gastric hyperplastic polyp fundic gland polyp multiple adenomatous lesions with high-grade dysplasia foveolar hyperplasia

incidence 4/7 2/7 1/7

GNAS mutated lesions 3/4 0/2 1/1

1/7

1/1

duodenum incidence gastric heterotopia/metaplasia 7/7 -adjacent neuroendocrine dysplasia 1/7 hamartomatous-type polyp 1/7

GNAS mutated lesions 9/13 wild-type wild-type

pancreas branch duct IPMN main duct IPMN

GNAS mutated lesions

NGS/digital NGS pancreatic cyst fluid patient 1 patient 4 patient 7

incidence 7/7 5/7

2/2

mutated genes GNAS (R201C), RNF43 (R343H) GNAS (R201C), KRAS (Q61H), PIK3CA (Q546R) GNAS (R201C), CDKN2A (V115fs)

Conclusion G. Neuroendocrine cell proliferations under areas of nodular gastric heterotopia. It is not clear whether these represent hyperplasia or neoplasia; H. Synaptophysin confirms neuroendocrine differentiation; I. Intraductal papillary mucinous neoplasm (IPMN); J. Gastric-type IPMN with low-grade dysplasia; K. IPMN with prominent papillae; L. The epithelium of this IPMN shows high-grade dysplasia and intestinal differentiation with elongated pencillate nuclei

We report the pathologic spectrum of gastrointestinal and pancreatic lesions in patients with McCune-Albright Syndrome. There is enrichment for lesions known to have GNAS mutations when they occur sporadically, including pancreatic IPMNs, gastric heterotopia, and gastric adenomas with pyloric gland and oxyntic differentiation.