Sporadic Adenomas Research Articles

Colorectal dysplasia in chronic inflammatory bowel disease: a contemporary consensus classification and interobserver study

The clinical management of patients with dysplasia in chronic inflammatory bowel disease (IBD) is currently guided by Riddell et al.'s grading system (negative, indefinite, low grade, high grade) from 1983 which was based primarily on nuclear cytoarchitectural characteristics. Although most dysplasia in IBD resembles sporadic adenomas morphologically, other distinctive potential cancer precursors in IBD have been described over time. Recognizing the need for a updated comprehensive classification for IBD-associated dysplasia, an international working group of pathologists with extensive clinical and research experience in IBD devised a new classification system and assessed its reproducibility by having each participant assess test cases selected randomly from a repository of electronic images of potential cancer precursor lesions. The new classification system now encompasses three broad categories and nine sub-categories: 1) intestinal dysplasia (tubular/villous adenoma-like, goblet cell deficient, crypt cell, traditional serrated adenoma-like, sessile serrated lesion-like and serrated NOS), 2) gastric dysplasia (tubular/villous and serrated), and 3) mixed intestinal-gastric dysplasia. In the interobserver analysis, 67% of the diagnoses were considered definitive and achieved substantial inter-rater agreement. The key distinctions between intestinal and gastric lesions and between serrated and non-serrated lesions achieved substantial and moderate inter-rater agreement overall, respectively, however, the distinctions among certain serrated sub-categories achieved only fair agreement. Based on the Riddell grading system, definite dysplasia accounted for 86% of the collective responses (75% low grade, 11% high grade). Based on these results, this new classification of dysplasia in IBD can provide a sound foundation for future clinical and basic IBD research.

Long-term recurrence after endoscopic versus surgical ampullectomy of sporadic ampullary adenomas: a systematic review and meta-analysis.

Ampullary adenomas are treated both surgically and endoscopically, however, data comparing both techniques are lacking. We aimed to compare long-term recurrence of benign sporadic adenomas after endoscopic (EA) and surgical ampullectomy (SA). A comprehensive literature search of multiple databases (until December 29, 2020) was performed to identify studies reporting outcomes of EA or SA of benign sporadic ampullary adenomas. The outcome was recurrence rate at 1year, 2-year, 3year and 5years after EA and SA. A total of 39 studies with 1753 patients (1468 EA [age 61.1 ± 4.0years, size 16.1 ± 4.0mm], 285 SA [mean age 61.6 ± 4.48years, size 22.7 ± 5.4mm]) were included in the analysis. At year 1, pooled recurrence rate of EA was 13.0% (95% confidence interval [CI] 10.5-15.9], I2 = 31%) as compared to SA 14.1% (95% CI 9.5-20.3 I2 = 15.8%) (p = 0.82). Two (12.5%, [95% CI, 8.9-17.2] vs. 14.3 [95% CI, 9.1-21.6], p = 0.63), three (13.3%, [95% CI, 7.3-21.6] vs. 12.9 [95% CI, 7.3-21.6], p = 0.94) and 5 years (15.7%, [95% CI, 7.8-29.1] vs. 17.6% [95% CI, 6.2-40.8], p = 0.85) recurrence rate were comparable after EA and SA. On meta-regression, age, size of lesion or enbloc and complete resection were not significant predictors of recurrence. EA and SA of sporadic adenomas have similar recurrence rates at 1, 2, 3 and 5years of follow up.

Sporadic parathyroid adenoma: an updated review of molecular genetics.

Primary HPT (PHPT) is a common disorder, affecting approximately 1% of the general population. Parathyroid adenomas emerge as non-familial sporadic in 90% of cases. The aim of this review is to give a detailed update of molecular genetics of sporadic parathyroid adenoma reported in international literature. A bibliographic research was conducted in PubMed, Google Scholar, and Scopus. Seventy-eight articles were included in our review. CaSR, MEN1, CCND1/PRAD, CDKI, angiogenic factors like VEGF, FGF, TGFβ, and IGF1, and apoptotic factors are important genes in parathyroid adenomas pathogenesis that have been established by several studies. A huge list of proteins is differently expressed in parathyroid adenomas measured by Western Blotting, MALDI/TOF, MS spectrometry, and immunohistochemistry. These proteins take part in several cell processes such as cell metabolism, cytoskeleton structural stability, cell oxidative stress regulation, cell death, transcription, translation, cell connection, and cell signaling transmission, while they can be found over- or underexpressed in abnormal tissues. This review gives a detailed analysis of all reported data on genomics and proteomics of parathyroid adenoma. Further studies should be applied on understanding parathyroid adenoma pathogenesis and introducing new biomarkers for early detection of primary hyperparathyroidism.

Low frequency of AIP mutations in patients with young-onset sporadic pituitary macroadenomas

PurposeMutations in the aryl hydrocarbon receptor interacting protein (AIP) gene cause familial isolated pituitary adenomas (FIPA). AIP mutations have also been found in patients with apparently sporadic pituitary adenomas, particularly in young patients with large adenomas. The aim of this study was to determine the frequency of AIP germline mutations in patients with young-onset sporadic pituitary macroadenomas.MethodsThe AIP gene was sequenced in 218 Portuguese patients with sporadic pituitary macroadenomas diagnosed before the age of 40 years.ResultsHeterozygous rare sequence variants in AIP were identified in 18 (8.3%) patients. However, only four (1.8%) patients had pathogenic or likely pathogenic variants. These consisted of two already known mutations (p.Arg81* and p.Leu115Trpfs*41) and two novel mutations (p.Glu246*, p.Ser53Thrfs*36). All four patients had GH-secreting adenomas diagnosed between the ages of 14 and 25 years. The frequency of AIP pathogenic or likely pathogenic variants in patients under the age of 30 and 18 years was 3.4% and 5.0%, respectively.ConclusionThe frequency of AIP mutations in this cohort was lower than in other studies. Previous reports may have overestimated the contribution of AIP mutations due to the inclusion of genetic variants of uncertain significance. The identification of novel AIP mutations expands the known spectrum of genetic causes of pituitary adenomas and may help understand the role of AIP mutations in the molecular mechanisms underlying pituitary tumorigenesis.

High frequency of colorectal neoplasia in patients with sporadic adenomas or adenocarcinomas of the papilla of Vater: The same adenoma-carcinoma sequence?

Data on the frequency of colorectal neoplasia in sporadic ampullary tumors remains scarce. We retrospectively reviewed 135 patients undergoing endoscopic ampullectomy from January 2018 to July 2021, and identified 95 patients with sporadic ampullary adenoma who underwent total colonoscopy. Colonoscopy findings were compared with 380 asymptomatic controls using the chi-squared test. Whole-exome sequencing (WES) was performed on one patient with synchronous adenomas of the ampulla of Vater and ascending colon. Colorectal polyps were present in 60% of Cases vs. 34.7% of Controls (P=0.001), advanced adenoma in 20% vs. 5.5%, and adenocarcinoma in 4.2% vs. 0.8%. Cases tended to have larger polyps than Controls (P<0.001), while there was no difference in polyp location and histology between the two groups. The odds ratio of all the colorectal lesions, advanced colorectal adenoma and adenocarcinoma in Cases was 1.7, 4.2, and 4, respectively. WES in one patient revealed that both of ampullary adenoma and colonic adenoma shared somatic ABCB1 mutation. The frequency of colorectal polyps or neoplasia was significantly higher in Cases than Controls. We proposed that ampullary neoplasia is analogous to colon lesions and warrants total colonoscopy screening in patients diagnosed with ampullary tumors.

Abstract 5279: Molecular analysis of AMBRA1 as a candidate tumor suppressor in sporadic parathyroid adenomas

Abstract Primary hyperparathyroidism is a common endocrine disorder that is most often caused by a sporadic single-gland parathyroid adenoma. Currently, the only known and experimentally validated oncoprotein for parathyroid adenomas is cyclin D1. Overexpression of cyclin D1 has been reported in 20-40% of cases; about 8 percent of cases harbor a DNA rearrangement involving the cyclin D1 (CCND1) locus. Other molecular mechanisms underlying this cyclin D1 overexpression have yet to be identified. Here, we explored a potential parathyroid tumorigenic mechanism that could increase cyclin D1 stability through a defect in the AMBRA1 E3 ligase adaptor, a molecule responsible for its degradation. Evidence that AMBRA1 may be a tumor suppressor gene includes: accumulation of cyclin D with hyperproliferation in AMBRA1-deficient cells, context-dependent growth of tumors in Ambra1-deficient mice, and the correlation between low levels of AMBRA1 and poor clinical outcomes in The Cancer Genome Atlas. Therefore, we examined AMBRA1 for evidence of tumor suppressor-type inactivation in a cohort of 98 typical parathyroid adenomas. Tumor genomic DNA was subjected to PCR-amplification of all 18 coding exons of AMBRA1, followed by Sanger sequencing. Sequences were analyzed by comparison to the normal reference sequence (ENST00000683756.1), seeking to assess any observed intragenic or splice-site variants as potential or likely loss-of-function mutations. Thus far, with 97 percent of the coding region for this 1298-amino acid protein fully sequenced, we have identified an inactivating mutation in 1 of 98 tumors (1%): c.126G&amp;gt;A, resulting in an early stop codon p.Trp42. This mutation showed loss of heterozygosity and was confirmed to be somatic by sequencing of the patient’s matched germline DNA. We also identified likely non-pathogenic variants in 5 tumors: missense variant c.3385G&amp;gt;T (p.Ala1129Ser), 3’ UTR variants c.*576A&amp;gt;T and c.*491T&amp;gt;C and synonymous variants c.579C&amp;gt;T and c.2776C&amp;gt;T, each in a single tumor. 4 of 5 were found as germline variants in the normal population and the one missense scored as benign by in silico criteria. To conclude, our observations suggest that AMBRA1 may function as a classical tumor suppressor gene in sporadic parathyroid adenomas at very low frequency. Further study may include protein expression analysis of AMBRA1 to investigate influences on gene expression. To further elucidate the mechanisms behind cyclin D1 overexpression in parathyroid adenomas, other molecules that participate in its degradation should be explored as potential tumor suppressors. Citation Format: Stephanie Chinwo, Justin Bellizzi, Jessica Costa-Guda, Andrew Arnold. Molecular analysis of AMBRA1 as a candidate tumor suppressor in sporadic parathyroid adenomas. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5279.

Germline- and Somatic-Inactivating FLCN Variants in Parathyroid Cancer and Atypical Parathyroid Tumors.

Parathyroid cancer (PC) is a rare endocrine neoplasm with high mortality. While surgery is the treatment for patients with the disease, recurrence rates are high, and patients usually succumb to severe hypercalcemia. There is no effective systemic therapy for the disease. To investigate for novel genes causing parathyroid cancer. We analyzed the germline DNA of 17 patients with "sporadic" PC and 3 with atypical parathyroid tumors (APTs) who did not have germline CDC73 or MEN1 pathogenic variants. Sequencing of available tumor tissue from 14 patients with PC and 2 with APT was also performed (including 2 patients with no available germline DNA). In addition, sporadic parathyroid adenomas from 74 patients were analyzed for FLCN variants. We identified germline FLCN variants in 3 unrelated patients with PC. The 2 frameshift variants have been described in patients with Birt-Hogg-Dubé (BHD) syndrome, while the pathogenicity of the missense variant c.124G > C (p.G42R) has not been definitively established. Functional analysis of the missense variant showed a potential effect on posttranslational modification. All 3 patients with germline FLCN variants were noted to have renal cysts and 2 had lung cysts, features associated with BHD syndrome. Somatic FLCN variants were identified in tumors from 2 (1 APT) of 16 patients with PC/APT and in none of the 74 sporadic parathyroid adenomas. No second hits in FLCN were noted on sequencing; however, loss of heterozygosity at the locus was demonstrated in 2 of 3 patients with the identified germline FLCN variant. The finding of FLCN variants associated with PC may provide the foundation for the development of therapy for this malignancy.

P267 Real-world artificial intelligence-aided colonoscopy does not improve adenoma detection rates in patients with Inflammatory Bowel Disease

Abstract Background Recently, the implementation of artificial intelligence-aided colonoscopy (AIAC) has resulted in improved performance of colorectal cancer (CRC) screening. The adenoma detection rate (ADR) is a key quality indicator in screening colonoscopies and achieving high ADRs is crucial for optimal prevention of CRC. Guidelines suggest that ADRs of 20% in women and 30% in males are indicative of adequate performance. Patients with inflammatory bowel disease (IBD) may be at increased risk for CRC based on disease extent and duration. However, ADR in patients with IBD can be generally lower than in average-risk patients, mainly due to an age gap and the presence of dysplasia associated lesions as opposed to sporadic adenomas. Indeed, there is no consensus for an accepted ADR target in these patients. In addition, the impact of AIAC on ADR in these patients has yet to be described. We aimed to explore the ADR of patients with IBD in a large-volume endoscopic center and evaluate the effect of AIAC on ADR. Methods This was a retrospective study conducted at a high-volume gastroenterology department where all endoscopy suites were equipped with an AIA device (GI Genius, Medtronic, Ireland) starting from July 1st 2021. Data was collected on all colonoscopies performed in the 11 months before the mentioned date and compared to a 15-month period afterwards. We excluded patients that performed colonoscopy due to evaluation of IBD severity, for known or suspected malignancy, therapeutic endoscopies, incomplete colonoscopies and colonoscopies with inadequate preparation. The primary outcome of the study was ADR. Results Our study included 996 colonoscopies (237 pre-AIAC, 759 AIAC). The groups were similar in age (median 43.8 years, interquartile ratio (IQR) 28.7-61.2 vs 44.5 years, IQR 30.7-59.1, p=0.76) and gender distribution (55.3% vs 54.3% males, p=0.82). In both groups, there were more Crohn’s disease (62.9% pre-AIAC, 57.2% AIAC, p=0.13) than ulcerative colitis patients. The ADR in the pre-AIAC group tended to be higher in comparison to AIAC (6.3% vs 4%, p=0.15); When limiting to experienced gastroenterologists only (≥ 5 years), ADR results were significant higher in the pre-AIAC group (7.6% vs 3.8%, p=0.035). In addition, total procedure time (considered the time from procedure start and end as recorded by the endoscopy nurse) was significantly shorter in the AIAC group (21 minutes, IQR 17-28 vs 25 minutes, IQR 19-37, p&amp;lt;0.0001). Conclusion In a large-volume tertiary center cohort, the introduction of AIAC to real-world colonoscopies did not improve ADR in patients with IBD, questioning the integration of AIAC in routine practice.

Genomic Profiling Reveals the Variant Landscape of Sporadic Parathyroid Adenomas in Chinese Population.

To define somatic variants of parathyroid adenoma (PA) and to provide novel insights into the underlying molecular mechanism of sporadic PA. Basic clinical characteristics and biochemical indices of 73 patients with PA were collected. Whole-exome sequencing was performed on matched tumor-constitutional DNA pairs to detect somatic alterations. Functional annotation was carried out by ingenuity pathway analysis afterward. The protein expression of the variant gene was confirmed by immunohistochemistry, and the relationship between genotype and phenotype was analyzed. Somatic variants were identified in 1549 genes, with an average of 69 variants per tumor (range, 13-2109; total, 9083). Several novel recurrent somatic variants were detected, such as KMT2D (15/73), MUC4 (14/73), POTEH (13/73), CD22 (12/73), HSPA2 (12/73), HCFC1 (11/73), MAGEA1 (11/73), and SLC4A3 (11/73), besides the previously reported PA-related genes, including MEN1 (11/73), CASR (6/73), MTOR (4/73), ASXL3 (3/73), FAT1 (3/73), ZFX (5/73), EZH1 (2/73), POT1 (2/73), and EZH2 (1/73). Among them, KMT2D might be the candidate driver gene of PA. Crucially, 5 patients carried somatic mutations in CDC73, showed an aggressive phenotype similar to that of parathyroid carcinoma (PC), and had a decreased expression of parafibromin. Pathway analysis of recurrent potential PA-associated driver variant genes revealed functional enrichments in the signaling pathway of Notch. Our study expanded the pathogenic variant spectrum of PA and indicated that KMT2D might be a novel candidate driver gene and be considered as a diagnostic biomarker for PA. Meanwhile, CDC73 mutations might be an early developmental event from PA to PC. The results provided insights into elucidating the pathogenesis of parathyroid tumorigenesis and a certain basis for clinical diagnosis and treatment.

Expanded application of pancreas sparing duodenectomy: A case series

Background: A pancreas sparing duodenectomy (PSD) consists of full thickness resection of the entire duodenum including the ampulla of Vater. The proximal jejunum is advanced to reconstruct a single biliary-pancreatic orifice and re-establish gastrointestinal continuity with pyloro-jejunostomy. First described in 1995 in Cleveland, Ohio for advanced duodenal polyposis in familial adenomatous polyposis that remains the most common indication, with expanding indications such as sporadic villous adenomas and gastrointestinal stromal tumor. The aim of this case series is to present additional unique indications for PSD as a novel solution in patients with complex surgical conditions.

Further Study on Field Cancerization in the Human Colon.

Nearly 70 years ago, Slaughter launched the hypothesis of field cancerization for oral carcinomas; that hypothesis was subsequently also claimed for carcinomas in other organs. We previously found in the colon mucosa adjacent to nonpolypoid adenomas, branching crypts lined by normal epithelium (BCNE). Here, we explored whether BCNE could also be found in the colon mucosa adjacent to sporadic polypoid tubular adenomas (TA), the most prevalent of all colon adenomas. Nondysplastic mucosa adjacent to TA was found in 103 out of 131 TA. All BCNE adjacent to TA were recorded. In 98 (95.1%) out of 103 TA having nondysplastic adjacent mucosa, 645 BCNE were registered: 82.6% were in asymmetric branching and 17.4% in symmetric branching. Thus, BCNE in asymmetric branching predominated. The frequency of BCNE adjacent to TA was influenced by the adenoma size and degree of dysplasia severity. Contrarywise, the frequency of BCNE adjacent to TA was neither influenced by the age or sex of the patients, nor by the colon localization of TA. BCNE often occur in the normal mucosa adjacent to TA. BCNE emerge as integral components of TA. The majority of the BCNE were in asymmetric branching, considered as aberrations of cryptogenesis. We propose that the accretion of asymmetric BCNE adjacent to TA supports Slaughter's hypothesis of field cancerization.

Top tips for endoscopic ampullectomy of sporadic ampullary adenoma (with video)

Top tips for endoscopic ampullectomy of sporadic ampullary adenoma (with video)

Associations of dietary, lifestyle, and other participant characteristics with APC, β-catenin, E-cadherin, and MSH2 expression in the normal mucosa of sporadic colorectal adenoma patients

Abnormal expression of Wnt pathway and DNA mismatch repair proteins is common during colorectal carcinogenesis. To investigate cross-sectional associations of lifestyle, dietary, and other participant characteristics with the expression of such proteins, we measured APC, β-catenin, E-cadherin, and MSH2 colorectal crypt expression in biopsies of normal-appearing colorectal mucosa from 104 sporadic colorectal adenoma patients using automated immunohistochemistry and quantitative image analysis. We used multivariable general linear models to compare adjusted mean biomarker expression across categories of participant characteristics. Example findings include that among women relative to men, mean APC expression in whole crypts, the upper 40% of crypts (differentiation zone), and the lower 60% of crypts (proliferation zone) was 322.9% higher (p&amp;lt;0.01), 296.7% higher (p&amp;lt;0.01), and 399.1% higher (p&amp;lt;0.01), respectively. Among participants with higher alcohol consumption, APC expression in the crypt differentiation zone was estimated to be 15.9% lower (p=0.08). Among those with higher total meat consumption, β-catenin expression in whole crypts and the crypt proliferation zone was estimated to be 20.5% higher (p=0.07) and 19.6% higher (p=0.06), respectively, and MSH2 expression in the crypt differentiation zone was estimated to be 64.4% lower (p=0.10). Among those with a higher body mass index, MSH2 expression in the crypt differentiation zone was estimated to be 87.5% lower (p=0.15). These pilot study findings suggest that being male, higher adiposity, and higher alcohol and meat consumption may be unfavorably associated with biomarkers of colorectal carcinogenesis pathway proteins in the normal-appearing colorectal mucosa of sporadic colorectal adenoma patients and support further investigation in larger studies.

PSAT176 Molecular Analysis of AMBRA1 as a Candidate Tumor Suppressor in Sporadic Parathyroid Adenomas

Abstract Primary hyperparathyroidism is a common endocrine disorder that is most often caused by a sporadic single-gland parathyroid adenoma. Currently, the only known and experimentally validated oncoprotein for parathyroid adenomas is cyclin D1. The overexpression of cyclin D1 protein has been reported in twenty to forty percent of cases. Eight percent of this overexpression can be explained by DNA rearrangement involving the cyclin D1 locus. The remaining molecular mechanisms behind this overexpression have yet to be identified. In this study, we explored a potential parathyroid tumorigenic mechanism that could increase cyclin D1 stability through a defect in the AMBRA1 E3 ligase adaptor, a molecule responsible for its degradation. Evidence that AMBRA1 may be a tumor suppressor gene includes the accumulation of cyclin D with hyperproliferation in AMBRA1-deficient cells, the context-dependent growth of tumors in Ambra1-deficient mice, and the finding that low levels of AMBRA1 correlated with poor clinical outcomes in The Cancer Genome Atlas (TCGA). We have therefore proceeded examine AMBRA1 for evidence of tumor suppressor-type inactivation within a cohort of parathyroid adenomas. Genomic DNA from twenty-six typical sporadic parathyroid adenomas was subjected to PCR-amplification of all eighteen coding exons of AMBRA1, followed by Sanger sequencing. Sequences were analyzed by comparison to the normal reference sequence, seeking to assess any observed intragenic or splice-site variants as potential or likely loss-of-function mutations. Thus far, with ninety-seven percent of the coding region fully sequenced, no intragenic AMBRA1 inactivating mutations were observed. Three known single nucleotide polymorphisms, considered non-pathogenic, were identified: missense variant c.3028G&amp;gt;T, and 3' UTR variants c.*491T&amp;gt;C and c.*576A&amp;gt;T, each in a single tumor. Future study of increased numbers of parathyroid adenomas is needed to exclude the possibility that AMBRA1 inactivation could play a driver role in a small percentage of cases, and the possibility that AMBRA1 might contribute less directly e.g. via secondarily altered expression also warrants investigation. Nonetheless, our current observations strongly suggest that AMBRA1 does not have a frequent role as a classic 2-hit tumor suppressor gene in sporadic parathyroid adenomas. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.

ODP328 Longitudinal Multidisciplinary Approach for Cabergoline-Resistant Aggressive Prolactinoma Complicated by Multiple Endocrine Neoplasia Type 1

Abstract Background Cabergoline-resistant prolactinomas comprise approximately 10% of all prolactinomas, and sometimes show aggressive features including invasion or higher proliferation profiles. The treatment for such cabergoline-resistant aggressive prolactinomas is challenging and requires a multidisciplinary approach. Clinical case: A 47-year-old woman was diagnosed with hyperprolactinemia after complaining of menstrual irregularities at 20 years old. No neoplastic lesion was identified in the suprasellar region, and 0.25 mg/week cabergoline was initiated. At 35 years’ old, an adenoma was suspected on the right side of the pituitary gland, though plasma prolactin values were sustained without any clinical symptoms. When the patient was 46 years old, her prolactin levels elevated to 202 ng/ml, and magnetic resonance imaging showed a tumor invaded bilateral cavernous sinuses. Because prolactin levels and tumor size continued to increase despite increasing the cabergoline dose to 1 mg/week, endoscopic transsphenoidal surgery was performed. The tumor nearly total removal, the postoperative prolactin levels decreased to 00, but started to increase again in a short period of time. Pathologic assessment revealed a high Ki-67 index (20%) and diffusely positive prolactin alongside negative expression of other anterior hormones. The tumor remained in the cavernous sinus and postoperative prolactin levels tended to increase over time. Cabergoline was restarted and increased to 7mg/week, although prolactin levels were not suppressed. Magnetic resonance imaging and computed tomography scanning showed no metastasis, and octreotide scintigraphy revealed no abnormal accumulation except for the tumor in the cavernous sinus. Radiation therapy was administered to the remaining tumor, and prolactin levels gradually decreased. Thereafter, hypercalcemia and high intact parathyroid hormone levels were found in the presence of left-inferior parathyroid enlargement, leading to a diagnosis of multiple endocrine neoplasia type 1 (MEN1). The patient had no family history of endocrine disease. MEN1 gene mutation was not detected by direct sequencing. Discussion Functional pituitary adenomas including prolactinomas and growth hormone-producing pituitary adenomas are usually benign with a Ki-67 index of approximately 1%, little mitosis, and slow progression 1) . However, pituitary adenomas in MEN1 patients have a higher rate of drug resistance and histological invasiveness than sporadic adenomas, which results in a higher postoperative recurrence rate and a lower normalization rate of approximately 40% 2) . For this case, close monitoring for tumor growth and metastasis was essential.

PMON115 Long term follow-up of patient with gigantism harboring an exon 2 deletion in the AIP gene

Abstract Introduction Pituitary gigantism is a rare endocrinopathy that has been linked to inactivating germline mutations in AIP gene with a prevalence of 30%. AIP is a tumor suppressor gene associated with high predisposition to pituitary adenoma. Thus, the genetic screening of AIP mutations has been recommended to cases with sporadic young-onset pituitary adenoma. Even with a phenotype suggesting gigantism the diagnosis could be delayed, making the treatment more complex, due the large pituitary tumor. Here we describe a giant patient with deletion of exon 2 of the AIP gene detected by Multiplex Ligation-dependent Probe Amplification assay (MLPA) 33 years after the diagnosis. Material and Methods In 1988, a 13-year-old afro-descendent boy with no history of familial pituitary adenoma, presented with seizures and tall stature. On exam he showed signs of gigantism and hypopituitarism: height 2.05 m (SD: + 7), target height was 1.65 (SD: -1), weight 75 kg (SD: + 3.2), no signs of puberty and impaired vision field. Basal GH was &amp;gt; 40 ng/mL, IGF-1: &amp;gt; 1200 ng/mL (ULN: +4). MRI revealed an invasive macroadenoma (Knosp IV). He underwent pituitary surgery twice with an adenoma GH/PRL positive with no remission. He did not respond to the treatment with somatostatin receptor analogue presenting remission only after radiotherapy, developing permanent deficiency of ACTH/TSH/LH/FSH/GH and diabetes insipidus. Peripheral blood was collected to genetic analysis in 2021. Results The genetic analysis supported by Sanger sequencing resulted negative to pathogenic germline variants in intron-exon frontiers and coding areas of the AIP and MEN1 genes. Thus, MLPA was performed using the SALSA MLPA kit P244 designed to detect large deletions or amplifications in AIP, CDKN1B and MEN1 genes (MRC-Holland, Amsterdam, The Netherlands). Once the exon 2 heterozygous deletion from the AIP gene was found via MLPA the confirmation was carried out through long-range PCR covering full open reading frame of the AIP gene. By agarose gel electrophoresis, the presence of two bands of different sizes confirmed this deletion. Discussion More than 130 AIP mutations have been described over the last decade and most of them, 70% generate truncated proteins (including insertions/deletions). However, gross AIP deletions were exceptionally reported so far (13 cases only: 11 had gigantism or acromegaly). Despite rarity, the present case reinforces the importance of investigate large AIP deletions, especially in gigantism. Cases harboring AIP mutations are associated with more aggressive tumors, lesser response to somatostatin receptor analogues needing, frequently, of an extensive multidisciplinary approach. It was also suggested that cases harboring truncated AIP mutations may develop pituitary adenoma in younger age than patients with non-truncated mutations. Thus, the characterization of genotype could help to refine making-decision on management of this complex disorder in an earlier stage avoiding multimodal treatment. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

OR12-6 Rocking Around the Cortex and Medulla

Abstract Introduction Pituitary gigantism is a rare endocrinopathy that has been linked to inactivating germline mutations in AIP gene with a prevalence of 30%. AIP is a tumor suppressor gene associated with high predisposition to pituitary adenoma. Thus, the genetic screening of AIP mutations has been recommended to cases with sporadic young-onset pituitary adenoma. Even with a phenotype suggesting gigantism the diagnosis could be delayed, making the treatment more complex, due the large pituitary tumor. Here we describe a giant patient with deletion of exon 2 of the AIP gene detected by Multiplex Ligation-dependent Probe Amplification assay (MLPA) 33 years after the diagnosis. Material and Methods In 1988, a 13-year-old afro-descendent boy with no history of familial pituitary adenoma, presented with seizures and tall stature. On exam he showed signs of gigantism and hypopituitarism: height 2. 05 m (SD: + 7), target height was 1.65 (SD: -1), weight 75 kg (SD: + 3.2), no signs of puberty and impaired vision field. Basal GH was &amp;gt; 40 ng/mL, IGF-1: &amp;gt; 1200 ng/mL (ULN: +4). MRI revealed an invasive macroadenoma (Knosp IV). He underwent pituitary surgery twice with an adenoma GH/PRL positive with no remission. He did not respond to the treatment with somatostatin receptor analogue presenting remission only after radiotherapy, developing permanent deficiency of ACTH/TSH/LH/FSH/GH and diabetes insipidus. Peripheral blood was collected to genetic analysis in 2021. Results The genetic analysis supported by Sanger sequencing resulted negative to pathogenic germline variants in intron-exon frontiers and coding areas of the AIP and MEN1 genes. Thus, MLPA was performed using the SALSA MLPA kit P244 designed to detect large deletions or amplifications in AIP, CDKN1B and MEN1 genes (MRC-Holland, Amsterdam, The Netherlands). Once the exon 2 heterozygous deletion from the AIP gene was found via MLPA the confirmation was carried out through long-range PCR covering full open reading frame of the AIP gene. By agarose gel electrophoresis, the presence of two bands of different sizes confirmed this deletion. Discussion More than 130 AIP mutations have been described over the last decade and most of them, 70% generate truncated proteins (including insertions/deletions). However, gross AIP deletions were exceptionally reported so far (13 cases only: 11 had gigantism or acromegaly). Despite rarity, the present case reinforces the importance of investigate large AIP deletions, especially in gigantism. Cases harboring AIP mutations are associated with more aggressive tumors, lesser response to somatostatin receptor analogues needing, frequently, of an extensive multidisciplinary approach. It was also suggested that cases harboring truncated AIP mutations may develop pituitary adenoma in younger age than patients with non-truncated mutations. Thus, the characterization of genotype could help to refine making-decision on management of this complex disorder in an earlier stage avoiding multimodal treatment. Presentation: Sunday, June 12, 2022 11:00 a.m. - 12:30 p.m.

A Common Variant in the CDK8 Gene Is Associated with Sporadic Pituitary Adenomas in the Portuguese Population: A Case-Control Study.

The majority of pituitary adenomas occur in a sporadic context, and in the absence of known genetic predisposition. Three common variants at the NEBL (rs2359536), PCDH15 (rs10763170) and CDK8 (rs17083838) loci were previously associated with sporadic pituitary adenomas in the Han Chinese population, but these findings have not yet been replicated in any other population. The aim of this case-control study was to assess if these variants are associated with susceptibility to sporadic pituitary adenomas in the Portuguese population. Genotype and allele frequencies were determined in 570 cases and in 546 controls. The CDK8 rs17083838 minor allele (A allele) was significantly associated with sporadic pituitary adenomas, under an additive (odds ratio (OR) 1.73, 95% confidence interval (CI) 1.19–2.50, p = 0.004) and dominant (OR 1.82, 95% CI 1.24–2.68, p = 0.002) inheritance model. The NEBL rs2359536 and PCDH15 rs10763170 variants were not associated with the overall risk for the disease, although a borderline significant association was observed between the PCDH15 rs10763170 minor allele (T allele) and somatotrophinomas (dominant model, OR 1.55, 95% CI 1.02–2.35, p = 0.035). These findings suggest that the CDK8 rs17083838 variant, and possibly the PCDH15 rs10763170 variant, may increase susceptibility to sporadic pituitary adenomas in the Portuguese population.

S2696 An Unusual Cause of GI Blood Loss

Introduction: Gastric adenomas are relatively rare, estimated to represent 10% of all gastric polyps. These typically arise in the setting of chronic mucosal inflammation and are thought to represent a premalignant phase along the inflammation-dysplasia-neoplasia sequence during which intervention can prevent or minimize progression to carcinoma. Foveolar-type adenomas, however, typically arise in areas of relatively unremarkable gastric mucosa and are generally less aggressive than other adenoma subtypes. These lesions are commonly associated with hereditary tumor syndromes such as familial adenomatous polyposis but can also occur sporadically. We present a case of newly identified iron deficiency anemia (IDA) that was found to have a gastric foveolar-type adenoma as a rare cause of GI blood loss. Case Description/Methods: A 73-year-old male with granulomatous hepatitis and metabolic syndrome presented for evaluation of IDA. Colonoscopy was notable for one 3 mm polyp in the transverse colon. EGD revealed a 15 mm gastric polyp with a raspberry appearance in the cardia with stigmata of bleeding and a 5 mm sessile polyp with mild central depression in the gastric body. Histology revealed that the larger polyp had low-grade polypoid dysplasia consistent with a foveolar-type adenoma. The smaller polyp was found to be a well-differentiated neuroendocrine tumor. The singular colonic polyp returned as a simple tubular adenoma. A repeat EGD was performed 6 months after polypectomies with no residual lesions. It was determined that the foveolar adenoma located at the cardia was the source of IDA, while the neuroendocrine tumor was just an incidental finding. (Figure) Discussion: While sporadic foveolar-type adenomas and GNET’s in helicobacter pylori- uninfected stomachs are infrequently encountered in clinical practice, their incidence is continuing to rise, due to the increased use of upper endoscopy as a diagnostic tool. Although foveolar-type adenomas are usually benign, this case had low-grade dysplasia and chronic oozing blood as the main reason for iron-deficiency anemia. In addition, this patient also needed prompt evaluation regarding the management of GNET as angioinvasion and metastasis are common. Although these lesions are typically identified incidentally, it is important for the gastroenterologist to keep them in the differential for common complaints such as gastrointestinal bleeding (GIB). This case highlights the importance of early endoscopic evaluation of GIB.Figure 1.: A. Gastric polyp with raspberry-like appearance located in the cardia. Stigmata of recent bleeding seen. B. Histology of gastric foveolar-type adenoma showing surface papillary projections lined with foveolar-type epithelium. Surface epithelium with cytoplasmic neutral mucins.

Serum metabolite signatures in normal individuals and patients with colorectal adenoma or colorectal cancer using UPLC-MS/MS method

Colorectal cancer (CRC) is one of the main causes of cancer-related deaths worldwide. Sporadic CRC develops from normal mucosa via adenoma to adenocarcinoma, which provides a long screening window for clinical detection. However, early diagnosis of sporadic colorectal adenoma (CRA) and CRC using serum metabolic screening remains unclear. The purpose of this study was to identify some promising signatures for distinguishing the different pathological metabolites of colorectal mucosal malignant transformation. A total of 238 endogenous metabolites were elected. We found that CRA and CRC patients had 72 and 73 different metabolites compared with healthy controls, respectively. There were 20 different metabolites between CRA and CRC patients. The potential metabolites of tumor growth (including patients with CRA and CRC) were found, such as A-d-glucose, D-mannose, N-acetyl-D-glucosamine, L-cystine, Sarcosine, TXB 2, 12-Hete, and chenodeoxycholic acid. Compared with CRA, 3,4,5-trimethoxybenzoic acid was significantly higher in CRC patients. There results prompt us to use the potential serum signatures to screen CRC as the novel strategy. Serum metabolite screening is useful for early detection of mucosal intestinal malignancy. We will further investigate the roles of these promising biomarkers during intestinal tumorigenesis in future. SignificanceCRC is one of the main causes of cancer-related deaths worldwide. Sporadic CRC develops from normal mucosa via adenomas to adenocarcinoma, which provides a long screening window for about 5–10 years.We adopt the metabolic analysis of extensive targeted metabolic technology. The main purpose of the metabolic group analysis is to detect and screen the different metabolites, thereby performing related functional prediction and analysis of the differential metabolites.In our study, 30 samples are selected, divided into 3 groups for metabolic analysis, and 238 metabolites are elected. In 238 metabolites, we find that CRA patients have 72 different metabolites compared with health control. Compared with health control, CRC have 73 different metabolites. Compared with CRA and CRC patients, there are 20 different metabolites.The annotation results of the significantly different metabolites are classified according to the KEGG pathway type. The potential metabolites of tumor growth stage (including patients with CRA and CRC) are found, such as A-d-glucose, D-mannose, N-acetyl-D-glucosamine, L-cystine, sarcosine, TXB 2, 12-Hete and chenodeoxycholic acid. Compared with CRA patients, CRC patients had significantly higher 3,4,5-trimethoxybenzoic acid level. It is prompted to use serum different metabolites to screen CRC to provide new possibilities.