Faculty Bibliography

INTRODUCTION: The majority of "giant" hemangiomas remain asymptomatic with no cause for surgical intervention; however, this may not hold true for massive tumors. The following case will review the challenges facing both patients and physicians when managing these atypical tumors. CASE DESCRIPTION/METHODS: A 49-year-old male with no medical problems presented with complaints of post-prandial bloating, early satiety and mild epigastric discomfort. The bloating was intermittent for several years; however, symptoms have recently curtailed his eating habits. CBC, BMP and liver enzymes were unremarkable. An ultrasound highlighted a massively enlarged liver extending into the pelvis and displacing surrounding organs. The liver parenchyma appeared to be replaced with a homogenous, hyperechoic lesion. An MRI then illustrated a 29.5x20.1x19.4 cm, strongly hyperintense mass on T-2 weighted sequences consistent with the diagnosis of a hemangioma. He was referred to a hepatobiliary surgeon and an extended right hepatectomy was eventually performed. Histopathology results described vast endothelial lined channels supported by thin fibrous stroma without features of malignancy. The patient returned to clinic four weeks after surgery reporting complete resolution of his symptoms. DISCUSSION: Hemangiomas are the most common benign solid tumor of the liver with little to no risk of malignant transformation. Often discovered incidentally on imaging studies, the majority of these tumors remain indolent without the need for routine surveillance. Rarely these tumors become symptomatic, often correlating with tumor size. The definition of "giant" liver hemangioma remains controversial, with most authors assigning the label to tumors greater than 4cm or 5cm in size. It is for this reason that management of giant hemangiomas remains highly debated (i.e. observation versus resection). Recent studies have shown that tumors greater than 20cm in size pose a higher risk for GI symptoms related to mass effect on surrounding organs as well as causing a disturbance in the hematologic and coagulation systems. Surgical resection should be considered for symptomatic or complicated lesions, or when the diagnosis remains inconclusive. It is our belief that size classifications for giant hemangiomas requires further subgrouping to consider the danger of these massive tumors as well as the increased morbidity of surgery. Proper management of these tumors should be individualized to each patient and include [2259] Figure 1. a multidisciplinary team approach. (Figure Presented)

Pancreatic neuroendocrine tumors (PNETs) occur in the context of tuberous sclerosis complex (TSC). To date, PNETs in association with TSC have been described almost exclusively in adults and in the context of TSC2. We present the evaluation of a PNET in a young child with TSC1. A 3-year, 6-month-old boy with TSC1 was found on surveillance to have a small pancreatic lesion measuring 0.4 cm on magnetic resonance imaging (MRI). The lesion showed interval enlargement to 1 cm on serial MRI studies during the ensuing 16 weeks. Endocrine laboratory tests did not reveal a functional tumor. The patient underwent enucleation of the pancreatic lesion. Microscopic examination defined a well-differentiated PNET, grade II/intermediate grade with a mitotic rate of two mitotic figures per 10 high-powered field and Ki-67 proliferation index of ∼15%. The tumor was positive for the TSC1 gene mutation. The patient was free of tumor recurrence at the 5-year follow-up examination, as determined by endocrine surveillance and annual MRI of the abdomen. In the reported data, PNET in patients with TSC has been primarily reported in association with TSC2. Our case demonstrates that patients with TSC1 can develop PNETs, even at an early age. The international TSC consensus group 2012 recommendation was to obtain MRI of the abdomen every 1 to 3 years for surveillance of renal angiomyolipomas and renal cystic disease. It might be beneficial to add a pancreatic protocol to the surveillance guidelines to evaluate for PNET.

We present an 81-year-old woman with remote breast cancer who presented with melena and hemorrhagic shock requiring intensive care hospitalization. Endoscopic evaluation showed a 5-cm pedunculated gastric mass with ulceration and friability. She underwent sleeve gastrectomy for definitive treatment of her bleeding. Pathology was consistent with a solitary fibrous tumor (SFT). There are only a few reported cases of gastric SFTs presenting with gastrointestinal bleeding. If a large brown/tan bleeding mass is identified on upper endoscopy, SFT should be considered.

Through the action of two virus-encoded decapping enzymes (D9 and D10) that remove protective caps from mRNA 5'-termini, Vaccinia virus (VACV) accelerates mRNA decay and limits activation of host defenses. D9- or D10-deficient VACV are markedly attenuated in mice and fail to counter cellular double-stranded RNA-responsive innate immune effectors, including PKR. Here, we capitalize upon this phenotype and demonstrate that VACV deficient in either decapping enzyme are effective oncolytic viruses. Significantly, D9- or D10-deficient VACV displayed anti-tumor activity against syngeneic mouse tumors of different genetic backgrounds and human hepatocellular carcinoma xenografts. Furthermore, D9- and D10-deficient VACV hyperactivated the host anti-viral enzyme PKR in non-tumorigenic cells compared to wild-type virus. This establishes a new genetic platform for oncolytic VACV development that is deficient for a major pathogenesis determinant while retaining viral genes that support robust productive replication like those required for nucleotide metabolism. It further demonstrates how VACV mutants unable to execute a fundamental step in virus-induced mRNA decay can be unexpectedly translated into a powerful anti-tumor therapy.

Background: Russell Body Gastritis (RBG) is considered to be a rare histologic finding that has an unclear pathogenesis and an unpredictable clinical outcome. We sought to clarify the frequency and significance of RBG by assessing their associated histology and relationship with the local microbiome. Design: We reviewed all 220 gastric biopsies over a 2-month period at 1 institution for the presence and density of Russell bodies (RB). In biopsies with RB, the quantity of RB was manually counted using light microscopy at 200x magnification in every biopsy level (3068 sections) and the sectional area was estimated using a 1x1 mm grid overlay. RB density was calculated by dividing the total quantity of RB in all sections by the total sectional area. 48 additional patients, which corresponded to an extra 100 histologic biopsies, were consented at the same visit for an extra gastric biopsy for 16S rRNA sequencing, and these microbiome profiles were correlated with the highest RB density per patient. Results: Russell bodies (RB) were frequent in gastric biopsies (43% of all gastritides) and the RB density significantly increased with more severe gastritides (p<0.001, n=320). The gastric microbiome globally differed in beta diversity between RB-positive and RB-negative cases by unweighted and weighted principal component analysis (p=0.03, p=0.007, n=48, respectively). In particular, Helicobacter and Streptococcus were significantly enriched in gastritis with RB and their abundances correlated with RB density (p=0.0002, r=0.51; p=0.009, r=0.37, n=48, respectively). Protonpump inhibitor (PPI) use reduced RB density per unit abundance of Streptococcus (p=0.0021, n=48). H. pylori abundance significantly correlated with RB density and two Streptococcus species (an unclassified Streptococcal species and S. anginosus) significantly correlated with RB density in H. pylori-negative gastritis (p=0.009, n=36, r=0.36; p=0.0025, n=36, r=0.51, respectively). 7 H. pylorinegative patients were followed for 1 year and variation in Streptococcus abundance reflected RB density (p=0.085, n=7). Conclusions: RB are common within the inflamed gastric mucosa and gastritis with RB is associated with Helicobacter and Streptococcus enrichment and consequent global shifts in the gastric microbiome. PPI dampens RB production, presumably through anti-inflammatory effects. Gastritis with RB might represent a reactive humoral response to bacteria within the gastric microbiome. Streptococcus species may influence chronic gastritis

Cytologic diagnosis of extra-adrenal paraganglioma presenting as a peripancreatic mass is challenging with a high error rate due to its rarity. We report two cases of peripancreatic masses identified by radiology. Endoscopic ultrasound-guided fine needle aspiration (FNA) of the masses showed a moderately cellular tumor composed of small to medium sized neoplastic cells with round to oval nuclei, arranged singly and in loose clusters. Focal rosette-like structures were present. The cells were positive for neuroendocrine markers (synaptophysin and chromogranin). A diagnosis of a neoplasm with neuroendocrine differentiation and neuroendocrine tumor was made respectively on FNA for each case. The subsequent surgical resection of the tumors revealed peripancreatic paraganglioma. Although paraganglioma has been reported in the literature, the detailed comparison of perpancreatic paraganglioma versus pancreatic/gastrointestinal neuroendocrine tumor is still lacking. Therefore using these two cases with literature review, we wish to illustrate the differential diagnosis between these two entities based on cytomorphology and immunohistochemical study.

Regulatory T (Treg) cell infiltration constitutes a prominent feature of pancreatic ductal adenocarcinoma (PDA). However, the immunomodulatory function of Treg cells in PDA is poorly understood. Here, we demonstrate that Treg cell ablation is sufficient to evoke effective anti-tumor immune response in early and advanced pancreatic tumorigenesis in mice. This response is dependent on interferon-gamma (IFN-gamma)-producing cytotoxic CD8+ T cells. We show that Treg cells engage in extended interactions with tumor-associated CD11c+ dendritic cells (DCs) and restrain their immunogenic function by suppressing the expression of costimulatory ligands necessary for CD8+ T cell activation. Consequently, tumor-associated CD8+ T cells fail to display effector activities when Treg cell ablation is combined with DC depletion. We propose that tumor-infiltrating Treg cells can promote immune tolerance by suppressing tumor-associated DC immunogenicity. The therapeutic manipulation of this axis might provide an effective approach for the targeting of PDA.

PURPOSE: To evaluate whole-lesion ADC histogram metrics for assessing the malignant potential of pancreatic intraductal papillary mucinous neoplasms (IPMNs), including in comparison with conventional MRI features. METHODS: Eighteen branch-duct IPMNs underwent MRI with DWI prior to resection (n = 16) or FNA (n = 2). A blinded radiologist placed 3D volumes-of-interest on the entire IPMN on the ADC map, from which whole-lesion histogram metrics were generated. The reader also assessed IPMN size, mural nodularity, and adjacent main-duct dilation. Benign (low-to-intermediate grade dysplasia; n = 10) and malignant (high-grade dysplasia or invasive adenocarcinoma; n = 8) IPMNs were compared. RESULTS: Whole-lesion ADC histogram metrics demonstrating significant differences between benign and malignant IPMNs were: entropy (5.1 +/- 0.2 vs. 5.4 +/- 0.2; p = 0.01, AUC = 86%); mean of the bottom 10th percentile (2.2 +/- 0.4 vs. 1.6 +/- 0.7; p = 0.03; AUC = 81%); and mean of the 10-25th percentile (2.8 +/- 0.4 vs. 2.3 +/- 0.6; p = 0.04; AUC = 79%). The overall mean ADC, skewness, and kurtosis were not significantly different between groups (p >/= 0.06; AUC = 50-78%). For entropy (highest performing histogram metric), an optimal threshold of >5.3 achieved a sensitivity of 100%, a specificity of 70%, and an accuracy of 83% for predicting malignancy. No significant difference (p = 0.18-0.64) was observed between benign and malignant IPMNs for cyst size >/=3 cm, adjacent main-duct dilatation, or mural nodule. At multivariable analysis of entropy in combination with all other ADC histogram and conventional MRI features, entropy was the only significant independent predictor of malignancy (p = 0.004). CONCLUSION: Although requiring larger studies, ADC entropy obtained from 3D whole-lesion histogram analysis may serve as a biomarker for identifying the malignant potential of IPMNs, independent of conventional MRI features.