High risk features in colorectal adenomatous polyps: A multi-institutional study.

High risk features in colorectal adenomatous polyps include size >1 cm and advanced histology: high-grade dysplasia and villous architecture. We investigated whether the diagnostic rates of advanced histology in colorectal adenomatous polyps were similar among institutions across the United States, and if not, could differences be explained by patient age, polyp size, and/or CRC rate. Nine academic institutions contributed data from three pathologists who had signed out at least 100 colorectal adenomatous polyps each from 2018 to 2019 taken from patients undergoing screening colonoscopy. For each case, we recorded patient age and sex, polyp size and location, concurrent CRC, and presence or absence of HGD and villous features. A total of 2700 polyps from 1886 patients (mean age: 61 years) were collected. One hundred twenty-four (5 %) of the 2700 polyps had advanced histology, including 35 (1 %) with HGD and 101 (4 %) with villous features. The diagnostic rate of advanced histology varied by institution from 1.7 % to 9.3 % (median: 4.3 %, standard deviation [SD]: 2.5 %). The rate of HGD ranged from 0 % to 3.3 % (median: 1 %, SD: 1.2 %), while the rate of villous architecture varied from 1 % to 8 % (median: 3.7 %, SD: 2.5 %). In a multivariate analysis, the factor most strongly associated with advanced histology was polyp size >1 cm with an odds ratio (OR) of 31.82 (95 % confidence interval [CI]: 20.52-50.25, p < 0.05). Inter-institutional differences in the rate of polyps >1 cm likely explain some of the diagnostic variance, but pathologic subjectivity may be another contributing factor.

Serum Cytomegalovirus Polymerase Chain Reaction Test Is a Valuable Negative Predictor of Infection in Acute Severe Ulcerative Colitis.

BACKGROUND: Diagnosis of cytomegalovirus (CMV) colitis in the setting of severe ulcerative colitis (UC) remains a clinical challenge. This study aimed to determine the utility of serum CMV polymerase chain reaction (PCR) as a non-invasive test for the diagnosis of CMV superinfection in patients hospitalized with UC. METHODS: This retrospective study included consecutive admitted patients with UC who had serum testing for CMV completed as part of standard hospital procedure and CMV colitis diagnosed by expert pathologists. RESULTS: Two hundred and six patients with UC were included; 13 patients (6%) had histologically confirmed CMV colitis. Eleven of 13 patients with CMV colitis (84%) and 3 of 193 (1.5%) patients without CMV colitis had a positive serum PCR test (p < 0.0001). ROC analysis showed that a CMV PCR level of 259 IU/mL had a sensitivity and specificity of 77% and 99%, respectively, for diagnosis of CMV colitis with an AUC of 0.9 (p < 0.0001). Serum CMV PCR level significantly correlated to the number of inclusion bodies on biopsy specimens with data available (n = 8) (r = 0.8, p = 0.02). CMV positivity did not predict the need for salvage therapy, admission or 1-year colectomy rates. CONCLUSION: Serum CMV PCR has an excellent negative predictive value and demonstrates a strong correlation with CMV positivity on histology. This work supports a rationale for serum CMV PCR testing on admission to assess the risk of CMV colitis in patients with severe UC.

The histological spectrum of ARB-induced gastritis.

AIMS: Olmesartan, an angiotensin receptor blocker (ARB) used for hypertension management, is known to cause a sprue-like enteropathy in a subset of patients. Rare cases of gastritis occurring with ARB use have also been reported, but the histological features of ARB-induced gastritis and the response to drug cessation have not been examined in a dedicated case-series. METHODS AND RESULTS: Cases of suspected ARB-induced gastritis were identified from the pathology archives of four institutions. Haematoxylin and eosin (H&E) slides from gastric biopsies were reviewed. Fifteen patients (14 female, one male) were identified. The most common presenting symptoms were diarrhoea (10) and weight loss (six). Gastric biopsies commonly showed a full-thickness active chronic gastritis with surface epithelial injury involving the antrum and body. Glandular atrophy, intra-epithelial lymphocytosis and/or subepithelial collagen thickening were also present in some cases. Duodenal involvement, including villous atrophy, intra-epithelial lymphocytosis and/or collagenous sprue, was identified in 11 of 13 cases with concurrent duodenal biopsies. Following drug cessation, symptomatic improvement occurred in all 11 cases for which follow-up data were available. Histological resolution occurred in five of eight cases with follow-up gastric biopsies, with improvement seen in the remaining three biopsies. CONCLUSION: ARB-induced gastritis typically presents as active chronic gastritis, frequently with associated surface epithelial injury. Glandular atrophy, intra-epithelial lymphocytosis and/or subepithelial collagen thickening may also be present. These gastric changes can be seen without associated duodenal injury in rare cases, and they should alert the pathologist to the possibility of ARB-induced injury. Drug cessation results in marked symptomatic and histological improvement.

Morphologic and molecular analysis of early-onset gastric cancer.

BACKGROUND: Evidence suggests that early-onset gastric cancers are distinct from traditional gastric cancers; however, detailed genomic and morphologic characterization of these cancers has not been performed. METHODS: Genomic analysis was performed for 81 patients with gastric cancer who were 50 years old or younger; pathology slides were available for 53 of these patients, and they were re-reviewed to perform a morphologic-molecular correlation analysis. The results were compared with corresponding cBioPortal data and The Cancer Genome Atlas (TCGA) analysis, which represent traditional gastric cancers. The TP53 molecular signature was established to determine the pattern of somatic mutational damage. Variants of potential germline origin were also identified from next-generation sequencing data. RESULTS: A higher rate of CDH1 mutations (22.2% of early-onset gastric cancers vs 11.4% of traditional gastric cancers; P = .0042) but a similar rate of TP53 mutations (63% of early-onset gastric cancers vs 56.6% of traditional gastric cancers; P = .2674) were seen in early-onset cancers in comparison with traditional gastric cancers. The diffuse/mixed types correlated with the TCGA genomically stable type, and the remaining Lauren types correlated with the TCGA chromosomal instability type. Diffuse and indeterminate histologic types (overall survival, 26.25 months for the intestinal type, 20.5 months for the mixed type, 12.62 months for the diffuse type, and 9 months for the indeterminate type; P = .027) and the presence of a CDH1 gene mutation (overall survival, 9 months for mutant CDH1 and 22 months for wild-type CDH1; P = .013) significantly correlated with worse survival. The TP53 gene frequently showed transition mutations (65.5%) involving the CpG sites (49%). Variants of potential germline origin were seen in high-penetrance genes (CDH1 and APC) and moderate-penetrance genes (ATM, NBN, and MUTYH) in 9.9% of cancers. CONCLUSIONS: Early-onset gastric cancer has distinct genomic alterations, such as CDH1 mutations, but shares with traditional gastric cancers a high frequency of TP53 mutations and the TP53 mutagenic signature. Diffuse and indeterminate histologic types and the presence of a CDH1 mutation are associated with worse overall survival. Endogenous factors leading to cytosine deamination and potential germline alterations in moderate-penetrance cancer susceptibility genes may be implicated in the pathogenesis of these cancers.

Sunitinib-Loaded Chondroitin Sulfate Hydrogels as a Novel Drug-Delivery Mechanism for the Treatment of Pancreatic Neuroendocrine Tumors.

BACKGROUND: Pancreatic neuroendocrine tumors (PanNETs) are increasingly common. Experts debate whether small tumors should be resected. Tumor destruction via injection of cytotoxic agents could offer a minimal invasive approach to this controversy. We hypothesize that a new drug delivery system comprising chondroitin sulfate (CS) hydrogels loaded with sunitinib (SUN) suppresses tumor growth in PanNET cells. METHODS: Injectable hydrogels composed of CS modified with methacrylate groups (MA) were fabricated and loaded with SUN. Loading target was either 200 µg (SUN200-G) or 500 µg (SUN500-G) as well as sham hydrogel with no drug loading (SUN0-G). SUN release from hydrogels was monitored in vitro over time and cytotoxicity induced by the released SUN was evaluated using QGP-1 and BON1 PanNET cell lines. QGP-1 xenografts were developed in 35 mice and directly injected with 25 µL of either SUN200-G, SUN500-G, SUN0-G, 100 µL of Sunitinib Malate (SUN-inj), or given 40 mg/kg/day oral sunitinib (SUN-oral). RESULTS: SUN-loaded CSMA hydrogel retained complete in vitro cytotoxicity toward the QGP-1 PanNET and BON-1 PanNET cell lines for 21 days. Mouse xenograft models with QGP-1 PanNETs showed a significant delay in tumor growth in the SUN200/500-G, SUN-inj and SUN-oral groups compared with SUN0-G (p = 0.0014). SUN500-G hydrogels induced significantly more tumor necrosis than SUN0-G (p = 0.04). There was no difference in tumor growth delay between SUN200/500G, SUN-inj, and SUN-oral. CONCLUSIONS: This study demonstrates that CSMA hydrogels loaded with SUN suppress PanNETs growth. This drug delivery could approach represents a novel way to treat PanNETs and other neoplasms via intratumoral injection.

Histologic changes caused by injection of a novel submucosal lifting agent for endoscopic resection in GI lesions.

BACKGROUND AND AIMS: ORISE Gel is a recently introduced, U.S. Food and Drug Administration-approved submucosal lifting agent used in endoscopic resection of GI lesions. Histologically evident gel deposits in resected specimens may pose a potential diagnostic pitfall. To aid in recognition of this procedure-related artifact, we report the largest histologic series of ORISE Gel in endoscopic and surgical resection specimens to date. METHODS: Fifty-eight EMR/endoscopic submucosal dissection (ESD) specimens with ORISE Gel injection and 5 interval surgical resection specimens with previous ORISE Gel injection were included. Patient demographics and endoscopy reports were obtained. Histologic slides from all cases were reviewed. Histochemical stains were performed on select cases. RESULTS: Fifty-one EMR and 7 ESD specimens were identified. In 51 of 58 (88%) endoscopic resection specimens, amorphous, pale blue-gray, finely granular material was evident in the submucosa, as well as focally within the mucosa in 4 cases. Most cases showed homogeneous near-complete filling of the submucosa with this material, whereas a few demonstrated areas of condensation and retraction. Mucicarmine and periodic acid-Schiff stains were negative for mucin. Interval surgical resection specimens revealed extensive deposition of dense, eosinophilic material with associated multinucleated giant cells in the submucosa in all cases, with transmural extension in 3 cases. CONCLUSION: ORISE Gel injection during endoscopic resection of GI lesions results in deposition of amorphous, blue-gray material seen in histologic sections, whereas interval surgical resection specimens demonstrate dense, eosinophilic material with an associated giant cell reaction. Awareness of these artifacts will help avoid misinterpretation of their presence as pathologic findings.

Clinicopathological features of pyloric gland adenomas of the duodenum: a multicentre study of 57 cases.

AIMS: To determine the clinicopathological features of pyloric gland adenomas (PGA) that arise in the duodenum. METHODS AND RESULTS: Fifty-seven cases of duodenal PGA were identified and analysed from 56 patients. Clinicopathological and immunohistochemical analyses were performed. PGA tend to occur in older individuals (median age = 73.5), with a slight female predominance (25 males, 31 females). PGA arise more commonly in the proximal duodenum (68.75% in D1, 25% in D2 and 6.25% in D3) and usually present as mucosal nodules (98.2%) or plaques (1.8%), with a mean size of 14.8 mm. There is associated gastric heterotopia in 22.8% of cases. PGA showing features of high-grade dysplasia were significantly larger in size than PGA, showing only low-grade dysplasia (23.1 versus 8.7 mm; P = 0.0001) and more likely to show a tubulovillous rather than a pure tubular architecture (P = 0.025). In our series, 10 of 56 patients had intramucosal or invasive carcinoma associated with the duodenal PGA (17.9%). Three of these carcinomas showed lymph node metastasis. Following definitive treatment, local recurrence occurred in only three patients. CONCLUSIONS: Duodenal PGA tend to occur in the proximal duodenum of older individuals. Larger size and tubulovillous architecture correlates with high-grade dysplasia and associated adenocarcinoma. The low recurrence rate of these lesions would suggest that endoscopic management is appropriate, provided that the lesion can be completely resected.

Spectrum of gastrointestinal tract pathology in a multicenter cohort of 43 Cowden syndrome patients.

Most patients with Cowden syndrome have lesions in the gastrointestinal tract, characterized by multiple polyps of various histologic types in the large bowel, polyps in the upper gastrointestinal tract, and esophageal glycogenic acanthosis. However, pathologists are often unaware of the distinctive polyposis phenotype of Cowden syndrome. In this multicenter study, we report the spectrum of gastrointestinal manifestations in a series of 43 Cowden syndrome patients who had at least one endoscopy. The median age at the first endoscopy was 46 years and 58% were women. In 24 of 29 (83%) tested patients, a pathogenic germline mutation in PTEN was identified. The histology from 199 endoscopy procedures (67 upper gastrointestinal endoscopy and 132 colonoscopies) was reviewed. Hamartomatous polyps of the large bowel were the most common lesions, present in 85% of patients. Hamartomatous polyps showed varied histology, including lymphoid aggregates in 55% of patients, a lipomatous component in 52%, a ganglioneuromatous component in 52%, and a fibrous-rich component in 14%. Polyps with at least two different stromal components were found in 55% of patients. Inflammatory polyps were present in 21% of patients. Conventional adenomas and serrated polyps were identified in 48% and 62% of patients, respectively. In the upper gastrointestinal tract, the most common lesions were esophageal glycogenic acanthosis (37%), gastric hamartomatous polyps (47%), and duodenal hamartomatous polyps (20%). All patients with glycogenic acanthosis who had a colonoscopy had hamartomatous polyps of the large bowel. In five patients, the diagnosis of Cowden syndrome was established after the pathology report raised suspicion for the diagnosis. Pathologists who are aware of the characteristic admixture of lesions in Cowden syndrome can play an essential role in recommending referral to genetic counseling and gene testing. Early diagnosis of Cowden syndrome is important, as these patients and their relatives are at increased risk for developing multiple cancers.

Actinomyces in Crohn's-like appendicitis.

AIMS: Appendicitis with a Crohn's-like histological appearance generally raises concern for Crohn's disease, Yersinia infection, and interval appendectomy. Actinomyces infection is a recognised cause of chronic appendicitis that can histologically mimic Crohn's disease. METHODS AND RESULTS: We report on 20 cases of appendicitis with Crohn's-like histological features that were due to Actinomyces. Most patients presented with acute or chronic abdominal pain. Imaging studies suggested a mass in five cases. Two patients had interval appendectomy. Histological features showed Crohn's-like appendicitis in 16 cases, with moderate to marked fibrosis and granulomas in seven cases. The other four cases had less consistent histological findings. None of the patients developed Crohn's disease during the follow-up interval (median, 37 months). CONCLUSIONS: Actinomyces can be associated with Crohn's-like appendicitis with marked fibrosis, transmural inflammation, lymphoid hyperplasia, and granulomas.

Loss of SMAD4 protein expression in gastrointestinal and extra-gastrointestinal carcinomas.

AIMS: SMAD4 (DPC4) is a tumour suppressor gene that is dysregulated in various tumour types, particularly pancreaticobiliary and gastrointestinal carcinomas. Corresponding loss of protein expression has been reported in approximately 50% of pancreatic and 25% of colonic adenocarcinomas. In the evaluation of carcinoma of unknown primary site, immunohistochemical loss of SMAD4 expression is often used to suggest pancreaticobiliary origin, but there are limited data on the spectrum of SMAD4 expression in carcinomas of other sites. This study evaluates the frequency of SMAD4 loss in a large cohort of carcinomas from diverse anatomical sites. METHODS AND RESULTS: Immunohistochemistry for SMAD4 was performed on tissue microarrays or whole tissue sections of 1210 carcinomas from various organs: gastrointestinal tract, liver, pancreas/biliary tract, lung, breast, thyroid, kidney, ovary and uterus. Expression was considered lost when there was complete absence of staining in tumour cell nuclei, in the presence of intact staining in non-neoplastic cells. SMAD4 loss was seen in 58% of pancreatic adenocarcinomas, 27% of appendiceal adenocarcinomas, 19% of colorectal adenocarcinomas, 16% of cholangiocarcinomas, 10% of lung adenocarcinomas and <5% of oesophageal, breast, gastric and mucinous ovarian adenocarcinomas. All papillary thyroid, hepatocellular, non-mucinous ovarian, endometrial and renal cell carcinomas showed intact SMAD4 nuclear expression. CONCLUSION: In addition to pancreaticobiliary, appendiceal and colonic tumours, SMAD4 loss is also seen in a small subset of other carcinomas, specifically breast, lung, oesophageal and gastric adenocarcinomas, all of which are typically CK7-positive, similar to pancreaticobiliary carcinoma. Awareness of SMAD4 loss in these other carcinoma types is helpful in the evaluation of carcinomas of unknown or uncertain primary site.

Gastric pyloric gland adenoma: a multicentre clinicopathological study of 67 cases.

AIMS: There is limited information regarding the clinicopathological and immunohistochemical characteristics of gastric pyloric gland adenomas (PGAs). METHODS AND RESULTS: Sixty-seven cases of gastric PGA from 57 patients were analysed. PGAs occurred with similar frequency in men and women (47.4 and 52.6%, respectively), with a mean age of 66 years. Most presented in the gastric body/fundus (67.2%). Fifteen cases (22.4%) developed against a background of autoimmune gastritis (AIG), whereas normal mucosa was seen in 35.8%. Only 16.4% (11 cases) developed in patients with a genetic predisposition, most commonly familial adenomatous polyposis. Low-grade lesions had a mean size of 1.5 cm, while PGAs with high-grade dysplasia (HGD) or adenocarcinoma had a mean size of 3.5 cm (P < 0.001) and more commonly showed tubulovillous architecture (50.0 versus 25.6% in low-grade dysplasia; P = 0.040). Most PGAs (61.2%) co-expressed mucin (MUC)5AC and MUC6 (mixed type), which was associated significantly with HGD or adenocarcinoma (P = 0.013). AIG was also associated with HGD (P = 0.027), but genetic predisposition did not correlate with the grade of dysplasia (P = 0.793). The recurrence rate of PGA was similar for high- (11.8%) and low-grade lesions (7.4%) (P = 0.624). CONCLUSIONS: The risk of HGD increases with the size of PGA, tubulovillous architecture and the presence of AIG as well as mixed immunophenotype. As the overall local recurrence rate is less than 10%, PGAs may be treated conservatively, but they should be excised completely if possible, particularly if they are large or show high-grade features.

Critical role of microbiota within cecal crypts on the regenerative capacity of the intestinal epithelium following surgical stress.

Cecal crypts represent a unique niche that are normally occupied by the commensal microbiota. Due to their density and close proximity to stem cells, microbiota within cecal crypts may modulate epithelial regeneration. Here we demonstrate that surgical stress, a process that invariably involves a short period of starvation, antibiotic exposure, and tissue injury, results in cecal crypt evacuation of their microbiota. Crypts devoid of their microbiota display pathophysiological features characterized by abnormal stem cell activation as judged by leucine-rich repeat-containing G protein-coupled receptor 5 (Lgr5) staining, expansion of the proliferative zone toward the tips of the crypts, and an increase in apoptosis. In addition, crypts devoid of their microbiota display loss of their regenerative capacity as assessed by their ability to form organoids ex vivo. When a four-member human pathogen community isolated from the stool of a critically ill patient is introduced into the cecum of mice with empty crypts, crypts become occupied by the pathogens and further disruption of crypt homeostasis is observed. Fecal microbiota transplantation restores the cecal crypts' microbiota, normalizes homeostasis within crypts, and reestablishes crypt regenerative capacity. Taken together, these findings define an emerging role for the microbiota within cecal crypts to maintain epithelial cell homeostasis in a manner that may enhance recovery in response to the physiological stress imposed by the process of surgery. NEW & NOTEWORTHY: This study provides novel insight into the process by which surgical injury places the intestinal epithelium at risk for colonization by pathogenic microbes and impairment of its regenerative capacity via loss of its microbiota. We show that fecal transplant restores crypt homeostasis in association with repopulation of the microbiota within cecal crypts.

A protein and mRNA expression-based classification of gastric cancer.

The overall survival of gastric carcinoma patients remains poor despite improved control over known risk factors and surveillance. This highlights the need for new classifications, driven towards identification of potential therapeutic targets. Using sophisticated molecular technologies and analysis, three groups recently provided genetic and epigenetic molecular classifications of gastric cancer (The Cancer Genome Atlas, 'Singapore-Duke' study, and Asian Cancer Research Group). Suggested by these classifications, here, we examined the expression of 14 biomarkers in a cohort of 146 gastric adenocarcinomas and performed unsupervised hierarchical clustering analysis using less expensive and widely available immunohistochemistry and in situ hybridization. Ultimately, we identified five groups of gastric cancers based on Epstein-Barr virus (EBV) positivity, microsatellite instability, aberrant E-cadherin, and p53 expression; the remaining cases constituted a group characterized by normal p53 expression. In addition, the five categories correspond to the reported molecular subgroups by virtue of clinicopathologic features. Furthermore, evaluation between these clusters and survival using the Cox proportional hazards model showed a trend for superior survival in the EBV and microsatellite-instable related adenocarcinomas. In conclusion, we offer as a proposal a simplified algorithm that is able to reproduce the recently proposed molecular subgroups of gastric adenocarcinoma, using immunohistochemical and in situ hybridization techniques.

Familial Gastric Cancers.

Although the majority of gastric carcinomas are sporadic, approximately 10% show familial aggregation, and a hereditary cause is determined in 1%-3% cases. Of these, hereditary diffuse gastric cancer is the most recognized predisposition syndrome. Although rare, the less commonly known syndromes also confer a markedly increased risk for development of gastric cancer. Identification and characterization of these syndromes require a multidisciplinary effort involving oncologists, surgeons, genetic counselors, biologists, and pathologists. This article reviews the molecular genetics, clinical and pathologic features, surveillance guidelines, and preventive measures of common and less common hereditary gastric cancer predisposition syndromes.

A novel telomere biology disease-associated gastritis identified through a whole exome sequencing-driven approach.

A whole exome sequencing (WES)-driven approach to uncover the etiology of unexplained inflammatory gastritides has been underutilized by surgical pathologists. Here, we discovered the pathobiology of an unusual chronic atrophic gastritis in two unrelated patients using this approach. The gastric biopsies were notable for an unusual pattern of gastritis with persistent dense inflammation, loss of both parietal and neuroendocrine cells in the oxyntic mucosa, and sparing of the antral mucosa. The patients were found to harbor pathogenic variants in telomeropathic genes (POT1 and DCLRE1B). Clonality testing for one of the patients showed evidence of evolving clonality of TCR-gene rearrangement. Both patients showed significantly decreased numbers of stem/progenitor cells by immunohistochemistry, which appears to be responsible for the development of mucosal atrophy. No such cases of unusual chronic atrophic gastritis in the setting of telomeropathy have been previously reported. The loss of stem/progenitor cells suggests that stem/progenitor cell exhaustion in the setting of telomere dysfunction is the likely mechanism for development of this unusual chronic atrophic gastritis. The results underscore the need for close monitoring of these gastric lesions, with special regard to their neoplastic potential. This combined WES-driven approach has promise to identify the cause and mechanism of other uncharacterized gastrointestinal inflammatory disorders.

Follow-up biopsies in gastrointestinal immune checkpoint inhibitor toxicity may show markedly different inflammatory patterns than initial injury.

Colitis is a common manifestation of immune checkpoint inhibitor (ICI) toxicity and can present with varied histologic patterns of inflammation, some of which have been shown to be associated with specific ICI drug types. Although the histologic features of ICI colitis seen at the time of diagnosis have been described, there have been few reports following these patients over time. We evaluated initial and follow-up biopsies in 30 patients with ICI colitis and found that 37% of patients developed a different pattern of injury on follow-up biopsy compared to the initial biopsy. Patients with a different inflammatory pattern were more likely to have restarted ICI therapy before their follow-up biopsy (64%) compared to those without a change in inflammatory pattern (11%; P < 0.01). The majority of these patients had changed ICI drug types (86%). Additionally, many cases changed to an inflammatory bowel disease (IBD)-like pattern (36%), raising a question of de novo IBD. However, all of our patients with an IBD-like pattern experienced sustained resolution of symptoms without steroids or other immunosuppressive medications following discontinuation of ICI therapy, consistent with a diagnosis of ICI toxicity. Our findings suggest that follow-up biopsies in patients with ICI colitis may show a different histology and that this does not necessarily warrant a change in the histologic diagnosis to another disease.

Single center outcomes from parenchymal-sparing resections and microwave ablations for neuroendocrine tumor liver metastases.

BACKGROUND: Reported outcomes after surgical debulking in patients with advanced neuroendocrine tumor liver metastases (NETLM) are sparse. METHODS: NETLM patients that underwent surgical debulking from 2019 to 2021 were reviewed. Trends in perioperative liver function, complications, symptom response, and progression-free survival were examined. RESULTS: 1069 liver lesions were debulked from 53 patients using a combination of parenchymal-sparing resections (PSR) and ultrasound-guided microwave ablations (MWA). Post-operative transaminitis and thrombocytopenia were common, and severity correlated with increasing number of lesions. Laboratory markers for synthetic liver function did not differ according to the number of lesions debulked. 13% of patients sustained a Clavien-Dindo grade 3 or 4 complication which was not associated with the number of lesions targeted. All patients with preoperative symptoms had improvement after surgery. Median time to progression was 10.9 months. CONCLUSIONS: PSR with MWA for large numbers of NETLM is safe and effective for symptom control and does not affect synthetic liver function.

Esophageal squamous cell carcinoma with pagetoid spread: a clinicopathologic study.

Pagetoid spread in esophageal squamous epithelium associated with underlying esophageal adenocarcinoma (EAC) has been well studied. Case reports describing pagetoid spread of esophageal squamous cell carcinomas (ESCC) also exist in the literature. The latter, however, has not been systematically studied. In this study, we report seven cases of pagetoid spread associated with ESCC. The clinical, morphologic, and immunophenotypic profiles of pagetoid spread in the context of ESCC and EAC are compared. Cases of pagetoid spread of ESCC were identified through computerized search of pathology archives at five institutions. Additional cases were identified through manual review of surgical resection cases of treatment naive ESCC in Mass General Brigham (MGB) pathology archive. Clinical history was collected via chart review. Immunohistochemistry for CK7, CK20, CDX2, p53, p63, and p40 was performed on selected cases. A computerized search of pathology archives of five institutions revealed only two cases. A manual review of 76 resected untreated ESCC revealed five additional cases with unequivocal pagetoid spread of ESCC, indicating the condition was not uncommon but rarely reported. Patient age ranged from 54 to 78 years (median, 65). There were six women and one man. One case had in situ disease, five had pT1 (1 pT1a and 4 pT1b), and one had pT3 disease. One of the patients with pT1 tumor had a positive lymph node, while the remaining six patients were all N0. Four tumors were in the proximal to mid esophagus, and three in the distal esophagus. Patient survival ranged from 25 months to more than 288 months. The pagetoid tumor cells demonstrated enlarged, hyperchromatic nuclei with variable amounts of eosinophilic cytoplasm. The cytoplasm was often condensed to the perinuclear area, creating peripheral clearing. By immunohistochemistry, the pagetoid cells were positive for p40 (6/6) and p63 (7/7) and negative for CDX2 (7/7). The tumor cells showed mutant-type staining for p53 in five of seven cases. One of the patients had pagetoid tumor cells at the resection margin and subsequently had recurrent disease 2 years later. All other patients had negative resection margins and did not have local recurrence. Four cases of pagetoid spread in the context of EAC were used as a comparison group. Previously published studies were also analyzed. These tumors were all located in the distal esophagus or gastroesophageal junction. All cases were associated with underlying invasive EAC. Pagetoid spread associated with EAC often had cytoplasmic vacuoles or mucin. They were more frequently positive for CK7 than pagetoid ESCC (p = 0.01). Both ESCC and EAC may give rise to pagetoid spread of tumor cells within surface squamous epithelium. Pagetoid spread from ESCC and EAC have overlapping morphologic features. P40 and p63 immunostains can facilitate the distinction between ESCC and EAC. P53 immunostain can aid in confirmation of malignancy. Understanding their overlapping pathologic features will help pathologists avoid pitfalls and diagnose these lesions correctly on biopsy specimens.