Exogenous copper exposure causing clinical wilson disease in a patient with copper deficiency.

BACKGROUND: Human Swayback is a disease characterized by acquired copper deficiency which primarily manifests as myeloneuropathy. Common causes include malabsorptive disorders, gastric surgery, total parenteral nutrition and excessive zinc intake. In contrast, copper supplementation should be closely monitored as excessive doses can lead to acute intoxication and in chronic cases, cirrhosis. Copper derangements are rare, however it is important to consider them due to potential severe complications. CASE PRESENTATION: We present a middle-aged man who had been previously diagnosed with Human Swayback after presenting with various neurological symptoms. The patient was subsequently placed on copper supplementation. A decade later, he was referred to our hospital for liver transplant evaluation due to new diagnosis of decompensated end-stage liver disease after an abdominal surgery. His initial workup was suggestive of Wilson disease-subsequent ATP7B gene was negative. Ultimately, the patient underwent liver transplantation; liver explant was significant for a copper dry weight concentration of 5436 mcg/g. CONCLUSIONS: Human Swayback is a very rare copper-related disease which deserves awareness due to its potential irreversible health effects in the human body. Additionally, in patients who require copper supplementation, serial levels should be monitored to ensure adequate copper levels.

Knowledge gaps in the appendix: a multi-institutional study from seven academic centers.

Appendix pathology represents uncommonly encountered specimens with unique diagnostic challenges. To delineate common knowledge gaps, extramural consults submitted to seven institutions between 2016-2017 were reviewed. All appendix consults were resections (100%, n = 43), and the majority were directed for consultation by the originating pathologist (95%, n = 41) with no additional studies performed by the consultant (65%, n = 28). This study was dominated by inquiries related to low grade appendiceal mucinous neoplasms (44%, n = 19) and goblet cell carcinoid related neoplasms (19%, n = 8). Of the 43 appendiceal consults, 19 were submitted by the contributing pathologist as low grade appendiceal mucinous neoplasm, but only half of these were diagnosed by the consultant as such (n = 9). Low grade appendiceal mucinous neoplasm-related consultation themes included diverticular disease, criteria for invasion, high grade atypia, extra-appendiceal mucin, and staging. Examples of major disagreements that were downgraded included consults submitted as low grade appendiceal mucinous neoplasm and diagnosed by the consultant as serrated polyp (n = 3), appendicitis (n = 1), and benign appendix (n = 1). Examples of major disagreements-upgraded included cases submitted as low grade appendiceal mucinous neoplasm and diagnosed by the consultant as low grade appendiceal mucinous neoplasm with high-risk features (n = 2) and mucinous adenocarcinoma (n = 2). One case contained both a major disagreement-upgrade (low grade appendiceal mucinous neoplasm changed to high grade appendiceal mucinous neoplasm) and a major disagreement-downgrade (pT3 changed to Tis). Of the 15 cases diagnosed by the consultants as low grade appendiceal mucinous neoplasm, submitted diagnoses included low grade appendiceal mucinous neoplasm (n = 9), adenocarcinoma (n = 5), and one case was submitted without a diagnosis. For goblet cell carcinoid-related consults, the usual inquiry related to distinguishing goblet cell carcinoid from goblet cell carcinoid with adenocarcinoma (adenocarcinoma ex-goblet cell carcinoid). Of the 38 overall consults with a submitted diagnosis, 53% (n = 20) were disagreements, and most of these were major disagreements-downgraded (n = 13).

The inverted appendix - a potentially problematic diagnosis: clinicopathologic analysis of 21 cases.

AIMS: Inverted appendices are rare, but have the potential to cause diagnostic confusion among endoscopists and pathologists. The aim of this study was to describe the clinicopathological features of inverted appendices seen at our institution over the last 30 years. METHODS AND RESULTS: Twenty-one inverted appendices were identified and the clinical and pathological features reviewed. Patients were predominantly middle-aged women. Most cases were detected incidentally on colonoscopy. Endoscopically, inverted appendices appeared polypoid in the proximal caecum. All resections featured associated pathological processes, including endometriosis (n = 3), inflammatory mucocoele (n = 1), low-grade appendiceal mucinous neoplasm (n = 2), traditional serrated adenoma (n = 1) and inflammatory fibroid polyp (n = 1). Five cases were endoscopically mischaracterised as caecal polyps and removed via polypectomy; initial pathological impressions were erroneous in most cases. All polypectomies featured a dome-like configuration covered by mucosa on the convex surface; the majority had aggregates of ganglion cells and neural plexi embedded in muscularis propria. The vast majority of cases, regardless of the procedure, showed lymphoid aggregates. Among post-polypectomy patients with follow-up, none experienced perforation-associated morbidity despite the histological presence of muscularis propria. CONCLUSIONS: The diagnosis of an inverted appendix should be considered in polypectomy specimens from the caecum or appendiceal orifice with (i) dome-like tissue configuration covered by mucosa on the convex surface, (ii) a deep, robust smooth muscle component with ganglion cells (muscularis propria) and (iii) associated lymphoid aggregates. Prompt recognition on H&E will avoid unnecessary time and resource investment.

Intestinal metaplasia of the gastric cardia: findings in patients with versus without Barrett's esophagus.

BACKGROUND AND AIMS: There is controversy about finding intestinal metaplasia (IM) of the gastric cardia on biopsy. The most recent American College of Gastroenterology guideline comments that IM cardia is not more common in patients with Barrett's esophagus (BE). It provides limited guidance on whether the cardia should be treated when patients with BE undergo endoscopic eradication therapy (EET) and whether the cardia should undergo biopsy after ablation. The aims of our study were to determine the frequency in the proximal stomach of (1) histologic gastric cardia mucosa and (2) IM cardia. A third aim was to explore the frequency of advanced pathology (dysplasia and adenocarcinoma) in the cardia after patients with BE have undergone EET. METHODS: Consecutive patients undergoing esophagogastroduodenoscopy between January 2008 and December 2014 who had proximal stomach biopsies were included. Patients who had histologically confirmed BE were compared with those without BE. RESULTS: Four hundred sixty-two patients, 289 with BE and 173 without BE, were included. Histologically confirmed cardiac mucosa was found in 81.6% of all patients. This was more frequent in those with versus without BE (86% vs 75%; odds ratio [OR], 2.06; 95% confidence interval [CI], 1.28-3.32; P = .003). IM cardia was more common in the BE group (17% vs 7%; OR, 2.67; 95% CI, 1.38-5.19; P = .004). Advanced pathology was more likely in the patients with BE who had undergone EET. CONCLUSIONS: Cardiac mucosa is present in most patients who undergo endoscopy for upper GI symptoms. IM cardia is more common in patients with BE than those without. Advanced histologic changes in the cardia were seen only in the subgroup of patients with BE who had undergone EET.

Molecular testing for the clinical diagnosis of fibrolamellar carcinoma.

Fibrolamellar carcinoma has a distinctive morphology and immunophenotype, including cytokeratin 7 and CD68 co-expression. Despite the distinct findings, accurate diagnosis of fibrolamellar carcinoma continues to be a challenge. Recently, fibrolamellar carcinomas were found to harbor a characteristic somatic gene fusion, DNAJB1-PRKACA. A break-apart fluorescence in situ hybridization (FISH) assay was designed to detect this fusion event and to examine its diagnostic performance in a large, multicenter, multinational study. Cases initially classified as fibrolamellar carcinoma based on histological features were reviewed from 124 patients. Upon central review, 104 of the 124 cases were classified histologically as typical of fibrolamellar carcinoma, 12 cases as 'possible fibrolamellar carcinoma' and 8 cases as 'unlikely to be fibrolamellar carcinoma'. PRKACA FISH was positive for rearrangement in 102 of 103 (99%) typical fibrolamellar carcinomas, 9 of 12 'possible fibrolamellar carcinomas' and 0 of 8 cases 'unlikely to be fibrolamellar carcinomas'. Within the morphologically typical group of fibrolamellar carcinomas, two tumors with unusual FISH patterns were also identified. Both cases had the fusion gene DNAJB1-PRKACA, but one also had amplification of the fusion gene and one had heterozygous deletion of the normal PRKACA locus. In addition, 88 conventional hepatocellular carcinomas were evaluated with PRKACA FISH and all were negative. These findings demonstrate that FISH for the PRKACA rearrangement is a clinically useful tool to confirm the diagnosis of fibrolamellar carcinoma, with high sensitivity and specificity. A diagnosis of fibrolamellar carcinoma is more accurate when based on morphology plus confirmatory testing than when based on morphology alone.

The outlet patch: gastric heterotopia of the colorectum and anus.

AIMS: Gastric heterotopia (GH) has been described throughout the gastrointestinal tract. However, the colorectal region is an extremely rare location for it. We describe the clinicopathological features of GH of the colon, rectum and anus. METHODS AND RESULTS: We identified 33 cases in 20 males and 13 females (median age = 54 years; range = 4 months-73 years). Sites included the rectum (n = 26), anus (n = 4), ileocaecal junction (n = 1), ascending colon (n = 1) and descending colon (n = 1). Presenting symptoms (n = 27) included haematochezia (41%) and altered bowel habits (4%); 15 patients (55%) were asymptomatic. On colonoscopy (n = 31), all appeared as solitary lesions (median size = 6.5 mm, range = 2-55 mm), either as polyps (61%), raised erythematous patches (23%), an ulcer (10%), within a rectal diverticulum (3%) or a haemorrhoid (3%). Patients were managed by polypectomy. One with an associated carcinoma in the area of GH underwent resection. No morbidity related to GH itself was reported following excision. Histologically, heterotopic gastric mucosa was oxyntic (85%), mixed oxyntic and non-oxyntic (12%) and not specified (3%) types. In five patients a pyloric gland adenoma (PGA) arose from heterotopic gastric mucosa, two of which contained a focus of invasive adenocarcinoma. One case had associated surface foveolar-type low-grade dysplasia. Another had associated adenocarcinoma arising from the heterotopic mucosa. One example harboured Helicobacter pylori organisms. CONCLUSIONS: We highlight the features of GH in the distal GIT - the 'outlet patch'. Association with PGA, surface dysplasia and adenocarcinoma suggests that lower tract GH can undergo neoplastic transformation.

Some observations on Barrett esophagus and associated dysplasia.

Biopsy samples from esophageal columnar metaplasia and dysplasia are commonly encountered in Western pathology practice and knowing a few pitfalls can save both pathologists and patients a great deal of anxiety. Herein we discuss criteria for Barrett esophagus, evaluation of dysplasia, and some pitfalls in reviewing endoscopic mucosal resections. Also included is a summary of suggested follow-up for patients with Barrett esophagus.

Targeted next-generation sequencing supports epidermoid metaplasia of the esophagus as a precursor to esophageal squamous neoplasia.

Esophageal epidermoid metaplasia is a rare condition that involves the proximal-to-middle third of the esophagus. It is sharply demarcated and defined histologically by epithelial hyperplasia, a prominent granular cell layer, and superficial hyperorthokeratosis. In addition, preliminary studies have suggested an association between esophageal epidermoid metaplasia and esophageal squamous neoplasia (squamous dysplasia and esophageal squamous cell carcinoma). To further characterize esophageal epidermoid metaplasia and better define its relationship to squamous neoplasia of the esophagus, we performed targeted next-generation sequencing on uninvolved esophageal squamous mucosa and matching esophageal epidermoid metaplasia specimens from 18 patients. Further, we evaluated both synchronous and metachronous high-grade squamous dysplasia/esophageal squamous cell carcinoma by next-generation sequencing from 5 of the 18 (28%) patients, and compared these findings to corresponding esophageal epidermoid metaplasia specimens. Targeted next-generation sequencing revealed 12 of 18 (67%) esophageal epidermoid metaplasia specimens' harbored alterations in genes often associated with esophageal squamous cell carcinoma. The most frequently mutated genes consisted of TP53 (n=10), PIK3CA (n=2), EGFR (n=2), MYCN (n=1), HRAS (n=1), and the TERT promoter (n=1). Sequencing of synchronous and metachronous high-grade squamous dysplasia/esophageal squamous cell carcinoma identified shared genetic alterations with corresponding esophageal epidermoid metaplasia specimens that suggests a clonal relationship between these entities. In addition, the presence of a TP53 mutation in esophageal epidermoid metaplasia specimens correlated with concurrent or progression to high-grade squamous dysplasia/esophageal squamous cell carcinoma. No genetic alterations were detected in uninvolved esophageal squamous mucosa. On the basis of these findings, we conclude esophageal epidermoid metaplasia is a precursor to in situ and invasive esophageal squamous neoplasia. Further, the detection of TP53 mutations in esophageal epidermoid metaplasia specimens may serve as an early detection biomarker for high-grade squamous dysplasia/esophageal squamous cell carcinoma.

Analysis of Biopsies From Duodenal Bulbs of All Endoscopy Patients Increases Detection of Abnormalities but has a Minimal Effect on Diagnosis of Celiac Disease.

BACKGROUND & AIMS: In patients with positive results from serologic tests for celiac disease, analysis of tissues samples from the duodenal bulb, in addition to those from other parts of the small bowel, might increase the diagnostic yield. However, biopsies are not routinely collected from the duodenal bulb because of concerns that villous atrophy detected there could be caused by other disorders (Brunner glands or peptic duodenitis, gastric metaplasia, shorter villi, or lymphoid follicles). We investigated whether analysis of biopsies from duodenal bulbs of all patients undergoing endoscopy (a population with a low probability for celiac disease) increases diagnoses of celiac disease. METHODS: We performed a retrospective analysis of data from 679 patients (63% female; mean age, 50 years) from whom duodenal bulb and small bowel biopsies were collected during endoscopy at 3 Mayo Clinic sites, from January 1, 2011 through December 31, 2011. Records were reviewed for age, sex, pathology findings, serology test results (HLA DQ2 or DQ), indications for biopsy analyses, and adherence to a gluten-free diet. Patients with celiac disease were identified on the basis of increased intraepithelial lymphocytosis, with or without villous atrophy and crypt hyperplasia, and results from serology tests. Findings from duodenal bulbs were compared with diagnoses using the Fisher exact test. RESULTS: Of all patients undergoing endoscopy, 16 patients (2%) were found to have celiac disease. Analysis of the duodenal bulb biopsies identified 1 patient (0.1%) with celiac disease limited to this region. Of 399 patients whose celiac serology was not known before endoscopic examination, only 2 patients had histologic changes consistent with celiac disease but not limited to duodenal bulb. Abnormal duodenal histology was detected in 265 patients (39%), most commonly in the bulb (n = 241; P < .0001). Of abnormal bulb histologies, chronic peptic duodenitis was most common (observed in 114 patients, 47%). In patients with a normal distal duodenum (n = 576), the duodenal bulb had abnormal histology in 162 (28%). CONCLUSIONS: In a low pretest probability cohort, separate sampling of the duodenal bulb had minimal effect on celiac disease detection. Abnormal histologic findings are more commonly detected in the duodenal bulb; although they do not seem to impair identification of celiac disease, their clinical implications are unclear.

Helicobacter pylori Clarithromycin Resistance and Treatment Failure Are Common in the USA.

BACKGROUND: Helicobacter pylori antibiotic resistance leads to frequent treatment failure. However, the current US prevalence of H. pylori clarithromycin resistance and treatment failure is unknown. AIMS: To determine the prevalence of clarithromycin-resistant H. pylori and its impact on treatment failure in the USA. METHODS: A multicenter, retrospective, cohort study for clarithromycin-resistant H. pylori was conducted over four academic medical centers in different geographic regions of the USA. Gastric biopsy material, residual from standard clinical pathologic examination, was examined for clarithromycin resistance by DNA sequencing of H. pylori 23S rRNA. RESULTS: One hundred and twenty-four cases of H. pylori gastritis were examined from medical centers in four different geographic regions of the USA. The overall prevalence of clarithromycin resistance was 32.3 % (range 23.1-45.8 %). There was no significant difference in the prevalence of clarithromycin resistance by study site, gender, age, or race/ethnicity. In a subset of 67 patients that had clinical follow-up data, the overall prevalence of clarithromycin resistance was 31.3 %. There was a 2.9-fold increase (p = 0.002) in treatment failure for cases with clarithromycin resistance (57.1 %) compared to wildtype H. pylori (19.6 %). CONCLUSIONS: H. pylori clarithromycin resistance in the USA exceeds the estimated 20 % prevalence compatible with successful empiric antibiotic therapy. This resistance resulted in a significant rate of treatment failure in all sites surveyed. Empiric therapy in the USA should be used with caution until there is better regional or local determination of H. pylori antibiotic resistance.

Magnetic resonance elastography can discriminate normal vs. abnormal liver biopsy in candidates for live liver donation.

PURPOSE: The aim of this study was to define liver shear stiffness by magnetic resonance elastography (MRE) that distinguishes normal from abnormal liver biopsy, especially when steatosis ≥20%, among potential live liver donors. METHODS: Baseline clinical, laboratory, imaging, MRE, and liver biopsy results were recorded. Using MRE, hepatic shear stiffness in kilopascals (kPa) was measured and compared to liver biopsy. Comparison between groups was done using χ(2) or Fisher's exact test for categorical variables and Wilcoxon test for continuous variables. Receiver operating characteristic (ROC) curve was calculated to assess diagnostic accuracy. Statistical significance was set at p < 0.05. RESULTS: 38 healthy adults were included. Liver biopsy was normal in 27 and abnormal in 11. ROC curve for MRE defined optimal cutoff at 2.6 kPa (sensitivity 0.72, specificity 0.85, AUC 0.81) to distinguish these 2 groups. Hepatic steatosis ≥20% on biopsy is a contraindication for liver donation in our center. We evaluated the ability of MRE to distinguish this degree of steatosis: 8 persons had steatosis ≥20% and were excluded from donation. ROC curve for MRE defined optimal cutoff at 2.82 kPa (sensitivity 0.88, specificity 1, AUC 0.98) to identify this group. CONCLUSIONS: Liver stiffness measured by MRE, even in the absence of liver fibrosis, can be useful in differentiating normal from abnormal liver histology, and most importantly in patients under evaluation for live liver donation, can very accurately distinguish those with complicated hepatic steatosis ≥20%, our cutoff for donation. In the future, MRE might provide supplementary information to make liver biopsy unnecessary in the donor evaluation process.

Esophageal leukoplakia or epidermoid metaplasia: a clinicopathological study of 18 patients.

Oral leukoplakia is a relatively common, painless disorder of the oral mucosa. It predominantly affects middle-aged to elderly men and has a strong association with tobacco smoking and alcohol intake. Concomitant histological findings of hyperorthokeratosis and a well-developed granular cell layer, termed orthokeratotic dysplasia, are often associated with oral squamous cell carcinoma. In contrast, analogous lesions within the esophagus, termed esophageal epidermoid metaplasia, are rarely encountered and poorly described in the literature. To better characterize the clinicopathological features of this entity, we have collected 25 cases from 18 patients. Patients ranged in age from 37 to 81 years (mean, 61.5 years), with a slight female predominance (10/18, 56%). On presentation, a majority of patients complained of dysphagia (10/18, 56%). Past medical history was significant for tobacco smoking or long history of second-hand smoke in 11 (61%) patients and alcohol intake in 7 (39%) patients. Seventeen (94%) patients with esophageal epidermoid metaplasia were located within the middle-to-distal esophagus. Histologically, all cases were sharply demarcated and characterized by epithelial hyperplasia, a thickened basal layer, acanthotic midzone, a prominent granular cell layer, and superficial hyperorthokeratosis. Adjacent high-grade squamous dysplasia and/or squamous cell carcinoma were seen in 3 out of 18 (17%) patients. Follow-up information was available for 13 out of 18 (72%) patients and ranged from 2 to 8.3 years (mean, 2.3 years). Seven of the 13 (54%) patients had persistent disease; however, none of them developed squamous dysplasia or squamous cell carcinoma. In an effort to assess the incidence of esophageal epidermoid metaplasia, 198 consecutive esophageal biopsies were prospectively surveyed over a 6-month period at three academic institutions. No cases were identified within this time frame. In summary, esophageal epidermoid metaplasia is a rare condition affecting the middle-to-distal esophagus in middle-aged to elderly females. The occurrence of adjacent high-grade squamous dysplasia and/or squamous cell carcinoma warrants close follow-up.

Histologic characteristics of vaginal cuff tissue from patients with vaginal cuff dehiscence.

STUDY OBJECTIVE: To describe the histologic characteristics of vaginal tissue in patients with vaginal cuff dehiscence (VCD) after robotic hysterectomy and to compare this group with patients without dehiscence. DESIGN: Retrospective analysis (Canadian Task Force classification II-3). SETTING: Academic center. PATIENTS: Seven patients with VCD and 6 patients without VCD. INTERVENTIONS: Vaginal cuff tissue was obtained from all patients and was stained using hematoxylin-eosin and evaluated for acute and chronic inflammation markers including neutrophils, lymphocytes, and plasma cells. Immunohistochemical staining was performed and evaluated using the semiquantitative method for collagen types I and III, smooth muscle actin, and SM22α (myofibroblast) content. Grading was performed by 4 blinded investigators. The Mann-Whitney test was used to evaluate the 2 groups, and correlation coefficients for interobserver variability. MEASUREMENTS AND MAIN RESULTS: The VCD group, compared with the non-VCD group, demonstrated significantly greater numbers of neutrophils (1.71 vs 1.0; p = .04), lymphocytes (2.85 vs 1.33; p = .002), and plasma cells (2.2 vs 1.0; p = .001). There was no statistical difference between the groups in amounts of collagen I (1.71 vs 1.27; p = .09) and collagen III (1.66 vs 1.38; p = .37), smooth muscle actin (1.23 vs 1.33; p = .65), and SM22α (1.85 vs 1.27; p = .09). Interobserver variability was low (κ = 0.86; p = .76). CONCLUSION: Compared with the control group, patients with VCD demonstrated significantly higher levels of acute and chronic inflammatory cells. This finding suggests that a prolonged inflammatory phase may be delaying normal progression to reparation in patients with dehiscence.

Some Morphology Frontiers of Dysplasia in the Tubular Gastrointestinal Tract: The Rodger C. Haggitt Memorial Lecture.

This review, based on the content of the 2020 US Gastrointestinal Pathology Society's Rodger Haggitt Lecture, concerns an array of tubular gastrointestinal tract dysplastic or possible "predysplastic lesions" with an almost purely morphologic focus based on our collaborative efforts over the past few years. These processes include esophageal epidermoid metaplasia, Barrett esophagus-associated dysplasia, polypoid gastric dysplastic lesions, small intestinal dysplasia, and the ability of metastases to mimic it, the controversial "serrated epithelial change" encountered in the setting of long-standing ulcerative and Crohn colitis, and recently described anal columnar human papilloma virus-associated neoplasms.

Plexiform leiomyoma of the esophagus: a complex radiographic, pathologic and endoscopic diagnosis.

Radiographic identification of an abnormal lesion in the esophagus routinely occurs during workup of patients with symptomatic dysphagia. Leiomyoma is the most common benign finding; however, plexiform leiomyoma, a distinctive but rare variant, follows an unusual pattern of growth which can be a challenging surgical resection. A review of indexed literature identified a single previous report. We contribute a second case of plexiform leiomyoma with a discussion of the clinical, radiographic, and pathologic characteristics, as well as the differential diagnosis for plexiform lesions.

RNA-Seq Reveals Differences in Expressed Tumor Mutation Burden in Colorectal and Endometrial Cancers with and without Defective DNA-Mismatch Repair.

Tumor mutation burden (TMB) is an emerging biomarker of immunotherapy response. RNA sequencing in FFPE tissue samples was used for determining TMB in microsatellite-stable (MSS) and microsatellite instability-high (MSI-H) tumors in patients with colorectal or endometrial cancer. Tissue from tumors and paired normal tissue from 46 MSI-H and 12 MSS cases were included. Of the MSI-H tumors, 29 had defective DNA mismatch-repair mutations, and 17 had MLH1 promoter hypermethylation. TMB was measured using the expressed somatic nucleotide variants (eTMB). A method of accurate measurement of eTMB was developed that removes FFPE-derived artifacts by leveraging mutation signatures. There was a significant difference in the median eTMB values observed between MSI-H and MSS cases: 27.3 versus 6.7 mutations/megabase (mut/Mb) (P = 3.5 × 10-9). Among tumors with defective DNA-mismatch repair, those with mismatch-repair mutations had a significantly higher median eTMB than those with hypermethylation: 28.1 versus 17.5 mut/Mb (P = 0.037). Multivariate analysis showed that MSI status, tumor type (endometrial or colorectal), and age were significantly associated with eTMB. Additionally, using whole-exome sequencing in a subset of these patients, it was determined that DNA TMB correlated well with eTMB (Spearman correlation coefficient, 0.83). These results demonstrate that RNA sequencing can be used for measuring eTMB in FFPE tumor specimens.

Management of large hepatocellular carcinoma in adult patients with Alagille syndrome: a case report and review of literature.

BACKGROUND: Alagille syndrome is a multi-system developmental disorder associated with paucity of interlobular bile ducts and cholestasis, rarely associated with hepatocellular carcinoma. Associated syndromic co-morbidities may complicate surgical management. As such, we herein review the modern management of a large hepatocellular carcinoma in an adult patient with Alagille syndrome and review the literature of adult Alagille patients with hepatocellular carcinoma. CASE PRESENTATION: A 29-year-old woman with a history of Alagille syndrome was referred with biopsy-proven 12 × 8 cm hepatocellular carcinoma replacing her right liver. Biopsy of the contralateral liver demonstrated findings consistent with Alagille syndrome, but no underlying cirrhosis. CT volumetrics demonstrated a future liver remnant of 40%. Extensive hematologic and cardiac work-up was performed pre-operatively, given the syndrome's associated bleeding dyscrasias and cardiac abnormalities. The patient underwent a margin-negative right hepatectomy using the "hanging" technique through a thoracoabdominal approach. The patient developed a transient hyperbilirubinemia but no hepatic insufficiency and did well post-operatively. CONCLUSION: Since Alagille syndrome affects multiple organ systems, preoperative evaluation of cardiac, hematologic, and hepatic function should be considered. This case illustrates the peri-operative management of an Alagille patient, and highlights several key technical points that contributed to a successful resection.