Wu, Tsung‐Teh

Abstract Eosinophilic esophagitis is an immune-mediated chronic disease of the esophagus. It is clinically characterized by symptoms related to esophageal dysfunction and histologically by eosinophil-rich inflammation with a peak intraepithelial eosinophil count of at least 15 eosinophils per high-power field. Both children and adults can be affected with a strong male predominance. Food appears to be the key trigger, although the exact mechanisms remain unclear. Treatment for eosinophilic esophagitis can be summarized as the 3 D's: dietary, drugs, and dilatation. The differential diagnosis includes gastroesophageal reflux disease, eosinophilic gastroenteritis, drug hypersensitivity, hypereosinophilic syndrome, infection, Crohn disease, connective tissue diseases, and vasculitis.

Subtyping hepatic adenomas is important for patient management due to differing complication risks. Immunohistochemical staining with C-reactive protein (CRP) and serum amyloid-A (SAA) is widely accepted as a surrogate for molecular classification to identify inflammatory hepatocellular adenomas. Limited data, however, has been published on how these 2 stains compare for sensitivity. We conducted a large, multicenter, retrospective study to examine the sensitivity and staining characteristics of CRP and SAA in inflammatory hepatic adenomas, with focal nodular hyperplasia (FNHs) as a control group. Inflammatory adenomas were identified in 133 patients (average age 37 years, 109 were female). In all, 69.9% of cases were resection specimens and 90.2% of all cases showed positive staining for both CRP and SAA; 10 (7.5%) were positive for CRP only and 3 (2.3%) were positive for SAA only. CRP was more sensitive than SAA (97.74% vs. 92.48%, P-value = 0.0961) and showed more extensive and intense staining, with a significantly higher modified H-score (P<0.001). Focal nodular hyperplasia can also show positive CRP and SAA staining but with a lower modified H-score (P<0.0001). Based on beta-catenin and glutamine synthetase staining, 26 of inflammatory adenomas also had beta-catenin activation (19.5%). All 3 cases with positive SAA and negative CRP staining were beta-catenin activated. In contrast, the proportion of cases that were CRP positive and SAA negative was similar regardless of beta-catenin activation. The data affirms the strategy of using both CRP and SAA immunostains for hepatic adenoma subtyping and raises the awareness of the highly variable nature of SAA staining characteristics.

Hepatic angiosarcomas are aggressive malignant tumors of the liver with variable morphology. One of the rare morphologies is that of the sinusoidal growth pattern, which is challenging to diagnose because of its subtle imaging and morphologic findings. This retrospective study characterizes the clinical, histologic, and immunohistochemical features of sinusoidal hepatic angiosarcomas. Thirteen cases were included in the study, comprising 12 (92.3%) needle core biopsies and 1 wedge biopsy; one of the needle biopsies also had a subsequent resection specimen available for review. Multiple biopsies were needed to make the diagnosis in 4 cases. At least moderate sinusoidal dilatation was seen in 53.8% of cases. Increased cellularity within the sinusoids was seen at both low-power and high-power magnification (69.2% and 84.6%, respectively). Cytologic atypia ranged from mild to marked. Multinucleated tumor cells were present in most cases (10/13 cases) but were often sparse. Mitotic activity was identified in 5/13 cases. ERG immunostains were more reliable than CD31 and CD34 in identifying the tumor cells. Ki-67 proliferative index ranged from 5% to 30%. p53 immunostains were available in 9 cases and c-MYC in 7 cases; they were positive in 62.5% and 33.3% of cases, respectively and had a mutually exclusive staining pattern. In summary, this rare pattern of hepatic angiosarcoma is challenging to diagnose but has distinctive morphologic findings that can be supplemented with immunostains to establish the diagnosis.

SummaryBackgroundDietary therapy successfully treats eosinophilic oesophagitis (EoE), but limited data exist on predictors of patient response.AimsTo determine response rates and to identify predictors of histologic response to elimination diets in adults with EoEMethodsThis was a retrospective, single‐centre study of adults with PPI‐refractory EoE undergoing dietary therapy with six food elimination diet (SFED) or extended six food elimination diet (ExSFED) in an outpatient setting from January 2012 to January 2019. Patient demographics, radiologic and endoscopic findings, endoscopic reference (EREF) scores, histology and symptoms were evaluated before and after food elimination. Histologic response was assessed via tissue obtained from endoscopically‐guided biopsy or Cytosponge. Dietary therapy adherence was assessed via structured phone interview. Multivariable logistic regression analysis was performed to identify predictors of dietary response.ResultsWe included 68 patients, of whom 62% had a histologic response to dietary therapy (81% to SFED, 19% to ExSFED). Median duration of follow‐up was 45 months (IQR, 34–53 months). On multivariable analysis, higher pre‐SFED EREF score was the only variable associated with dietary non‐response (OR 0.07, 95% CI 0.49, 0.98; p = 0.04).ConclusionsIn adults with EoE, histologic dietary non‐response to SFED was associated with a higher pre‐SFED EREF score, suggesting that fixed structural disease may predict dietary non‐response. Our additional observations of poor correlation between symptomatic and histologic flares, and identification of ExSFED responders, suggest that histologic confirmation should be sought before committing patients to lifelong dietary changes. We also recommend the consideration of restricting legumes and corn in SFED non‐responders as ExSFED detected additional dietary responders.

Hepatic adenomas occur most commonly in women between the ages of 20 and 40 years, but rarely they occur in older aged persons, including those 60 years of age or older. This group of adenomas, however, has not been systemically examined. Twenty-six hepatic adenomas in persons 60 years of age or older were studied, along with a control group of 50 hepatic adenomas in persons aged 30 to 39. Hepatic adenomas in persons 60 or more years of age were found in 21 women and 5 men, while the control group had 44 women and 6 men. Subtyping the adenomas in persons 60 years or older showed the following results: 18 HNF1A-inactivated adenomas (69%), 4 inflammatory adenomas (15%), and 4 unclassified adenomas (15%). In contrast, the control group showed a significantly different pattern (P=0.003), with a greater percentage of inflammatory adenomas (28, 56%), fewer HNF1A-inactivated adenomas (8, 16%), and more unclassified adenomas (14, 28%). Atypia and malignant transformation within the hepatic adenomas was studied next. Of the hepatic adenomas in persons age 60 or greater, 3 (12%) showed atypical histologic features, and 6 (23%) had a malignant transformation. In contrast, for hepatic adenomas in the control group, only 4 (8%) adenomas showed atypical histologic features, and 3 (6%) had undergone malignant transformation. In addition, the hepatic adenomas that were atypical or showed early malignant transformation were less likely to have beta-catenin activation in patients over 60 (2/9 cases) compared with those between 30 and 39 years (5/7 cases). Myxoid change and heavy lipofuscin deposition were also more common in adenomas in older aged persons. In conclusion, hepatic adenomas in persons 60 years of age or older are enriched for HNF1A-inactivated adenomas and have a higher frequency of malignant transformation. Malignant transformation, however, is less likely to develop through activation of the beta-catenin pathway.

Hepatocellular adenomas are rare in children. A large study focused on pediatric patients has not been undertaken. A natural language search was performed at 5 institutions for hepatocellular adenomas in patients younger than 21 years old. Clinical characteristics as well as immunohistochemical staining profile was reviewed and adenomas subtyped per standard classification. Patients were divided into prepubescent and postpubescent age group. Thirty-one patients were included. Eleven (35%) were male and 10 (32%) were prepubescent. Fifteen (54%) of 28 patients with known clinical histories had adenomas associated with a syndrome. The percentage of the different adenoma subtypes was: 16% β-catenin activated, 10% combined inflammatory and β-catenin activated, 29% HFN1α-inactivated, 35% inflammatory, and 10% unclassified subtype by immunohistochemical staining. Interestingly 53% of patients with syndromes were male, while 85% of patients in the nonsyndromic group were female. The total number of β-catenin activated tumors was greater in the syndromic group (5/15, 33%) and prepubescent group (5/10, 50%) than in the nonsyndromic group (2/13, 16%) and postpubescent group (3/21, 14%), P=0.4 and 0.07, respectively. Inflammatory type adenoma was more frequent in the postpubescent (10/21, 48%) than in the prepubescent group (1/10, 10%), P=0.06, trending toward significance. Pediatric patients with hepatocellular adenomas frequently have syndromes, especially in the prepubescent group. In patients with syndromes a greater percentage of adenomas were β-catenin activated. In patients without a known syndrome the distribution of hepatocellular adenoma subtypes appears similar to adults.

AbstractThrough our involvement in KEYNOTE‐059, we unexpectedly observed durable responses in two patients with metastatic gastroesophageal adenocarcinoma (mGEA) who received ramucirumab (anti‐VEGFR‐2)/paclitaxel after immune checkpoint inhibition (ICI). To assess the reproducibility of this observation, we piloted an approach to administer ramucirumab/paclitaxel after ICI in more patients, and explored changes in the immune microenvironment. Nineteen consecutive patients with mGEA received ICI followed by ramucirumab/paclitaxel. Most (95%) did not respond to ICI, yet after irRECIST‐defined progression on ICI, all patients experienced tumor size reduction on ramucirumab/paclitaxel. The objective response rate (ORR) and progression‐free survival (PFS) on ramucirumab/paclitaxel after ICI were higher than on the last chemotherapy before ICI in the same group of patients (ORR, 58.8% vs 11.8%; PFS 12.2 vs 3.0 months; respectively). Paired tumor biopsies examined by imaging mass cytometry showed a median 5.5‐fold (range 4‐121) lower frequency of immunosuppressive forkhead box P3+ regulatory T cells with relatively preserved CD8+ T cells, post‐treatment versus pre‐treatment (n = 5 pairs). We then compared the outcomes of these 19 patients with a separate group who received ramucirumab/paclitaxel without preceding ICI (n = 68). Median overall survival on ramucirumab/paclitaxel was longer with (vs without) immediately preceding ICI (14.8 vs 7.4 months) including after multivariate analysis, as was PFS. In our small clinical series, outcomes appeared improved on anti‐VEGFR‐2/paclitaxel treatment when preceded by ICI, in association with alterations in the immune microenvironment. However, further investigation is needed to determine the generalizability of these data. Prospective clinical trials to evaluate sequential treatment with ICI followed by anti‐VEGF(R)/taxane are underway.

4541 Background: Anti-VEGFR2 therapy (ramucirumab/paclitaxel [RAM/TAX]) and ICI are approved as 2nd- and 3rd-line therapy (Tx), respectively, for pts with mGEA. We unexpectedly saw durable responses in 2 pts on RAM/TAX after progression on an ICI trial (KN-059; PMID 29674442). We performed a pilot to examine the clinical activity of ICI followed by RAM/TAX. Then we retrospectively compared the outcomes of pts who received this serial Tx to pts who received RAM/TAX without prior ICI. Methods: All pts with mGEA at Mayo Clinic who received RAM/TAX (2014-19) were included (N = 87). Outcomes were best objective response rate (ORR: complete [CR] or partial response) per RECIST1.1, progression-free survival (PFS), duration of response (DOR), and overall survival (OS). Chi square and multivariate (MV) logistic and Cox regression were used. Results: 15 consecutive pts with measurable mGEA received ICI immediately followed by RAM/TAX after irRECIST progression. Most pts (95%) did not respond to ICI. Yet on RAM/TAX, 100% (15/15) had tumor reduction (range -8% to -100%) with an ORR of 73% (11/15), including 3 CRs. In these pts (who received ICI followed by RAMTAX), PFS on RAMTAX was longer than on last chemotherapy before ICI (12.3 vs 3.0 m, P < .001). Outcomes on RAM/TAX in these pts were significantly better than in pts who received RAM/TAX alone (see Table). Associations were strengthened after adjusting for total lines of Tx, line of Tx of RAM/TAX, age, and ECOG PS. Exploratory analysis of paired tumor biopsies collected pre-ICI and on RAM/TAX in a small subset revealed that the frequency of intratumoral immunosuppressive FOXP3+ Tregs decreased on RAM/TAX, whereas the frequency of antitumor CD8+ T cells was preserved. Conclusions: RAM/TAX immediately preceded by ICI was associated with significantly higher OS, ORR, and DOR than RAM/TAX alone, suggesting ICI may enhance efficacy of subsequent anti-VEGFR/taxane therapy. This novel sequence of therapy will be tested prospectively in a new randomized phase 2 trial (NCT04069273). [Table: see text]

Angiosarcoma of the colon is rare, as is colonic amyloidosis. To our knowledge, there have been no reported cases of angiosarcoma arising in association with amyloid deposition. Herein, we described a case of 77-year-old man who presented with hematochezia, and a sigmoid mass was found on colonoscopy. Histologic examination of the resected specimen showed extensive nodular deposition of AL-lambda amyloid material in the colonic wall, as well as high-grade angiosarcoma which was closely intermingled with the amyloid deposits. While the occurrence of both colonic amyloidosis and angiosarcoma in this patient may represent pure coincidence, given the intimate association of the angiosarcoma and the amyloid deposition and the rarity of both of these lesions, we hypothesize that angiosarcoma could be secondary to amyloid deposition.