Citations

3599 Background: Existing tools for post-treatment CRC surveillance and monitoring are insensitive and expensive. MDMs are broadly informative for early detection of CRC but have not been extensively studied for disease monitoring. As a first step, we sought to assess the concordance of novel CRC-associated MDMs in pCRC and mCRC. Methods: A panel of 14 MDMs previously identified to be highly discriminant for pCRC was selected on the basis of high median fold-change of MDM levels relative to buffy coat (682 (IQR: 132-19347)). Surgically resected pCRC and paired mCRC were identified from institutional pathology databases. Quantitative methylation-specific PCR was used to assay MDMs. 30 paired samples per metastatic subtype were calculated to be sufficient. MDM levels were compared using two-sample and paired Wilcoxon rank sum tests. Results: 87 patients with paired pCRC and mCRC including 57 synchronous and 30 metachronous metastases were included. 41/87 (47%) had neoadjuvant and 59/87 (68%) had adjuvant chemotherapy. All synchronous metastases were to liver. Metachronous metastases were to liver in 19/30 (63%) and to lung in 11/30 (37%). The levels of 14 selected MDMs were remarkably similar between paired pCRC and mCRC (Table). Individual MDM levels and the average level of all MDMs combined were not significantly different ( p> 0.0018 by Bonferroni correction). Conclusions: MDM levels are highly concordant in pCRC and mCRC. Thus, MDMs discovered from pCRC should be further studied for non-invasive surveillance after surgical resection and monitoring of treatment response in mCRC. [Table: see text]

Abstract Objectives To examine the immunohistochemical and ultrastructural features of hepatocellular cytoplasmic globules in venous outflow impairment (VOI). Methods Sixty-four liver core biopsies were screened. Patients with α-1 antitrypsin (AAT) deficiency were excluded. All biopsies were stained with H&E, Masson trichrome, periodic acid-Schiff with diastase digestion (PAS-D), phosphotungstic acid hematoxylin (PTAH), complement protein 4d (C4d) immunostain, and AAT immunostain. Electron microscopy was also performed. Results Hepatocellular globules were identified in 8% of in-house cases. Causes of VOI included heart failure and Budd-Chiari syndrome. The hepatocellular cytoplasmic globules showed size variability, random distribution, and positivity for PAS-D, PTAH, and AAT. C4d was inconsistently positive. Electron microscopy showed that the globules were lysosome-bound inclusions containing microfibrillar material and fibrinogen. Conclusions PAS-D–positive hepatocellular globules occur in VOI. They cross-react with AAT but have different appearance, localization, and ultrastructural composition from globules in AAT deficiency.

ABSTRACT Objectives Albumin messenger RNA (mRNA) expression is a marker of hepatocellular differentiation. Most published data are from review of tissue microarrays, and albumin in situ hybridization (ISH) expression across several tumor types is incompletely characterized. Methods Sections from 221 tumors were evaluated for albumin mRNA. Immunohistochemistry was used to confirm diagnoses. Albumin ISH was performed according to manufacturer-provided instructions. Fifty-nine cases were evaluated with both commercial ISH assays. Results Albumin mRNA was detected in all hepatocellular carcinomas (HCCs) and 81% of intrahepatic cholangiocarcinomas. Lung (20%), gallbladder (39%), hepatoid pancreatic (n = 1 of 1) adenocarcinoma, breast invasive ductal carcinoma (18%), yolk sac tumor (25%), and acinar cell carcinoma (29%) showed expression. Both assays were concordant in 93% of cases. Conclusions Albumin ISH was expressed in all HCCs studied. It was also positive in intrahepatic cholangiocarcinoma and patchy positive in gallbladder adenocarcinoma and a subset of other neoplasms, which can be a potential pitfall.

Background: Our purpose was to evaluate the prognostic impact of pathologically confirmed esophageal adenosquamous carcinoma (ASC) and its association with HER2 status and clinicopathologic characteristics. Methods: Among 796 patients with esophageal or gastroesophageal junction adenocarcinoma who underwent curative resection, surgical pathology reports were reviewed, and suspected ASC was confirmed utilizing p63 and CK5/6 immunostaining. HER2 status was determined using immunohistochemistry and fluorescence in situ hybridization. Cox models were used to assess the impact of ASC on disease-specific survival and overall survival. Results: Overall, 2.0% (16/796) of patients had esophageal ASC, mostly demonstrating a close intermingling of squamous and adenocarcinoma cells within the same tumor. The percentage of squamous versus adenocarcinoma cells in the primary was generally recapitulated in nodal metastases, and intrapatient internodal heterogeneity was uncommon. Patients with esophageal ASC were statistically significantly more likely to be female (vs. male), have normal (vs. excess) body mass index, and harbor HER2-negative (vs. positive) tumors, as compared with patients with adenocarcinoma only. No ASC tumor was HER2-positive as compared with 16% of adenocarcinoma only tumors (P=0.018). Compared with patients with adenocarcinoma only, those with ASC demonstrated profoundly worse disease-specific survival (5-year event-free rate, 34% vs. 6%; multivariate hazard ratio, 2.87 [95% confidence interval, 1.59-4.76]; P=0.0010) and overall survival (P=0.0027) that was independent of known prognostic factors and HER2 status. Conclusion: ASC identifies a rare aggressive HER2-negative subgroup of esophageal/gastroesophageal junction adenocarcinoma.

Aims To examine copper deposition in focal nodular hyperplasia (FNH) and inflammatory hepatocellular adenoma (IHA) and to determine if it can play a role in their differentiation. Methods 28 FNHs and 19 IHAs from surgical resections showing typical morphological and immunohistochemical features were stained with rhodanine to evaluate for copper deposition. Histological features such as nodularity, fibrous bands, ductular proliferation, steatosis, ballooned hepatocytes and lymphocytic inflammation were also scored. Results Copper deposition was detected in 96% (27/28) of FNHs and 37% (7/19) of IHAs, P<0.001. In all cases, copper was seen within the hepatocytes only around the pseudo-portal tracts or areas of fibrosis. Copper deposition in IHA was significantly associated with presence of lymphocytic inflammation (P=0.04) but not associated with features like nodularity, fibrous bands, ductular proliferation, ballooned hepatocytes and steatosis (P>0.05, for all). In FNH, the presence and degree of copper deposition was not significantly associated with any histological features (P>0.05, for all). Conclusions Copper deposition occurs more frequently in FNH (96%) than IHA (37%), P<0.001. However, the presence of copper alone cannot be used as a feature to differentiate between FNH and IHA.

7 Background: The organ preserving strategy of selective esophageal resection after definitive chemoradiation was evaluated in a multi-center, prospective Phase II trial. Methods: Treatment involved induction chemotherapy with 5-FU (650 mg/mg2/d), cisplatin (15 mg/mg2/d) and paclitaxel (200 mg/mg2/d) for 2 cycles followed by concurrent chemoradiation with 50.4 Gy (1.8 Gy/fx) and daily 5-FU (300 mg/mg2/d) with cisplatin (15 mg/mg2/d) over the first 5 days. Following definitive chemoradiation, pts were evaluated for residual locoregional disease with chest and abdominal CT scans, EUS and optional PET scans. If there was no suspected residual disease patients were observed and monitored serially for recurrent disease at 3 mos x 2, 6 mos x 3 and then yrly. Esophageal resection was considered only for pts with suspected residual or recurrent locoregional esophageal cancer that did not have systemic disease. Results: 43 pts from Sept 2003 to March 2006 with non-metastatic resectable esophageal cancer were entered from 19 sites to RTOG 0246. 41 pts were eligible for analysis. 29 pts (73%) were adenocarcinoma histology with pretreatment clinical stage T3 or greater in 31 pts (76%) and N1 in 29 pts (71%). Following induction chemotherapy and chemoradiation 3 pts (7.3%) died of treatment related deaths and 1 pt died of disease progression. 21 pts (51%) underwent surgical resection following chemoradiation because of suspected residual disease 17 pts (41%), pt choice (1) or recurrent locoregional disease 3 pts (7%). 1 pt died postoperatively from esophageal anastomotic leak. 11 pts (27%) are alive and free of disease 70 to 90 months after chemoradiation, of which 5 (12%) did not have esophagectomy. With a median follow-up of 6.7 yrs (for 16 alive pts), the estimated overall 2.5 and 5-year survival rates (95% CI) are 46.3% (30.7%-60.6%) and 36.6% (22.3%-51.0%). Conclusions: The long-term results from this multi-center, prospective Phase II trial demonstrates the efficacy of a selective surgical resection approach following definitive chemoradiation in a predominantly adenocarcinoma population of locoregionally advanced esophageal cancer. Clinical trial information: NCT00081289.

2 Background: Testing for HER2 in EAC has become routine given its ability to predict benefit from HER2-targeted therapy. HER2 protein analysis by immunohistochemistry (IHC) is more rapid and generally less expensive than assessment of gene amplification by fluorescence in situ hybridization (FISH). However, the accuracy of IHC for predicting HER2 amplification has not been examined in a large EAC cohort. Methods: Surgical EAC specimens were examined from 675 patients who underwent curative resection at a single institution without preoperative therapy. Tumors were located in the esophagus (47%) or gastroesophageal junction (53%); most were node-positive (73%). Every tumor was evaluated by IHC in parallel with FISH in a blinded manner using FDA-approved assays. A consensus IHC score was determined by 2 pathologists using tumor-specific criteria (negative, 0 or 1+; equivocal, 2+; positive, 3+). Gene amplification by FISH was defined as a HER2/CEP17ratio ≥ 2. Results: HER2 amplification was detected in 89% of IHC 3+ cases, 13% of IHC 2+ cases, and 4% of IHC 0-1+ cases (Table). Accordingly, using FISH as the reference standard, the positive predictive value (PPV) of a positive IHC test (3+) was 89% (79/89 [95% CI 82%-95%]), and the negative predictive value of a negative IHC test (0-1+) was 96% (401/417 [94%-98%]). Importantly, the PPV of an equivocal IHC score (2+) for detecting HER2 amplification was 13% (22/169 [8%-18%]). Conclusions: In the largest study to date comparing HER2 testing methods in EAC, a negative IHC result (0 or 1+) nearly excludes the presence of gene amplification by FISH. Whereas a positive IHC result (3+) strongly predicts for the presence of amplification, an equivocal IHC result (2+) is a weak predictor. These findings in EAC support a HER2 testing algorithm where IHC is used for initial screening and FISH testing is restricted to cases with equivocal IHC results. [Table: see text]

Although HER2‐positive breast cancers demonstrate a propensity for central nervous system (CNS) metastasis, it is unknown whether other HER2‐positive tumors, including adenocarcinomas of the esophagus/gastroesophageal junction (EAC), share this characteristic. Insight into this association may inform the development of HER2‐targeted therapies that penetrate the blood‐brain barrier. We examined HER2 overexpression and gene amplification in 708 patients with EAC who underwent curative‐intent surgery during a time period (1980–1997) when no patient received HER2‐targeted therapy. We identified patients whose site of first cancer recurrence was CNS and those who had a CNS relapse at any time. After a median follow‐up of 61.2 months, 3.4% (24/708) of patients developed CNS relapse (all involved the brain). Patients with HER2‐positive (vs ‐negative) primary tumors showed a higher 5‐year cumulative incidence of CNS relapse as first recurrence (5.8% vs. 1.2%; p = 0.0058) and at any time (8.3% vs. 2.4%; p = 0.0062). In a multivariable model that included covariates previously associated with HER2 or with CNS relapse in breast cancer, HER2 positivity was the only variable that was statistically significantly associated with shorter time to CNS relapse as first recurrence (p = 0.0026) or at any time (hazard ratio 4.3 [95% confidence interval 1.8 to 10.3]; p = 0.001). These are the first data in a non‐breast cancer to demonstrate an association between HER2 positivity and higher CNS relapse risk after surgery, and suggest that HER2‐positive EACs have a predilection for CNS metastases.