Jeannelyn S. Estrella

Post‐therapy pathologic stage and survival in patients with pancreatic ductal adenocarcinoma treated with neoadjuvant chemoradiation

Neoadjuvant chemoradiation before surgery is an emerging treatment modality for pancreatic ductal adenocarcinoma (PDAC). However, analysis of prognostic factors is limited for patients with PDAC treated with neoadjuvant chemoradiation and pancreaticoduodenectomy (PD).

Solid pseudopapillary neoplasm of the pancreas: clinicopathologic and survival analyses of 64 cases from a single institution.

Although solid pseudopapillary neoplasms (SPNs) are considered tumors of low malignant potential, patients may present with aggressive disease (ie, liver metastasis/invasion into adjacent organs) and, rarely, die from disease. Although the clinicopathologic features associated with aggressive SPNs have been reported, important prognostic factors of survival remain unclear. We systematically reviewed 64 cases of SPN resected at our institution for tumor size, extent of invasion, margin status, presence of lymphovascular, muscular vessel, and perineural invasion, and lymph node and distant metastases. Clinicopathologic characteristics were correlated with the presence of metastasis/recurrence and disease-specific survival. Five (8%) patients presented with stage IV disease. During follow-up, 5 (13%) of 39 patients with stage I-II disease had recurrences. Patients with metastatic/recurrent SPNs had significantly larger tumor size (P<0.001) and more frequent tumor invasion into muscular vessels (P=0.02). In a median follow-up of 76 months, only 2 died of disease (1 who presented with extensive peritoneal tumor involvement who died 2.5 mo after surgery, and 1 unusual case who presented with multiple liver metastasis and peritoneal seeding who died 19 mo after surgery), and 5 were alive with disease. The 10-year disease-specific survival rate was 96%. Muscular vessel invasion (P=0.001), tumor (T) stage by European Neuroendocrine Tumors Society (ENETS) classification (P<0.001), ENETS stage grouping (P<0.001), and stage grouping by the American Joint Committee on Cancer (AJCC stage, P<0.001) were important predictors of disease-specific survival in patients with SPN. Our study highlights the importance of pathologic evaluation in risk assessment in patients with SPNs.

Histologic tumor involvement of superior mesenteric vein/portal vein predicts poor prognosis in patients with stage II pancreatic adenocarcinoma treated with neoadjuvant chemoradiation

Studies have shown that superior mesenteric vein (SMV)/portal vein (PV) resection with pancreaticoduodenectomy (PD) is safe and feasible for patient with pancreatic adenocarcinoma (PAC). However, the prognostic significance of tumor involvement of the resected vein in patients who received neoadjuvant therapy is unclear.

Medical management of gastric cancer: A 2014 update

Gastric cancer represents a serious health problem on a global scale. It is the second leading cause of cancer-related death worldwide. Novel therapeutic targets are desperately needed because the meager improvement in the cure rate of about 10% realized by adjunctive treatments to surgery is unacceptable as > 50% patients with localized gastric cancer succumb to their disease. Either postoperative chemoradiotherapy (United States), pre-and post-operative chemotherapy (Europe), and adjuvant chemotherapy after a D2 resection (Asia) can all be regarded as standards of care in the localized gastric cancer management. In metastatic disease the addition of trastuzumab to chemotherapy is standard of care in Her2 positive disease. In the HER2 negative population, the treatments remain limited. In the first line setting, the standard of care is a combination of fluoropyrimidine and platinum containing chemotherapy, with or without epirubicin or docetaxel. The results of targeted therapy trials have by and large been disappointing, but none of these trials looked at an appropriately enriched population. Finally there is a meager overall survival benefit in treating patients with metastatic disease in the second line setting, with either irinotecan, docetaxel or ramucirumab however none of these drugs have been compared head to head in a well-powered randomized controlled trial.

Duplicated muscularis mucosae invasion has similar risk of lymph node metastasis and recurrence-free survival as intramucosal esophageal adenocarcinoma.

Duplicated muscularis mucosae (MM) in early esophageal adenocarcinoma (EAC) can cause overstaging of the disease on endoscopic ultrasound and pathology specimens. No study has determined the correlation between lymph node metastasis and invasion in the space between duplicated MM in pathologic tumor stage (pT) 1 EAC. Hematoxylin and eosin-stained slides from surgically resected pT1 EAC (n=99) were reviewed for tumor configuration, grade, level of invasion (lamina propria/inner MM, space between duplicated MM, and submucosa), quantitative depth of invasion in millimeter, and lymphovascular invasion (LVI). These pathologic characteristics were correlated with lymph node status and recurrence-free survival (RFS). All specimens had duplicated MM with thick-walled blood vessels. Tumor differentiation was well in 37, moderate in 47, and poor in 15 specimens. EAC invaded the lamina propria/inner MM in 28 cases, duplicated MM space in 41 cases, and submucosa in 30 cases. LVI was identified in 23 tumors. Eleven patients had lymph node metastasis. Quantitative depth of invasion as a continuous variable (P=0.002), poorly differentiated histology (P=0.028), presence of LVI (P=0.001), and submucosal invasion versus duplicated MM/lamina propria invasion (P=0.02) were associated with increased risk of lymph node metastasis and shorter RFS by univariate analysis. By multivariate analysis, LVI was an independent predictor of lymph node status and RFS. EAC invasion into the space between duplicated MM confers a similar risk of lymph node metastasis and recurrence as those of intramucosal EAC, and LVI is the best predictor of lymph node status and RFS in pT1 EAC.

Superior mesenteric artery margin of posttherapy pancreaticoduodenectomy and prognosis in patients with pancreatic ductal adenocarcinoma

Negative-margin resection is crucial to favorable prognosis in patients with pancreatic ductal adenocarcinoma. However, the definition of a negative superior mesenteric artery margin (SMAM) varies. The College of American Pathologists defines positive SMAM as the presence of tumor cells at the margin, whereas the European protocol is based on a 1 mm clearance. In this study, we examined the prognostic significance of the SMAM distance in 411 consecutive pancreatic ductal adenocarcinoma patients who completed neoadjuvant therapy and pancreaticoduodenectomy. Per College of American Pathologists criteria, 32 (7.8%) had positive margins, and 379 (92.2%) had negative margins. Among margin-negative group, SMAM was ⩽1, 1.0 to 5.0, and >5.0 mm in 66, 145, and 168 patients, respectively. There was no difference in either disease-free survival (DFS) or overall survival (OS) between the positive-margin group and SMAM⩽1 mm (P>0.05). However, patients with SMAM 1.0 to 5.0 mm had better OS than those with positive margins or SMAM⩽1 mm (P=0.02). Patients with SMAM>5.0 mm had better DFS and OS than those with SMAM 1.0 to 5.0 mm and those with positive margins or SMAM⩽1 mm (P<0.01). By multivariate analysis, the SMAM distance, tumor differentiation, lymph node metastasis, and histopathologic tumor response grade were independent prognostic factors for both DFS and OS. SMAM distance correlated with lower ypT and AJCC stages, smaller tumor size, better histopathologic tumor response grade, fewer lymph node metastases, and recurrences (P<0.05). Thus our results strongly support use of SMAM>1 mm for R0 resection in posttherapy pancreaticoduodenectomy specimens.

Utility of BRAF V600E Immunohistochemistry Expression Pattern as a Surrogate of BRAF Mutation Status in 154 Patients with Advanced Melanoma

Successful BRAF inhibitor therapy depends on the accurate assessment of the mutation status of the BRAF V600 residue in tissue samples. In melanoma, immunohistochemical (IHC) analysis with monoclonal anti-BRAF V600E has emerged as a sensitive and specific surrogate of BRAF V600E mutation, particularly when BRAF V600E protein expression is homogeneous and strong. A subset of melanomas exhibit heterogeneous labeling for BRAF V600E, but our understanding of the significance of heterogeneous BRAF V600E IHC expression is limited. We used next-generation sequencing to compare BRAF V600E IHC staining patterns in 154 melanomas: 79 BRAF(WT) and 75 BRAF (including 53 V600E) mutants. Agreement among dermatopathologists on tumor morphology, IHC expression, and intensity was excellent (ρ = 0.99). A predominantly epithelioid cell phenotype significantly correlated with the BRAF V600E mutation (P = .0085). Tumors demonstrating either heterogeneous or homogeneous IHC expression were significantly associated with the BRAF V600E mutation (P < .0001), as was increased intensity of staining (P < .0001). The positive predictive value was 98% for homogenous IHC expression compared with 70% for heterogeneous labeling. Inclusion of both heterogeneous and homogeneous BRAF V600E IHC expression as a positive test significantly improved IHC test sensitivity from 85% to 98%. However, this reduced BRAF V600E IHC test specificity from 99% to 96%. Cautious evaluation of heterogeneous BRAF V600E IHC expression is warranted and comparison with sequencing results is critical, given its reduced test specificity and positive predictive value for detecting the BRAF V600E mutation.

Predictors of Survival in Patients with Resectable Gastric Cancer Treated with Preoperative Chemoradiation Therapy and Gastrectomy

BACKGROUND The purpose of this study was to determine the overall survival (OS) of patients with resectable gastric cancer treated with preoperative chemoradiation therapy and gastrectomy. STUDY DESIGN The medical records of patients with gastric adenocarcinoma presenting to our institution (January 1995 to August 2012) were reviewed to identify patients who underwent diagnostic laparoscopy, preoperative chemoradiation, and gastrectomy. Associations between various clinicopathologic factors and OS were examined with Cox proportional hazards models. RESULTS Of 192 patients who met inclusion criteria, 103 (54%) required total gastrectomy. One hundred sixty-eight patients (88%) had an extended lymph node dissection, 26 (14%) had resection of adjacent organs, and 178 (93%) had an R0 resection. Median follow-up time for surviving patients was 4.2 years. Median OS for all patients was 5.8 years, and 5-year OS rate was 56%. Multivariable Cox regression model results identified variables associated with diminished OS including age ≥ 65 years (hazard ratio [HR] 1.62; 95% CI 1.05 to 2.51), male sex (HR 1.76; 95% CI 1.13 to 2.74), adjacent organ resection (HR 1.97; 95% CI 1.16 to 3.35), R1 status (HR 2.29; 95% CI 1.17 to 4.48), pathologic N1 stage (HR 1.92; 95% CI 1.24 to 2.98), N2 stage (HR 2.58; 95% CI 1.01 to 6.58), and N3 stage (HR 6.54; 95% CI 2.69 to 15.93). Five-year OS rates for patients with pathologic N0, N1, N2, and N3 disease were 67%, 42%, 43%, and 0%, respectively. CONCLUSIONS Patients with gastric cancer who undergo diagnostic laparoscopy, preoperative chemoradiation, and gastrectomy have a high frequency of obtaining an R0 resection and excellent OS rates. Nodal status after surgery remains an important determinant of OS.

Intrabiliary growth of liver metastases: clinicopathologic features, prevalence, and outcome.

Intrabiliary growth by metastatic colorectal carcinoma (CRC) is an unusual finding that can clinically mimic cholangiocarcinoma. We evaluated prevalence of intrabiliary growth by retrospective review of 1596 diagnostic reports and by prospective evaluation of 223 hepatectomies. Positive cases were scored for extent of intrabiliary growth (major vs. minor duct involvement), architectural pattern (colonization of biliary epithelium and/or intrabiliary tumor plugs), and secondary sclerosing cholangitis in non-neoplastic parenchyma. By retrospective review, we identified intrabiliary growth in 41 (3.6%) of 1144 metastatic CRCs but only 3 (0.7%) of 452 noncolorectal tumors (P<0.001). Prospectively, we found intrabiliary growth in 18 (10.6%) of 170 metastatic CRCs and 1 (1.9%) of 53 other tumors (P=0.05). Among our final population of 43 CRCs with intrabiliary growth, 24 (56%) had major and 19 (44%) had minor duct involvement, 35 (81%) showed colonization of biliary epithelium, and 35 (81%) showed intrabiliary tumor plugs. Compared with minor duct involvement and 51 controls without intrabiliary growth, major duct involvement was more likely to produce obstructive liver chemistries (P=0.004), radiographic evidence of biliary disease (P<0.0001), and sclerosing cholangitis in non-neoplastic liver (P<0.0001). However, there was no impact on overall survival. Clinically, 5 (21%) cases of major duct involvement resulted in diagnostic uncertainty between metastatic CRC and cholangiocarcinoma. These findings underscore the frequency of intrabiliary growth by metastatic CRCs and its rarity with other metastases. Major duct involvement should be recognized because of its distinctive clinical features, which can overlap with cholangiocarcinoma.

Assessment of BRAF V600E Status in Colorectal Carcinoma: Tissue-Specific Discordances between Immunohistochemistry and Sequencing

Although sequencing provides the gold standard for identifying colorectal carcinoma with BRAF V600E mutation, immunohistochemistry (IHC) with the recently developed mouse monoclonal antibody VE1 for BRAF V600E protein has shown promise as a more widely available and rapid method. However, we identified anecdotal discordance between VE1 IHC and sequencing results and therefore analyzed VE1 staining by two different IHC methods (Leica Bond and Ventana BenchMark) in whole tissue sections from 480 colorectal carcinomas (323 BRAF wild-type, 142 BRAF V600E mutation, and 15 BRAF non-V600E mutation). We also compared the results with melanomas and papillary thyroid carcinomas (PTC). With the Bond method, among 142 BRAF V600E-mutated colorectal carcinomas, 77 (54%) had diffuse VE1 staining and 48 (33%) had heterogeneous staining, but 17 (12%) were negative. Among 323 BRAF wild-type colorectal carcinomas, 196 (61%) were negative, but 127 (39%) had staining, including 7 with diffuse staining. When positivity was defined as staining in ≥20% of tumor cells, VE1 IHC had sensitivity of 75% and specificity of 93% for BRAF V600E mutation. With the Ventana method, among 57 BRAF V600E-mutated colorectal carcinomas, 36 (63%) had diffuse VE1 staining, whereas 6 (11%) had no or weak (<20% of tumor cells) staining. Among 33 BRAF wild-type colorectal carcinomas, 16 (48%) had no or weak staining, whereas 15 (45%) had heterogeneous staining. In contrast with colorectal carcinoma, Bond and Ventana VE1 IHC in melanoma and PTC were highly concordant with sequencing results. We conclude that VE1 IHC produces suboptimal results in colorectal carcinoma and should not be used to guide patient management. Mol Cancer Ther; 14(12); 2887–95. ©2015 AACR.