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Öğe Calculation of the Ki67 index in pancreatic neuroendocrine tumors: A comparative analysis of four counting methodologies(Nature Publishing Group, 2015) Reid, Michelle Dian; Bağcı, Pelin; Ohike, Nobuyuki; Saka, Burcu; Erbarut Seven, İpek; Dursun, Nevra; Balcı, Serdar; Gucer, Hasan; Jang, Kee-Taek; Tajiri, Takuma; Baştürk, Olca; Kong, So Yeon; Goodman, Michael; Akkaş, Gizem; Adsay, VolkanKi67 index is now an essential part of classification of pancreatic neuroendocrine tumors. However, its adaptation into daily practice has been fraught with challenges related to counting methodology. In this study, three reviewers used four counting methodologies to calculate Ki67 index in 68 well-differentiated pancreatic neuroendocrine tumors: (1) 'eye-ball' estimation, which has been advocated as reliable and is widely used; (2) automated counting by image analyzer; (3) manual eye-counting (eye under a microscope without a grid); and (4) manual count of camera-captured/printed image. Pearson's correlation (R) was used to measure pair-wise correlation among three reviewers using all four methodologies. Average level of agreement was calculated using mean of R values. The results showed that: (1) 'eye-balling' was least expensive and fastest (average time <1 min) but had poor reliability and reproducibility. (2) Automated count was the most expensive and least practical with major impact on turnaround time (limited by machine and personnel accessibility), and, more importantly, had inaccuracies in overcounting unwanted material. (3) Manual eye count had no additional cost, averaged 6 min, but proved impractical and poorly reproducible. (4) Camera-captured/printed image was most reliable, had highest reproducibility, but took longer than 'eye-balling'. In conclusion, based on its comparatively low cost/benefit ratio and reproducibility, camera-captured/printed image appears to be the most practical for calculating Ki67 index. Although automated counting is generally advertised as the gold standard for index calculation, in this study it was not as accurate or cost-effective as camera-captured/printed image and was highly operator-dependent. 'Eye-balling' produces highly inaccurate and unreliable results, and is not recommended for routine use.Öğe Pancreatic ductal adenocarcinoma is spread to the peripancreatic soft tissue in the majority of resected cases, rendering the AJCC T-stage protocol (7th Edition) inapplicable and Insignificant: A size-based staging system (pT1: ?2, pT2: >2–?4, pT3: >4 cm) is more valid and clinically relevant(Springer New York LLC, 2016) Saka, Burcu; Balcı, Serdar; Baştürk, Olca; Bağcı, Pelin; Postlewait, Lauren Mc Lendon; Maithel, Shishir Kumar; Knight, Jessica; El Rayes, Bassel; Kooby, David; Sarmiento, Juan Martinez; Muraki, Takashi; Oliva, Irma; Bandyopadhyay, Sudeshna; Akkaş, Gizem; Goodman, Michael; Reid, Michelle Dian; Krasinskas, Alyssa; Everett, Rhonda; Adsay, Nazmi VolkanBackground: Most studies have failed to identify any prognostic value of the current T-stage protocol for pancreatic ductal adenocarcinoma (PDAC) by the American Joint Committee on Cancer and the Union for International Cancer Control unless some grouping was performed. Methods: To document the parameters included in this T-stage protocol, 223 consecutive pancreatoduodenectomy specimens with PDAC were processed by a uniform grossing protocol. Results: Peripancreatic soft tissue (PST) involvement, the main pT3 parameter, was found to be inapplicable and irreproducible due to lack of a true capsule in the pancreas and variability in the amount and distribution of adipose tissue. Furthermore, 91 % of the cases showed carcinoma in the adipose tissue, presumably representing the PST, and thus were classified as pT3. An additional 4.5 % were qualified as pT3 due to extension into adjacent sites. The T-stage defined as such was not found to have any correlation with survival (p = 0.4). A revised T-stage protocol was devised that defined pT1 as 2 cm or smaller, pT2 as >2–4 cm, and pT3 as larger than 4 cm. This revised protocol was tested in 757 consecutive PDACs. The median and 3-year survival rates of this size-based protocol were 26, 18, 13 months, and 40 %, 26 %, 20 %, respectively (p < 0.0001). The association between higher T-stage and shorter survival persisted in N0 cases and in multivariate modeling. Analysis of the Surveillance, Epidemiology, and End Results database also confirmed the survival differences (p < 0.0001). Conclusions: This study showed that resected PDACs are already spread to various surfaces of the pancreas, leaving only about 4 % of PDACs to truly qualify as pT1/T2, and that the current T-stage protocol does not have any prognostic correlation. In contrast, as shown previously in many studies, size is an important prognosticator, and a size-based T-stage protocol is more applicable and has prognostic value in PDAC.Öğe Substaging nodal status in ampullary carcinomas has significant prognostic value: Proposed revised staging based on an analysis of 313 well-characterized cases(Society of Surgical Oncology, 2015) Balcı, Serdar; Baştürk, Olca; Saka, Burcu; Bağcı, Pelin; Postlewait, Lauren Mc Lendon; Tajiri, Takuma; Jang, Kee-taek; Ohike, Nobuyuki; Kim, Grace Eun Hye; Krasinskas, Alyssa; Choi, Hyejeong; Sarmiento, Juan Martinez; Kooby, David; El-Rayes, Bassel; Knight, Jessica; Goodman, Michael; Akkaş, Gizem; Reid, Michelle Dian; Maithel, Shishir Kumar; Adsay, Nazmi VolkanBackground: Current nodal staging (N-staging) of ampullary carcinoma in the TNM staging system distinguishes between node-negative (N0) and node-positive (N1) disease but does not consider the metastatic lymph node (LN) number. Methods: Overall, 313 patients who underwent pancreatoduodenectomy for ampullary adenocarcinoma were categorized as N0, N1 (1–2 metastatic LNs), or N2 (?3 metastatic LNs), as proposed by Kang et al. Clinicopathological features and overall survival (OS) of the three groups were compared. Results: The median number of LNs examined was 11, and LN metastasis was present in 142 cases (45 %). When LN-positive cases were re-classified according to the proposed staging system, 82 were N1 (26 %) and 60 were N2 (19 %). There was a significant correlation between proposed N-stage and lymphovascular invasion, perineural invasion, increased tumor size (each p < 0.001), and surgical margin positivity (p = 0.001). The median OS in LN-negative cases was significantly longer than that in LN-positive cases (107.5 vs. 32 months; p < 0.001). Patients with N1 and N2 disease had median survivals of 40 and 24.5 months, respectively (p < 0.0001). In addition, 1-, 3-, and 5-year survivals were 88, 76, 62 %, respectively, for N0; 90, 55, 31.5 %, respectively, for N1; and 68, 34, 30 %, respectively for N2 (p < 0.001). Even with multivariate modeling, the association between higher proposed N stage and shorter survival persisted (hazard ratio 1.6 for N1 and 1.9 for N2; p = 0.018). Conclusions: Classification of nodal status in ampullary carcinomas based on the number of metastatic LNs has a significant prognostic value. A revised N-staging classification system should be incorporated into the TNM staging of ampullary cancers.Öğe Substaging of lymph node status in resected pancreatic ductal adenocarcinoma has strong prognostic correlations: Proposal for a revised N classification for TNM staging(Springer, 2015) Baştürk, Olca; Saka, Burcu; Balcı, Serdar; Postlewait, Lauren Mc Lendon; Knight, Jessica; Goodman, Michael; Kooby, David; Sarmiento J.M.; El-Rayes, Bassel; Choi, Hyejeong; Bağcı, Pelin; Krasinskas, Alyssa; Quigley, Brian Christopher; Reid, Michelle Dian; Akkaş, Gizem; Maithel, Shishir Kumar; Adsay, Nazmi VolkanBackground: The current tumor-node-metastasis staging system for the pancreas does not incorporate the number of lymph nodes (LNs) with metastasis. Methods: Among 1649 pancreaticoduodenectomies, 227 stringently defined pancreatic ductal adenocarcinomas (PDACs) that had undergone a specific approach of LN harvesting were analyzed for the prognostic value of LN substaging protocols used for other gastrointestinal (GI) organs. Results: The median number of LNs harvested was 18, and the median number of LNs with metastasis was 3. Lymph node metastasis was detected in 175 cases (77 %). The number of LNs involved correlated significantly with clinical outcome. When cases were substaged with the protocol already in use for the upper GI organs (N0: no metastasis, N1: metastasis to 1–2 LNs; N2: metastasis to ?3 LNs), the median overall survival times were 35, 21, and 18 months, and the respective 3-year survival rates were 46, 34, and 20 % (p = 0.004). Analysis of the Surveillance, Epidemiology and End Results (SEER) database also confirmed the survival differences between these substages (median overall survival times of 23, 15, and 14 months and respective 3-year survival rates of 37, 22, and 18 %; p < 0.0001). The substaging protocol for the lower GI organs (N0: no metastasis; N1: metastasis to 1–3 LNs; N2: metastasis to ?4 LNs) also was significant, with median overall survival times of 35, 21, 18 months and respective 3-year survival rates of 46, 26, and 23 %; p = 0.009). The association between higher N stage and shorter survival persisted with multivariate modeling for both protocols, although the prognostic value of the upper GI protocol appeared to be slightly stronger according to the Akaike Information Criterion method. Conclusion: In conclusion, with proper LN harvesting, the LN metastasis rate in PDACs is very high (77 %). Substaging of LN metastasis has significant prognostic value and needs to be considered in the N staging of PDACs. The protocol already in use for other upper GI tract organs, which currently also is proven significant for ampulla, would be preferable, although the lower GI tract protocol also is applicable.
