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This investigation centered on fundamental understanding of a hybrid post-processing method that synergistically combines electrochemical polishing and ultrasonic cavitation to improve the surface roughness and mechanical properties of additively manufactured parts efficiently and simultaneously in a single step. High-speed imaging was utilized to understand the effect of the DC bias applied during electropolishing on the cavitation generated at various ultrasonic amplitudes. This was aimed at validating the hypothesis that the hybrid process is characterized by more bubbles than with ultrasonic excitation alone, and, in the presence of the DC bias, the bubbles are transported from the cathode to the anode (workpiece) where their impacts cause surface hardening. High-speed imaging confirmed a higher bubble count in the hybrid process than in the cavitation-only process at different ultrasonic amplitudes. Microhardness measurements confirmed that the hybrid process yielded higher microhardness compared to cavitation peening alone, while microhardness in electrochemical polishing showed only incremental changes. This observation was also corroborated by the grain size measurements, with the hybrid process exhibiting more grain refinement than cavitation-only or electropolishing-only post-processing modes. Surface topography analysis revealed minimal improvement in surface roughness due to cavitation-only, emphasizing the importance of the hybrid process in enhancing both surface roughness and the mechanical properties. Scanning electron microscope (SEM) images showed randomly distributed micro-dimples on the surface produced by the hybrid process at the highest ultrasonic amplitude, attributed to the increased number of cavitation bubbles. This research provides fundamental insights into why the hybrid process excels in simultaneously reducing surface roughness and achieving superior surface microhardness.

Wire Arc Additive Manufacturing (WAAM) holds great promise for revolutionizing modern manufacturing. It combines the advantages of Additive Manufacturing, such as geometrical flexibility and material efficiency, while overcoming its limitations through high material output and energy efficiency. However, the widespread adoption of WAAM is hindered by its tendency to produce large residual stresses and geometrical inaccuracies. The latter is often approached by modeling the influence of process parameters on the bead geometry using Machine Learning (ML). This work, for the first time, combines data from multiple published sources to generate a more holistic and transferable ML model. To assess and improve model transferability, different sets of WAAM process parameters and ML models, including physics-informed ML models, are tested. It is shown that these steps can significantly improve bead geometry prediction model transferability thereby minimizing the need for researchers to conduct their own experimental investigations.

Neoadjuvant therapy is increasingly used to treat patients with pancreatic ductal adenocarcinoma (PDAC). Pathologic parameters of treated PDAC, including tumor (ypT) and lymph node (ypN) stage, and tumor response grading (TRG) are important prognostic factors in this group of patients. To our knowledge, a multifactorial prognostic score combining pathologic features including ypT, ypN, and TRG in treated PDAC patients has not been reported. Our cohort consisted of 398 PDAC patients who received neoadjuvant therapy and underwent pancreaticoduodenectomy at our institution. All pancreaticoduodenectomy specimens were grossly and microscopically evaluated using a standard protocol. The integrated pathologic score (IPS) was calculated as the sum of the scores for ypT, ypN, and TRG according to either the MD Anderson grading system (IPSMDA) or the College of American Pathologists (CAP) grading system (IPSCAP). The IPSMDA and IPSCAP were correlated with clinicopathologic parameters and patient survival. Using either IPSMDA or IPSCAP, PDAC patients were stratified into 3 distinct prognostic groups for both disease-free survival (DFS) (P<0.001) and overall survival (OS) (P<0.001). The IPSMDA and IPSCAP correlated with tumor differentiation, margin status, the American Joint Committee on Cancer (AJCC) stage, and tumor recurrence (P<0.05). In multivariate analysis, IPSMDA, IPSCAP, margin status, and tumor differentiation were independent prognostic factors for both DFS (P<0.05) and OS (P<0.05). However, patients with AJCC stage IB, IIA, or IIB disease had no significant difference in either DFS or OS (P>0.05). The IPS appears to provide improved prognostic information compared with AJCC staging for preoperatively treated patients with PDAC.

Hepatocellular carcinoma has high recurrence rates after surgery; however, there are no approved standard-of-care neoadjuvant or adjuvant therapies. Immunotherapy has been shown to improve survival in advanced hepatocellular carcinoma; we therefore aimed to evaluate the safety and tolerability of perioperative immunotherapy in resectable hepatocellular carcinoma.

Wind power is one of the cheapest and direct methods to alleviate negative impacts on environment therefore the demand of efficient wind energy conversion system is increasing. Uneven distribution of wind impacts the performance of Wind Turbine (WT) system so constant and noise free power at output is required. The pitching angle varies according to the Wind Speed (WS), and the power output equation of the entire WT system depends upon WT pitch angle. Pitch control is widely used to optimize power above rated WS. This paper proposes an efficient adaptive pitch control controller to maintain the output power of a 5 MW WT in dynamic wind conditions. Compared to low level control loops (such as PI), this illustrates the effectiveness of the proposed controller. The model was tested in a 5 MW WT GH bladed system.

Pathological staging of primary anorectal mucosal melanoma is often performed according to the American Joint Commission on Cancer (AJCC) guidelines for cutaneous melanoma, as an anorectal melanoma-specific staging system does not exist. However, it remains unknown whether prognostic factors derived for cutaneous melanoma also stratify risk in anorectal melanoma. We retrospectively determined correlations between clinicopathological parameters and disease-specific survival in 160 patients. Patients were grouped by clinical stage at presentation (localized disease, regional or distant metastases). Cox proportional hazards regression models determined associations with disease-specific survival. We also summarized the somatic mutations identified in a subset of tumors analyzed for hotspot mutations in cancer-associated gene panels. Most of the patients were white (82%) and female (61%). The median age was 62 years. With a median follow-up of 1.63 years, median disease-specific survival was 1.75 years, and 121 patients (76%) died of anorectal melanoma. Patients presenting with regional (34%) or distant metastases (24%) had significantly shorter disease-specific survival compared to those with disease localized to the anorectum (42%). Of the 71 anorectal melanoma tumors analyzed for hotspot genetic alterations, somatic mutations involving the KITgene (24%) were most common followed by NRAS(19%). Increasing primary tumor thickness, lymphovascular invasion, and absence of regression also correlated with shorter disease-specific survival. Primary tumor parameters correlated with shorter disease-specific survival in patients presenting with localized disease (tumor thickness) or regional metastases (tumor thickness, absence of regression, and lymphovascular invasion), but not in patients presenting with distant metastases. Grouping of patients according to a schema based on modifications of the 8th edition AJCC cutaneous melanoma staging system stratified survival in anorectal melanoma. Our findings support stage-specific associations between primary tumor parameters and disease-specific survival in anorectal melanoma. Moreover, the AJCC cutaneous melanoma staging system and minor modifications of it predicted survival among anorectal melanoma patients.

Pathological staging of primary anorectal mucosal melanoma is often performed according to the American Joint Commission on Cancer (AJCC) guidelines for cutaneous melanoma, as an anorectal melanoma-specific staging system does not exist. However, it remains unknown whether prognostic factors derived for cutaneous melanoma also stratify risk in anorectal melanoma. We retrospectively determined correlations between clinicopathological parameters and disease-specific survival in 160 patients. Patients were grouped by clinical stage at presentation (localized disease, regional or distant metastases). Cox proportional hazards regression models determined associations with disease-specific survival. We also summarized the somatic mutations identified in a subset of tumors analyzed for hotspot mutations in cancer-associated gene panels. Most of the patients were white (82%) and female (61%). The median age was 62 years. With a median follow-up of 1.63 years, median disease-specific survival was 1.75 years, and 121 patients (76%) died of anorectal melanoma. Patients presenting with regional (34%) or distant metastases (24%) had significantly shorter disease-specific survival compared to those with disease localized to the anorectum (42%). Of the 71 anorectal melanoma tumors analyzed for hotspot genetic alterations, somatic mutations involving the KITgene (24%) were most common followed by NRAS(19%). Increasing primary tumor thickness, lymphovascular invasion, and absence of regression also correlated with shorter disease-specific survival. Primary tumor parameters correlated with shorter disease-specific survival in patients presenting with localized disease (tumor thickness) or regional metastases (tumor thickness, absence of regression, and lymphovascular invasion), but not in patients presenting with distant metastases. Grouping of patients according to a schema based on modifications of the 8th edition AJCC cutaneous melanoma staging system stratified survival in anorectal melanoma. Our findings support stage-specific associations between primary tumor parameters and disease-specific survival in anorectal melanoma. Moreover, the AJCC cutaneous melanoma staging system and minor modifications of it predicted survival among anorectal melanoma patients.

Wire Arc Additive Manufacturing as a Directed Energy Deposition technology has disruptive potential for modern manufacturing. The technology comes with the flexibility and material efficiency of additive manufacturing processes while mitigating the disadvantages through high material deposition rates and high energy efficiency. However, the prevalence of the technology is inhibited by its geometrical inaccuracy and the large induced residual stresses. This work tackles the former problem by capturing the process parameter-geometry relationship using Machine Learning. To do so, multiple mild steel welding beads with varying shape features like corner angles are printed using a Metal Inert Gas welding machine attached to an industrial robot. The cross-sectional profile of the printed beads is measured using a point laser sensor and correlated through a Multilayer Perceptron to input features such as travel speed, wire feed speed, and shape features. By incorporating varying corner angles, a holistic model, not limited to geometry prediction of straight beads only, is trained. Using the model, excess material at the inner angle of corners determined by the overlapping regions of the two adjacent beads can be predicted. By generating a database of possible bead shapes an inverse algorithm that suggests welding parameter combinations that yield a smooth bead shape at the corner is created, thus enabling improvement of the overall accuracy of the Wire Arc Additive Manufacturing process.

Mucinous cystic neoplasm (MCN) of pancreas is one of the precursor lesions of pancreatic ductal adenocarcinoma. The 5-year disease-specific survival for noninvasive MCNs was 100% and 20% to 60% for those with pancreatic ductal adenocarcinoma arising in a MCN. However, the significance of T1a (≤0.5 cm) and T1b (>0.5 and <1.0 cm) carcinoma arising in MCN as defined by the upcoming American Joint Committee on Cancer, eighth edition is unclear. In this study, we examined 3 cases of MCN with T1a or T1b carcinoma and compared their clinicopathologic characteristics and survival to 46 cases of MCN with low-grade dysplasia (MCN-LGD), 7 cases of MCN with high-grade dysplasia (MCN-HGD), and 7 cases of MCN with advanced invasive carcinoma (T2 or higher T stage). The tumors from all 3 cases were submitted in their entirety in 123, 296, and 200 blocks, respectively. All 3 patients were alive with no recurrence during the follow-up of 20.0, 113.8, and 137.2 months, respectively. Similarly, none of the patients who had MCN with either LGD or HGD had recurrence or died of disease. In contrast, 5 of 7 patients who had MCN with advanced invasive carcinoma had recurrence and later died of disease with a median survival of 22.9 months (P<0.001). Our study showed that MCN with T1a and T1b carcinoma had an excellent prognosis similar to MCNs with LGD or HGD after complete tumor sampling for histologic examination. Our results along with the previous studies suggest that close follow-up, rather than aggressive systemic therapy, may be a better approach for these patients.

The American Joint Committee for Cancer has adopted a size-based T stage system (eighth edition) for pancreatic ductal adenocarcinoma (PDAC), defined as follows: pT1≤2 cm (pT1a≤0.5 cm, pT1b>0.5 and<1 cm, and pT1c 1-2 cm); pT2>2 and ≤4 cm; and pT3> 4 cm. However, the prognostic value of this new T staging system has not been validated in patients who underwent pancreaticoduodenectomy (PD) after neoadjuvant therapy. In this study, we analyzed 398 PDAC patients who underwent neoadjuvant therapy and PD at our institution from 1999 to 2012. The results were correlated with clinicopathologic parameters and survival. The new T stage correlated with lymph nodes metastasis (P<0.001), tumor response grade (P<0.001), disease-free survival (DFS, P<0.001) and overall survival (OS, P<0.001). None of the patients with ypT0 had recurrence or died of disease. Among the patients with ypT1 disease, patients with ypT1a and ypT1b had better DFS (P=0.046) and OS (P=0.03) than those with ypT1c. However, there was no significant difference in either DFS or OS between ypT1c and ypT2 or between ypT2 and ypT3 groups (P>0.05). In multivariate analysis, new ypT3 stage was associated with shorter OS (P=0.04), but not DFS (P=0.16). Our results show that the new ypT stage better stratify survival than the ypT stage in American Joint Committee for Cancer seventh edition for PDAC patients who received PD after neoadjuvant therapy, and that tumor size cutoff of 1.0 cm work better for ypT2 than the proposed tumor size cutoff of 2.0 cm in this group of patients.

Neoadjuvant therapy has been increasingly used to treat patients with potentially resectable pancreatic ductal adenocarcinoma (PDAC). Although the College of American Pathologists (CAP) grading scheme for tumor response in posttherapy specimens has been used, its clinical significance has not been validated. Previously, we proposed a 3-tier histologic tumor regression grading (HTRG) scheme (HTRG 0, no viable tumor; HTRG 1, <5% viable tumor cells; HTRG 2, ≥5% viable tumor cells) and showed that the 3-tier HTRG scheme correlated with prognosis. In this study, we sought to validate our proposed HTRG scheme in a new cohort of 167 consecutive PDAC patients who completed neoadjuvant therapy and pancreaticoduodenectomy. We found that patients with HTRG 0 or 1 were associated with a lower frequency of lymph node metastasis (P=0.004) and recurrence (P=0.01), lower ypT (P<0.001) and AJCC stage (P<0.001), longer disease-free survival (DFS, P=0.004) and overall survival (OS, P=0.02) than those with HTRG 2. However, there was no difference in either DFS or OS between the groups with CAP grade 2 and those with CAP grade 3 (P>0.05). In multivariate analysis, HTRG grade 0 or 1 was an independent prognostic factor for better DFS (P=0.03), but not OS. Therefore we validated the proposed HTRG scheme from our previous study. The proposed HTRG scheme is simple and easy to apply in practice by pathologists and might be used as a successful surrogate for longer DFS in patients with potentially resectable PDAC who completed neoadjuvant therapy and surgery.

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 SMAMas 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.

The indolent nature and expression of progesterone receptor (PR), a well-known estrogen-induced gene, in a subset of pancreatic neuroendocrine tumors (PanNETs), raise the possibility of hormonal regulation in these tumors.

Although solid pseudopapillary neoplasms (SPNs) are considered tumors of low malignant potential, patients may present with aggressive disease (ie, liver metastasisinvasion 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 metastasisrecurrence 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 metastaticrecurrent 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.

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 andor 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.

High-level microsatellite instability (MSI-high) is found in approximately 15 of all colorectal adenocarcinomas (CRCs) and in at least 20 of right-sided cancers. It is most commonly due to somatic hypermethylation of the MLH1gene promoter region, with familial cases (Lynch syndrome) representing only 2 to 3 of CRCs overall. In contrast to CRC, MSI-high in appendiceal adenocarcinomas is rare. Only 4 MSI-high appendiceal carcinomas and 1 MSI-high appendiceal serrated adenoma have been previously reported, and the prevalence of MSI in the appendix is unknown. We identified 108 appendiceal carcinomas from MD Anderson Cancer Center in which MSI status had been assessed by immunohistochemistry for the DNA mismatch-repair proteins MLH1, MSH2, MSH6, and PMS2 (n=83), polymerase chain reaction (n=7), or both (n=18). Three cases (2.8) were MSI-high, and 1 was MSI-low. The 3 MSI-high cases included: (1) a poorly differentiated nonmucinous adenocarcinoma with loss of MLH1PMS2 expression, lack of MLH1promoter methylation, and lack of BRAFgene mutation, but no detected germline mutation in MLH1from a 39-year-old man; (2) an undifferentiated carcinoma with loss of MSH2MSH6, but no detected germline mutation in MSH2or TACSTD1, from a 59-year-old woman; and (3) a moderately differentiated mucinous adenocarcinoma arising in a villous adenoma with loss of MSH2MSH6 expression, in a 38-year-old man with a strong family history of CRC who declined germline testing. When the overall group of appendiceal carcinomas was classified according to histologic features and precursor lesions, the frequencies of MSI-high were: 3 of 108 (2.8) invasive carcinomas, 3 of 96 (3.1) invasive carcinomas that did not arise from a background of goblet cell carcinoid tumors, and 0 of 12 (0) signet ring and mucinous carcinomas arising in goblet cell carcinoid tumors. These findings, in conjunction with the previously reported MSI-high appendiceal carcinomas, highlight the low prevalence of MSI in the appendix as compared with the right colon and suggest that MLH1promoter methylation is not a mechanism for MSI in this location.

Lymphovascular invasion (LVI) is a prognostic factor in many types of human malignancies, including pancreatic ductal adenocarcinoma (PDAC). However, the prognostic significance of LVI in patients with PDAC who have received neoadjuvant therapy and pancreaticoduodenectomy is unclear. In this study, we analyzed LVI in 212 patients who had received neoadjuvant chemoradiation and subsequent pancreaticoduodenectomy at our institution between January 1999 and December 2007. LVI was present in 61.8 (131212) of the patients. Of the 131 patients who were positive for LVI, 67 (31.6) had tumor invasion into lymphovascular spaces without muscle layer (nonmuscular lymphovascular spaces), and 64 (30.2) had tumor invasion into muscular vessels. Tumor invasion into muscular vessels correlated with higher frequencies of positive resection margin, lymph node metastasis, and locoregionaldistant recurrence. Patients with tumor invasion into muscular vessels had significantly shorter disease-free survival and overall survival than did patients who had no LVI or who had tumor invasion of nonmuscular lymphovascular spaces (P<0.01). Tumor invasion into muscular vessels is an independent prognostic factor in patients with PDAC who have received neoadjuvant therapies. Our results showed that tumor invasion into muscular vessels plays an important role in the progression of PDAC and in predicting prognosis in this group of patients.

Perineural invasion (PNI) is one of the established prognostic factors in pancreatic ductal adenocarcinoma (PDAC). However, the prognostic significance of PNI in patients with PDAC who received neoadjuvant therapy and pancreaticoduodenectomy is not clear. In this study, we performed a detailed examination of neural invasion in pancreaticoduodenectomy specimens from 212 patients with PDAC who received neoadjuvant chemoradiation (treated group) and in 60 untreated patients at our institution between January 1999 and December 2007. The frequency of PNI was higher in the untreated group (80, 4860) than in the treated group (58, 123212). For the 123 treated cases that were positive for PNI, extratumoral PNI, intratumoral PNI, intrapancreatic PNI only, extrapancreatic PNI, and intraneural invasion were identified in 86 (69.9), 37 (30.1), 11 (8.9), 112 (91.1), and 35 cases (28.5), respectively. The presence of PNI correlated with tumor size, margin status, lymph node metastasis, pathologic tumor, and American Joint Committee on Cancer stages in the treated group. Tumor involvement of nerves >0.8 mm correlated with higher frequency of positive margin compared with tumors with PNI involving nerves 0.8 mm but not with other clinicopathologic parameters and survival. In the treated group, the presence of PNI or intraneural invasion correlated significantly with shorter disease-free survival and overall survival compared with no PNI or PNI only, respectively. PNI was an independent prognostic factor for both disease-free survival and overall survival in multivariate analysis. Our results showed that PNI plays an important role in the progression of PDAC and in predicting prognosis in this group of patients.

Hereditary colorectal adenocarcinomas only represent a small proportion of all colorectal cancers and, of those, only a fraction have distinct clinical or pathologic features and a mutation of a gene associated with a hereditary syndrome. These hereditary conditions include hereditary nonpolyposis colorectal cancer, familial adenomatous polyposis, MUTYH-associated polyposis, Peutz–Jeghers syndrome, and juvenile polyposis syndrome. Histopathologic features in patients with colorectal lesions (polyps, adenocarcinoma) that suggest the presence of a hereditary condition include the number and type of polyps, the morphologic features of the colorectal carcinoma, and the presence of extracolonic lesions or tumors. In addition, immunohistochemical stains can assist in identifying patients with hereditary nonpolyposis colorectal cancer.

The gastrointestinal (GI) tract is a common site for both primary and metastatic carcinomas. Distinguishing the two can occasionally be difficult, particularly when metastatic tumor reaches the mucosal surface. Features that are typically used to make this distinction include the presence of an adenomatous precursor lesion, regional lymph node involvement, and gross configuration of the tumor. However, we recently encountered 2 index cases of metastatic carcinoma in the small intestine (1from the colorectum and 1 of endocervical origin) that were initially misinterpreted as primary small bowel carcinomas because of apparent in situ growth in the mucosal surface resembling polypoid, adenomatous precursor lesions. We, therefore, studied 100 GI resections from 1987 to 2009 that were reported to show mucosal involvement by metastatic carcinoma, and compared the histologic features with a control group of 29 primary small bowel adenocarcinomas. Gross descriptions and histologic sections were evaluated for the following: (1) tumor spread along an intact basement membrane of villicrypts (mucosal colonization), (2) resemblance to an adenomaprecursor lesion, (3) gross configuration of the tumor, (4) lymphovascular invasion, and (5) regional lymph node involvement in the metastatic site. Metastatic sites included the small intestine (n=74), colorectum (n=16), or both (n=10). Primary tumors were GI (n=55, with 47 from colorectum), gynecologic (n=28), pulmonary (n=8), genitourinary (n=6), head and neck (n=2), and breast (n=1). Overall, 42 (42) of the metastases that reached the mucosal surface of the bowel showed at least focal mucosal colonization, 26 resembled a precursor adenoma, 62 had regional lymph node positivity, and only 24 cases showed a classic serosal-based configuration. In 4 cases (2 of GI origin and 2 of gynecologic origin), metastatic tumors were initially interpreted as new primaries by the pathologist (n=2) or clinicians (n=2). Metastatic carcinomas originating from the GI tract were significantly more likely to show mucosal colonization (60 vs. 20, P<0.0001) and resemblance to a precursor lesion (45 vs. 2, P<0.0001) than other primary tumors. In a comparison between 29 primary small bowel carcinomas and 41 metastatic colorectal carcinomas in the small bowel, metastatic tumors were distinguished by a higher prevalence of multiple lesions (0 vs. 39, P<0.0001), whereas small bowel primaries were more likely to show high tumor grade (41 vs. 17, P=0.03). There were no significant differences in the mean age (61.4 y vs. 60.9 y), number of male participants (69 vs. 56), growth along basement membranes (62 vs. 63), apparent precursor lesion (55 vs. 46), lymphovascular invasion (69 vs. 73), or lymph node positivity (68 vs. 37.5, P=0.065). These results confirm that metastatic carcinomas involving the mucosal surface of the intestines frequently exhibit gross and histologic features, which mimic second primaries, especially when they originate from the GI tract. In situ growth and presence of an apparent adenoma cannot be taken as prima facie evidence of a primary neoplasm.

The high interobserver variability in grading dysplasia in Barrett's esophagus demands a biomarker that can be applied in routine surgical pathology practice. Immunohistochemistry for phosphorylated histone H3 is a reliable marker of identifying mitotic figures and has not been evaluated in Barrett's esophagus-associated neoplastic lesions. We retrospectively studied the expression of phosphorylated histone H3 in 88 endoscopic biopsy samples of Barrett's esophagus without dysplasia (n=19), indefinite for dysplasia (n=11), low-grade dysplasia (n=27), high-grade dysplasia (n=19), or adenocarcinoma (n=12) from a sample of 54 patients. The samples were included after consensus diagnosis of two gastrointestinal pathologists on the hematoxylin–eosin (HE)-stained sections. Anti-phosphorylated histone H3-labeled mitotic figures were counted per 10 consecutive high-power fields (HPFs) in three distinct regions: surface epithelium, upper 2/3, and lower 1/3 of the crypts. Anti-phosphorylated histone H3-labeled mitotic counts for the three compartments of the crypts and the total scores for Barrett's esophagus, indefinite for dysplasia, low-grade dysplasia, high-grade dysplasia, and adenocarcinoma were compared using the Mann–Whitney Utest. For each compartment, the number of anti-phosphorylated histone H3-positive nuclei was higher in low-grade dysplasia than in Barrett's esophagus without dysplasia or indefinite for dysplasia (P<0.001), but no difference was found between Barrett's esophagus without dysplasia and indefinite for dysplasia. High-grade dysplasia biopsies had significantly more anti-phosphorylated histone H3-labeled mitotic figures in the surface epithelium than the low-grade dysplasia (P<0.001). Adenocarcinoma had higher anti-phosphorylated histone H3-labeled mitotic figures than the high-grade dysplasia (P<0.001). Our data support the previous findings of expansion of the proliferative zone and importance of surface mitotic figure in the progression of Barrett's esophagus—low-grade dysplasia–high-grade dysplasia. In addition, phosphorylated histone H3 is a potential supportive marker to histology in differentiating low-grade dysplasia from indefinite for dysplasia and high-grade dysplasia from adenocarcinoma in the mucosal biopsy samples.