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Summary Perineural invasion (PNI) on biopsy is associated with adverse features in prostate cancer (PCa). Transrectal multiparametric magnetic resonance imaging (MRI)–targeted biopsy (TBx) has shown to detect higher presence of PNI than standard template biopsy (SBx). Transperineal biopsy provides effective cancer detection with lower complications than the transrectal approach. We compared PNI detection efficiency between SBx and TBx through transperineal approach. We identified patients with PCa who underwent transperineal TBx and concomitant standard 20-core template SBx from September 2019 to February 2021. Clinical, MRI imaging and biopsy characteristics were evaluated and compared between TBx and SBx. Two hundred thirty-eight patients with PCa underwent concomitant transperineal SBx and TBx procedures. Combined PNI+ (SBxPNI+ and/or TBxPNI+) was identified in 77 of 238 (32.4%) patients. SBx detected 23.9% PNI-positive patients and TBx detected 19.3% PNI-positive patients of all patients with PCa. Patients with PNI were with significantly different clinicopathological characteristics than patients without PNI. Although significantly more positive PCa cores and higher positive PCa core rate were found in the SBx method, patients with SBxPNI+ only shared similar features as TBxPNI+only patients. Of 176 cases with both SBxPCa and TBxPCa, TBx could detect 19 (15.1%) more PNI cases than SBx while SBx could detect 24 (18.3%) more PNI cases than TBx. Multiparametric MRI fusion–targeted biopsy in combination with template biopsy through transperineal approach achieved PNI detection rate over 30% of PCa cases. The increased PNI detection may improve the model to select active surveillance candidates in clinical practice.

As a new pattern-based classification, the Silva pattern system has been recently developed to evaluate invasive lymph node metastasis and the prognosis of endocervical adenocarcinoma (EAC). Therefore, our study was conducted to explore the reproducibility and prognostic significance of this system in a multi-institutional Chinese cohort, with the goal of revising and expanding its application. The clinicopathological data of 191 EAC patients from 3 medical centers were examined in a retrospective manner. The Silva pattern system demonstrated great prognostic value, significance in guiding treatment selection, and acceptable reproducibility in 191 patients that included additional histologic variants and 124 usual-type EAC patients. Collectively, compared with usual-type EAC, the whole cohort demonstrated similar statistical significance for relevant clinicopathological parameters, such as International Federation of Gynecology and Obstetrics stage (R = 0.612 versus R = 0.600), tumor thickness (P .0001 versus P .0001), lymphovascular invasion (P .0001 versus P .0001), lymph node metastasis (P = .033 versus P = .018), perineural invasion (P = .003 versus P = .001), and recurrence-free survival (P = .047 versus P = .020). Moreover, perineural invasion was significantly correlated (P = .001) with the Silva pattern system and appeared in most Silva C tumors. In conclusion, the Silva pattern system is consistent with the biological behavior of EAC and has acceptable reproducibility. Compared with International Federation of Gynecology and Obstetrics stage, it can predict patient prognosis before surgery. We suggest revising the Silva C criteria by adding perineural invasion as a factor and propose expanding the Silva pattern system to include more histologic variants. It seems that the Silva pattern system can be applied in routine clinical practice to guide EAC therapeutic strategies in the near future.

Summary Tumor budding (TB) has been shown to be an adverse prognostic factor in several gastrointestinal malignancies, most notably colorectal carcinoma (CRC). TB has undergone some evaluation in Eastern cohorts of cholangiocarcinoma (CC), and we undertook this study to evaluate whether TB in CC was linked to other clinicopathologic factors or to outcome in a Western cohort. We evaluated 112 cases of CC for age, sex, margin status, location, size, grade, lymphovascular invasion (LVI), perineural invasion (PNI), subtype (large or small duct), staging parameters, recurrence-free survival, disease-specific survival (DSS), and TB. Budding was scored using International Tumor Budding Consensus Conference recommendations for CRC: The highest tumor bud count at the invasive tumor front in a 0.785 mm2 area was recorded and stratified into Bd1 (0–4 buds), Bd2 (5–9 buds), and Bd3 (≥10 buds). Our cohort included 54 (48%) extrahepatic CCs and 58 (52%) intrahepatic CCs. TB was more commonly seen in the settings of higher-grade lesions, males, extrahepatic CC, PNI, LVI, and positive resection margin (all P ≤ 0.021). In multivariate analysis, worse DSS was correlated with budding score Bd2/Bd3 (hazard ratio [HR] 2.6687, 95% confidence interval [CI] 1.585–5.217, P = 0.001) and with nodal disease (HR 2.876, 95% CI 1.585–5.217, P = 0.001). TB is associated with higher-grade disease in CC, and increased TB is associated with poor disease-specific survival. Our findings support the notion that TB may serve as useful information for clinicians with respect to patient prognosis in CC, as in CRC.

GATA3 immunostaining is a sensitive marker for mammary and urothelial carcinomas. It is routinely used in surgical pathology during workup of carcinomas of unknown origin. To the best of our knowledge, this is the first focused study of GATA3 expression in gallbladder adenocarcinomas. In this study, we evaluated GATA3 expression in 38 gallbladder adenocarcinomas. Eight of 38 (21%) gallbladder adenocarcinomas were positive for GATA3. The expression of GATA3 tended to be moderate to strong when present. It was patchy (50% positivity) in 4 cases, characterized by discrete clusters or groups of malignant cells with areas of intervening negative tumor cells, whereas it was diffuse (50% positivity) in the other 4 cases. GATA3 expression did not show any significant correlation with clinicopathologic features such as sex, histologic grade, perineural invasion, vascular invasion, pathologic stage, or distance metastasis. The results of our study show that a subset of gallbladder adenocarcinomas (21%) can be GATA3 positive. Awareness of this phenomenon is important while working up GATA3-positive carcinomas immunohistochemically.

Standardized pathologic reporting for cancers improves patient care and prognostic determination. However, access in many countries is limited. To address this issue, the International Collaboration on Cancer Reporting (ICCR), a not-for-profit organization, has the mission to develop and disseminate standardized data sets for global use. Within endocrine organs, the parathyroid gland has rarely been included in formal pathologic data sets. Utilizing an expert international panel of eleven members, an evidence-based data set was developed for parathyroid carcinoma and atypical parathyroid neoplasms. This data set consists of sixteen core (required) elements viewed as essential for documentation of these conditions. Characterizing parathyroid carcinomas and atypical neoplasms begins with correlative clinical information, the operative procedure, specimens submitted, and site of the disease. The pathologic features essential to document include parathyroid weight, size, classification, and, when a carcinoma, the tumor grade. Histologic grade of parathyroid carcinoma incorporates other core elements including necrosis, mitotic count, perineural invasion, and lymphovascular invasion. Documenting the extent of disease locally into adjacent organs, regionally, and distally is critical for staging. Pathologic staging is now included as part of the American Joint Committee on Cancer 8th edition and is included in this data set. Ancillary studies should be recorded when performed as noncore elements. Standardized pathologic data sets for endocrine organs including the parathyroid gland are now available through the ICCR website. These essential resources enhance international standardization for documenting these rare tumors for both patient care and future guidelines.

Summary To investigate the clinicopathological features and prognostic factors of primary anorectal melanoma, we described the clinical presentations, histopathology, and prognosis of 60 cases in China. Patients' age ranged from 17 to 86 years, with a female-to-male ratio of 2.33:1. The prevalent anatomic site of tumor was the anorectum. The mean tumor thickness was 11.5 mm, and mean tumor size was 2.9 cm. Abdominoperineal resection was performed on 38 (63.3%) patients, whereas wide local excision was performed on 22 (36.7%) patients. Thirty-three (55.0%) patients were pathologically confirmed to have lymph node metastasis, and 9 (15%) patients had clinically distant metastasis at diagnosis. Histologically, epithelioid cell (91.7%) was the predominant cell type, followed by spindle (31.7%), pleomorphic (25.0%), and small round cell (5.0%). Solid sheet, nest, pseudopapillary, and pseudoalveolar growth patterns were noted in 45 (75.0%), 22 (36.7%), 13 (21.7%), and 6 (10.0%) cases, respectively. After a median follow-up of 44 months, the 5-year disease-specific survival rate was 33.3%. Age, tumor size, depth of invasion, tumor thickness, lymphatic metastasis, and lymphovascular and perineural invasion were significantly correlated with survival in univariate analysis. Multivariate analysis revealed that age greater than 70 years and tumor invasion beyond deep muscular layer/sphincter ani externus were independent poor prognostic factors. As the largest single-institution study of anorectal melanoma in an Asian population, we concluded that anorectal melanoma is a rare and lethal malignant neoplasm with morphologic diversity. Large population–based studies are still needed to establish an efficient staging system in evaluation of prognosis and facilitation of treatment for anorectal melanoma patients.

Von Meyenburg complex (VMC) is generally thought to be benign, although its preneoplastic potential for intrahepatic cholangiocarcinoma (iCC) has been a subject of contention. We retrospectively reviewed 86 hepatectomy specimens with a diagnosis of iCC. Morphologically, an association between iCC and VMC was appreciated in 35% of cases that illustrated a gradual neoplastic progression from benign VMC to dysplasia and then to iCC. Among them, 24 cases had VMC lined by epithelial cells with low-grade biliary dysplasia and 13 with high-grade biliary dysplasia. VMC-associated iCCs were smaller in size and well to moderately differentiated, with features of anastomosing glandular architecture, ductal carcinoma in situ-like growth pattern, peritumoral lymphocytic infiltrate, central fibrous scar, and complete pushing border. They often presented as T1 tumors. In contrast, non-VMC-associated iCCs were moderately to poorly differentiated with solid, cribriform or papillary growth patterns. They likely exhibited necrosis, perineural invasion, positive surgical margin, lymphovascular invasion, and high T stage. Additionally, Ki67 and p53 immunostains support the continuing neoplastic evolution from benign VMC to dysplasia and then to iCC. VMC could become neoplastic, serving as an in situ carcinoma lesion to transform to iCC. The underlying molecular alteration and clinical implication of this neoplastic transformation deserves further investigation.

In recent years, multiparametric magnetic resonance imaging and magnetic resonance/ultrasound fusion targeted biopsy (TB) have become more widely adopted to aid in prostate cancer (PCa) detection. Previously, TB has been found to increase the yield of clinically significant PCa and is more likely to sample the index tumor compared with traditional 12-core extended sextant biopsies. Currently, the prognostic significance of perineural invasion (PNI) when identified on TB (PNI-TB) is unknown. We identified 95 men at 2 tertiary referral centers who underwent TB followed by radical prostatectomy between January 2014 and January 2017. Clinical, radiological, and pathological variables were retrospectively reviewed. PNI was identified on TB in 27 of 95 (28.4%) patients. On multivariable logistic regression, independent predictors of extraprostatic extension were prostate-specific antigen, TB maximum % core involvement, and PNI-TB (all P

Perineural invasion (PNI) is widely studied in malignant tumors, and its prognostic significance is well demonstrated in the head and neck and prostate carcinomas, but its significance in rectal cancer is controversial. Most studies have focused on evaluating mural PNI (mPNI); however, extramural PNI (ePNI) may influence the prognosis after rectal cancer resection. We evaluated the prognostic value of ePNI compared with mPNI and with non-PNI, in rectal resections after preoperative chemoradiotherapy in 148 patients with pT3 and pT4 rectal carcinomas. PNI was identified in 35 patients (23.6%), 60% of which were in the mPNI group. Factors associated with PNI were tumor invasion depth, lymph node metastasis, lymphovascular invasion, and venous invasion; patients with PNI were more likely to have positive resection margins (65.7% versus 11.6%). ePNI, compared with mPNI, was associated with female sex (64.3% versus 28.6%), positive surgical margins (42.8% versus 28.6%), recurrence (50% versus 28.6%), and death (92.9% versus 28.6%). The 5-year disease-specific survival rate was 78.1% for patients without PNI, compared with 63.7% for the mPNI group and 26.4% for the ePNI group (P

Summary Tumor budding (TB) in colorectal carcinoma (CRC) is related to epithelial-mesenchymal transition and has been recently characterized as an indicator of poor prognosis along with lymphovascular tumor emboli, perineural invasion, and an infiltrative growth pattern. Mutations in the genes of the Ras–mitogen-activated protein kinase and phosphatidylinositol-4,5-bisphosphate 3-kinase pathways are associated with epithelial-mesenchymal transition and an aggressive CRC phenotype and have been used in patient stratification for anti–epidermal growth factor receptor therapies; however, the impact of these mutations on CRC morphology and behavior remains unclear. In this study, using a multigene panel, we detected KRAS , NRAS , BRAF , PIK3CA , TP53 , and POLE mutations in 90 CRCs and investigated their associations with clinicopathological parameters, including TB. Our results showed that 21 of 34 tumors with high-grade TB had KRAS mutations ( P =.001) and KRAS G12D and PIK3CA exon 9 variants were significantly associated with high-grade TB ( P =.002 and .006, respectively); furthermore, tumors with KRAS mutations in exons 3 and 4 tended to have lymphovascular tumor emboli and perineural invasion ( P =.044 and .049, respectively). PIK3CA exon 9 mutations indicated a tendency for shorter disease-free survival ( P =.030), whereas BRAF mutations were associated with extracellular mucin deposition ( P =.016). Our study revealed a correlation of KRAS mutations with high-grade TB, an association of certain KRAS and PIK3CA variants with aggressive clinicopathological features, as well as a possible relationship between BRAF mutations and mucin production in CRC.

Prostatic carcinoma, like many other carcinomas, generates a stromal reaction. This phenomenon is well established in the scientific literature. The normal parenchymal smooth muscle phenotype switches to a myofibroblastic phenotype in response to the presence of cancer cells, with an expansion of the extracellular matrix compartment. The amount of reactive stroma is a predictor of biochemical recurrence in both radical prostatectomies and biopsies. It is a predictor of prostate cancer-specific death in prostatectomies. The aim of this study is to improve our histologic understanding of reactive stroma in prostate cancer and to determine the histologic features of the malignant epithelium found in stromogenic carcinomas or carcinomas with reactive stromal grade 3. Tissue microarrays of 800 patients and hematoxylin and eosin-stained sections of 120 radical prostatectomies, previously determined to contain a high proportion of areas with stromogenic carcinoma, were evaluated and findings systematically recorded. We identified 3 histologic patterns of reactive stroma: extracellular matrix-rich, cellular variant and edematous/myxoid variant. The most common pattern of carcinoma in stromogenic areas is of the acinar type with angulated glands and periglandular halos. The nuclei are enlarged, opened, with prominent nucleoli. Luminal borders are undulated, and amorphous pink secretion is often seen. Perineural invasion is frequently identified. Because of the clinical relevance, identification and quantification of areas with high reactive stromal grade by pathologists and reproducibility of our findings by others become essential. We believe that with the previously proposed grading system and the present morphologic description, both can be achieved.

Summary The aim of the current study was to test whether the grade group assessed in the index tumor nodule predicts biochemical recurrence after surgery. The study cohort series included 144 consecutive patients treated by laparoscopic radical prostatectomy. The following parameters were evaluated in each case: type of radical prostatectomy (with/without lymphadenectomy), pT and pN status, histologic type of prostate carcinoma (acinar versus mixed histology), surgical margin resection status, perineural invasion, lymphovascular invasion, biochemical recurrence status, presence of tertiary Gleason 5 pattern, and grade group that was assessed both in overall prostate cancer and in index (dominant) tumor nodule. Twenty patients (13.9%) experienced postoperative biochemical recurrence at a mean follow-up time of 12.2 months. The univariate survival analysis selected type of radical prostatectomy, histological subtype, lymphovascular invasion, American Joint Committee on Cancer pT and pN classification, tertiary Gleason 5 pattern, preoperative serum prostate specific antigen level, and the grade group assessed in both the overall prostate and index tumor nodule as significant for biochemical recurrence-free survival. Type of radical prostatectomy (P = .020), histological subtype (P = .002), lymphovascular invasion (P = .023), tertiary Gleason pattern 5 (P = .016), and grade group classification in index tumor nodule (P ≤ .0001) were selected as independent predictors of biochemical recurrence-free survival. In conclusion, our results validate grade group in the index tumor nodule as an independent predictor of biochemical recurrence-free survival, thus emphasizing the value of reporting grade group in index tumor nodule. The main limitation of our study is the relatively low number of cases in the current series, suggesting the need of large confirmatory studies.

Summary Loss of the NF1 allele, coding for the protein neurofibromin, and polymorphism in the proto-oncogene RET ( RETp ) are purportedly common in desmoplastic melanoma (DM). DM is categorized into pure (PDM) and mixed (MDM) subtypes, which differ in prognosis. Most NF1 mutations result in a truncated/absent protein, making immunohistochemical screening for neurofibromin an ideal surrogate for NF1 allelic loss. Using antineurofibromin, our aims were to ascertain the incidence of neurofibromin loss in DM subtypes and to evaluate the relationship with RET , perineural invasion (PNI) and established histopathologic prognosticators. A total of 78 archival samples of DM met criteria for inclusion (54 cases of non-DM serving as controls). Immunohistochemistry was performed for neurofibromin, whereas direct DNA sequencing was used for RETp and BRAF mutation status. Statistical analyses included χ 2 test as well as Fisher exact test. Neurofibromin loss was more common in DM than non-DM (69% versus 54%; P =.02). In DM, significant differences in neurofibromin loss were noted in the following: non–head and neck versus head and neck biopsy site (88% versus 55%) and PDM versus MDM variants (80% versus 56%). No significant associations were noted with sex, presence of a junctional component, Breslow depth, ulceration, mitoses, host response, RETp , BRAF status, or PNI. RETp was marginally associated with PNI-positive DM versus PNI-negative DM (36 versus 18%; P =.08). Our findings, the largest to date investigating neurofibromin in DM, validate the incidence of NF1 mutations/allelic loss in DM and suggest that the DM subtypes have distinct genetic drivers.

Summary Adenocarcinomas of the ampulla of Vater account for 0.5% of malignant neoplasms of the gastrointestinal tract and 6% to 20% of malignant periampullary neoplasms, with most patients being candidates for elective surgery. Our objective was to evaluate the clinicopathological prognostic factors of ampullary adenocarcinomas after surgical resection in a Mexican population. From the records of the Department of Pathology at the Instituto Nacional de Cancerologia, Mexico, cases diagnosed as adenocarcinomas of the ampulla of Vater were selected over a period of 11 years, from January 2005 to September 2015. Cases with a pancreaticoduodenectomy report were included, and from each case, demographic and pathological data of the surgical specimen were obtained. Univariate and multivariate statistical analyses were performed using the log-rank test and Cox regression. Of 157 cases diagnosed as ampullary adenocarcinomas, 104 patients were excluded as not eligible for surgical treatment at the time of diagnosis. In the remaining 53 patients, a pancreaticoduodenectomy was performed. The mean age of the entire group was 55.4 years, and most were men. Intestinal-type adenocarcinomas were more frequent (77.4%) than pancreatobiliary-type (15.1%), with most being without perineural invasion, well to moderately differentiated, and less than 3 cm in size. Lymph node metastasis and age greater than 65 years had a negative impact on overall survival of the patients. The most convenient classification of malignant epithelial tumors of the Vaterian system is according to the histopathologic phenotype grouped into intestinal-, pancreatobiliary-, and mixed-type adenocarcinomas, as well as uncommon variants.

Perineural invasion (PNI) has been recently added to the American Joint Committee on Cancer cutaneous squamous cell carcinoma (cSCC) staging criteria as a high-risk tumor characteristic and is purportedly more common in cSCCs of the head and neck (HN). Expression of the high-affinity nerve growth factor receptor TrkA has been shown to be associated with PNI in noncutaneous neoplasms. Given this, we sought to ascertain the incidence of PNI in cSCCs using double immunostaining (DIS) and to investigate PNI's relationship with TrkA and established histopathologic prognosticators. Fifty-seven cSCCs from the HN and 53 from non-HN areas were immunohistochemically analyzed for PNI (DIS with S-100 and p63) and TrkA expression. Comparing HN versus non-HN areas, using hematoxylin and eosin, PNI was detected in 11% versus 6% cases, respectively, and, using DIS, in 23% versus 15%, respectively, with significant disagreement between both methods (κ = 0.47; P = .002). There was a 2.33-fold increase in PNI detection with DIS compared to hematoxylin and eosin (95% confidence interval, 1.12-4.87; P = .02). TrkA expression was 1.96 times more frequently observed in cSCCs from the HN compared to those from non-HN areas (P = .01). Regardless of site, TrkA expression was associated with decreased degree of differentiation (odds ratio, 6.46; P = .0006) and high-risk morphologic variants (odds ratio, 6.53; P = .002) but not significantly associated with PNI (P = .33). Increased PNI detection with DIS underscores the adjunctive utility of immunohistochemistry in microstaging. Significantly more common TrkA expression in cSCCs of the HN argues in favor of heterogeneity among SCCs from different anatomical sites.

Undifferentiated carcinoma of the esophagus is a rare histologic variant of esophageal carcinoma. Using criteria based on studies of undifferentiated carcinomas arising at other sites, we have collected 16 cases of resected esophageal undifferentiated carcinomas. Patients ranged in age from 39 to 84 years (mean, 65.5 years) and were predominantly male (94%). The tumors were characterized by an expansile growth pattern of neoplastic cells organized in solid sheets and without significant glandular, squamous, or neuroendocrine differentiation. The neoplastic cells had a syncytial-like appearance, little intervening stroma, and patchy tumor necrosis. In a subset of cases, the tumor cells adopted a sarcomatoid (n = 2), rhabdoid (n = 1), or minor component (

Aurora kinase A (AURKA) gene amplification has been documented in 67% of hormone-naive prostate cancer cases that progress to a highly aggressive variant of castrate-resistant disease, clinically referred to as “neuroendocrine” prostate cancer, “small cell” prostate carcinoma, or “anaplastic” prostate cancer. Therefore, AURKA amplification is a potential prognostic biomarker that may help to identify patients with prostate cancer who are at high risk for developing castrate-resistant disease with clinical features of small cell carcinoma. Furthermore, AURKA inhibitors are currently being tested in clinical trials. In a previous study, we found AURKA amplification in 6 cases of prostate cancer with Paneth cell–like cells. This morphologic pattern has been suggested to represent low-grade neuroendocrine differentiation (NED) with generally favorable prognosis. We sought to investigate the frequency of AURKA amplification and the histologic characteristics of prostate cancer with Paneth cell–like NED. Twenty-five cases from 172 prostatectomies were evaluated for the presence of 18 morphologic features and AURKA amplification. Most prostate cancers with Paneth cell–like NED had macronucleoli (92%), basophilic appearance (88%), perineural invasion (72%), and nuclear stratification (76%). The frequency of AURKA amplification was 45%, present throughout the examined tumor nodule including areas without Paneth cell–like cells. When histologically similar cases with and without AURKA amplification were compared, this gene alteration was associated with larger extent of Paneth cell–like NED identified at magnification ×20 (P = .015), higher percentage of Paneth cell–like NED throughout the tumor nodule (P = .033), ductal features (P = .02), and higher overall Gleason grade (P = .039). AURKA amplification was not associated with age, serum prostate specific antigen, or tumor stage. The high frequency of AURKA amplification (45%) in localized prostate cancer with Paneth cell–like NED and its potential prognostic significance warrant further investigation.

We analyzed a series of 55 disseminated appendiceal mucinous neoplasms treated at our institution for GNAS and KRAS mutations in an attempt to correlate mutation status with clinicopathological findings and patient survival. GNAS mutations (p.R201H, c.602G>A and p.R201C, and c.602C>T) were identified in 17 (31%) of 55 of disseminated mucinous neoplasms and were found in 8 (35%) of 23 low-grade mucinous neoplasms, 7 (37%) of 19 high-grade mucinous adenocarcinomas lacking a signet ring cell component, and 2 (15%) of 13 high-grade mucinous adenocarcinomas with a signet ring cell component. All 7 mucinous adenocarcinomas composed of pure (>95%) signet ring cells harbored wild-type GNAS. There was no significant association between GNAS mutations and sex and age (both with P > .05) or between GNAS mutations and individual adverse histologic features including cytologic grade, destructive invasion, tumor cellularity, angiolymphatic invasion, perineural invasion, and signet ring cells (all with P > .05). KRAS mutations were identified in 22 (40%) of 55 disseminated mucinous neoplasms. GNAS-mutated disseminated appendiceal mucinous neoplasms more frequently harbored concurrent KRAS mutations compared with GNAS wild-type tumors (65% versus 29%, P = .018). GNAS mutations were not significantly associated with overall survival (both with P > .05). Only overall tumor grade was an independent predictor of overall survival in the multivariate analysis (P = .01). Our results indicate that GNAS mutations are frequently identified in both low-grade and high-grade disseminated appendiceal mucinous neoplasms indicating that GNAS mutation status cannot be used to distinguish between low-grade from high-grade appendiceal mucinous neoplasms.

Glucose transporter (GLUT)-1 is expressed in malignant tumors and correlated with poor outcome in several cancers. Biliary intraepithelial neoplasia (BilIN) is considered to be a precursor or a noninvasive lesion of invasive cholangiocarcinoma. We examined GLUT-1 and GLUT-2 expression in 149 intrahepatic cholangiocarcinomas and 39 BilINs immunohistochemically and evaluated their correlation with clinicopathological findings and patient outcome in intrahepatic cholangiocarcinoma. Furthermore, we examined the role of GLUT-1 on migration and invasion of cholangiocarcinoma cells using GLUT-1 siRNA. In intrahepatic cholangiocarcinoma, GLUT-1 expression was frequently observed near the necrotic areas, whereas GLUT-2 expression tended to be observed in adenocarcinoma of large bile ducts. Compared with the GLUT-1-negative group, the GLUT-1-positive group showed significantly larger tumor size (P = .0031), poor differentiation (P < .0001), frequent lymphatic invasion (P = .0031) and lymph node metastasis (P < .0001), and high HIF-1α expression (P = .0297). GLUT-2 expression was significantly correlated with good differentiation (P = .0015), perihilar location (P < .0001), perineural invasion (P = .0049), and lymph node metastasis (P = .0248). The patients with GLUT-1-positive tumors showed poor disease related survival (P < .0001). The numbers of migrating and invading cells were significantly decreased in GLUT-1 siRNA transfectants of cholangiocarcinoma cells. Although, GLUT-1 was expressed in all grades of BilINs, GLUT-2 was expressed only in high-grade BilINs. Our results suggest that GLUT-1 expression correlates aggressive behavior and poor prognosis, and that GLUT-1 might be a therapeutic target of cholangiocarcinoma. GLUT-2 expression may be associated with cholangiocarcinogenesis of large bile duct and is a helpful marker for detecting high-grade BilIN lesions in atypical bile ducts.

Mortalin, an essential mitochondrial chaperone protein, is involved in the tumorigenesis of a number of malignancies. This study aimed to investigate the expression of Mortalin in pancreatic ductal adenocarcinoma (PDAC) cells and to determine its clinicopathological and prognostic significance. The localization of Mortalin protein was detected in BXPC-3 PDAC cells using immunofluorescence. Immunohistochemistry was also used to detect Mortalin expression in well-defined tissues obtained from 106 PDAC patients and 46 corresponding nontumor pancreatic tissues. Clinicopathological parameters and overall survival data were collected and compared between different Mortalin statuses. The results of immunohistochemistry and immunofluorescence showed that Mortalin was primarily present in the cytoplasm of PDAC cells. The ratio of strong positive staining for Mortalin was higher in PDAC tissues (55.66%; 59/106) than in normal adjacent tissues (23.91%; 11/46). Positive relationships between Mortalin expression and clinical stage, perineural invasion, lymph node metastasis, and lower overall survival were observed. Multivariate Cox regression analysis identified Mortalin as a significant independent prognostic factor, in addition to location, clinical stage, and perineural invasion, for survival of PDAC patients. Therefore, we present strong evidence that Mortalin may function as a practical marker to predict prognosis and as a potential therapeutic target in PDAC treatment.

Penile carcinoma (PC) is more frequent in underdeveloped countries, generally is diagnosed at an advanced stage when therapeutic options are restricted, and thus is associated with high morbidity/mortality rates. Recent studies have demonstrated clinical benefits with epidermal growth factor receptor (EGFR)-targeted therapy in patients with PC, although there is no test that provides accurate patient selection. The aim of the present study was to evaluate the prognostic value of EGFR gene and protein status in tumor samples from patients with primary penile squamous cell carcinoma. We assessed the expression of wild-type and 2 mutant EGFR isoforms (delA746-E750 and mL858R) by immunohistochemistry in 139 samples, of which 49 were also evaluated for EGFR copy number by fluorescence in situ hybridization (FISH). Positive immunohistochemical staining of wild-type and mutant EGFR was evidenced by complete and strong membranous staining. For FISH analysis, cases were considered unaltered, polysomic, or amplified, as determined by signals of the EGFR gene and chromosome 7. An independent cohort of 107 PC samples was evaluated for mutations in EGFR, KRAS, and BRAF. Protein overexpression was noted in nearly half of the cases and was associated with cancer recurrence (P=.004) and perineural invasion (P=.005). Expression of the 2 mutated EGFR isoforms was not observed. The FISH status was not associated with protein expression. Altered FISH (polysomy and gene amplification) was an independent risk factor for dying of cancer. Only 1 patient of 107 presented KRAS mutations, and no mutations of EGFR or BRAF were observed.

Small intestinal adenocarcinoma is a rare malignant neoplasm, and its clinicopathologic characteristics have not been well elucidated. A total of 197 small intestinal adenocarcinoma cases were collected from 22 institutions in South Korea and were evaluated for clinicopathologic factors that affect the prognosis of small intestinal adenocarcinoma patients using univariate and multivariate analyses. The mean patient age was 59 years, and the male-to-female ratio was 1.7:1. Tumors were located in the duodenum of 108 cases (55%), the jejunum in 59 (30%), and the ileum in 30 (15%). Predisposing conditions were observed in 23 cases (12%), including 17 cases with sporadic adenomas, 3 with Peutz-Jeghers syndrome, 2 with Meckel diverticulum, and 1 with Crohn disease. Synchronous or metachronous malignant tumors were identified in 31 cases (16%), including 13 colorectal and 10 stomach cancers. About 90% of tumors were classified as either pT3 (63 cases) or pT4 (112 cases). The median survival time for all small intestinal adenocarcinoma patients was 39.7 months. Compared with small intestinal adenocarcinomas without accompanying sporadic adenomas, small intestinal adenocarcinomas with accompanying adenomas were more well differentiated (P < .0001), with a more polypoid growth pattern (P < .0001), a lower pT classification (P < .0001), less perineural invasion (P = .01), and less lymphatic invasion (P = .03). Small intestinal adenocarcinoma patients with associated sporadic adenomas (77%) had a significantly better 5-year survival rate than those without sporadic adenomas (38%, P = .02). By univariate analysis, small intestinal adenocarcinoma patients had significantly different survival based on pT classification (P = .003), lymph node metastasis (P < .0001), distal location (jejunal and ileal carcinomas) (P = .003), retroperitoneal tumor seeding (P < .0001), vascular invasion (P = .007), lymphatic invasion (P = .001), peritumoral dysplasia (P = .004), and radiation therapy (P = .006). By multivariate analysis, lymph node metastasis (P = .01) and distal location (P = .003) were independent predictors of a worse prognosis. In conclusion, (1) small intestinal adenocarcinomas are diagnosed at an advanced disease stage; therefore, the development of strategies for detection at an earlier stage is needed. (2) Small intestinal adenocarcinoma patients with an adenomatous component had a better survival than those without an adenomatous component. (3) Lymph node metastasis and distal location (jejunum and ileum) of tumor are the most important independent prognostic factors.

Summary We present 9 consult cases, the largest series to date, of colorectal adenocarcinoma involving the prostate. Mean age of patients at diagnosis was 61 years (range, 42-78 years). Six cases were initially diagnosed on needle biopsy and the others by transurethral resection. Three cases were diagnosed before biopsy of the colon, which led to the discovery of a primary colonic tumor. The mean interval between the detection of the primary colonic tumor and prostatic involvement in the other 6 cases was 30 months (range, 1-52 months). At diagnosis, the stages of colorectal carcinomas were pT1 (n = 2), pT2 (n = 2), pT3 (n = 2), and pT4 (n = 3). Two cases involved the prostate after the recurrence of rectal adenocarcinoma at the anastomotic site of the previous colonic resection. In most cases, the tumors were typical moderately differentiated with occasional poorly differentiated foci. Other histologic features included desmoplastic stromal reaction (100%, n=9), necrosis (77.8%, n=7), chronic inflammatory response (77.8%, n=7), cribriform pattern (66.7%, n=6), villous architecture (22.2%, n=2), mucin production (22.2%, n=2), signet-ring cells (11.1%, n=1), and perineural invasion (11.1%, n=1). Immunohistochemical stains were positive for β -catenin in 6 of 6 cases, CDX2 in 6 of 6 cases, carcinoembryonic antigen in 7 of 7 cases, CK20 in 5 of 6 cases, high-molecular-weight cytokeratin in 5 of 6 cases, and α -methylacyl-CoA racemase in 3 of 6 cases. Stains were negative in all cases for prostate-specific antigen, P501S (prostein), and CK7. Six patients (66.7%) died of disease within an average of 34 months (range, 8-88 months) after diagnosis of prostatic involvement. There are critical therapeutic and prognostic implications for distinguishing between prostatic adenocarcinoma and colorectal carcinoma involving the prostate. Colorectal adenocarcinoma should be considered on prostate sampling when carcinoma exhibits either "dirty" necrosis, tall columnar epithelium with mucin production, mucin-positive signet-ring cells, villous architecture, or associated inflammation. Immunohistochemical stains for β -catenin, CDX2, carcinoembryonic antigen, high-molecular-weight cytokeratin, prostate-specific antigen, P501S (prostein), CK20, and CK7 can be helpful in making a definitive diagnosis.

The presence of positive surgical margins is a negative prognostic indicator in patients undergoing prostatectomy for prostate cancer; whether the extent of the positive margins affects the clinical outcome with regards to prostate-specific antigen (PSA) recurrence remains uncertain. We evaluated the linear extent of margin positivity as a prognostic indicator in a series of radical prostatectomy specimens. One hundred seventy-four consecutive margin-positive prostatectomy specimens were evaluated. The linear extent of margin positivity was measured with an ocular micrometer and ranged from 0.05 to 75.0 mm (mean, 8.94; median, 5.0). The linear extent of margin positivity was associated with tumor volume (P = .03) but was not associated with patients' age at surgery, preoperative PSA level, prostate weight, pathologic stage, Gleason score, extraprostatic extension, seminal vesicle invasion, perineural invasion, high-grade prostatic intraepithelial neoplasia, or PSA recurrence. In the full model multiple Cox regression, significant predictors for PSA recurrence were Gleason score (P = .001) and preoperative PSA (P = .01); extent of margin positivity was not predictive of PSA recurrence (hazard ratio, 1.00; 95% confidence interval, 0.98-1.02; P = .97) nor was tumor volume a significant factor when adjusted for other covariates (P = .27). Preoperative PSA, tumor stage, and Gleason score remained significant prognostic factors in evaluating the likelihood of PSA recurrence in patients with positive surgical margins; the extent of margin positivity, however, is not a prognostic factor for PSA recurrence and should, therefore, not necessarily be included in the final report for radical prostatectomy specimens.

The 14-3-3sigma gene has been implicated in G2/M cell cycle arrest by p53, and the loss of 14-3-3sigma protein expression has been reported in diverse human cancers. However, the role of 14-3-3sigma in the signaling pathway of the cell cycle in the progression of intrahepatic cholangiocarcinoma has not been well understood. To clarify the role of 14-3-3sigma, we examined the protein expressions of 14-3-3sigma, cyclin B1, and p53 in 93 cases of intrahepatic cholangiocarcinoma by immunohistochemical staining. We also examined the correlation between these expressions and survival rate and clinicopathologic factors such as sex, age, tumor grade (ie, pathologic differentiation, tumor size, lymphatic permeation, vascular invasion, perineural invasion, lymph node metastasis), and tumor stage. Positive 14-3-3sigma protein expression (>30% of tumor cells) was observed in 67.7% (63/93) of cases of intrahepatic cholangiocarcinoma and was inversely correlated with cyclin B1 expression. No correlation was found between 14-3-3sigma expression and p53 expression or clinicopathologic factors; however, decreased 14-3-3sigma expression was an independent prognostic factor by multivariate survival analysis (P = .0282). Extensive methylation of 14-3-3sigma was found by methylation-specific polymerase chain reaction and sequence; however, no significant correlation was detected between methylation states and protein expression. These results indicate that depressed 14-3-3sigma protein is involved in the uncontrolled cell cycle in intrahepatic cholangiocarcinoma and that the decreased expression of 14-3-3sigma protein is a significant indicator of poor prognosis for patients with intrahepatic cholangiocarcinoma.

Pancreatic cancer (PanCa) is characterized by perineural invasion (PNI), early lymph node and liver metastasis, and poor prognosis. PNI is one of the important causes of local recurrence. Little is known about the mechanism of PNI in PanCa. We presented a novel model system that may shed light on the mystery of PNI in PanCa. In this study, mouse dorsal root ganglia (DRGs) and human PanCa cell line (MIA PaCa-2) were cocultured in Matrigel matrix (BD Biosciences, San Jose, CA) to build this PNI model. MIA PaCa-2 cell line alone (control 1) or DRG alone (control 2) was cultured with Matrigel matrix as controls. Neurite outgrowth, cell colony growth, neurite-colony contact, and retrograde extension were observed under inverted microscopy and then were photographed and quantitated with the Optimas imaging system (Optimas Corp., Bothell, MA). At day 14, both the experimental and control 2 samples were harvested and subjected to total RNA isolation and fixed in paraffin-embedded blocks. Slides cut from paraffin blocks were studied with Ki-67 immunostaining and TUNEL assay. Gene profiling was performed using complementary DNA microarray. Overexpressed target genes were verified by quantitative reverse transcriptase polymerase chain reaction. The results showed that reciprocity was observed between neurites and MIA PaCa colonies with 24 hours of coculture. Neurite outgrowth was stimulated in the presence of pancreatic carcinoma cells, which showed 2-fold more area than did control 2. After 72 hours, MIA PaCa colonies cocultured with DRG exhibited 58% more colony area than did control 1. The Ki-67 index of the DRG/MIA PaCa cells (mean, 5.02%) was significantly higher than that in control 1 (mean, 1.18%) (P < .05); in contrast, the apoptotic index in the DRG/MIA PaCa cells was significantly lower (mean, 0.45%) than that in the control 1 (mean, 1.85%) (P < .001). Prosurvival genes MALT1 and TRAF were increased 2-fold in DRG/MIA PaCa compared with controls. We demonstrated that neural-epithelial interaction is a mutually beneficial process for the growth of nerves and PanCa cells. It is possible that oncogenes and growth factors might act synergistically in promoting proliferation and/or inhibiting apoptosis, a survival strategy crucial to the development of PNI in PanCa.

To investigate the clinicopathological and immunohistochemical features and prognostic factors for invasive extramammary Paget disease (EMPD) on penoscrotum, we described the clinical presentations, histopathology, and follow-up courses of 41 cases. The age of the patients ranged from 42 to 84 years. All the patients were treated with wide surgical excision, and 14 were confirmed to have lymph node metastasis. During follow-up, 18 patients (43.9%) developed local or distant recurrence, and 13 patients (31.7%) died of the disease. Histologically, glandular formation with true lumina within the epidermis was found in 29 cases, and signet ring cells were seen in 11 cases. In invasive components, nodular/micronodular growth pattern, glandular formation, and strands/solid sheets existed in 95.1% (39/41), 43.9% (18/41), and 24.4% (10/41) of the cases, respectively. More than half of the cases had at least 2 different types of invasive growth pattern. CK7 was diffusely positive in all cases, whereas CK20 was focally positive in 8 cases. GCDFP-15 was expressed to a variable degree in 24 cases. Presence of strands/solid sheets, lymphovascular invasion, and perineural invasion in invasive EMPD were found to be correlated with higher lymph node metastatic rate. Univariate analysis revealed that patients with one of the following prognostic factors: delay in diagnosis more than 7.5 years, depth of invasion more than 1 mm, invasive pattern of strands/solid sheets, marked inflammation, lymphovascular invasion, and lymph node metastasis at diagnosis, had significantly shorter cancer-specific survival. We concluded that invasive EMPD is a rare malignant skin neoplasm with morphological diversity. Invasive pattern of strands/solid sheets is significantly associated with both lymph node metastasis and worse prognosis. Delay in diagnosis, depth of invasion, marked inflammation, lymphovascular invasion, and regional lymph node status are important prognostic factors.

Summary Basal cell hyperplasia (BCH) is a well-recognized entity on transurethral resection specimens, but it is an uncommon finding on prostatic needle biopsies, and the diagnostic difficulties with it have not been fully defined on this material. A 13-year (1991-2003) retrospective review of the consult files of one of the authors was performed. In all cases, the focus of BCH was referred for consultation to rule out adenocarcinoma. Thirty-three cases of prominent BCH were identified. The dominant pattern of BCH consisted of either glands (26/33) or solid nests (7/33). Other minor patterns included cribriform (5), pseudocribriform (4), cords (1), and adenoid basal (1). Twelve of 33 cases showed an infiltrative pattern. Other features of BCH included prominent nucleoli (14/33), abnormal secretions (17/33 with dense pink and/or blue mucin), mitoses (6/33), altered stroma with increased cellularity (6/33), calcifications (6/33), intraluminal crystalloids (3/33) and perineural invasion (1/33). By immunohistochemistry, 7 (100%) out of 7 were positive for p63 and 14 (88%) of 16 were positive for high molecular weight cytokeratin. No cases (0/6) were positive for α-methylacyl-coenzyme A racemase. Basal cell hyperplasia, as a mimicker of cancer, is an uncommon entity encountered on prostatic needle biopsies. Helpful features for its diagnosis include solid nests, pseudocribriform glands, multilayering of cells, calcifications, and cellular stroma. Immunohistochemistry can be useful for documenting the basal cell layer and demonstrating negative racemase staining.

Adenoid cystic carcinoma (ACC) is a common salivary gland neoplasm with a lengthy clinical course and often late local recurrences after surgical resection. This is accounted for histologically by its infiltrative capacity and distinct propensity for perineural invasion. The expression of biological markers may help explain the clinicopathologic course in ACCs. Brain-derived neurotrophic factor (BDNF) is a growth factor known to be involved in neurogenesis. The aim of this study is to elucidate the expression of BDNF in ACCs, which is currently unknown. Twenty-nine cases of primary ACCs of the head and neck were immunostained to analyze BDNF protein expression. Staining intensity was described as focal or diffuse and graded on a 3-tiered scale. The study group comprised 20 adult females (age 30 to 78) and 9 adult males (age 22 to 70). Sites of involvement included the parotid gland (6 cases), nasopharynx (5), maxilla (4), palate (3), trachea (3), submandibular gland (2), buccal mucosa (2), mandible (1), tongue (1), lacrimal gland (1), and temporal region (1). All tumors exhibited diffuse cytoplasmic staining; 11 cases were classified as 1+ intensity, 12 cases as 2+, and six cases as 3+. Based on the results presented here, BDNF is unformly expressed by ACC and may play a causative role in its predilection for perineural invasion. ACCs may display neurogenesis with high levels of BDNF expression in some tumors. Further studies are warranted to gain better understanding of this possible relationship.

High-mobility group AT-hook 2 (HMGA2) regulates cell growth, differentiation, apoptosis, and neoplastic transformation. Previous studies have shown that malignant tumors expressing HMGA2, such as gastric, lung, and colorectal carcinomas, usually have a poor prognosis. HMGA2 expression and its clinical significance in intrahepatic cholangiocarcinomas have not been studied. We identified 55 intrahepatic cholangiocarcinomas resected at our institution from 1994 to 2003. Hematoxylin-eosin-stained slides were reviewed, and histopathologic characteristics were recorded, including mitotic count, tumor grade, vascular and perineural invasion, lymph node metastasis, and margin status. Using immunohistochemical stains, we examined expression of HMGA2, p53, p16, Kit, α-fetoprotein, and Ki-67, and we analyzed the correlation of survival with clinicopathological characteristics and immunohistochemical findings. Positive staining for HMGA2, p53, p16, Kit, α-fetoprotein, and Ki-67 was seen in 18 (33%), 37 (69%), 26 (47%), 21 (38%), 2 (4%), and 34 (63%) tumors, respectively. HMGA2 expression correlated positively with p53 expression (P = .02; ρ = 0.32) and negatively with p16 expression (P = .04; ρ = -0.28). Univariate analysis showed that HMGA2 expression and lymph node metastasis were associated with shorter patient survival and were independent indicators of poor survival (P = .02 and P = .03, respectively). Tumorigenic effects of HMGA2 in intrahepatic cholangiocarcinoma may partly reflect its ability to negatively regulate expression of p16 tumor suppressors and to be associated with p53 abnormalities.

Perineural invasion is a symbiotic relationship between cancer cells and nerves and is most frequently seen in "neurotropic" cancers such as prostate cancer. It results in increased perineural space cancer cell growth and decreased apoptosis and induces nerve growth. Tissue microarrays were constructed from 640 radical prostatectomy specimens with prostate cancer. The perineural diameter was measured as previously described. Multiple biomarkers have been previously performed on this tissue microarray cohort, and all data were kept in the same database. The biomarker results database was queried for correlations between perineural invasion diameter and tissue biomarkers. Increased perineural invasion diameter correlated with increased proliferation of prostate cancer cells and with apoptosis. It also correlated with proteins involved in survival pathways such as nuclear factor κB, c-Myc, phosphorylated AKT, and its downstream effector FHKR, but not with GSK. Unlike nerve density, it did not correlate with decreased PTEN expression. Increased perineural invasion diameter was associated with higher levels of hormonal receptors such as androgen receptor, but not estrogen receptor. Also associated with perineural invasion diameter were coregulators and corepressors including SRC1 and TIF2. Perineural invasion diameter had the strongest correlation with tumor volume (ρ = 0.579, P = .000), not identified with nerve density. These data demonstrate that perineural invasion has the same biologic correlations as neural density. However, we found a distinct and very strong correlation with increased tumor volume. These data confirm that perineural invasion is the ultimate and most successful interaction between cancer cells and nerve fibers, resulting in increased tumor growth.

Over a period of 25 weeks 434 needle biopsy specimens of the prostate were sent to the author for consultation because of diagnostic concerns. The final diagnoses were cancer (69%), benign (13%), atypical but not diagnostic (10%), high grade prostatic intraepithelial neoplasia (PIN) (5%), and miscellaneous (3%). The most common benign entities mimicking cancer were atrophy (29 specimens) and adenosis (19 specimens). The 300 cancer specimens were analyzed further. Architecturally, the presence of small glands between larger benign glands was the most common pattern seen in 80% of carcinomas; haphazard growth patterns, single cells, and cribriform glands were seen less frequently. The following diagnostic features were helpful: nuclear enlargement (77% of specimens); prominent nucleoli (76%); pink acellular intraluminal secretions (53%); amphophilic cytoplasm (39%); blue-tinged mucinous secretions (34%); crystalloids (25%); PIN (13%); mitotic figures (11%); and perineural invasion (3%). The mean and median numbers of malignant glands in this series were 31 and 20, respectively (range, two to 300). Tumors with a Gleason score lower than 6 caused greater diagnostic problems for referring physicians because these tumors had a greater number of malignant glands, yet were still sent in for consultation (P = .0018). Gleason score was positively correlated with prominent nucleoli and amphophilic cytoplasm and inversely correlated with the presence of crystalloids. Prominent nucleoli, which often are quoted as being essential for the diagnosis of prostate cancer, were not seen in 24% of the specimens and seen only rarely in another 25%. The diagnosis of prostate cancer is based on a constellation of features. Even in this series with a limited number of malignant glands, 85% of specimens contained three or more of the above-listed diagnostic features in addition to architectural atypia.

Despite an overall decrease in colorectal carcinoma incidence, rates of colorectal carcinoma have increased substantially in patients aged less than 40 years. Several authors have characterized morphologic features of colorectal carcinoma in young patients, with variable results. To date, there has been 1 detailed molecular and immunohistochemical study in young patients with colorectal carcinoma. We sought to expand the data regarding young patients with colorectal carcinoma by a detailed assessment of morphologic features and by assaying expression of p27, COX-2, MLH1, and MSH2, markers with prognostic or therapeutic implications in colorectal carcinoma. We searched our pathology database from 1985 to 2009 and, after exclusion of cases with insufficient data or neoadjuvant therapy, identified a study population of 23 patients aged 40 or younger, 35 patients between 41 and 49 years of age, and a control group of 83 colorectal carcinoma patients aged 50 or older. Younger patients had higher tumor grade (P = .0085), with a trend toward mucinous differentiation and lymphovascular and perineural invasion. Loss of MSH2 was more prominent in younger patients (P = .02). Loss of p27 expression was not associated with age, but was associated with higher tumor stage (P = .0278), mucinous/signet ring differentiation (P = .0185), loss of either MLH1 or MSH2 (P = .0035), and larger tumor size (P = .0019). There was a trend toward lower COX-2 expression in younger patients, with less COX-2 expression relative to previously published data. Our findings support some prior reports regarding morphologic features in colorectal carcinoma in young patients and provide novel data on expression of several markers in this population.

Carcinomas of the extrahepatic bile ducts are uncommon and morphologically heterogeneous. We report 3 unique examples of adenocarcinomas that show predominantly pyloric gland differentiation (80%-100%) and compare their immunohistochemical profile with that of pyloric gland adenomas of the gallbladder, foveolar, and intestinal-type adenocarcinomas of the extrahepatic bile duct. The 3 patients with pyloric gland adenocarcinomas were younger than those with conventional adenocarcinomas. The 3 tumors were very well differentiated but showed extensive perineural invasion. They consisted of a variable proportion of small, medium-sized, and cystically dilated glands separated by abundant desmoplastic stroma. The glands were lined by columnar cells with abundant mucin-containing cytoplasm and small hyperchromatic basally placed nuclei with inconspicuous nucleoli. A characteristic feature of these pyloric gland adenocarcinomas was that the glands had a stellar pattern that was not seen in foveolar-, intestinal-, or biliary-type adenocarcinomas. Two pyloric gland adenocarcinomas coexpressed MUC6 and MUC5AC. The diffuse pattern of reactivity of MUC5AC and MUC6 was similar to that of 10 pyloric gland adenomas of the gallbladder and 2 foveolar adenocarcinomas of the extrahepatic bile duct. In contrast, 5 intestinal adenocarcinomas of the extrahepatic bile duct labeled with the intestinal marker CDX2 and 3 with the colonic MUC2 but were negative for MUC6 and MUC5AC. We believe that these pyloric gland adenocarcinomas represent a previously unrecognized distinct clinicopathologic entity. Despite their deceptively benign microscopic appearance, 1 patient died with local recurrence and liver metastasis, another patient is living with tumor, and the third patient is asymptomatic but only 5 months after surgery.

Predicting the biologic behavior of pancreatic endocrine neoplasm in the absence of local invasion or metastasis is difficult. We recently proposed an immunohistochemical classification system based on a combination of KIT and CK19 expression: low risk (KIT-/CK19-), intermediate risk (KIT-/CK19+), and high risk (KIT+/CK19+). In the current study, we sought histopathologic features that correlated with the immunohistochemical categories and that could be used in predicting tumor behavior. We assessed histologic findings of 97 pancreatic endocrine neoplasm that had been classified into 3 risk groups based on KIT/CK19 expression. Clinicopathologic associations with prognosis were evaluated using Cox proportional hazards regression models. Tumor size, mitoses, infiltrative border, extrapancreatic extension, perineural invasion, and presence of amyloid were significantly different among the 3 risk groups, and tumor necrosis approached statistical significance as well (P = .089). A scoring system using mitoses, necrosis, and tumor border was developed as follows: mitosis: 0 (0/50 high-power field), 1 (1-3/50 high-power field), and 2 (≥4/50 high-power field); necrosis: 0 (absent) and 1 (present); tumor border: 0 (noninfiltrating) and 1 (infiltrating), giving a possible histology score of 0 to 4. Although there was an overall difference in disease-specific survival among the 4 histology scores (P.001), there was not a statistically significant difference between patients with scores of 0 and 1 or between patients with scores of 3 and 4. Therefore, a 3-tied grading system was developed by combining score 0 and 1 tumors as grade 1, score 2 tumors as grade 2, and score 3 and 4 tumors as grade 3. There was a significant difference in survival, tumor metastasis, tumor recurrence, and functioning status among the 3 grades. By analyzing histopathologic features in KIT/CK19 risk groups, we developed a 3-tiered histopathologic grading system using reproducible parameters (mitoses, tumor necrosis, and infiltrative border) that are easy to apply in practice.

The cortactin gene, mapped at 11q13, has been associated with an aggressive clinical course in many cancers because of its function of invasiveness. This study evaluated CTTN protein and its prognostic value in the deep invasive front and superficial areas of laryngeal squamous cell carcinomas. The transcript expression levels were evaluated in a subset of cases. Overexpression of CTTN cytoplasmatic protein (80% of cases in both the deep invasive front and superficial areas) and transcript (30% of samples) was detected in a significant number of cases. In more than 20% of cases, observation verified membrane immunostaining in the deep invasive front and superficial areas. Perineural invasion was significantly associated with N stage and recurrence (P = .0058 and P = .0037, respectively). Higher protein expression levels were correlated with perineural invasion (P = .004) in deep invasive front cells, suggesting that this area should be considered a prognostic tool in laryngeal carcinomas. Although most cases had moderate to strong CTTN expression on the tumor surface, 2 sets of cases revealed a differential expression pattern in the deep invasive front. A group of cases with absent to weak expression of CTTN in the deep invasive front showed good prognosis parameters, and a second group with moderate to strong expression of CTTN were associated with an unfavorable prognosis, suggesting an association with worse outcome. Taken together, these results suggest that the deep invasive front might be considered a grading system in laryngeal carcinomas and that cortactin is a putative marker of worse outcome in the deep invasive front of laryngeal carcinomas.

Summary Advances in whole slide digital imaging in the past decade necessitate validation of these tools in each organ system in advance of clinical adoption. We assessed reproducibility in reporting prostate needle biopsy parameters among urologic pathologists using routine and digital microscopy in a consultation/second opinion-like setting. Four urologic pathologists evaluated a single core level from 50 diagnostically challenging needle biopsy specimens by routine microscopy and whole slide digital imaging. Interobserver and intraobserver agreement were calculated for primary and secondary Gleason grades, Gleason score, tumor quantitation (percentage and size in millimeters), and perineural invasion. Interobserver agreement for routine microscopy was excellent for primary Gleason grade ( κ = 0.72) and good for all other parameters ( κ ranging from 0.36 to 0.55). Whole slide digital imaging assessment yielded similar agreement for all parameters. Intraobserver agreement for primary Gleason grade and Gleason score was very good to excellent for all pathologists (all κ ≥ 0.65 and ≥0.73, respectively). Size of tumor in millimeters consistently displayed higher levels of agreement than percentage of tumor across media and pathologists. Digital assessment of routinely reported cancer parameters on prostatic needle biopsy for a given scanned core level is comparable to that of routine microscopy. These findings imply that histologic interpretation using dynamic whole slide images may accurately simulate routine microscopic evaluation in the consultation setting. Implementation of whole slide digital imaging in these scenarios may significantly reduce the workload of large referral centers in the near future and impact the manner in which pathologists seek second opinion consultation on challenging cases.

Growth arrest-specific gene 1 had been associated with cell-cycle arrest, proliferation, and apoptosis. The aim of this study was to investigate the correlations between clinicopathologic factors and survival time and growth arrest-specific gene 1 expression in patients with stage II and III colorectal cancer (CRC). Quantitative real-time polymerase chain reaction was performed in 64 fresh CRC tissues to examine growth arrest-specific gene 1 mRNA expression. Six metastasis-derived and primary-derived cell lines were subjected to quantitative real-time polymerase chain reaction and Western blotting for further examination of both mRNA and protein concentrations. Growth arrest-specific gene 1 protein was immunostained in 118 paraffin-embedded specimens. Growth arrest-specific gene 1 expression was down-regulated both in tissues with recurrence and in metastasis-derived cell lines. Expression was unrelated to sex, age, tumor grade, or lymphovascular or perineural invasion. However, it was positively related to disease-free survival time (P < .05). Furthermore, lower growth arrest-specific gene 1 expression indicated a poorer survival rate (P < .05; log-rank test). Multivariate analysis also showed weak growth arrest-specific gene 1 protein expression to be an independent adverse prognosticator (P < .05). Taken together, our results support the idea that growth arrest-specific gene 1 contributes to predicting metastasis or recurrence in stage II and III CRC.

Neural invasion represents an important prognostic factor in pancreatic cancer, and it is thought to be one of the main causes for the high rate of postoperative local recurrences in pancreatic ductal adenocarcinomas. In contrast to the latter, systematic investigations of the mode and extent of neural invasion in pancreatic endocrine tumors have not yet been carried out, although this process represents an important feature in the classification of these tumors. In the present study, a total of 48 pancreatic endocrine tumors were analyzed including 10 well-differentiated endocrine tumors of uncertain behavior, 33 well-differentiated endocrine carcinomas, and 5 poorly differentiated endocrine carcinomas. Neural invasion was found in a large subset (73%) of pancreatic endocrine tumors. The frequency of neural invasion correlated with the grade of malignancy but occurred irrespective of functional activity, hormone phenotype, or histomorphology. Analogous to pancreatic ductal adenocarcinoma, the expression of epidermal growth factor receptor and nerve growth factor, which were expressed in 50% and 100% of the tumors, respectively, seemed to be associated with the frequency of neural invasion. However, in contrast to pancreatic ductal adenocarcinoma, neural invasion in pancreatic endocrine tumors was only detected within the tumor boundaries and did not reach beyond the tumor invasion front. This phenomenon may explain the low rate of local relapses after tumor resection in pancreatic endocrine tumors despite the high frequency of neural invasion.

Cholangiocarcinoma of the perihilar, hilar, and extrahepatic bile ducts (collectively referred to as the large bile ducts) is an intractable disease, and a papillary phenotype and well-differentiated histologic grade have been proposed as indicators of a favorable prognosis after surgical resection. In this study, we examined the significance of matrix metalloproteinases (MMPs) in cholangiocarcinoma with respect to clinicopathologic features. We subjected 66 surgically resected specimens of cholangiocarcinoma of the large bile ducts to clinicopathologic examination, including postoperative survival, papillary phenotype, and immunohistochemical expression of MMP-2,-7, -9, and membrane type 1 MMP (MT1-MP). Nonneoplastic biliary epithelium did not express these 4 MMPs, whereas cholangiocarcinoma frequently expressed MMP-2 (33.9%), -7 (75.8%), -9 (47.5%), and MT1-MMP (54.5%). In particular, conventional (nonpapillary) cholangiocarcinoma expressed MMP-7 and MT1-MMP more frequently than papillary cholangiocarcinoma. The expression of MMP-7 and MT1-MMP significantly correlated with the nonpapillary phenotype, poorly differentiated histologic grade, perineural invasion, and advanced TNM stage. In contrast, the expression of MMP-2 and -9 was not associated with any of the clinicopathologic features. Univariate analysis of disease-specific survival revealed that a papillary phenotype and expression of MMP-7 were prognostic factors of cholangiocarcinoma, in addition to TNM stage, poorly differentiated histologic grade, perineural invasion, and microscopic margin status. Multivariate analysis showed only TNM stage to be an independent prognostic factor. Expression of MMP-7 in cholangiocarcinoma is an unfavorable postoperative prognostic factor of cholangiocarcinoma arising from the large bile ducts. Underexpression of MMPs in papillary cholangiocarcinoma might be associated with a favorable prognosis.

As there is a lack of hard data in the literature about many of the issues relating to diagnosing and reporting prostate cancer, we sought to survey current practices. A questionnaire was sent to 93 genitourinary pathologists with a response rate of 69%. Almost all respondents (95%) used formalin as fixative for needle biopsies. Unstained intervening sections were retained by 47%. Three levels of needle biopsies were used routinely by 63%. For verification of a diagnosis of cancer, high-molecular-weight cytokeratin was still the most commonly used immunohistochemical marker (91%), followed by p63 (58%) and alpha-methylacyl-CoA-racemase (50%). Features considered pathognomonic for cancer were glomeruloid bodies (58%), collagenous micronodules (64%), circumferential perineural invasion (84%), and growth in fat (36%). With none of these present, 39% required a minimum of 2 to 10 glands (median, 3) to diagnose cancer, whereas the others had no lower limit. A Gleason score was always given to even minute cancer foci by 86% and typically a Gleason score 6 was assigned (77%). Perineural invasion was mentioned by 86%. The extent of cancer on needle biopsies was quantified by all respondents with number of involved cores (80%) being the most commonly used measure. Linear extent was estimated by almost all, either as a percentage (80%) or millimeters of cancer length (41%) or both (22%). Measuring cancer from end to end or subtracting intervening benign tissue were almost equally common. For those general pathologists who would like to be in the mainstream of most urological pathologists, our survey data provide a guideline on how to diagnose and report prostate cancer.

"Flat" colorectal adenomas and adenocarcinomas are well documented in the Japanese literature but only sporadically reported in the English literature. The present study involved systematic morphological analysis of a large series of colorectal carcinomas (CRCs) to determine the frequency of these "flat" CRCs (FCRCs) and analyze their pathological characteristics and associated patient survival. The study group comprised 47 patients (19 females and 28 males) with primary CRC who underwent colorectal resection at the H. Lee Moffitt Cancer Center between 1997 and 2002. These cases were selected based on the gross appearance of the tumors and after review of all of the hematoxylin and eosin-stained tumor sections in a series of 190 consecutive colorectal resections for CRCs. Application of strict morphological criteria classified 22 tumors as FCRCs. For comparison, 25 "polypoid" CRCs (PCRCs) were also identified. Cases of ulcerative fungating annular CRCs and CRCs with mixed gross appearance were excluded from this analysis. Clinicopathologic data, including patient survival, were compared for FCRCS and PCRCs. Statistical analyses were carried out using the chi(2) or Fisher's exact test and log-rank tests. Overall, 22 of 190 CRCs (11%) were found to meet the morphological criteria of FCRCs. Mean patient age was 70.6 years (range, 55 to 87) for FCRCs versus 68.5 years (range, 54 to 91) for PCRCs, and mean tumor size was 4.7 cm (range, 1.6 to 9) for FCRCs versus 4.4 cm (range, 0.5 to 10) for PCRCs. None of the 22 FCRCs and only 1 of 25 (4%) PCRCs were well differentiated; 17 of 22 (77%) FCRCs and 23 of 25 (92%) PCRCs were moderately differentiated; and 5 of 22 (22%) FCRCs and 1 of 25 (4%) PCRCs were poorly differentiated (P = 0.0087). FCRC cases were staged as 0 stage T1, 3 (14%) stage T2, and 19 (86%) stage T3; PCRC cases, as 4 (16%) stage T1, 14 (56%) stage T2, and 7 (28%) stage 3 (P = 0.000031). Similarly, angiolymphatic invasion was identified in 12 of 22 (54%) FCRCs versus 4 of 25 (16%) PCRCs (P = 0.0123). Although some differences between FCRCs and PCRCs were observed on resection in terms of nodal status (N), presence of metastases (M), and perineural invasion, these differences were not statistically significant. In comparison with PCRCs, FCRCs were associated with significantly shorter postresection patient survival at 1 to 5 years (P = 0.028). We have demonstrated in this report that a proportion of primary CRCs resected at our institution were indeed "flat." Furthermore, these FCRCs exhibited higher histological grades, higher T stage, more frequent angiolymphatic invasion, and shorter patient survival compared with PCRCs. Based on these data, FCRC appears to be a worse subtype of colon cancer than PCRC. Further appraisal of FCRCs and additional studies to further elucidate the molecular mechanisms underlying their morphogenesis are warranted.