SIK2 attenuates proliferation and survival of breast cancer cells with simultaneous perturbation of MAPK and PI3K/Akt pathways.

Salt Inducible Kinase2 (SIK2) has been shown to contribute to tumorigenesis in multiple tumor types in a dichotomous manner. However, little is known about its contribution to breast malignancies. Here, we report SIK2 as a potential tumor suppressor in breast cancer whose expression was reduced in tumor tissues and breast cancer cell lines compared to normal counterparts. In vitro loss- and gain-of-function experiments combined with xenograft studies demonstrated that SIK2-mediated attenuation of proliferation and survival of breast cancer cells with parallel inhibition of both Ras/Erk and PI3K/Akt pathways. Our findings elucidated that SIK2 has also an inhibitory role in migration/invasion ability of breast cancer cells through regulation of epithelial mesenchymal transition. Immunostaining of patient tumors revealed that SIK2 protein level is frequently downregulated in invasive mammary carcinomas and negatively correlated with the mitotic activity of the cells in triple negative breast cancers and hormone positive tumors. Strikingly, patient survival analysis indicated that higher levels of SIK2 are significantly associated with better survival, especially in basal breast cancer cases. Overall, our findings suggest SIK2 as a potential tumor suppressor in the control of breast tumorigenesis, at least in part, via inhibiting PI3K/Akt and Ras/ERK signaling cascades simultaneously and a novel prognostic marker, especially in basal subtypes of breast cancer.

Increased micronucleus count predicts malignant behavior in pleural effusion fluid

Background/aim: Micronucleus (MN) frequency is used as a biomarker of chromosomal damage, genome instability, and cancer risk. The aim of this study was to evaluate the diagnostic usefulness of MN frequency to differentiate between malignant and benign pleural effusion samples. Materials and methods: Retrospectively, 78 pleural fluid cytology samples (including 20 cases of benign reactive mesothelial cells, 22 cases of suspicious cytology, and 36 cases of malignant cytology) were examined. The number of micronucleated cells in 1000 well- preserved cells was counted. Statistical tests were performed to compare the study groups. Recover operating characteristics (ROC) curve analysis was performed to suggest a cut-off value for predicting malignant behavior. Results: We evaluated a total of 78 cases of pleural effusion cytology. The number of micronucleated cells was significantly higher in cases with malignant outcome compared to cases with benign outcome. We observed that malignant samples had more micronucleated cells than suspicious ones, and suspicious cases had more micronucleated cells than reactive ones. There was a significant difference among all study groups. In addition, the frequency of MN-containing cells in suspicious cases correlates well with their outcomes. Conclusion: The results of this study reveal that there is an absolute, consistent, and proportional relationship between MN counts and malignancy in cytological samples of pleural effusions. MN scoring may be a helpful diagnostic tool for distinguishing malignant effusions from benign ones, and may be used as an adjunct tool to predict malignant behavior in challenging cases.

Interobserver reproducibility of tumor-infiltrating lymphocyte evaluations in breast cancer.

AIM: Tumor-infiltrating lymphocytes (TILs) have a prognostic value in breast cancer (BC); however, because of the lack of standard evaluation methods, we aimed to assess the interobserver agreement of stromal TILs (sTILs) and intratumoral TILs (iTILs) as well as the effect of hot spot areas and molecular subtyping on the overall agreement. METHODS: The study consisted of 121 haematoxylin and eosin (H and E)-stained slides of invasive BC samples obtained from the pathology archives. The TIL assessment was based on the International TIL Working Group recommendations for the percentage of sTILs and was conducted by four pathologists. The percentage of iTILs, the number of lymphocytes in hot spot areas (iTILs-HS), and the overall interobserver agreement for the molecular subtypes were evaluated. The interclass correlation coefficient (ICC) was used to assess interobserver agreement among the four pathologists. RESULTS:: The ICC score among the observers for the sTIL percentages was 0.74, and the individual ICC values for each molecular subtype were 0.55, 0.88, and 0.79 for luminal, HER2-positive, and triple-negative tumors, respectively. The compliance value for the iTILs was 0.29 (95% confidence interval (CI) = 0.06-0.48], whereas the compliance value for the iTILs-HS was 0.63 (95% CI = 0.49-0.71). The compliance values for the iTILs-HS subtypes were 0.72, 0.43, and 0.55 for luminal, HER2-positive, and triple-negative tumors, respectively. CONCLUSION: The IWTILG recommendations are reproducible and reliable. The interobserver agreement of the sTIL percentages was considerably higher for the triple-negative and HER2-positive cases than the luminal cases, whereas the interobserver agreement for the assessment of iTILs-HS in tumors was higher for the luminal subtype.

Micronuclei and nuclear buds: Highlighting overlooked indicators of chromosomal damage in thyroid aspiration smears.

BACKGROUND: We aimed to examine the diagnostic utility of micronuclei (MN) and nuclear buds (NBs) in aspiration smears of the well-differentiated epithelial lesions of thyroid. METHODS: One hundred five cases composed of 34 follicular nodular disease (FND), 31 Hashimoto's thyroiditis (HT), and 40 papillary thyroid carcinoma (PTC) were compiled retrospectively. May- Grünwald Giemsa (MGG) stained smears of each case were selected to count cells with nuclear protrusions (NPs) per 1000 cells. The frequency of cells with NPs (MN&NBs) was compared by using Mann-Whitney U test and Kruskal-Wallis tests when appropriate. Post-Hoc Tukey test was used for pairwise comparison of different diagnostic categories. By running a ROC curve analysis, diagnostic usefulness of the frequency of cells with NPs (MN&NBs) and their cut-off values to predict malignant behavior were calculated. P < 0.05 was regarded as significant. RESULTS: NPs (MN&NBs) were significantly more frequent in malignant cases than benign ones. NBs were more frequent in conventional PTC compared to FV of PTC, but the frequency of MN did not significantly differ between these. ROC curve analysis revealed that evaluation of the frequency of cells with NPs (MN&NBs) was a highly specific, sensitive, and diagnostically useful method to identify malignant behavior. CONCLUSION: To the best of our knowledge, this is the first study in the literature to evaluate the frequency of cells with NPs (MN&NBs) in human thyroid aspiration smears. Our results show that evaluation of NPs (MN&NBs) may be a useful diagnostic tool to detect PTC in thyroid aspiration smears. Diagn. Cytopathol. 2017;45:673-680. © 2017 Wiley Periodicals, Inc.

Immunohistochemical expression profiles of BRAF (V600E/VE1) in serrated colon polyps in Turkish population.

BACKGROUND AND AIM: Colon carcinoma, as one of the most common cancers, has been investigated for genetic alterations. Besides well-known adenoma-carcinoma sequence, it is recently found that BRAF mutation had an important role particularly in early stages of adenocarcinomas with serrated features. There are no any studies concerning immunohistochemical expression status of BRAF V600E (VE1) antibody in serrated polyps in the Turkish population. The objective of this study is to observe the immunohistochemical staining of BRAF V600E (VE1) antibody in colon polyps in the Turkish population and investigate the frequency of presence of mutated BRAF proteins indicating malignant potential. MATERIALS AND METHODS: 59 cases of serrated polyps (27 cases of hyperplastic polyps, 18 cases of sessile serrated adenoma/polyps and 14 cases of traditional serrated adenomas) and 10 tubular adenomas, and 10 samples of normal colonic mucosa were immunohistochemically evaluated for the presence of BRAF V600E mutated proteins with the VE1 antibody. Results were statistically compared. RESULTS: All SSA/Ps; 92.8% of TSAs; 37% of HPs were stained positively. Of the 27 hyperplastic polyps, all GCHPs were negative but 10 of 12 MVHPs (83.3%) were weakly positive with the VE1 antibody. Cases in control groups and tubular adenomas didn't show any cytoplasmic staining. CONCLUSION: Serrated adenoma/polyps have been gaining much more importance because of their malignant potential. Their frequency is also relatively high in the Turkish population and they should be carefully handled. Detection of BRAF V600E status can be easily achieved immunohistochemically by VE1 antibody. It is easily applicable and reproducible method and it might be helpful in identifying serrated lesions of the colon in addition to morphological features.

Ampullary carcinoma is often of mixed or hybrid histologic type: an analysis of reproducibility and clinical relevance of classification as pancreatobiliary versus intestinal in 232 cases.

Histologic classification of ampullary carcinomas as intestinal versus pancreatobiliary is rapidly becoming a part of management algorithms, with immunohistochemical classification schemes also being devised using this classification scheme as their basis. However, data on the reproducibility and prognostic relevance of this classification system are limited. In this study, five observers independently evaluated 232 resected ampullary carcinomas with invasive component >3 mm. Overall interobserver agreement was 'fair' (κ 0.39; P<0.001) with complete agreement in 23%. Using agreement by 3/5 observers as 'consensus' 40% of cases were classified as 'mixed' pancreatobiliary and intestinal. When observers were asked to provide a final diagnosis based on the predominant pattern in cases initially classified as mixed, there was 'moderate' agreement (κ 0.44; P<0.0001) with 5/5 agreeing in 35%. Cases classified as pancreatobiliary by consensus (including those with pure-pancreatobiliary or mixed-predominantly pancreatobiliary features) had shorter overall (median 41 months) and 5-year survival (38%) than those classified as pure-intestinal/mixed-predominantly intestinal (80 months and 57%, respectively; P=0.026); however, on multivariate analysis this was not independent of established prognostic parameters. Interestingly, when compared with 476 cases of pancreatic ductal adenocarcinomas, the pancreatobiliary-type ampullary carcinomas had better survival (16 versus 41 months, P<0.001), even when matched by size and node status. In conclusion, presumably because of the various cell types comprising the region, ampullary carcinomas frequently show mixed phenotypes and intratumoral heterogeneity, which should be considered when devising management protocols. Caution is especially warranted when applying this histologic classification to biopsies and tissue microarrays. While ampullary carcinomas with more pancreatobiliary morphology have a worse prognosis than intestinal ones this does not appear to be an independent prognostic factor. However, pancreatobiliary-type ampullary carcinomas have a much better prognosis than their pancreatic counterparts.

Spontaneous Acroangiodermatitis.

Acroangiodermatitis is a rare self-limited angioproliferative lesion which can be associated with congenital vascular malformations or acquired venous insufficiency. Despite of its benign character, differential diagnosis of this lesion is very important because it closely resembles Kaposi sarcoma. Here we present a 26-year-old male patient with unilateral, purplish-red colored papules on his right ankle which diagnosed as acroangiodermatitis and discuss histopathological features, differential diagnosis and treatment of this unusual condition.

Emerin expression in well differentiated epithelial lesions of thyroid: implications in papillary thyroid carcinoma diagnosis and predicting malignant behavior.

Recently, it has been reported that identifying nuclear membrane irregularities with anti-emerin antibody is useful for papillary thyroid carcinoma diagnosis. However, literature regarding the significance of emerin immunohistochemistry in thyroid is limited. We evaluated the diagnostic accuracy of the well-established nuclear alterations, nuclear protrusions and recently described nuclear shapes (garlands and star-like shapes) with emerin immunohistochemistry and hematoxylin- eosin stain in thyroid lesions. We further evaluated the diagnostic accuracy measures of tissue microarrays evaluated with both stains, to detect whether emerin immunohistochemistry improves the diagnostic accuracy for papillary thyroid carcinoma. For papillary thyroid carcinoma, pseudo- inclusions were best performers with emerin (diagnostic accuracy: 0.91), whereas with hematoxylin- eosin diagnostic accuracy of grooves was the highest (0.92). For follicular variant of papillary thyroid carcinoma, with both stains, predominately oval nuclear shape had the best diagnostic performance (diagnostic accuracy: 0.95). Nuclear protrusions were poor identifiers for papillary thyroid carcinoma. However, with emerin immunohistochemistry, they could successfully identify malignancy in 83% of the cases. Using emerin immunohistochemistry, in addition to hematoxylin- eosin improved the diagnostic accuracy for papillary thyroid carcinoma when compared to hematoxylin- eosin evaluation only (sensitivity: 0.70 vs 0.86, negative predictive value: 0.81 vs. 0.94, diagnostic accuracy: 0.87 vs. 0.94). Consistent with the previous literature, our findings indicate that emerin immunohistochemistry may be used as an adjunct diagnostic method to identify papillary thyroid carcinoma. Additionally, we suggest that nuclear protrusions detected with emerin imunohistochemistry may be used as indicators of malignant behavior in small tissue samples of thyroid.

Low-grade fibromyxoid sarcoma of the vagina: A tumor, not previously reported at this site.

This report presents the first case of low-grade fibromyxoid sarcoma (LGFMS) arising from the vaginal wall (a rare soft-tissue sarcoma of subfascial planes) and draws attention to differential diagnosis of masses arising from the vaginal wall. A patient presenting with abdominal pain to emergency department was diagnosed to have an ovarian mass filling the Douglas space. At laparoscopy, the origin of the mass was identified as the posterior vaginal wall. After vaginal excision of the gelatinous mass, pathologic diagnosis revealed a rare tumor, LGFMS. We discussed the differential diagnosis of vaginal LGFMS.

Tumoral and angiogenesis factors in hepatocellular carcinoma after locoregional therapy.

Locoregional therapy (LRT) is used as a bridge to orthotopic liver transplant (OLT) for hepatocellular carcinoma (HCC) patients. Liver explants in OLT patients with HCC were studied regarding both tumor stage, histology, and immunohistochemical staining for cytokeratin (CK)7, CK19, P53, Ki-67, and vascular endothelial growth factor (VEGF). Patients receiving no LRT (control) (n=30) were compared with LRT treatment groups with conventional transarterial chemoembolization (cTACE) (n=25) or drug-eluting bead transarterial chemoembolization (DEB TACE) (n=17). Tumor stage and histology were similar between treatment and control groups. The mean percent necrosis was significantly higher for treatment groups versus the control group (p<0.0001 for both groups versus control) and was significantly higher in the cTACE group versus the DEB TACE group. Only the DEB TACE group showed peritumoral CK19 positivity, and tumors were all CK19-negative. Using a threshold of 50% of tumoral cells, tumoral VEGF was significantly different between groups, with the control group having the highest degree of positivity; however, peritumoral VEGF was not significantly different between the groups. The Ki-67 proliferation fraction was higher in the treated groups with a statistically significant difference between the DEB-treated group and those without treatment (p=0.02). There were no statistically significant differences in tumoral or peritumoral CK7 or p53. Percent necrosis and percent Ki-67 positivity were higher with LRT, with a significant difference between groups for percent necrosis, confirming that LRT causes necrosis and suggesting that treatment leads to increased proliferation and decreased tumoral VEGF.

Differential expression of ERCC1 in pancreas adenocarcinoma: high tumor expression is associated with earlier recurrence and shortened survival after resection.

BACKGROUND: Increased tumor expression of excision repair cross-complementing gene-1 (ERCC1) is associated with decreased survival in patients with various cancers. Its effect in pancreatic adenocarcinoma (PAC) is not defined. METHODS: Ninety-five patients were selected from a prospective database of all patients (n = 220) who underwent pancreaticoduodenectomy for PAC between January 2000 and October 2008. Tumor was isolated to perform immunohistochemistry for ERCC1 expression and was graded by a single pathologist. Main outcomes were recurrence-free survival (RFS) and overall survival (OS). RESULTS: Median age was 63 years; 50 patients (53%) were male and 73 (77%) received adjuvant chemotherapy. Median follow-up was 25 months. Median RFS and OS was 9 and 16 months. Median tumor size was 3 cm; 26% had a positive resection margin, 34% had poorly differentiated tumors, 61% had positive lymph nodes, 88% had perineural invasion, and 45% had lymphovascular invasion. Tumors exhibited differential ERCC1 expression in terms of intensity staining [none-weak: 61%; moderate-strong: 39%], percentage staining [0: 39%; 1-10: 29%; 11-50: 20%; 51-100: 12%], and overall expression [low: 84%; high: 16%]. High ERCC1 expression was associated with reduced RFS (6 vs. 10 months; P = 0.03) and decreased OS (9 vs. 18 months; P = 0.019). After accounting for adverse tumor factors, high ERCC1 expression persisted as a negative prognostic factor on multivariate Cox regression for both RFS and OS [hazards ratio (HR), 2.1; 95% confidence interval (CI), 1.1-3.9; P = 0.02; HR, 3; 95% CI, 1.6-6; P = 0.001, respectively]. A subset analysis of only those 73 patients who received adjuvant therapy revealed the same negative effect of high ERCC1 expression on RFS (4 vs. 15 months; P = 0.001) and OS (9 vs. 20 months; P < 0.001). CONCLUSIONS: Pancreas cancer exhibits differential expression of ERCC1. High ERCC1 expression is associated with both reduced RFS and OS after resection. ERCC1 expression levels may help to predict patient outcome with adjuvant chemotherapy.

Serious skin reaction associated with imatinib in a patient with chronic myeloid leukemia.

Imatinib mesylate (STI 571) is one of the fundamental chemotherapeutic agents used in the treatment of the chronic, accelerated and blastic phases of chronic myelocytic leukemia (CML), gastrointestinal stromal tumors and Philadelphia chromosome-positive acute lymphoblastic leukemia. It selectively inhibits receptor tyrosine kinases. Its effects limit the use of this drug. We present a case with a serious skin reaction requiring the discontinuation of the drug and that developed in relation to imatinib therapy. Six months prior, a 61-year-old male patient presenting to the hematology polyclinic with complaints of weight loss and sweating was hospitalized due to high leukocyte value. As a result of the hemogram, biochemistry analyses, peripheral blood smear examination, bone marrow aspiration evaluation, cytogenetic examination using FISH and PCR that were performed, CML was diagnosed. Additionally, to exclude myelofibrosis, we examined a bone marrow biopsy. Imatinib mesylate was started at 400 mg/day orally. In the fourth month of treatment, the patient complained of itching and a skin rash. Although the drug dose was reduced (300 mg/day), his complaints gradually increased. The skin biopsy result was superficial perivascular dermatitis. Imatinib was discontinued, and the patient was started on corticosteroid. The lesions disappeared completely. A month later, the patient was restarted on imatinib mesylate. However, the lesions recurred more prominently. His itching increased. The patient was considered intolerant to imatinib mesylate, and a second-generation tyrosine kinase inhibitor, dasatinib 100 mg/day, was started orally. The follow-up and treatment continues for the patient, who has been taking dasatinib 100 mg/day for the last two months without any skin finding or complaints. Imatinib mesylate-induced skin reactions are associated with the pharmacologic effect of the drug rather than hypersensitivity to the drug. Skin reactions are frequently observed, and this side effect is dose dependent. However, the interesting aspect of our case was that despite dose reduction, skin findings gradually increased, and eventually the drug had to be discontinued.

Intra-ampullary papillary-tubular neoplasm (IAPN): characterization of tumoral intraepithelial neoplasia occurring within the ampulla: a clinicopathologic analysis of 82 cases.

BACKGROUND: There has been no uniform terminology for systematic analysis of mass-forming preinvasive neoplasms (which we term tumoral intraepithelial neoplasia) that occur specifically within the ampulla. Here, we provide a detailed analysis of these neoplasms, which we propose to refer to as intra-ampullary papillary-tubular neoplasm (IAPN). MATERIALS AND METHODS: Three hundred and seventeen glandular neoplasms involving the ampulla were identified through a review of 1469 pancreatoduodenectomies and 11 ampullectomies. Eighty-two neoplasms characterized by substantial preinvasive exophytic component that grew almost exclusively (>75%) within the ampulla (in the ampullary channel or intra-ampullary portions of the very distal segments of the common bile duct or pancreatic duct) were analyzed. RESULTS: (1) Clinical: The mean age was 64 years, male/female ratio was 2.4, and mean tumor size was 2.7 cm. (2) Pathology: The tumors had a mixture of both papillary and tubular growth (each constituting at least 25% of the lesion) in 57%; predominantly (>75%) papillary in 23%, and predominantly (>75%) tubular in 20%. High-grade dysplasia was present in 94% of cases, of which 39% showed focal (<25% of the lesion), 28% showed substantial (25% to 75%), and 27% showed extensive (>75%) high-grade dysplasia. In terms of cell-lineage morphology, 45% had a mixture of patterns. However, when evaluated with a forced-binary approach as intestinal (INT) versus gastric/pancreatobiliary (GPB) based on the predominant pattern, 74% were classified as INT and 26% as GPB. (3) Immunohistochemistry: Percent sensitivity/specificity of cell-lineage markers were, for INT phenotype: MUC2 85/78 and CDX2 94/61; and for GBP: MUC1 89/79, MUC5AC 95/69, and MUC6 83/76, respectively. Cytokeratin 7 and 20 were coexpressed in more than half. (4) Invasive carcinoma: In 64 cases (78%), there was an associated invasive carcinoma. Size of the tumor and amount of dysplasia correlated with the incidence of invasion. Invasive carcinoma was of INT-type in 58% and of pancreatobiliary-type in 42%. Cell lineage in the invasive component was the same as that of the preinvasive component in 84%. All discrepant cases were pancreatobiliary-type invasions, which occurred in INT-type preinvasive lesions. (5) OUTCOME: The overall survival of invasive cases were significantly worse than that of noninvasive ones (57% vs. 93%; P=0.01); and 3 years, 69% versus 100% (P=0.08); and 5 years, 45% versus 100% (P=0.07), respectively. When compared with 166 conventional invasive carcinomas of the ampullary region, invasive IAPNs had significantly better prognosis with a mean survival of 51 versus 31 months (P<0.001) and the 3-year survival of 69% versus 44% (P<0.01). CONCLUSIONS: Tumoral intraepithelial neoplasia occurring within the ampulla are highly analogous to pancreatic or biliary intraductal papillary and tubular neoplasms as evidenced by their papillary and/or tubular growth, variable cell lineage, and spectrum of dysplastic change (adenoma-carcinoma sequence), and thus we propose to refer to these as IAPN. IAPNs are biologically indolent; noninvasive examples show an excellent prognosis, whereas those with invasion exhibit a malignant but nevertheless significantly better prognosis than typical invasive ampullary carcinomas unaccompanied by IAPNs. Twenty eight percent (64 of 230) of invasive carcinomas within the ampulla arise in association with IAPNs.

Tumor budding as a strong prognostic indicator in invasive ampullary adenocarcinomas.

Prognostication of invasive ampullary adenocarcinomas (AACs) and their stratification into appropriate management categories have been highly challenging owing to a lack of well-established predictive parameters. In colorectal cancers, recent studies have shown that tumor budding confers a worse prognosis and correlates significantly with nodal metastasis and recurrence; however, this has not been evaluated in AAC.To investigate the prevalence, significance, and clinical correlations of tumor budding in AAC, 244 surgically resected, stringently defined, invasive AAC were analyzed for tumor budding---defined as the presence of more than or equal to 5 isolated single cancer cells or clusters composed of fewer than 5 cancer cells per field measuring 0.785 mm using a 20× objective lens in the stroma of the invasive front. The extent of the budding was then further classified as "high" if there were greater than or equal to 3 budding foci and as "low" if there were <3 budding foci or no budding focus.One hundred ninety-four AACs (80%) were found to be high-budding and 50 (20%) were low-budding. When the clinicopathologic features and survival of the 2 groups were compared, the AACs with high-budding had larger invasion size (19 mm vs. 13 mm; P<0.001), an unrecognizable/absent preinvasive component (57% vs. 82%; P<0.005), infiltrative growth (51% vs. 2%; P<0.001), nonintestinal-type histology (72% vs. 46%; P<0.001), worse differentiation (58% vs. 10%; P<0.001), more lymphatic (74% vs. 10%; P<0.001), and perineural invasion (28% vs. 2%; P<0.001); more lymph node metastasis (44% vs. 17%; P<0.001), higher T-stage (T3 and T4) (42% vs. 10%; P<0.001), and more aggressive behavior (mean survival: 50 mo vs. 32 mo; 3-year and 5-year survival rates: 93% vs. 41% and 68% vs. 24%, respectively; P<0.001). Furthermore, using a multivariable Cox regression model, tumor budding was found to be an independent predictor of survival (P=0.01), which impacts prognosis (hazard ratio: 2.6) even more than T-stage and lymph node metastasis (hazard ratio: 1.9 and 1.8, respectively).In conclusion, tumor budding is frequently encountered in AAC. High-budding is a strong independent predictor of overall survival, with a prognostic correlation stronger than the 2 established parameters: T-stage and lymph node metastasis. Therefore, budding should be incorporated into surgical pathology reports for AAC.

Giant and complicated variants of cystic bile duct hamartomas of the liver: MRI findings and pathological correlations.

PURPOSE: To describe a new category of liver cyst we propose calling "giant bile duct hamartoma (giant-BDH)" and to provide a more complete record of the magnetic resonance imaging (MRI) features of BDHs with potential for clinical impact. MATERIALS AND METHODS: This study was Institutional Review Board (IRB)-approved and Health Insurance Portability and Accountability Act (HIPPA)-compliant. Fifteen patients were identified with surgical liver pathology in keeping with complicated BDH and MRI findings of giant cysts. RESULTS: In all, 14/15 patients presented with pain that resolved in 14/14 with surgery. Imaging features common to pretreatment cysts included sharply defined, lobulated margins with thin, smooth rim-enhancement. Treated symptomatic cysts measured 9.8 cm on average and 21.6 cm maximum. The 14/15 patients had coexistent <2.0 cm BDH. Elevated T1 signal corresponded with hemorrhagic cyst content (10/15 patients); cyst-wall rim-enhancement corresponded with histological findings of inflammation (15/15), fibrocystic changes (12/15), and smaller BDH in the adjacent liver (13/15). Histology of giant-BDH cyst walls corresponded with complicated BDH in 15/15. The incidence of symptomatic-treated BDH at our institution was 0.4%. CONCLUSION: BDH is a benign hepatic cystic lesion that may undergo cystic enlargement, internal hemorrhage, and clinically present with abdominal pain treatable by minimally invasive laparoscopic fenestration. Complicated giant-BDH coexists with smaller BDH and the MRI features of giant-BDH are characteristic.

Preferential expression of MUC6 in oncocytic and pancreatobiliary types of intraductal papillary neoplasms highlights a pyloropancreatic pathway, distinct from the intestinal pathway, in pancreatic carcinogenesis.

UNLABELLED: The expression of different MUC glycoproteins has helped define cellular lineage in variety of pancreatic neoplasms, and has helped identify distinct carcinogenic pathways such as the intestinal pathway characterized by diffuse/strong MUC2/CDX2 expression in intestinal-type intraductal papillary mucinous neoplasms (IPMNs) and their associated colloid carcinomas (CCs). In this study, the expression profile of MUC6, a pyloric-type mucin, was investigated in both preinvasive and invasive pancreatic neoplasia. Florid papillary ("in-situ") components of 9 intraductal oncocytic papillary neoplasms (IOPNs), 24 IPMNs, and 7 mucinous cystic neoplasms (MCNs), were analyzed immunohistochemically for MUC6 expression, as were 15 PanINs, 112 usual invasive ductal adenocarcinomas (DAs), and 14 CCs. In PanINs, MUC6 expression was limited to the very early areas of PanIN-1A that typically have pyloric features. Expression was lost in later stages. Similarly, in IOPNs or IPMNs or MCNs, MUC6 expression was detectable in the cystic or flat areas that have pyloric-like histology. However, in the more advanced (papillary) components of these neoplasms, MUC6 expression was mostly limited to the "cuboidal-cell" but was not seen in the "columnar-cell" phenotype: there was diffuse or strong expression in 8/9 IOPN and, relatively weaker but consistent expression in all 6/6 pancreatobiliary-type IPMNs; whereas virtually no expression in villous or intestinal-type IPMNs. The 7/8 gastric or foveolar-type IPMNs were also negative; in the single case with positivity, the labeling was limited to high-grade dysplastic areas. Interestingly, the papillae in MCNs were also mostly negative. Among invasive carcinomas, 39/112 DAs and only 1/14 CC expressed MUC6. In DA, the expression did not correlate with survival (P=0.94), or any of the markers of aggressiveness: more than 2-cm tumor size (P=0.76), positive surgical margins (P=0.27), lymph node metastasis (P=0.82), or high grade (P=0.08). IN CONCLUSION: (1) The expression of MUC6 in oncocytic and pancreatobiliary-type neoplasms but not in villous or intestinal-type neoplasms supports the presence of a pyloropancreatic pathway distinct from the MUC2/CDX2 expressing intestinal pathway in intraductal papillary neoplasia. (2) MUC6 expression is present in the earliest (nonpapillary) form of any type of preinvasive neoplasia regardless of whether it is PanIN or IOPN or IPMN or MCN suggesting that these entities may share some characteristics early on, but evolve along divergent pathways as they progress.

Important prognostic factors in adenocarcinoma of the ampulla of Vater.

Ampullary adenocarcinoma (AmpCA) carries a better overall survival (OS) rate than other periampullary cancers. We examined clinicopathologic features in AmpCA for impact on OS. Records of patients undergoing pancreaticoduodenectomy from 2000 to 2007 for AmpCA were reviewed and histological specimens were reanalyzed. Of 302 patients undergoing pancreaticoduodenectomy for malignancy, 45 (14.9%) had AmpCA. Mean age was 61.3 +/- 12.2 years, mean tumor size was 2.6 +/- 1.3 cm, 57 per cent were > or = T3 tumors, 42 per cent were N1 stage, 13 (49%) had perineural invasion (PNI), and 29 (64%) had lymphovascular invasion (LVI). Thirteen were intestinal (29%), 14 were pancreaticobiliary (31%), and 18 were mixed (40%). Median OS was 42 months (range 4-80 mos). On log rank testing, > or = T3 (24 vs 65 mos, P < 0.01), N1 (25 vs 61 mos, P < 0.01), poor differentiation (24 vs 44 mos, P = 0.01), pancreaticobiliary subtype (23 vs 44 mos, P = 0.01), and PNI (23 vs 44 mos, P < 0.01) were significant for worse survival. By multivariate analysis, N1 disease (hazard ratio [HR] 4.50, 95% confidence interval [CI] 1.16-17.40) and PNI (HR 4.62, CI 1.11-19.21) maintained associations with worse survival, whereas histological subtype did not. N1 disease and presence of PNI demonstrated independent associations with worse survival. Given high percentage of mixed histology, PNI may be more informative than the subtype in predicting outcome for patients with AmpCA.

Pancreatic cysts: pathologic classification, differential diagnosis, and clinical implications.

CONTEXT: Cystic lesions of the pancreas are being recognized with increasing frequency and have become a more common finding in clinical practice because of the widespread use of advanced imaging modalities and the sharp drop in the mortality rate of pancreatic surgery. Consequently, in the past 2 decades, the nature of many cystic tumors in this organ has been better characterized, and significant developments have taken place in the classification and in our understanding of pancreatic cystic lesions. OBJECTIVE: To provide an overview of the current concepts in classification, differential diagnosis, and clinical/biologic behavior of pancreatic cystic tumors. DATA SOURCES: The authors' personal experience, based on institutional and consultation materials, combined with an analysis of the literature. CONCLUSIONS: In contrast to solid tumors, most of which are invasive ductal adenocarcinomas with dismal prognosis, cystic lesions of the pancreas are often either benign or low-grade indolent neoplasia. However, those that are mucinous, namely, intraductal papillary mucinous neoplasms and mucinous cystic neoplasms, constitute an important category because they have well-established malignant potential, representing an adenoma-carcinoma sequence. Those that are nonmucinous such as serous tumors, congenital cysts, lymphoepithelial cysts, and squamoid cyst of pancreatic ducts have no malignant potential. Only rare nonmucinous cystic tumors that occur as a result of degenerative/necrotic changes in otherwise solid neoplasia, such as cystic ductal adenocarcinomas, cystic pancreatic endocrine neoplasia, and solid-pseudopapillary neoplasm, are also malignant and have variable degrees of aggressiveness.

Isolated solitary ducts (naked ducts) in adipose tissue: a specific but underappreciated finding of pancreatic adenocarcinoma and one of the potential reasons of understaging and high recurrence rate.

The distinction of ductal adenocarcinoma from chronic pancreatitis remains one of the most difficult challenges in surgical pathology. The glandular units of invasive carcinoma are often well formed with well-polarized cells, appearing deceptively benign. Conversely, the ducts of chronic pancreatitis may be atypical and pseudoinfiltrative as a result of acinar atrophy and fibrosis. We recently noted isolated solitary ductal units (ISDs) in adipose tissue to be a reliable indicator of adenocarcinoma. In this study, the frequency of ISDs was investigated in 105 pancreatic resections with ductal adenocarcinoma and 32 with chronic pancreatitis only. ISD was defined as a solitary gland lying individually in adipose tissue, either directly abutting adipocytes or separated from them by only a thin rim of fibromuscular tissue. ISD was detected in 50/105 (47.6%) of pancreatic resections for ductal adenocarcinoma, but not in any resections with chronic pancreatitis only (specificity 100%; sensitivity 47.6%). Most of the ISDs were very well differentiated and cytologically bland. A small subset of these units represented vascular invasion, in which the carcinoma cells epithelialized the vessel lining, transforming the vessel into a duct-like structure, virtually indistinguishable from normal ducts or PanINs. The vascular nature of these units was verified by Elastic-Van Gieson stain and muscular markers highlighting the elastic lamina and muscular wall, respectively. ISDs were often located in histologic sections taken for the evaluation of the retroperitoneal margin and pancreatic-free surfaces where adipose tissue is more abundant. In conclusion, ISD lying in adipose tissue unaccompanied by other elements, present in 47.6% of pancreatic resections when peripancreatic soft tissues away from the tumor are sampled, is a very specific finding for carcinoma that may be instrumental in the diagnosis and staging of carcinoma as well as margin evaluation.

The number of lymph nodes identified in a simple pancreatoduodenectomy specimen: comparison of conventional vs orange-peeling approach in pathologic assessment.

Lymph node status is one of the most important predictors of survival in resectable pancreatic ductal adenocarcinoma; therefore, thorough lymph node evaluation is a critical assessment in pancreatoduodenectomy specimens. There is considerable variability in pancreatoduodenectomy specimens processed histologically. This study compares two approaches of lymph node dissection and evaluation (standard vs orange peeling) of pancreatoduodenectomy specimens. A different approach to dissection of pancreatoduodenectomy specimens was designed to optimize lymph node harvesting: All peripancreatic soft tissues were removed in an orange-peeling manner before further dissection of the pancreatic head. This approach was applied to 52 consecutive pancreatoduodenectomy specimens performed for ductal adenocarcinoma at two institutions. Specimen dissection was otherwise performed routinely. Overall number of lymph nodes harvested, number of positive lymph nodes, and their anatomic distribution were analyzed and compared with cases that had been dissected by the conventional approach. The mean number of lymph nodes identified by the orange-peeling approach was 14.1 (by institution, 13.8 and 14.4), as opposed to 6.1 (by institution, 7 and 5.3) in cases processed by conventional approach (P=0.0001). The number of lymph node-positive cases also increased substantially from 50% (by institution, 54 and 46%) in the conventional method to 73% (by institution, 88 and 58%) in the orange-peeling method (P=0.02). The orange-peeling method of lymph node harvest in pancreatoduodenectomy specimens for ductal adenocarcinoma enhances overall and positive lymph node yield and optimizes ductal adenocarcinoma staging. Therefore, lymph node harvest by the orange-peeling method should be performed routinely before specimen sectioning in assessment of pancreatoduodenectomy for ductal adenocarcinoma.