Adenomyomas of the Gallbladder: An Analysis of Frequency, Clinicopathologic Associations, and Relationship to Carcinoma of a Malformative Lesion.

CONTEXT.­: The nature and associations of gallbladder (GB) "adenomyoma" (AM) remain controversial. Some studies have attributed up to 26% of GB carcinoma to AMs. OBJECTIVE.­: To examine the true frequency, clinicopathologic characteristics, and neoplastic changes in GB AM. DESIGN.­: Cholecystectomy cohorts analyzed were 1953 consecutive cases, prospectively with specific attention to AM; 2347 consecutive archival cases; 203 totally embedded GBs; 207 GBs with carcinoma; and archival search of institutions for all cases diagnosed as AM. RESULTS.­: Frequency of AM was 9.3% (19 of 203) in totally submitted cases but 3.3% (77 of 2347) in routinely sampled archival tissue. A total of 283 AMs were identified, with a female to male ratio = 1.9 (177:94) and mean size = 1.3 cm (range, 0.3-5.9). Most (96%, 203 of 210) were fundic, with formed nodular trabeculated submucosal thickening, and were difficult to appreciate from the mucosal surface. Four of 257 were multifocal (1.6%), and 3 of 257 (1.2%) were extensive ("adenomyomatosis"). Dilated glands (up to 14 mm), often radially converging to a point in the mucosa, were typical. Muscle was often minimal, confined to the upper segment. Nine of 225 (4%) revealed features of a duplication. No specific associations with inflammation, cholesterolosis, intestinal metaplasia, or thickening of the uninvolved GB wall were identified. Neoplastic change arising in AM was seen in 9.9% (28 of 283). Sixteen of 283 (5.6%) had mural intracholecystic neoplasm; 7 of 283 (2.5%) had flat-type high-grade dysplasia/carcinoma in situ. Thirteen of 283 cases had both AM and invasive carcinoma (4.6%), but in only 5 of 283 (1.8%), carcinoma arose from AM (invasion was confined to AM, and dysplasia was predominantly in AM). CONCLUSIONS.­: AMs have all the features of a malformative developmental lesion, and may not show a significant muscle component (ie, the name "adeno-myoma" is partly a misnomer). While most are innocuous, some pathologies may arise in AMs, including intracholecystic neoplasms, flat-type high-grade dysplasia or carcinoma in situ, and invasive carcinoma (1.8%, 5 of 283). It is recommended that gross examination of GBs include serial slicing of the fundus for AM detection and total submission if one is found.

Reappraisal of T1b gallbladder cancer (GBC): clinicopathologic analysis of 473 in situ and invasive GBCs and critical review of the literature highlights its rarity, and that it has a very good prognosis.

There are highly conflicting data on relative frequency (2-32%), prognosis, and management of pT1b-gallbladder carcinoma (GBC), with 5-year survival ranging from > 90% in East/Chile where cholecystectomy is regarded as curative, versus < 50% in the West, with radical operations post-cholecystectomy being recommended by guidelines. A total of 473 in situ and invasive extensively sampled GBCs from the USA (n = 225) and Chile (n = 248) were re-evaluated histopathologically per Western invasiveness criteria. 349 had invasive carcinoma, and only 24 were pT1. Seven cases previously staged as pT1b were re-classified as pT2. There were 19 cases (5% of all invasive GBCs) qualified as pT1b and most pT1b carcinomas were minute (< 1mm). One patient with extensive pTis at margins (but pT1b focus away from the margins) died of GBC at 27 months, two died of other causes, and the remainder were alive without disease (median follow-up 69.9 months; 5-year disease-specific survival, 92%). In conclusion, careful pathologic analysis of well-sampled cases reveals that only 5% of invasive GBCs are pT1b, with a 5-year disease-specific survival of > 90%, similar to findings in the East. This supports the inclusion of pT1b in the "early GBC" category, as is typically done in high-incidence regions. Pathologic mis-staging of pT2 as pT1 is not uncommon. Cases should not be classified as pT1b unless extensive, preferably total, sampling of the gallbladder to rule out a subtle pT2 is performed. Critical appraisal of the literature reveals that the Western guidelines are based on either SEER or mis-interpretation of stage IB cases as "pT1b." Although the prognosis of pT1b-GBC is very good, additional surgery (radical cholecystectomy) may be indicated, and long-term surveillance of the biliary tract is warranted.

Hepatic Cysts: Reappraisal of the Classification, Terminology, Differential Diagnosis, and Clinicopathologic Characteristics in 258 Cases.

The literature on liver cysts is highly conflicting, mostly owing to definitional variations. Two hundred and fifty-eight ≥1 cm cysts evaluated pathologically using updated criteria were classifiable as: I. Ductal plate malformation related (63%); that is, cystic bile duct hamartoma or not otherwise specified-type benign biliary cyst (35 with polycystic liver disease). These were female predominant (F/M=2.4), large (10 cm), often multifocal with degenerative/inflammatory changes and frequently misclassified as "hepatobiliary cystadenoma." II. Neoplastic (13%); 27 (10.5%) had ovarian-type stroma (OTS) and qualified as mucinous cystic neoplasm (MCN) per World Health Organization (WHO). These were female, solitary, mean age 52, mean size 11 cm, and 2 were associated with carcinoma (1 in situ and 1 microinvasive). There were 3 intraductal papillary neoplasms, 1 intraductal oncocytic papillary neoplasm, 1 cystic cholangiocarcinoma, and 2 cystic metastasis. III. Infectious/inflammatory (12%). These included 23 hydatid cysts (including 2 Echinococcus alveolaris both misdiagnosed preoperatively as cancer), nonspecific inflammatory cysts (abscesses, inflammatory cysts: 3.4%). IV. Congenital (7%). Mostly small (<3 cm); choledochal cyst (5%), foregut cyst (2%). V. Miscellaneous (4%). In conclusion, hepatic cysts occur predominantly in women (3/1), are mostly (90%) non-neoplastic, and seldom (<2%) malignant. Cystic bile duct hamartomas and their relative not otherwise specified-type benign biliary cysts are frequently multifocal and often misdiagnosed as "cystadenoma/carcinoma." Defined by OTS, MCNs (the true "hepatobiliary cystadenoma/carcinoma") are solitary, constitute only 10.5% of hepatic cysts, and have a significantly different profile than the impression in the literature in that essentially all are perimenopausal females, and rarely associated with carcinoma (7%). Since MCNs can only be diagnosed by demonstration of OTS through complete microscopic examination, it is advisable to avoid the term "cystadenoma/cystadenocarcinoma" solely based on radiologic examination, and the following simplified terminology would be preferable in preoperative evaluation to avoid conflicts with the final pathologic diagnosis: (1) noncomplex (favor benign), (2) complex (in 3 subsets, as favor benign, cannot rule out malignancy, or favor malignancy), (3) malignant features.

Sarcomatoid carcinomas of the gallbladder: clinicopathologic characteristics.

Sarcomatoid carcinomas recently came into the spotlight through genetic profiling studies and also as a distinct model of epithelial-mesenchymal transition. The literature on sarcomatoid carcinomas of gallbladder is limited. In this study, 656 gallbladder carcinomas (GBC) were reviewed. Eleven (1.7%) with a sarcomatoid component were identified and analyzed in comparison with ordinary GBC (O-GBC). Patients included 9 females and 2 males (F/M = 4.5 vs. 3.9) with a mean age-at-diagnosis of 71 (vs. 64). The median tumor size was 4.6 cm (vs. 2.5; P = 0.01). Nine patients (84%) presented with advanced stage (pT3/4) tumor (vs. 48%). An adenocarcinoma component constituting 1-75% of the tumor was present in nine, and eight had surface dysplasia/CIS; either in situ or invasive carcinoma was present in all cases. An intracholecystic papillary-tubular neoplasm was identified in one. Seven showed pleomorphic-sarcomatoid pattern, and four showed subtle/bland elongated spindle cells. Three had an angiosarcomatoid pattern. Two had heterologous elements. One showed few osteoclast-like giant cells, only adjacent to osteoid. Immunohistochemically, vimentin, was positive in six of six; P53 expression was > 60% in six of six, keratins in six of seven, and p63 in two of six. Actin, desmin, and S100 were negative. The median Ki67 index was 40%. In the follow-up, one died peri-operatively, eight died of disease within 3 to 8 months (vs. 26 months median survival for O-GBC), and two were alive at 9 and 15 months. The behavior overall was worse than ordinary adenocarcinomas in general but was not different when grade and stage were matched. In summary, sarcomatoid component is identified in < 2% of GBC. Unlike sarcomatoid carcinomas in the remainder of pancreatobiliary tract, these are seldom of the "osteoclastic" type and patients present with large/advanced stage tumors. Limited data suggests that these tumors are aggressive with rapid mortality unlike pancreatic osteoclastic ones which often have indolent behavior.

Hepatobiliary Mucinous Cystic Neoplasms With Ovarian Type Stroma (So-Called "Hepatobiliary Cystadenoma/Cystadenocarcinoma"): Clinicopathologic Analysis of 36 Cases Illustrates Rarity of Carcinomatous Change.

The literature is highly conflicting on hepatobiliary mucinous cystic neoplasms (MCNs), aka "hepatobiliary cystadenoma/cystadenocarcinoma," largely because ovarian stroma (OS) was not a requirement until WHO-2010 and is not widely applied even today. In this study, MCNs (with OS) accounted for 24 of 229 (11%) resected hepatic cysts in one institution. Eight of the 32 (25%) cysts that had been originally designated as hepatobiliary cystadenoma/cystadenocarcinoma at the time of diagnosis proved not to have an OS during this review and were thus re-classified as non-MCN. In total, 36 MCNs (with OS) were analyzed-24 from the institutional files and 12 consultation cases. All were women. Mean age was 51 (28 to 76 y). Mean size was 11 cm (5 to 23 cm). Most (91%) were intrahepatic and in the left lobe (72%). Preoperative imaging mentioned "neoplasm" in 14 (47%) and carcinoma was a differential in 6 (19%) but only 2 proved to have carcinoma. Microscopically, only 47% demonstrated diffuse OS (>75% of the cyst wall/lining); OS was often focal. The cyst lining was often composed of non-mucinous biliary epithelium, and this was predominant in 50% of the cases. Degenerative changes of variable amount were seen in most cases. In situ and invasive carcinoma was seen in only 2 cases (6%), both with small invasion (7 and 8 mm). Five cases had persistence/recurrence, 2 confirmed operatively (at 7 mo and 15 y). Of the 2 cases with carcinoma, one had "residual cyst or hematoma" by radiology at 4 months, and the other was without disease at 3 years. In conclusion, many cysts (25%) previously reported as hepatobiliary cystadenoma/cystadenocarcinoma are not MCNs. True MCNs are uncommon among resected hepatic cysts (11%), occur exclusively in females, are large, mostly intrahepatic and in the left lobe (72%). Invasive carcinomas are small and uncommon (6%) compared with their pancreatic counterpart (16%). Recurrences are not uncommon following incomplete excision.

Adenocarcinoma ex-goblet cell carcinoid (appendiceal-type crypt cell adenocarcinoma) is a morphologically distinct entity with highly aggressive behavior and frequent association with peritoneal/intra-abdominal dissemination: an analysis of 77 cases.

High-grade versions of appendiceal goblet cell carcinoids ('adenocarcinoma ex-goblet cell carcinoids') are poorly characterized. We herein document 77 examples. Tumors occurred predominantly in females (74%), mean age 55 years (29-84), most with disseminated abdominal (77% peritoneal, 58% gynecologic tract involvement) and stage IV (65%) disease. Many presented to gynecologic oncologists, and nine had a working diagnosis of ovarian carcinoma. Metastases to liver (n=3) and lung (n=1) were uncommon and none arose in adenomatous lesions. Tumors had various histologic patterns, in variable combinations, most of which were fairly specific, making them recognizable as appendiceal in origin, even at metastatic sites: I: Ordinary goblet cell carcinoid/crypt pattern (rounded, non-luminal acini with well-oriented goblet cells), in variable amounts in all cases. II: Poorly cohesive goblet cell pattern (diffusely infiltrative cords/single files of signet ring-like/goblet cells). III: Poorly cohesive non-mucinous cell (diffuse-infiltrative growth of non-mucinous cells). IV: Microglandular (rosette-like glandular) pattern without goblet cells. V: Mixed 'other' carcinoma foci (including ordinary intestinal/mucinous). VI: goblet cell carcinoid pattern with high-grade morphology (marked nuclear atypia). VII: Solid sheet-like pattern punctuated by goblet cells/microglandular units. Ordinary nested/trabecular ('carcinoid pattern') was very uncommon. In total, 33(52%) died of disease, with median overall survival 38 months and 5-year survival 32%. On multivariate analysis perineural invasion and younger age (<55) were independently associated with worse outcome while lymph-vascular invasion, stage, and nodal status trended toward, but failed to reach, statistical significance. Worse behavior in younger patients combined with female predilection and ovarian-affinity raise the possibility of hormone-assisted tumor progression. In conclusion, 'adenocarcinoma ex-goblet cell carcinoid' is an appendix-specific, high-grade malignant neoplasm with distinctive morphology that is recognizable at metastatic sites and recapitulates crypt cells (appendiceal crypt cell adenocarcinoma). Unlike intestinal-type adenocarcinoma, it occurs predominantly in women, is disguised as gynecologic malignancy, and spreads along peritoneal surfaces with only rare hematogenous metastasis. It appears to be significantly more aggressive than appendiceal mucinous neoplasms.

Pancreatic Ductal Adenocarcinoma is Spread to the Peripancreatic Soft Tissue in the Majority of Resected Cases, Rendering the AJCC T-Stage Protocol (7th Edition) Inapplicable and Insignificant: A Size-Based Staging System (pT1: ≤2, pT2: >2-≤4, pT3: >4 cm) is More Valid and Clinically Relevant.

BACKGROUND: Most studies have failed to identify any prognostic value of the current T-stage protocol for pancreatic ductal adenocarcinoma (PDAC) by the American Joint Committee on Cancer and the Union for International Cancer Control unless some grouping was performed. METHODS: To document the parameters included in this T-stage protocol, 223 consecutive pancreatoduodenectomy specimens with PDAC were processed by a uniform grossing protocol. RESULTS: Peripancreatic soft tissue (PST) involvement, the main pT3 parameter, was found to be inapplicable and irreproducible due to lack of a true capsule in the pancreas and variability in the amount and distribution of adipose tissue. Furthermore, 91 % of the cases showed carcinoma in the adipose tissue, presumably representing the PST, and thus were classified as pT3. An additional 4.5 % were qualified as pT3 due to extension into adjacent sites. The T-stage defined as such was not found to have any correlation with survival (p = 0.4). A revised T-stage protocol was devised that defined pT1 as 2 cm or smaller, pT2 as >2-4 cm, and pT3 as larger than 4 cm. This revised protocol was tested in 757 consecutive PDACs. The median and 3-year survival rates of this size-based protocol were 26, 18, 13 months, and 40 %, 26 %, 20 %, respectively (p < 0.0001). The association between higher T-stage and shorter survival persisted in N0 cases and in multivariate modeling. Analysis of the Surveillance, Epidemiology, and End Results database also confirmed the survival differences (p < 0.0001). CONCLUSIONS: This study showed that resected PDACs are already spread to various surfaces of the pancreas, leaving only about 4 % of PDACs to truly qualify as pT1/T2, and that the current T-stage protocol does not have any prognostic correlation. In contrast, as shown previously in many studies, size is an important prognosticator, and a size-based T-stage protocol is more applicable and has prognostic value in PDAC.

Cytopathologic diagnosis of oncocytic type intraductal papillary mucinous neoplasm: Criteria and clinical implications of accurate diagnosis.

BACKGROUND: Cytologic findings of pancreatic oncocytic-type intraductal papillary mucinous neoplasms (IPMNs)/intraductal oncocytic papillary neoplasms (IOPNs) are largely unknown. METHODS: Five IOPNs encountered by the authors were analyzed. RESULTS: Four IOPNs were located in the pancreatic head, and 1 was located in the pancreatic body/tail in 2 men and 3 women ages 56 to 84 years (mean age, 66 years). Radiologic diagnoses included pancreatic ductal adenocarcinoma (PDAC) in 2 patients, invasive cancer associated with IPMN in 1 patient, IPMN versus mucinous cystic neoplasm in 1 patient, and cystic mass in 1 patient. Cytologic findings included: hypercellular smears (4 of 5 cases) containing well formed clusters of oncocytic cells (5 of 5 cases) with prominent, slightly eccentric nucleoli (4 of 5 cases), predominantly arranged in sheets/papillary units (5 of 5 cases), with punched-out intercytoplasmic spaces (4 of 5 cases), and with occasional 3-dimensional groups and focal necrosis (3 of 5 cases). The intracytoplasmic mucin and thick extracellular mucin typical of other IPMNs were observed only in 2 cases and were very limited. The mean size on resection was 4.5 cm. Invasion was observed in 3 cases (0.1, 0.3, and 2.0 cm) of tubular-type IPMN. Initial cytologic evaluation was performed by the authors in 4 of 5 cases, which were diagnosed as IOPN (n = 3) and IPMN versus cystic PDAC (n = 1). One case was initially misdiagnosed as PDAC and, on resection, proved to be noninvasive IOPN. CONCLUSIONS: Cytologic features of IOPNs are classical, similar to their histologic counterparts, and differ significantly from other IPMN subtypes. Because of their highly complex appearance, they are often radiologically misdiagnosed as PDAC; thus, failure to recognize their characteristic features on fine-needle aspiration may lead to inappropriate treatment. Patients with IOPN have an incomparably better prognosis than patients with ordinary PDAC, even when their neoplasms are invasive.

Serous Neoplasms of the Pancreas: A Clinicopathologic Analysis of 193 Cases and Literature Review With New Insights on Macrocystic and Solid Variants and Critical Reappraisal of So-called "Serous Cystadenocarcinoma".

The literature on "variants" and "malignant" counterparts of pancreatic serous cystic neoplasms (SCNs) is highly conflicted. Clinicopathologic characteristics of 193 SCNs were investigated, along with a critical literature review. For the macrocystic (oligocystic) variant, in this largest series, a demographic profile in contrast to current literature was elucidated, with 21% frequency, predominance in female individuals (4:1), body/tail location (1.7×), younger age of patients (mean age, 50 y), and frequent radiologic misdiagnosis as other megacystic neoplasms. Solid SCNs were rare (n=4, 2%) and often misinterpreted radiologically as neuroendocrine tumors. Available fine-needle aspiration in 11 cases was diagnostic in only 1. Radiologic impression was "malignancy" in 5%. Associated secondary tumors were detected in 13% of resections, mostly neuroendocrine. Secondary "infiltration" (direct adhesion/penetration) of spleen, stomach, colon, and/or adjacent nodes was seen in 6 (3%) fairly large SCNs (mean, 11 cm) with no distant metastasis. Three SCNs recurred locally, but completeness of original resection could not be verified. Our only hepatic SCN lacked a concurrent pancreatic tumor. Literature appraisal revealed that there are virtually no deaths that are directly attributable to dissemination/malignant behavior of SCNs, and most cases reported as "malignant" in fact would no longer fulfill the more recent World Health Organization criteria but instead would represent either (1) local adhesion/persistence of tumor, (2) cases with no histologic verification of malignancy, or (3) liver SCNs with benevolent behavior (likely representing multifocality, rather than true metastasis, especially considering there was no fatality related to this and no reported metastases to other remote sites). In conclusion, in contrast to the literature, the clinicopathologic characteristics of solid and macrocystic SCN variants are similar to their microcystic counterpart, although their radiologic diagnosis is challenging. Recurrence/secondary invasion of neighboring organs occurs rarely in larger SCNs but seems innocuous. An SCN should not be classified as "malignant" unless there is clear-cut evidence of histologic malignancy or documented distant metastasis.

Determination-of apoptosis and cell cycle modulators (p16, p21, p27, p53, BCL-2, Bax, BCL-xL, and cyclin D1) in thyroid follicular carcinoma, follicular adenoma, and adenomatous nodules via a tissue microarray method.

BACKGROUND/AIM: To identify the role of gene products associated with apoptosis and cell cycle in the pathogenesis of thyroid follicular neoplasm. MATERIALS AND METHODS: Thirty follicular adenomas (FAs), 16 follicular carcinomas (FCs), and 20 adenomatous nodules (ANs) were investigated with immunohistochemical staining of p16, p21, p27, p53, Bcl-2, Bax, Bcl-xL, and cyclin D1 via a tissue microarray method. RESULTS: Bcl-2 showed a significant difference between the benign groups (AN and FA) and the malignant group (FC). Bax was significantly higher in the FC group. p53 was lowest in the AN group and highest in the FC group with significant differences between the groups. p16 was significantly higher in the FC group than in the other groups. There was a significant difference between the AN group and neoplastic lesions in terms of p21 staining. The number of cases with positive p27 was lower in the AN group than the neoplastic groups. There was no significant difference in terms of Bcl-xL and cyclin D1. CONCLUSION: Cell cycle modulators, led by the Bcl-2 family, played an important role in the pathogenesis of thyroid follicular neoplasm, and p53, p16, and p21 in particular played a role in the carcinogenesis of FC.

Substaging of Lymph Node Status in Resected Pancreatic Ductal Adenocarcinoma Has Strong Prognostic Correlations: Proposal for a Revised N Classification for TNM Staging.

BACKGROUND: The current tumor-node-metastasis staging system for the pancreas does not incorporate the number of lymph nodes (LNs) with metastasis. METHODS: Among 1649 pancreaticoduodenectomies, 227 stringently defined pancreatic ductal adenocarcinomas (PDACs) that had undergone a specific approach of LN harvesting were analyzed for the prognostic value of LN substaging protocols used for other gastrointestinal (GI) organs. RESULTS: The median number of LNs harvested was 18, and the median number of LNs with metastasis was 3. Lymph node metastasis was detected in 175 cases (77 %). The number of LNs involved correlated significantly with clinical outcome. When cases were substaged with the protocol already in use for the upper GI organs (N0: no metastasis, N1: metastasis to 1-2 LNs; N2: metastasis to ≥3 LNs), the median overall survival times were 35, 21, and 18 months, and the respective 3-year survival rates were 46, 34, and 20 % (p = 0.004). Analysis of the Surveillance, Epidemiology and End Results (SEER) database also confirmed the survival differences between these substages (median overall survival times of 23, 15, and 14 months and respective 3-year survival rates of 37, 22, and 18 %; p < 0.0001). The substaging protocol for the lower GI organs (N0: no metastasis; N1: metastasis to 1-3 LNs; N2: metastasis to ≥4 LNs) also was significant, with median overall survival times of 35, 21, 18 months and respective 3-year survival rates of 46, 26, and 23 %; p = 0.009). The association between higher N stage and shorter survival persisted with multivariate modeling for both protocols, although the prognostic value of the upper GI protocol appeared to be slightly stronger according to the Akaike Information Criterion method. CONCLUSION: In conclusion, with proper LN harvesting, the LN metastasis rate in PDACs is very high (77 %). Substaging of LN metastasis has significant prognostic value and needs to be considered in the N staging of PDACs. The protocol already in use for other upper GI tract organs, which currently also is proven significant for ampulla, would be preferable, although the lower GI tract protocol also is applicable.

Substaging Nodal Status in Ampullary Carcinomas has Significant Prognostic Value: Proposed Revised Staging Based on an Analysis of 313 Well-Characterized Cases.

BACKGROUND: Current nodal staging (N-staging) of ampullary carcinoma in the TNM staging system distinguishes between node-negative (N0) and node-positive (N1) disease but does not consider the metastatic lymph node (LN) number. METHODS: Overall, 313 patients who underwent pancreatoduodenectomy for ampullary adenocarcinoma were categorized as N0, N1 (1-2 metastatic LNs), or N2 (≥3 metastatic LNs), as proposed by Kang et al. Clinicopathological features and overall survival (OS) of the three groups were compared. RESULTS: The median number of LNs examined was 11, and LN metastasis was present in 142 cases (45 %). When LN-positive cases were re-classified according to the proposed staging system, 82 were N1 (26 %) and 60 were N2 (19 %). There was a significant correlation between proposed N-stage and lymphovascular invasion, perineural invasion, increased tumor size (each p < 0.001), and surgical margin positivity (p = 0.001). The median OS in LN-negative cases was significantly longer than that in LN-positive cases (107.5 vs. 32 months; p < 0.001). Patients with N1 and N2 disease had median survivals of 40 and 24.5 months, respectively (p < 0.0001). In addition, 1-, 3-, and 5-year survivals were 88, 76, 62 %, respectively, for N0; 90, 55, 31.5 %, respectively, for N1; and 68, 34, 30 %, respectively for N2 (p < 0.001). Even with multivariate modeling, the association between higher proposed N stage and shorter survival persisted (hazard ratio 1.6 for N1 and 1.9 for N2; p = 0.018). CONCLUSIONS: Classification of nodal status in ampullary carcinomas based on the number of metastatic LNs has a significant prognostic value. A revised N-staging classification system should be incorporated into the TNM staging of ampullary cancers.

The Influence of Different Nonsteroidal Anti-Inflammatory Drugs on Alveolar Bone in Rats: An Experimental Study.

THE AIM: The aim of this study was to investigate the effect of dexketoprofen trometamol, meloxicam, diclofenac sodium on any untreated alveolar bone when they are used as drugs for another indication. MATERIALS AND METHODS: Twenty eight male Spraque-Dawley rats were randomized into four groups as dexketoprofen trometamol (Group I), meloxicam (Group II), diclofenac sodium (Group III) and control group. Nonsteroidal anti-inflammatory drugs (NSAID) were administered after a fibula fracture for 10 days. Untreated alveolar bone was histopathologically examined for spongious bone density, osteoclastic density and osteoblastic density. RESULTS: Spongious bone density was lower in study groups (Group I, group II and group III) than the control group (p<0.05). In contrast, the increase in osteoclastic density was observed in other groups apart from the control group (p<0.05). Osteoblastic density was evaluated and it was determined that group II and group III had lower results than the control group (p<0.05) but group I was equal to the control group. CONCLUSION: This study showed that systemically administrated NSAIDs have the potential to affect untreated alveolar bone. This should also be considered in long term use of NSAIDs.

Calculation of the Ki67 index in pancreatic neuroendocrine tumors: a comparative analysis of four counting methodologies.

Ki67 index is now an essential part of classification of pancreatic neuroendocrine tumors. However, its adaptation into daily practice has been fraught with challenges related to counting methodology. In this study, three reviewers used four counting methodologies to calculate Ki67 index in 68 well-differentiated pancreatic neuroendocrine tumors: (1) 'eye-ball' estimation, which has been advocated as reliable and is widely used; (2) automated counting by image analyzer; (3) manual eye-counting (eye under a microscope without a grid); and (4) manual count of camera-captured/printed image. Pearson's correlation (R) was used to measure pair-wise correlation among three reviewers using all four methodologies. Average level of agreement was calculated using mean of R values. The results showed that: (1) 'eye-balling' was least expensive and fastest (average time <1 min) but had poor reliability and reproducibility. (2) Automated count was the most expensive and least practical with major impact on turnaround time (limited by machine and personnel accessibility), and, more importantly, had inaccuracies in overcounting unwanted material. (3) Manual eye count had no additional cost, averaged 6 min, but proved impractical and poorly reproducible. (4) Camera-captured/printed image was most reliable, had highest reproducibility, but took longer than 'eye-balling'. In conclusion, based on its comparatively low cost/benefit ratio and reproducibility, camera-captured/printed image appears to be the most practical for calculating Ki67 index. Although automated counting is generally advertised as the gold standard for index calculation, in this study it was not as accurate or cost-effective as camera-captured/printed image and was highly operator-dependent. 'Eye-balling' produces highly inaccurate and unreliable results, and is not recommended for routine use.

Serous cystic neoplasms of the pancreas: clinicopathologic and molecular characteristics.

We herein summarize the pathology and most recent advances in the molecular genetics of serous cystic neoplasms of the pancreas. They typically present as relatively large, well-demarcated tumors (mean size, 6cm), predominantly occurring in females. Pre-operative diagnosis remains challenging; imaging findings and cyst fluid analysis often prove non-specific and fine-needle aspiration often does not yield diagnostic cells. Pathologically, they are characterized by a distinctive cytology referred to as "serous." Although they have ductal differentiation, they distinctly lack the mucin production that characterizes most other pancreatic ductal tumors, including ductal adenocarcinoma and its variants, intraductal papillary mucinous neoplasm (IPMN) and mucinous cystic neoplasm (MCN). They instead produce abundant glycogen (glycogen-rich adenoma). Serous cystadenomas also lack the molecular alterations that characterize ductal neoplasms, such as mutation of KRAS (high prevalence in most mucinous ductal neoplasms), inactivation of SMAD4 (seen in ductal adenocarcinomas), and mutations in GNAS (seen in some IPMNs) and RNF43 (detected in MCNs and IPMNs). Instead, new molecular and immunohistochemical observations place serous pancreatic tumors closer to "clear cell neoplasms" seen in various other organs that are associated with the von Hippel-Lindau (VHL) pathway, such as clear cell renal cell carcinomas and capillary hemangioblastomas. Patients with VHL syndrome have an increased risk of developing serous pancreatic tumors and somatic mutations of the VHL gene are common in these tumors along with modification of its downstream effectors including hypoxia-inducible factor (HIF1), glucose uptake and transporter-1 (GLUT-1), a common factor in clear cell (glycogen-rich) tumors, as well as expression of vascular endothelial growth factor (VEGF), thought to be a factor in the striking capillarization of serous cystadenomas and other non-pancreatic clear cell tumors. VEGF may prove to be of significant diagnostic value since its elevation in cyst fluid has recently been found highly sensitive and specific for serous neoplasms. These molecular alterations establish serous tumors as prototypes of clear cell tumorigenesis and angiogenesis and may prove helpful both as diagnostic and non-surgical therapeutic targets.

Comparison of the effects of dexketoprofen trometamol, meloxicam and diclofenac sodium on fibular fracture healing, kidney and liver: an experimental rat model.

OBJECTIVES: Nonsteroidal anti-inflammatory drugs (NSAIDs) are particularly used in patients with bone fractures, but there are limited studies on whether one NSAID is superior to another. In this study, we used histopathological and biochemical parameters to determine whether there are differences between the effects of the administration of clinical doses of dexketoprofen trometamol (DEXT), meloxicam (MEL) and diclofenac sodium (DIC) on the healing of closed fibular fractures and the toxicity of both the liver and kidney. METHODS: Twenty-eight male Sprague-Dawley rats were randomly divided into four groups of seven each. Closed diaphyseal fractures were formed in the left fibulas of all of the rats. The NSAIDs dexketoprofen trometamol (DEXT) (Arveles(®)), meloxicam (MEL) (Melox(®)) and diclofenac sodium (DIC) (Voltaren(®)) were intramuscularly administered to Groups I, II, and III, respectively, for a period of 10 days after the fibular fractures were performed. No pharmacological agents were administered to Group IV (Control group). Blood samples were collected from all of the rats after the fractures were performed, and the rats were sacrificed on day 28. The histopathological findings were compared, and the blood samples were evaluated to determine any differences between the levels of superoxide dismutase (SOD), catalase (CAT), and malondialdehyde (MDA). RESULTS: Our results suggest that DEXT and MEL impair the healing of bone fractures and that DIC does not histopathologically affect the healing process of bone fractures. We also found that DEXT, MEL, and DIC impaired the renal histopathology compared with the control group. However, the liver histopathological analysis showed that DEXT and MEL caused a higher degree of parenchymal necrosis compared with DIC. CONCLUSION: Based on our results, DIC can be considered a relatively safe medication in patients with fractures.

Does asthma control as assessed by the asthma control test reflect airway inflammation?

BACKGROUND AND AIMS: The treatment of asthmatic patients is particularly focused on the control of symptoms as well as functional and inflammatory parameters. In our study, we investigated the relationship between the asthma control test (ACT) which evaluates symptoms and airway inflammation and functional parameters. MATERIALS AND METHODS: Stable asthmatic patients admitted to our pulmonary outpatient clinic were enrolled in the study consecutively and underwent the ACT, pulmonary function tests and methacholine bronchial provocation test (MBPT). Additionally, fractional exhaled nitric oxide level (FeNO) and induced sputum cell distribution were assessed. All these parameters were re-evaluated at the third month after adjusting medications of the patients according to baseline ACT scores. RESULTS: Of the 101 patients screened, we analyzed 83 who proceeded to the follow up visit. At the baseline visit, 8 were totally controlled, 36 partially controlled and 39 uncontrolled according to ACT. At the follow up visit, 10 were totally controlled, 39 partially controlled and 34 uncontrolled. Comparison of the two visits in terms of all parameters revealed significant reductions only in the percentages of patients with MBPT positivity (p = 0.029) and FeNO levels > 20 ppb (p = 0.025) at follow up. The percentages of patients with FeNO > 20 ppb, MBPT positivity, induced sputum eosinophilia or induced sputum neutrophilia did not show significant differences between totally controlled, partially controlled and uncontrolled groups at both baseline and follow up visits. CONCLUSION: Although the ACT scores did not show significant correlations with the airway inflammation parameters tested in this study, a marked reduction in the percentage of patients with MBPT positivity and FeNO > 20 ppb at follow up may suggest the importance of the control concept in the management of asthma.