Subgrading of G2 Pancreatic Neuroendocrine Tumors as 2A (Ki67 3% to < 10%) Versus 2B (10% to ≤ 20%) Identifies Behaviorally Distinct Subsets in Keeping with the Evolving Management Protocols.

BACKGROUND: Grade 1/2 PanNETs are mostly managed similarly, typically without any adjunct treatment with the belief that their overall metastasis rate is low. In oncology literature, Ki67-index of 10% is increasingly being used as the cutoff in stratifying patients to different protocols, although there are no systematic pathology-based studies supporting this approach. METHODS: Ki67-index was correlated with clinicopathologic parameters in 190 resected PanNETs. A validation cohort (n = 145) was separately analyzed. RESULTS: In initial cohort, maximally selected rank statistics method revealed 12% to be the discriminatory cutoff (close to 10% rule of thumb). G2b cases had liver/distant metastasis rate of almost threefold higher than that of G2a and showed significantly higher frequency of all histopathologic signs of aggressiveness (tumor size, perineural/vascular invasion, infiltrative growth pattern, lymph node metastasis). In validation cohort, these figures were as striking. When all cases were analyzed together, compared with G1, the G2b category had nine times higher liver/distant metastasis rate (6.1 vs. 58.5%; p < 0.001) and three times higher lymph node metastasis rate (20.5 vs. 65.1%; p < 0.001). CONCLUSIONS: G2b PanNETs act very similar to G3, supporting management protocols that regard them as potential therapy candidates. Concerning local management, metastatic behavior in G2b cases indicate they may not be as amenable for conservative approaches, such as watchful waiting or enucleation. This substaging should be considered into diagnostic guidelines, and clinical trials need to be devised to determine the more appropriate management protocols for G2b (10% to ≤ 20%) group, which shows liver/distant metastasis in more than half of the cases, which at minimum warrants closer follow-up.

Intra-ampullary Papillary Tubular Neoplasm (IAPN): Clinicopathologic Analysis of 72 Cases Highlights the Distinctive Characteristics of a Poorly Recognized Entity.

The guidelines recently recognized the intra-ampullary papillary tubular neoplasm (IAPN) as a distinct tumor entity. However, the data on IAPN and its distinction from other ampullary tumors remain limited. A detailed clinicopathologic analysis of 72 previously unpublished IAPNs was performed. The patients were: male/female=1.8; mean age=67 years (range: 42 to 86 y); mean size=2.3 cm. Gross-microscopic correlation was crucial. From the duodenal perspective, the ampulla was typically raised symmetrically, with a patulous orifice, and was otherwise covered by stretched normal duodenal mucosa. However, in 6 cases, the protrusion of the intra-ampullary tumor to the duodenal surface gave the impression of an "ampullary-duodenal tumor," with the accurate diagnosis of IAPN established only by microscopic correlation illustrating the abrupt ending of the lesion at the edge of the ampulla. Microscopically, the preinvasive component often revealed mixed phenotypes (44.4% predominantly nonintestinal). The invasion was common (94%), typically small (mean=1.2 cm), primarily pancreatobiliary-type (75%), and showed aggressive features (lymphovascular invasion in 66%, perineural invasion in 41%, high budding in 30%). In 6 cases, the preinvasive component was pure intestinal, but the invasive component was pancreatobiliary. LN metastasis was identified in 42% (32% in those with ≤1 cm invasion). The prognosis was significantly better than ampullary-ductal carcinomas (median: 69 vs. 41 months; 3-year: 68% vs. 55%; and 5-year: 51% vs. 35%, P =0.047). In conclusion, unlike ampullary-duodenal carcinomas, IAPNs are often (44.4%) predominantly nonintestinal and commonly (94%) invasive, displaying aggressive features and LN metastasis even when minimally invasive, all of which render them less amenable to ampullectomy. However, their prognosis is still better than that of the "ampullary-ductal" carcinomas, with which IAPNs are currently grouped in CAP protocols (while IAPNs are kindreds of intraductal tumors of the pancreatobiliary tract, the latter represents the ampullary counterpart of pancreatic adenocarcinoma/cholangiocarcinoma).

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.

Extensive Perivillous Fibrin and Intervillous Histiocytosis in a SARS-CoV-2 Infected Placenta From an Uninfected Newborn: A Case Report Including Immunohistochemical Profiling.

Placental infection by SARS-CoV-2 with various pathologic alterations reported. Inflammatory findings, such as extensive perivillous fibrin deposition and intervillous histiocytosis, have been postulated as risk factors for fetal infection by SARS-CoV-2. We describe the placental findings in a case of a 31-year-old mother with SARS-CoV-2 infection who delivered a preterm female neonate who tested negative for SAR-CoV2 infection. Placental examination demonstrated a small for gestational age placenta with extensive intervillous histiocytosis, syncytiotrophoblast karyorrhexis, and diffuse intervillous fibrin deposition. Immunohistochemical staining demonstrated infection of the syncytiotrophoblasts by SARS-CoV-2 inversely related to the presence of intervillous histiocytes and fibrin deposition. Our case demonstrates that despite extensive placental pathology, no fetal transmission of SARS-CoV-2 occurred, as well as postulates a relationship between placental infection, inflammation, and fibrin deposition.

Rapid Implementation of Telehealth Services During the COVID-19 Pandemic.

Telehealth is an important tool utilized to provide remote clinical care and has increased in prevalence during the coronavirus disease of 2019 (COVID-19) pandemic. It allows providers to conduct safe, timely, and high-quality ambulatory care for patients without increasing risk of disease exposure for both parties. Major organizations including the Centers for Disease Control and Prevention and American College of Obstetrics and Gynecology have released recommendations encouraging the use of telehealth systems for patient care. In obstetrics and gynecology, practice of telehealth has not been commonplace and no practical procedural guidelines have been published. The authors have created such guidelines for use of telehealth in a moderate-risk academic generalist practice in response to the COVID-19 pandemic. This document highlights the process to determine which obstetrics and gynecology patients are candidates for telehealth, the frequency of follow-up, and the technical aspects of designing and delivering a de novo telehealth system. The guidelines were vital in providing structure amid a sudden transition in an academic setting while ensuring patient and provider safety.

Mural Intracholecystic Neoplasms Arising in Adenomyomatous Nodules of the Gallbladder: An Analysis of 19 Examples of a Clinicopathologically Distinct Entity.

Intracholecystic neoplasms (ICNs) (pyloric gland adenomas and intracholecystic papillary neoplasms, collectively also called intracholecystic papillary/tubular neoplasms) form multifocal, extensive proliferations on the gallbladder mucosa and have a high propensity for invasion (>50%). In this study, 19 examples of a poorly characterized phenomenon, mural papillary mucinous lesions that arise in adenomyomatous nodules and form localized ICNs, were analyzed. Two of these were identified in 1750 consecutive cholecystectomies reviewed specifically for this purpose, placing its incidence at 0.1%. Median age was 68 years. Unlike other gallbladder lesions, these were slightly more common in men (female/male=0.8), and 55% had documented cholelithiasis. All were characterized by a compact multilocular, demarcated, cystic lesion with papillary proliferations and mucinous epithelial lining. The lesions' architecture, distribution, location, and typical size were suggestive of evolution from an underlying adenomyomatous nodule. All had gastric/endocervical-like mucinous epithelium, but 5 also had a focal intestinal-like epithelium. Cytologic atypia was graded as 1 to 3 and defined as 1A: mucinous, without cytoarchitectural atypia (n=3), 1B: mild (n=7), 2: moderate (n=2), and 3: severe atypia (n=7, 3 of which also had invasive carcinoma, 16%). Background gallbladder mucosal involvement was absent in all but 2 cases, both of which had multifocal papillary mucosal nodules. In conclusion, these cases highlight a distinct clinicopathologic entity, that is, mural ICNs arising in adenomyomatous nodules, which, by essentially sparing the "main" mucosa, not displaying "field-effect/defect" phenomenon, and only rarely (16%) showing carcinomatous transformation, are analogous to pancreatic branch duct intraductal papillary mucinous neoplasms.

Characterization of cardiac mechanics and incident atrial fibrillation in participants of the Cardiovascular Health Study.

BACKGROUND: Left atrial (LA) and left ventricular (LV) remodeling are associated with atrial fibrillation (AF). The prospective associations of impairment in cardiac mechanical function, as assessed by speckle-tracking echocardiography, with incident AF are less clear. METHODS: In the Cardiovascular Health Study, a community-based cohort of older adults, participants free of AF with echocardiograms of adequate quality for speckle tracking were included. We evaluated the associations of indices of cardiac mechanics (LA reservoir strain, LV longitudinal strain, and LV early diastolic strain rate) with incident AF. RESULTS: Of 4341 participants with strain imaging, participants with lower LA reservoir strain were older, had more cardiometabolic risk factors, and had lower renal function at baseline. Over a median follow-up of 10 years, 497 (11.4%) participants developed AF. Compared with the highest quartile of LA reservoir strain, the lowest quartile of LA reservoir strain was associated with higher risk of AF after covariate adjustment, including LA volume and LV longitudinal strain (heart rate [HR], 1.80; 95% CI, 1.31-2.45; P < 0.001). The association of LA reservoir strain and AF was stronger in subgroups with higher blood pressure, NT-proBNP, and LA volumes. There were no associations of LV longitudinal strain and LV early diastolic strain rate with incident AF after adjustment for LA reservoir strain. CONCLUSION: Lower LA reservoir strain was associated with incident AF, independent of LV mechanics, and with stronger associations in high-risk subgroups. These findings suggest that LA mechanical dysfunction precedes the development of AF. Therapies targeting LA mechanical dysfunction may prevent progression to AF. FUNDING: This research was supported by contracts HHSN268201200036C, HHSN268200800007C, HHSN268201800001C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, and N01HC85086 and grants KL2TR001424, R01HL107577, U01HL080295, and U01HL130114 from the NIH's National Center for Advancing Translational Sciences, and National Heart, Lung, and Blood Institute (NHLBI), with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided by R01AG023629 from the National Institute on Aging (NIA). A full list of principal CHS investigators and institutions can be found at CHS-NHLBI.org.

Variant anatomy of the biliary system as a cause of pancreatic and peri-ampullary cancers.

BACKGROUND: The cause of most pancreatic and periampullary cancers (PAC) is unknown. Recently, anatomic variations such as pancreatobiliary maljunction have been recognized as risk factors, similar to Barrett-related gastro-esophageal cancers. METHODS: Pre-operative MRI from 860 pancreatic/biliary resections, including 322 PACs, were evaluated for low-union (cystic duct joining the common hepatic duct inside of the pancreas or within 5 mm of the pancreatic border) RESULTS: Low-union, seen <10% of the population, was present in 44% of PACs (73% distal bile duct/cholangiocarcinoma, 42% pancreatic head, and 34% ampullary). It was significantly lower(11%) in conditions without connection to the ductal system (thus not exposed to the ductal/biliary tract contents), namely mucinous cystic neoplasms and intrahepatic cholangiocarcinomas(p < 0.0001). Intra-pancreatic type low-union was seen in 16% of PACs versus 2% of controls(p < 0.0001). DISCUSSION: This study establishes an association between low-union and PACs, and points to an anatomy-induced chemical/bilious carcinogenesis. This may explain why most pancreas cancers are in the head. It is possible that the same chemical milieu, caused by conditions other than low-union/insertion, may also play a role in the remaining half of PACs. This opens various treatment opportunities including milieu modifications (chemoprevention), focused screening of at-risk patients, and early detection with possible corrective actions.

Non-neoplastic Polyps of the Gallbladder: A Clinicopathologic Analysis of 447 Cases.

There is no systematic histopathologic analysis of non-neoplastic polyps in the gallbladder. In this study, in addition to a computer search for cases designated as "polyp," a systematic review of 2533 consecutive routinely sampled archival and 203 totally submitted prospective cholecystectomies were analyzed for >2 mm polyps (cut-off was based on radiologic sensitivity). A total of 447 non-neoplastic polyps were identified. The frequency was 3% in archival cases and 5% in totally submitted cases. Only 21 (5%) were ≥1 cm. The average age was 52 years, and the female to male ratio was 3.1. Two distinct categories were delineated: (1) injury-related polyps (n=273): (a) Fibro(myo)glandular polyps (n=214) were small (mean=0.4 cm), broad-based, often multiple (45%), almost always (98%) gallstone-associated, and were composed of a mixture of (myo)fibroblastic tissue/lobular glandular units with chronic cholecystitis. Dysplasia seen in 9% seemed to be secondary involvement. (b) Metaplastic pyloric glands forming polypoid collections (n=42). (c) Inflammatory-type polyps associated with acute/subacute injury (11 granulation tissue, 3 xanthogranulomatous, 3 lymphoid). (2) Cholesterol polyps (n=174) occurred in uninjured gallbladders, revealing a very thin stalk, edematous cores devoid of glands but with cholesterol-laden macrophages in 85%, and cholesterolosis in the uninvolved mucosa in 60%. Focal low-grade dysplasia was seen in 3%, always confined to the polyp, unaccompanied by carcinoma. In conclusion, non-neoplastic polyps are seen in 3% of cholecystectomies and are often small. Injury-related fibromyoglandular polyps are the most common. Cholesterol polyps have distinctive cauliflower architecture, often in a background of uninjured gallbladders with cholesterolosis and may lack the cholesterol-laden macrophages in the polyp itself. Although dysplastic changes can involve non-neoplastic polyps, they do not seem to be the cause of invasive carcinoma by themselves.

Intrapancreatic distal common bile duct carcinoma: Analysis, staging considerations, and comparison with pancreatic ductal and ampullary adenocarcinomas.

Distal common bile duct carcinoma is a poorly characterized entity for reasons such as variable terminology and difficulty in determining site of origin of intrapancreatic lesions. We compared clinicopathologic features of pancreatobiliary-type adenocarcinomas within the pancreas, but arising from the distal common bile duct, with those of pancreatic and ampullary origin. Upon careful review of 1017 pancreatoduodenectomy specimens with primary adenocarcinoma, 52 (5%) qualified as intrapancreatic distal common bile duct carcinoma. Five associated with an intraductal papillary neoplasm were excluded; the remaining 47 were compared to 109 pancreatic ductal adenocarcinomas and 133 ampullary carcinomas. Distal common bile duct carcinoma patients had a younger median age (58 years) than pancreatic ductal adenocarcinoma patients (65 years) and ampullary carcinoma patients (68 years). Distal common bile duct carcinoma was intermediate between pancreatic ductal adenocarcinoma and ampullary carcinoma with regard to tumor size and rates of node metastases and margin positivity. Median survival was better than for pancreatic ductal adenocarcinoma (P=0.0010) but worse than for ampullary carcinoma (P=0.0006). Distal common bile duct carcinoma often formed an even band around the common bile duct and commonly showed intraglandular neutrophil-rich debris and a small tubular pattern. Poor prognostic indicators included node metastasis (P=0.0010), lymphovascular invasion (P=0.0299), and margin positivity (P=0.0069). Categorizing the tumors based on size also had prognostic relevance (P=0.0096), unlike categorization based on anatomic structures invaded. Primary distal common bile duct carcinoma is seen in younger patients than pancreatic ductal adenocarcinoma or ampullary carcinoma. Its prognosis is significantly better than pancreatic ductal adenocarcinoma and worse than ampullary carcinoma, at least partly because of differences in clinical presentation. Use of size-based criteria for staging appears to improve its prognostic relevance. Invasive pancreatobiliary-type distal common bile duct carcinomas are uncommon in the West and have substantial clinicopathologic differences from carcinomas arising from the pancreas and ampulla.

Prognostic Utility and Clinical Significance of Cardiac Mechanics in Heart Failure With Preserved Ejection Fraction: Importance of Left Atrial Strain.

BACKGROUND: Left atrial (LA) enlargement is associated with adverse events in heart failure with preserved ejection fraction (HFpEF). However, the role of LA mechanics (ie, LA strain measures) in HFpEF has not been well studied. We hypothesized that in HFpEF, reduced (worse) LA strain is a key pathophysiologic abnormality and is a stronger correlate of adverse events than left ventricular or right ventricular longitudinal strain. METHODS AND RESULTS: We evaluated baseline LA function in 308 patients with HFpEF who were followed up longitudinally for adverse outcomes. All patients underwent speckle-tracking echocardiography for measurement of left ventricular longitudinal strain, right ventricular free wall strain, and LA booster, conduit, and reservoir strains. The clinical and prognostic significance of left ventricular, right ventricular, and LA strain measures was assessed by regression analyses. The mean age was 65±13 years, 64% were women, 26% had atrial fibrillation, and LA enlargement was present in the majority of patients (67%). Decreased LA reservoir strain was associated with increased pulmonary vascular resistance (P<0.0001) and decreased peak oxygen consumption (P=0.0001). Of the left ventricular, right ventricular, and LA strain measures, LA reservoir strain was the strongest correlate of adverse events and was independently associated with the composite outcome of cardiovascular hospitalization or death (adjusted hazard ratio per 1-SD decrease in LA strain, 1.54; 95% CI, 1.15-2.07; P=0.006). CONCLUSIONS: Abnormal indices of LA mechanics (particularly LA reservoir strain) are powerful clinical and prognostic factors in HFpEF. Unloading the LA and augmentation of LA function may be important future therapeutic targets in HFpEF. REGISTRATION INFORMATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01030991.

Whipple made simple for surgical pathologists: orientation, dissection, and sampling of pancreaticoduodenectomy specimens for a more practical and accurate evaluation of pancreatic, distal common bile duct, and ampullary tumors.

Pancreaticoduodenectomy (PD) specimens present a challenge for surgical pathologists because of the relative rarity of these specimens, combined with the anatomic complexity. Here, we describe our experience on the orientation, dissection, and sampling of PD specimens for a more practical and accurate evaluation of pancreatic, distal common bile duct (CBD), and ampullary tumors. For orientation of PDs, identification of the "trapezoid," created by the vascular bed at the center, the pancreatic neck margin on the left, and the uncinate margin on the right, is of outmost importance in finding all the pertinent margins of the specimen including the CBD, which is located at the upper right edge of this trapezoid. After orientation, all the margins can be sampled. We submit the uncinate margin entirely as a perpendicular inked margin because this adipose tissue-rich area often reveals subtle satellite carcinomas that are grossly invisible, and, with this approach, the number of R1 resections has doubled in our experience. Then, to ensure proper identification of all lymph nodes (LNs), we utilize the orange-peeling approach, in which the soft tissue surrounding the pancreatic head is shaved off in 7 arbitrarily defined regions, which also serve as shaved samples of the so-called "peripancreatic soft tissue" that defines pT3 in the current American Joint Committee on Cancer TNM. With this approach, our LN count increased from 6 to 14 and LN positivity rate from 50% to 73%. In addition, in 90% of pancreatic ductal adenocarcinomas there are grossly undetected microfoci of carcinoma. For determination of the primary site and the extent of the tumor, we believe bisectioning of the pancreatic head, instead of axial (transverse) slicing, is the most revealing approach. In addition, documentation of the findings in the duodenal surface of the ampulla is crucial for ampullary carcinomas and their recent site-specific categorization into 4 categories. Therefore, we probe both the CBD and the pancreatic duct from distal to the ampulla and cut the pancreatic head to the ampulla at a plane that goes through both ducts. Then, we sample the bisected pancreatic head depending on the findings of the case. For example, for proper staging of ampullary carcinomas, it is imperative to take the sections perpendicular to the duodenal serosa at the "groove" area, as ampullary carcinomas often extend to this region. Amputative (axial) sectioning of the ampulla, although good for documentation of the peri-Oddi spread of the intra-ampullary tumors, unfortunately disallows documentation of mucosal spread of the papilla of Vater tumors (those arising from the edge of the ampulla, where the ducts transition to duodenal mucosa and extending) into the neighboring duodenum. Axial sectioning also often fails to document tumor spread to the "groove" area. In conclusion, knowledge of the gross characteristics of the anatomic hallmarks is essential for proper dissection of PD specimens. The approach described above allows practical and accurate documentation and staging of pancreas, distal CBD, and ampullary cancers.

Mucinous carcinomas of the gallbladder: clinicopathologic analysis of 15 cases identified in 606 carcinomas.

CONTEXT: There are virtually no data in the literature regarding the incidence, patterns, and clinicopathologic characteristics of mucinous carcinomas (MCs) of the gallbladder (GB). OBJECTIVE: To determine the incidence of mucinous differentiation in invasive GB carcinomas and the clinicopathologic characteristics of those that qualify as MC. DESIGN: Primary invasive GB carcinomas (n  =  606) were reviewed for mucinous differentiation. Some degree of mucin production was identified in 40 cases (6.6%); however, only 15 (2.5%) were qualified for the World Health Organization definition of MC (stromal mucin deposition constituting >50% of the tumor). RESULTS: The mean age was 65 years, and the female to male ratio was 1.1 (versus 3.9 for conventional pancreatobiliary-type GB adenocarcinomas; P  =  .04). A significant proportion of the cases (8 of 12, 67%) presented with the clinical picture and intraoperative findings that were interpreted as acute cholecystitis. Mean and median tumor sizes were larger than those of conventional adenocarcinomas (4.8 and 3.4 cm versus 2.9 and 2.5 cm, respectively; P  =  .01). Most (13 of 15, 87%) cases presented with pT3 tumors (versus 48% for ordinary GB carcinomas; P  =  .01). Two cases had almost an exclusive colloid pattern (>90% composed of well-defined stromal mucin nodules that contained scanty carcinoma cells, most of which were floating within the mucin). Eight cases were of mixed-mucinous type, showing a mixture of colloid and noncolloid patterns. Five others had prominent signet-ring cells, both floating within the mucin (which constituted >50% of the tumor by definition) and infiltrating into the stroma as individual signet-ring cells in some areas. Immunohistochemical analysis performed on the 7 cases that had available tissue revealed CK7 in 4 of 7 (57%), CK20 in 2 of 7 (29%), MUC1 in 4 of 7 (57%), MUC2 in 6 of 7 (86%), CDX2 in 1 of 7 (14%), MUC5AC in 6 of 7 (86%), MUC6 in 0 of 7 (0%), and loss of E-cadherin in 6 of 7 (86%). The MLH1 and MSH2 were retained in 6 of 7 cases (100%). Follow-up information was available for 13 cases: 11 (85%) died of disease (1-37 months) and 2 (15%) were alive (23 months and 1 month). Overall survival of MCs was significantly worse than that of conventional adenocarcinomas (13 versus 26 months; P  =  .01); however, that did not seem to be independent of stage. CONCLUSIONS: Mucinous carcinomas constitute 2.5% of GB carcinomas. They present with an acute cholecystitis-type picture. Most MCs are a mixed-mucinous, not pure colloid, type. They are typically large and advanced tumors at the time of diagnosis and thus exhibit more-aggressive behavior than do ordinary GB carcinomas. Immunophenotypically, they differ from conventional GB adenocarcinomas by MUC2 positivity, from intestinal carcinomas by an often inverse CK7/20 profile, from pancreatic mucinous carcinomas by CDX2 negativity, and from mammary colloid carcinomas by a lack of MUC6. Unlike gastrointestinal MCs, they appear to be microsatellite stable.

Intracholecystic papillary-tubular neoplasms (ICPN) of the gallbladder (neoplastic polyps, adenomas, and papillary neoplasms that are ≥1.0 cm): clinicopathologic and immunohistochemical analysis of 123 cases.

The literature on the clinicopathologic characteristics of tumoral intraepithelial neoplasms (neoplastic polyps) of the gallbladder (GB) is fairly limited, due in part to the variability in definition and terminology. Most reported adenomas (pyloric gland type and others) were microscopic and thus regarded as clinically inconsequential, whereas papillary in situ carcinomas have been largely considered a type of invasive adenocarcinoma under the heading of "papillary adenocarcinomas." In this study, 123 GB cases that have a well-defined exophytic preinvasive neoplasm measuring ≥1 cm were analyzed. The patients were predominantly female (F/M=2:1) with a mean age of 61 y and a median tumor size of 2.2 cm. Half of the patients presented with pain, and in the other half the neoplasm was detected incidentally. Other neoplasms, most being gastrointestinal tract malignancies, were present in 22% of cases. Gallstones were identified in only 20% of cases. Radiologically, almost half were diagnosed as "cancer," roughly half with polypoid tumor, and in 10% the lesion was missed. Pathologic findings: (1) The predominant configuration was papillary in 43%, tubulopapillary in 31%, tubular in 26%. (2) Each case was assigned a final lineage type on the basis of the predominant pattern (>75% of the lesion) on morphology, and supported with specific immunohistochemical cell lineage markers. The predominant cell lineage could be identified as biliary in 50% (66% of which were MUC1), gastric foveolar in 16% (all were MUC5AC), gastric pyloric in 20% (92% MUC6), intestinal in 8% (100% CK20; 75% CDX2; 50%, MUC2), and oncocytic in 6% (17% HepPar and 17% MUC6); however, 90% of cases had some amount of secondary or unclassifiable pattern and hybrid immunophenotypes. (3) Of the cases that would have qualified as "pyloric gland adenoma," 21/24 (88%) had at least focal high-grade dysplasia and 18% had associated invasive carcinoma. Conversely, 8 of 47 "papillary adenocarcinoma"-type cases displayed some foci of low-grade dysplasia, and 15/47 (32%) had no identifiable invasion. (4) Overall, 55% of the cases had an associated invasive carcinoma (pancreatobiliary type, 58; others, 10). Factors associated significantly with invasion were the extent of high-grade dysplasia, cell type (biliary or foveolar), and papilla formation. Among systematically analyzed invasive carcinomas, tumoral intraepithelial neoplasia was detected in 6.4% (39/606). (5) The 3-year actuarial survival was 90% for cases without invasion and 60% for those associated with invasion. In contrast, those associated with invasion had a far better clinical outcome compared with pancreatobiliary-type GB carcinomas (3-yr survival, 27%), and this survival advantage persisted even with stage-matched comparison. Death occurred in long-term follow-up even in a few noninvasive cases (4/55; median 73.5 mo) emphasizing the importance of long-term follow-up. In conclusion, tumoral preinvasive neoplasms (≥1 cm) in the GB are analogous to their pancreatic and biliary counterparts (biliary intraductal papillary neoplasms, pancreatic intraductal papillary mucinous neoplasms, and intraductal tubulopapillary neoplasms). They show variable cellular lineages, a spectrum of dysplasia, and a mixture of papillary or tubular growth patterns, often with significant overlap, warranting their classification under 1 unified parallel category, intracholecystic papillary-tubular neoplasm. Intracholecystic papillary-tubular neoplasms are relatively indolent neoplasia with significantly better prognosis compared with pancreatobiliary-type GB carcinomas. In contrast, even seemingly innocuous examples such as those referred to as "pyloric gland adenomas" can progress to carcinoma and be associated with invasion and fatal outcome.

Vacuolated cell pattern of pancreatobiliary adenocarcinoma: a clinicopathological analysis of 24 cases of a poorly recognized distinctive morphologic variant important in the differential diagnosis.

Pancreatic ductal adenocarcinoma (PDCA) is characterized by well-defined tubular units in the vast majority of the cases; however, variations in this theme do occur. It is important to recognize the morphologic spectrum of PDCA to avoid misdiagnosis especially in small specimens and also in metastatic foci. Here, we document a morphologic variant of PDCA that is characterized by a distinctive pattern of infiltrating cribriform nests in a distinctive "microcystic" or "secretory" pattern. Twenty-four cases of PDCA have been identified in a review of 505 cases diagnosed with PDCA. Histologically, this pattern was characterized by infiltrating nests of tumor cells with large vacuoles and "signet-ring" like appearance imparting a cribriform growth pattern. The vacuoles were one to five cells in size, often merging to form multilocular spaces separated by a thin rim of cell membrane. Many of these spaces contained CA19.9 positive granular secretory material. The nuclei were often pushed to the periphery and compressed in a pattern resembling adipocytes, although the nuclei were often densely hyperchromatic and displayed significant atypia. Especially in biopsies from the peripancreatic fat and peritoneum, these neoplastic cells had been misdiagnosed as degenerating adipocytes, and in the lymph nodes, they had been misinterpreted as lipogranulomas. Clinical findings of the patients were similar to that of conventional PDCA, except higher incidence of history of smoking (83% vs. 60%; p=0.034). In conclusion, vacuolated cell adenocarcinoma is a distinct morphologic variant of PDCA, and the presence of this peculiar pattern in a metastatic site, although not specific, should raise the suspicion of a PDCA.

Is serous cystadenoma of the pancreas a model of clear-cell-associated angiogenesis and tumorigenesis?

BACKGROUND: Similar to the other von Hippel-Lindau (VHL)-related tumors such as renal cell carcinomas and capillary hemangioblastomas, serous cystadenomas (SCAs) of the pancreas are also characterized by clear cells. Over the years, we have also noticed that the tumor epithelium shows a prominent capillary network. METHODS: Eighteen cases of SCA were reviewed histologically, and immunohistochemical analysis was performed for CD31 and vascular endothelial growth factor (VEGF) as well as the molecules implicated in clear-cell tumorigenesis: GLUT-1, hypoxia-inducible factor-1 (HIF-1alpha), and carbonic anhydrase IX (CA IX). RESULTS: There was an extensively rich capillary network that appears almost intraepithelially in all cases of SCA, which was confirmed by CD31 stain that showed, on average, 26 capillaries per every 100 epithelial cells. VEGF expression was identified in 10/18 cases. Among the clear-cell tumorigenesis markers, CA IX was detected in all cases, GLUT-1 and HIF-1alpha in most cases. CONCLUSION: As in other VHL-related clear-cell tumors, there is a prominent capillary network immediately adjacent to the epithelium of SCA, confirming that the clear-cell- angiogenesis association is also valid for this tumor type. Molecules implicated in clear-cell tumorigenesis are also consistently expressed in SCA. This may have biologic and therapeutic implications, especially considering the rapidly evolving drugs against these pathways. More importantly, SCA may also serve as a model of clear-cell-associated angiogenesis and tumorigenesis, and the information gained from this tumor type may also be applicable to other clear-cell tumors.

TENS stimulates constitutive nitric oxide release via opiate signaling in invertebrate neural tissues.

BACKGROUND: There is a major societal concern relating to the addictive properties of analgesic drugs such as morphine with regard to alleviating pain. Because of this, alternative methods of pain relief are, and have been, actively pursued. An extremely promising method for treatment of low to moderate levels of chronic pain in humans is transcutaneous electrical nerve stimulation (TENS). MATERIAL/METHODS: All experiments utilized the invertebrate marine bivalve mollusc Mytilus edulis pedal ganglia. TENS was achieved using a stimulation apparatus developed by Professor Han of Peking University. TENS experiments employed 2 stimulation protocols: 1) low 2 Hz frequency at 5 mA current, 2) alternating low and high frequencies at 2 and 100 Hz, respectively at 5 mA current. Real-time measurements of nitric oxide (NO), using an amperometric probe, measured NO released into the tissue bath subsequent to TENS. RESULTS: Pooled M. edulis pedal ganglia exposed to TENS demonstrate that stimulation at 2 Hz and 5 mA current promotes time-dependent release of NO. In another experiment, pooled ganglia were stimulated at alternating frequencies of 2 Hz and 100 Hz and 5 mA, which also released NO in a time-dependent manner. Unstimulated control ganglia did not release significant amounts of NO. NO release was antagonized by naloxone and L-NAME exposure, demonstrating that it was receptor and nitric oxide synthase mediated, respectively. CONCLUSIONS: It would appear that TENS stimulates endogenous morphine release since NO release was blocked by naloxone and opioid peptides do not release NO. The present study is highly suggestive of the occurrence of this same mechanism in mammalian neural systems since all biochemical and signaling components are present. Furthermore, it would appear that this process has evolutionary survival value since it occurs in an animal that evolved 500 million years ago.

Lipid-rich variant of pancreatic endocrine neoplasms.

Most pancreatic endocrine neoplasms (PENs) show characteristic and well-recognized endocrine morphology; however, a lipid-rich pattern, which can present a diagnostic problem in biopsies, has been reported, mostly as individual cases. Some have been included in descriptions of the rare clear-cell variant associated with von Hippel-Lindau (VHL) syndrome. The histogenesis, clinicopathologic characteristics, and significance of this lipid-rich pattern have not been unraveled. In this study, 11 PENs exhibiting foamy, microvesicular cytoplasm were analyzed. In some cases, the nuclei were distorted by the vesicles, and the usual endocrine chromatin pattern was not evident. The growth pattern was relatively diffuse, with vague compartmentalization of the cells by a delicate vasculature; prominent nesting was noted in only 4 cases. Pathology reports indicated substantial diagnostic challenge in these cases; on biopsies, 1 case was originally diagnosed as adrenal cortical carcinoma, another as renal cell carcinoma, a third as solid-pseudopapillary tumor, and a fourth had a fine needle aspiration cytologic diagnosis of adenocarcinoma. All cases were chromogranin and synaptophysin positive. Electron microscopy in 3 cases confirmed the cytoplasmic vesicles to be lipid vacuoles. Neurosecretory granules were also evident. Clinically, as in conventional PENs, there appeared to be two distinct subsets: Two cases were familial or functional/syndromic (1 with VHL and the other with MEN-1 and glucagonoma syndrome) and occurred in younger adults (ages 41 and 47 years); the majority (n = 9) were nonfunctional/nonsyndromic and nonfamilial. The latter group was mostly represented by elderly males (mean age: 65 vs. 58 years in conventional sporadic PENs). Immunohistochemically, markers implicated in VHL-associated neoplasia, including HIF-1alpha, inhibin, and Melan-A (in clear-cell PENs) and MUC6 (in serous cystadenomas) were mostly negative in lipid-rich PENs (1 of 10, 1 of 10, 0 of 10 and 0 of 10, respectively). In conclusion, the lipid-rich pattern, reminiscent of adrenal cortical cells, represents a distinct subset of PENs. It presents a diagnostic challenge for surgical pathologists, especially in biopsies. EM supports the name lipid-rich for this variant. The findings suggest that the pathogenesis of lipid-rich tumors may be different from the VHL-associated clear-cell variants of PENs.