Squamous-lined cysts of the pancreas: lymphoepithelial cysts, dermoid cysts (teratomas), and accessory-splenic epidermoid cysts

In the pancreas, 3 types of morphologically similar lesions may present as "squamous cysts": Lymphoepithelial cysts, dermoid cysts (monodermal teratomas), and epidermoid cysts in intrapancreatic accessory spleen. Lymphoepithelial cysts (LECs) are seen predominantly in men (M/F: 4/1) and in adulthood (mean age, 56, and range, 35 to 74 years). They may occur at any site of the organ (head, body, or tail). LECs are well-delineated cysts that may be multilocular (60%) or unilocular (40%), and they are characterized microscopically by stratified squamous epithelium surrounded by a band of mature lymphoid tissue with intervening well-formed germinal centers. Solid lymphoepithelial clusters are seldom seen. The pathogenesis of LECs is unclear; clinical diseases that are known to be associated with their counterparts in the salivary glands such as Sjogren disease or human immunodeficiency virus have not been documented for the LECs of the pancreas. The second type of squamous-lined cyst in the pancreas is the epidermoid cyst arising in intrapancreatic accessory spleen. These are located almost exclusively in the tail of the pancreas, in the fourth decade of life (mean age = 38). Their mean size is 4.5 cm (range, 2.3 to 6.5). In some cases, the cyst lining may be partly mucinous. Dermoid cysts of the pancreas are also rare. The cases that appear to be true dermoid cysts occur in a younger age group (mean age, 23, range, 2 to 53 years), and in contrast with LEC, there is no gender predominance. Mucinous epithelium, respiratory-type mucosa and sebaceous units are more readily identifiable in dermoid cysts, and they may contain hair. Subepithelial lymphoid tissue is not a feature. They are sometimes complicated by suppurative infections. The importance of these lesions is in their distinction from other cystic neoplasms, especially mucinous cystic tumors.     

Paraduodenal pancreatitis: a clinico-pathologically distinct entity unifying "cystic dystrophy of heterotopic pancreas", "para-duodenal wall cyst", and "groove pancreatitis"

A distinct form of chronic pancreatitis occurring predominantly in and around the duodenal wall (near the minor papilla) has been reported under various names, including cystic dystrophy of heterotopic pancreas, pancreatic hamartoma of duodenum, para-duodenal wall cyst, myoadenomatosis, and groove pancreatitis. Our experience with these lesions and the review of the literature show that these lesions have the following common characteristics: (1) The duodenal wall contains dilated ducts, some with inspissated secretions, and pseudocystic changes as well as adjacent stromal reactions including hypercellular granulation tissue, foreign-body type giant cell reaction engulfing mucoprotein material, and myofibroblastic proliferation. (2) Brunner's gland hyperplasia is typically present. (3) Dense myoid stromal proliferation, with intervening rounded lobules of pancreatic acinar tissue, creates a histologic picture reminiscent of "myoadenomatosis," "pancreatic hamartoma," or even leiomyoma in some cases. (4) Spillover of fibrosis into the adjacent pancreas and soft tissue occurs, especially in the "groove" area (between the pancreas, common bile duct and duodenum), including the region around the common bile duct. (5) Clinically, these lesions often mimic "pancreas cancer" or periampullary tumors, because of marked scarring as well as the ill-defined borders of the process. Patients with these findings are predominantly males, 40-50 years old, with a history of alcohol abuse. That the process is often centered in the region of minor papilla (and the adjacent pancreas) suggests that an anatomic variation of the ductal system may render this area particularly susceptible to the effects of alcoholic injury, and the myo-adenomatoid and cystic changes on the duodenal wall may in turn represent changes related to a localized recurrent pancreatitis. In conclusion, these clinicopathologic findings characterize a distinctive process that can be referred to as paraduodenal pancreatitis.     

MUC1 and MUC2 in pancreatic neoplasia

MUCs are glycoproteins with various roles in homeostasis and carcinogenesis. Among other actions, MUC1 may inhibit cell-cell and cell-stroma interactions and function as a signal transducer, participating in cancer progression. In contrast, MUC2 is normally found only in goblet cells, where it contributes to the protective barrier function of these cells. Recently, a tumour suppressor role has been demonstrated for MUC2, and both MUC1 and MUC2 appear to have important roles in pancreatic neoplasia. MUC1 appears to be a marker of aggressive phenotype and may facilitate the vascular spread of carcinoma cells. In contrast, MUC2 is rarely detectable in aggressive pancreatic tumours, but is commonly expressed in intraductal papillary mucinous neoplasms (IPMNs), which are rare, indolent tumours, in intestinal IPMNs, and in indolent colloid carcinomas. MUC2 appears to be not only a marker of this indolent pathway, but also partly responsible for its less aggressive nature. Thus, in pancreatic neoplasia, MUC1 and MUC2 have potential diagnostic and prognostic value as markers of aggressive and indolent phenotypes, respectively, and have potential as therapeutic targets.     

Spindle cell tumors associated with mycobacteria in lymph nodes of HIV-positive patients: 'Kaposi sarcoma with mycobacteria' and 'mycobacterial pseudotumor'.

Patients infected with HIV often have unusual manifestations of common infections and neoplasms. One such example is "mycobacterial pseudotumor," an exuberant spindle cell lesion induced in lymph nodes by mycobacteria. Kaposi sarcoma also produces a spindle cell proliferation in lymph nodes of HIV-positive patients. These two entities must be differentiated from one another because of differences in treatment and prognosis. We report here, however, three cases of intranodal Kaposi sarcoma with simultaneous mycobacterial infection, the occurrence of which has not been clearly documented. For comparison, we also studied three cases of mycobacterial pseudotumor, of which 14 cases have been described to date. There was considerable histologic overlap between these two lesions. Acid-fast bacilli were present in all cases, predominantly in the more epithelioid histiocytes in the cases of Kaposi sarcoma, and in spindle and epithelioid cells in the cases of mycobacterial pseudotumor. The morphologic features that favored Kaposi sarcoma over mycobacterial pseudotumor were the prominent fascicular arrangement of spindle cells and slitlike spaces, the lack of granular, acidophilic cytoplasm, and the presence of mitoses. Immunohistochemistry was a reliable adjunct study in the differential diagnosis, as the spindle cells in mycobacterial pseudotumor were positive for S-100 protein and CD68 whereas those of Kaposi sarcoma were CD31- and CD34-positive but negative for S-100 protein and CD68. Awareness that Kaposi sarcoma may coexist with mycobacterial infection in the same biopsy specimen is important because these lesions may be misdiagnosed as mycobacterial pseudotumor. The clinical impact of distinguishing between Kaposi sarcoma with mycobacteria and mycobacterial pseudotumor is significant because the presence of Kaposi sarcoma alters treatment and prognosis.     

Foamy gland pattern of pancreatic ductal adenocarcinoma: a deceptively benign-appearing variant

Pathologic diagnosis of pancreatic adenocarcinoma is frequently a challenge, particularly in small biopsies, frozen sections, and in metastatic foci. Here we report a deceptively benign-appearing and morphologically distinctive pattern of ductal adenocarcinoma with prominent microvesicular cytoplasm, giving the cells a foamy appearance similar to that described in the prostate (Am J Surg Pathol 1996;20:419). This variant, which we refer to as foamy gland pattern (FGP), was frequently misdiagnosed in frozen sections or biopsies and its pathologic stage underestimated in surgical specimens. Histologically, the diagnostic features were: (1) white and crisply foamy, "microvesicular" cytoplasm; (2) often basally located and compressed, hyperchromatic nuclei reminiscent of endocervical glands (and so-called "adenoma malignum") or gastric foveolar glands; (3) irregular nuclear contours forming wrinkled (raisinoid) nuclei in some areas; and (4) a distinctive chromophilic condensation of the cytoplasmic material in the luminal aspect of the cells forming a brush border-like zone (BLZ). Histochemically, this BLZ was positive for mucicarmine, alcian blue, and high iron diamine, but not PAS. The remainder of the cytoplasm was negative for all these stains. In contrast, benign mucinous ducts, which constitute the major differential diagnosis, had more homogeneous acidophilic cytoplasm, lacked BLZ, and showed cytoplasmic staining with PAS. Immunohistochemically, the tumor cells were diffusely and strongly positive for CEA and cytokeratin 8 whereas B72.3 staining was focal and weak. MUC1 staining was largely confined to the BLZ. MUC2 was negative. P53 staining was detected in 16 of the 20 cases studied and was strong and diffuse in five. K-ras mutation was detected in 6 of 8 cases studied. The clinical findings in the 20 patients in this study (4 pure and 16 mixed with usual ductal carcinoma) did not appear to differ significantly from those of ordinary ductal adenocarcinoma of the pancreas. Eleven patients were men and nine were women; the mean age was 62 years and the mean tumor size was 4.4 cm. Follow-up information was available in 17 patients of whom 7 were alive at an average follow up of 23 months (range, 7-104 mos), and 10 were dead of disease at a median follow up of 15 months (range, 4-42 mos). The median survival of the four patients with pure FGP was 18 months. The median survival did not appear to be significantly longer than that of the patients with resectable ordinary ductal adenocarcinoma in the authors' experience (109 patients, median survival of 12 mos, p = 0.48). In conclusion, foamy gland pattern of invasive pancreatic ductal carcinoma is morphologically distinctive and is prone to misdiagnosis as a benign process. The pathologic stage is often underestimated as a result of the lack of its recognition and misinterpretation as mucinous ducts. Careful attention to its microscopic features is adequate for accurate diagnosis. Histochemical and immunohistochemical stains are useful in confirming the diagnosis of malignancy in challenging cases.     

Liver steatosis assessment: Correlations among pathology,radiology, clinical data and automated image analysis software

Quantitating hepatic steatosis is important in many liver diseases and liver transplantation. Since steatosis estimation by pathologists has inherent intra- and inter-observer variability, we compared and contrasted computerized techniques with magnetic resonance imaging measurements, pathologist visual scoring, and clinical parameters. Computerized methods applied to whole slide images included a commercial positive pixel count algorithm and a custom algorithm programmed at our institution. For all liver samples (n = 59), including pediatric, adult, frozen section, and permanent specimens, statistically significant correlations were observed between pathology, radiology, and each image analysis modality (r = 0.75–0.97, p < 0.0001), with the strongest correlations in the pediatric cohort. Statistically significant relationships were observed between each method and with body mass index (r = 0.37–0.56, p from <0.0001 to <0.05) and with albumin (r = 0.55–0.64, p < 0.05) but not with alanine aminotransferase or aspartate aminotransferase. Although pathologist assessments correlated (r = 0.64–0.86, 0.92–0.97, and 0.78–0.91 for microvesicular, macrovesicular, and overall steatosis, respectively), the absolute values of hepatic steatosis visual assessment were susceptible to intra- and inter-observer variability, particularly for microvesicular steatosis. Image analysis, pathologist assessments, radiology measurements, and several clinical parameters all showed correlations in this study, providing evidence for the utility of each method in different clinical and research settings.     

Early gallbladder carcinoma has a favorable outcome but Rokitansky–Aschoff sinus involvement is an adverse prognostic factor

The general impression about gallbladder carcinomas is that they are uniformly fatal; however, for the early forms, an entirely different picture indicating a very good prognosis is evolving from the high-incidence regions. We subjected 190 early gallbladder carcinomas (EGBC), defined as carcinomas confined to and above the tunica muscularis (AJCC's Tis, T1a, and T1b), and identified in cholecystectomy specimens sampled entirely according to an established protocol, to detailed analysis. Average patient age was 57.9 years (29–95). In more than half of the cases (114/190; 60 %), the tumor was inapparent by gross examination. In 81 cases (42.6 %), carcinomatous epithelium abutted the muscularis, whereas 57.4 % (n?=?109) were qualified as intramucosal with no overt contiguity with muscularis. Intraepithelial extension into Rokitansky–Aschoff sinuses (RAS) was found in 34 cases (17.8 %). At the time of data analysis, 171 patients (99 %) were alive. Overall actuarial survival was 92.3 % at 5 years and 90.4 % at 10 years. The 5- and 10-year actuarial survival rates of the intramucosal group (93.2 and 92.1 %, respectively) were not statistically different from that of the muscle-abutting group (89.7 % and 88.2 % ; p?=?0.334). Patients with RAS involvement had a significantly shorter survival than those without (p?<?0.001). Of the 33 patients with RAS involvement, 13 (39 %) died of disease, whereas only 6 of the 154 patients (4 %) without RAS involvement died of disease. Disease-related mortality in these cases occurred relatively late (median 48 months). EGBC has a very good prognosis with a 90 % 10-year survival rate. It is seen on average in patients almost a decade younger than those with advanced cancers. RAS involvement is an independent prognostic factor, and additional surgery may have to be considered for such cases. Occasional recurrences are encountered several years later, which suggests a field-effect phenomenon and warrants long-term follow-up.     

Neuroendocrine Tumors of the Pancreas: Current Concepts and Controversies

In the past decade, the clinico-pathologic characteristics of neuroendocrine tumors (NETs) in the pancreas have been further elucidated. Previously termed “islet cell tumors/carcinomas” or “endocrine neoplasms”, they are now called pancreatic NETs (PanNETs). They occur in relatively younger patients and may arise anywhere in the pancreas. Some are associated with von Hippel–Lindau, MEN1, and other syndromes. It is now widely recognized that, with the exception of tumorlets (minute incipient neoplasms) that occur in some syndromes like MEN1, all PanNETs are malignant, albeit low-grade, and although they have a protracted clinical course and overall 10-year survival of 60–70 %, even low-stage and low-grade examples may recur and/or metastasize on long-term follow-up. Per recent consensus guidelines adopted by both European and North American NET Societies (ENETS and NANETs) and WHO-2010, PanNETs are now graded and staged separately, unlike previous classification schemes that used a combination of grade, stage, and adjunct prognosticators in an attempt to define “benign behavior” or “malignant” categories. For staging, the ENETs proposal may be more applicable than CAP/AJCC, which is based on the staging of exocrine tumors. Current grading of PanNETs is based on mitotic activity and ki-67 index. Other promising prognosticators such as necrosis, CK19, c-kit, and others are still under investigation. It has also been recognized that PanNETs have a rather wide morphologic repertoire including oncocytic, pleomorphic, ductulo-insular, sclerosing, and lipid-rich variants. Most PanNETs are diagnosed by fine needle aspiration biopsy, in which single, monotonous plasmacytoid cells with fair amounts of cytoplasm and distinctive neuroendocrine chromatin are diagnostic. Molecular alterations of PanNETs are also very different than that of ductal or acinar tumors. Loss of expression of DAXX and ATRX proteins has been recently identified in 45 %. Along with these improvements, several controversies remain, including grading, value of current cutoff ranges, and the best methods for counting ki-67 index (manual count by computer-captured image may be the most practical for the time being). More important is the controversial use of the term “carcinoma”, which was previously employed in WHO-2004 only for invasive and metastatic cases but has now been made synonymous with grade 3 group of tumors. It is becoming clear that grade 3 group comprises two distinct categories: (1) differentiated but proliferatively more active tumors which typically have ki-67 indices in the 20–50 % range and (2) true poorly differentiated NE carcinomas as defined in the lung, with ki-67 typically >50 %. Further studies are needed to address these controversial aspects of PanNETs.     

CD95-related apoptotic machinery is functional in pancreatic cancer cells

The CD95 (FAS, Apo-1) system is a major death pathway in normal and tumor cells. Recent evidence indicates that pancreatic cancer cells express CD95R and CD95L but are insensitive to CD95-mediated apoptosis. Here we show that treatment of human pancreatic cancer cells with RNA synthesis inhibitor actinomycin D (ActD) converted the phenotype of cancer cells from CD95 resistant to CD95 sensitive. Flow cytometric analysis demonstrated that all pancreatic cancer cell lines studied responded with cell surface CD95R and CD95L upregulation to bleomycin treatment, and PANC1 (mt p53) cells demonstrated a dose-dependent response to interferon gamma and bleomycin treatment with CD95R and CD95L up-regulation. However, only bleomycin sensitized PANC1 cells to CD95-mediated apoptosis. Taxol sensitized PANC1 and HPAC cells to CD95-mediated apoptosis without surface up-regulation of CD95R. These data suggest that pancreatic cancer cells possess a p53-independent mechanism of CD95R and CD95L surface upregulation and that surface expression of CD95R is not predictive of apoptotic function. Protein extracts of HPAC and PANC1 cells treated for 24 hours with a combination of ActD/agonist anti-CD95 antibodies demonstrated significantly higher Acetyl-Asp-Glu-Val-Asp-ase (DEVDase) cleavage activity (caspase 3-like activity) than extracts from cells treated with ActD only. In the present study, we also investigated the time kinetics of DEVDase (caspase 3-like) activation in PANC1 (mt p53) and HPAC (wt p53) pancreatic cancer cell lines. We found that DEVDase activity in PANC1 cells responds to ActD and ActD/anti-CD95 antibodies earlier than in HPAC cells; however, at 24 hours HPAC cells demonstrated much stronger activation. Cytosolic protein extracts from untreated cells did not influence caspase 3-like activity when added to extracts from the ActD/anti-CD95 antibody-treated cells. Collectively, these data suggest that pancreatic cancer cells have functional CD95-related apoptotic machinery with preserved apoptotic signal transduction, CD95R upregulation. and caspase activation. However, this system is blocked by some unknown protein(s) that is either located in the organelle fraction of the cell and/or requires an intact cell for manifestation of its activity.