Objective: The nature and clinicopathologic associations of Löwenstein-Buschke disease are unclear. Materials and Methods: 78 anal condylomatous lesions (≥2 cm) were analyzed. Cases were classified based on size as “medium-large”(2-5 cm, n=59), “large” (5-10 cm, n=13) and “giant” (>10 cm, n=6). Results: Patients were predominantly males (male/female=70/8). The mean age was 38 years (range:20-66). Two distinct lining types were recognized: 1) Epidermal type, typically lacking overt koilocytotic change, with associated invasive carcinoma in 8%; 2) Mucosal type, often manifesting koilocytotic change, with associated invasive carcinoma in 21%. Three types of high-grade dysplasia were discerned: 1) Basaloid, 8/9 showing high-grade dysplasia/carcinoma in-situ but non-invasive lesions; 2) Keratinizing, innocuous-appearing, but 5/6 was associated with invasion; 3) Giant cell, showing scattered individual bizarre cells, with 3/5 showing invasive carcinoma. Overall, invasion was found in 14% of the cases. The bulbous, broad-based destructive pattern characterizing verrucous carcinomas of the upper aerodigestive tract was not observed. A statistically significant trend existed between the incidence of invasion and size: 8.5% for medium-large, 23% for large, and 50% for giant (p=0.02). There was no discernable trend in the depth of invasion relative to condyloma size. Conclusions: Our findings suggest that Löwenstein-Buschke lesions are mega versions of conventional condyloma. Being verrucoid, large and minimally invasive, they can be conceptually regarded as a form of verrucous carcinoma, but they do not display the histologic characteristics of verrucous carcinoma defined in the aerodigestive tract. They exhibit two types of linings: the mucosal type that often shows koilocytotic changes, and the epidermal type that can be difficult to recognize in biopsies. These lesions may be associated with invasive carcinoma, albeit limited in amount.

“Eosinophilic cholecystitis” has been an elusive concept. Around 1050 consecutive cholecystectomies with chronic (CC, n = 895), subacute (SAC, n = 100), and acute cholecystitis (AC, n = 55) were reviewed for eosinophilic infiltration. Eosinophilic hot spots (>40 eosinophils/HPF) were seen in 63% of SAC and 35% of AC (vs. 6% of CC, p < 0.001). Eosinophils were mostly encountered in areas of wall thickening, revealing edema with early collagenization and young tissue-culture-type fibroblasts. However, in ten chronic cholecystitis patients (<1%), prominent eosinophilia with eosinophil-rich foci (>100 eosinophils/HPF) was noted. These ten cases, classified as “eosinophilic cholecystitis”, were analyzed further: The patients were relatively young (mean age = 43 years), with a 9:1 female:male ratio. None had blood eosinophilia/eosinophilia syndromes. Although one had ulcerative colitis, others did not have any autoimmune diseases. The mean gallbladder wall thickness was 3.5 mm (vs. 4.2 mm in ordinary CC). In conclusion, eosinophils are a part of especially subacute injuries in the gallbladder. They are typically condensed in the areas of healing and appear to signify a distinctive state of injury in which there are erosions leading to slow/sustained exposure of the mural tissues to the bile contents that induce chemical injury/recruit eosinophils. Eosinophilic cholecystitis is a very uncommon occurrence and appears to be an exaggerated response in allergic patients who are prone to recruit eosinophils in reaction to injury.

Background Current nodal staging (N-staging) of am-pullary 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. Clinico-pathological 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.

BACKGROUND: Pancreatic neuroendocrine neoplasms with a Ki-67 labeling index greater than 20% were reclassified in 2017 by the World Health Organization into well differentiated (WD) and poorly differentiated grade 3 neuroendocrine carcinoma (NEC). The authors describe the cytologic features of grade 3 WD pancreatic neuroendocrine neoplasms compared with grade 2 neoplasms and NEC. METHODS: Fine-needle aspirates from 65 pancreatic neuroendocrine neoplasms were reviewed, and their cytomorphologic features were compared across grade 2, WD grade 3, and PD small cell type (PD-S), large cell type (PD-L), and type not otherwise specified (PD-NOS) neoplasms. RESULTS: The 65 aspirates consisted of 19 grade 2 neoplasms, 32 WD grade 3 neoplasms, and 14 NECs (6 PD-S, 5 PD-L, and 3 PD-NOS). The medians Ki-67 proliferation index was 11% (range, 3.2%-17%) in grade 2 neoplasms, 40% (range, 21%-89%) in WD grade 3 neoplasms, 80% (range, 63%-95%) in PD-S neoplasms, 39% (range, 25%-61%) in PD-L neoplasms, and 70% (range, 30%-80%) in PD-NOS neoplasms. Both grade 2 and WD grade 3 neoplasms were associated with plasmacytoid morphology and smooth nuclear contours, but WD grade 3 neoplasms had significant increases in abundant cytoplasm (72% vs 17%; P =.007), nuclear tangles (75% vs 42%; P =.006), and apoptosis (86% vs 58%; P =.005). Compared with NECs, WD grade 3 neoplasms had increased plasmacytoid morphology (75% vs 7%; P <.001), smooth nuclear contours (94% vs 64%; P =.02), round nuclei (59% vs 21%; P =.01), and less pleomorphism (13% vs 50%; P =.004), molding (9% vs 79%; P <.001), and necrosis (13% vs 43%; P =.003). WD grade 3 neoplasms had less pleomorphism (13% vs 50%; P =.04), less necrosis (13% vs 60%; P =.04), and more plasmacytoid morphology (75% vs 20%; P =.03) than PD-L. CONCLUSIONS: The prevalence of cytologic features differs in WD grade 3 pancreatic neuroendocrine neoplasms compared with grade 2 neoplasms and NECs, and these differences assist in the recognition of this newly classified entity.

Background Different perspectives exist regarding the clinicopathologic characteristics, biology and management of gallbladder polyps. Size is often used as the surrogate evidence of polyp behavior and size of ≥1cm is widely used as cholecystectomy indication. Most studies on this issue are based on the pathologic correlation of polyps clinically selected for resection, whereas, the data regarding the nature of polypoid lesions from pathology perspective -regardless of the cholecystectomy indication- is highly limited. Methods In this study, 4231 gallbladders -606 of which had gallbladder carcinoma- were reviewed carefully pathologically by the authors for polyps (defined as ≥2 mm). Separately, the cases that were diagnosed as “gallbladder polyps” in the surgical pathology databases were retrieved. Results 643 polyps identified accordingly were re-evaluated histopathologically. Mean age of all patients was 55 years (range: 20–94); mean polyp size was 9 mm. Among these 643 polyps, 223 (34.6%) were neoplastic: I. Non-neoplastic polyps (n = 420; 65.4%) were smaller (mean: 4.1 mm), occurred in younger patients (mean: 52 years). This group consisted of fibromyoglandular polyps (n = 196) per the updated classification, cholesterol polyps (n = 166), polypoid pyloric gland metaplasia (n = 41) and inflammatory polyps (n = 17). II. Neoplastic polyps were larger (mean: 21 mm), detected in older patients (mean: 61 years) and consisted of intra-cholecystic neoplasms (WHO’s “adenomas” and “intracholecystic papillary neoplasms”, ≥1 cm; n = 120), their “incipient” version (<1 cm) (n = 44), polypoid invasive carcinomas (n = 26) and non-neoplastic polyps with incidental dysplastic changes (n = 33). In terms of size cut-off correlations, overall, only 27% of polyps were ≥1 cm, 90% of which were neoplastic. All (except for one) ≥2 cm were neoplastic. However, 14% of polyps <1 cm were also neoplastic. Positive predictive value of ≥1 cm cut-off -which is widely used for cholecystectomy indication-, was 94.3% and negative predictive value was 85%. Conclusions Approximately a third of polypoid lesions in the cholecystectomies (regardless of the indication) prove to be neoplastic. The vast majority of (90%) of polyps ≥1 cm and virtually all of those ≥2 cm are neoplastic confirming the current impression that polyps ≥1 cm ought to be removed. However, this study also illustrates that 30% of the neoplastic polyps are <1 cm and therefore small polyps should also be closely watched, especially in older patients.

BACKGROUND: Pancreatoblastoma (PBL) is a rare malignant pancreatic tumor seen predominantly in childhood, and its cytologic diagnosis remains challenging. METHODS: Twelve fine-needle-aspirations from 11 adults were analyzed. RESULTS: In total, 6 men and 5 women (median age, 45 years; age range, 32–60 years) had tumors measuring a median 5.6 cm (range, 2.5–12 cm) located in the pancreatic head (n = 7) or tail (n = 4), including 3 with familial adenomatous polyposis (FAP)/FAP-related syndromes and 4 with metastasis at diagnosis. The median follow-up was 39.8 months (range, 0.8–348 months), and 5 patients died of disease. The original cytology diagnoses were: PBL (n = 2), neuroendocrine neoplasm (n = 2), poorly differentiated neuroendocrine carcinoma (n = 2), well differentiated neuroendocrine tumor (n = 1), poorly differentiated carcinoma (n = 2), “positive for malignancy” (n = 1), acinar cell carcinoma (n = 1), and epithelioid neoplasm with endocrine and acinar differentiation versus PBL (n = 1). Universal cytopathologic findings included hypercellularity; 3-dimensional clusters; and single, monotonous, blast-like cells that were from 1.5 to 2.0 times the size of red blood cells with high nuclear-to-cytoplasmic ratio, fine chromatin, small, distinct nucleoli, and a resemblance to well differentiated neuroendocrine tumor and poorly differentiated neuroendocrine carcinoma. Branching pseudopapillae (n = 7) and grooved nuclei (n = 3) raised the differential diagnosis of solid-pseudopapillary neoplasm, but with more atypia. Uncommon features included pleomorphism (n = 4) and numerous mitoses (n = 1). Squamoid morules were seen on smears (n = 5) or cell blocks (n = 6) in 70% of patients and were characterized by epithelioid cells with elongated, streaming nuclei, fine chromatin, absent nucleoli, and positive nuclear β-catenin (n = 6 of 8). The median Ki-67 index was 21% (range, 2%−70%), and neuroendocrine marker expression was common (100%), but acinar markers were variable (63%). CONCLUSIONS: A combination of cytologic findings in PBL, including a predominant population of primitive blast-like cells, subtle squamoid morules, frequent neuroendocrine and variable acinar phenotype, should facilitate accurate cytologic diagnosis and distinction from common mimics.

BACKGROUND: Hepatocellular carcinoma (HCC) rarely involves the biliary tree and may be inadvertently sampled on bile duct brushings (BDBs). METHODS: The pathology archives of 5 institutions were searched for BDBs with HCC involvement. RESULTS: A total of 17 BDBs from 14 patients were obtained. There was a male:female ratio of 6:1; the median age of the patients was 59.5 years (range, 22–80 years). The median hepatic tumor size was 6.2 cm (range, 2.2–13.0 cm). HCC risk factors included viral hepatitis (5 patients), cirrhosis (5 patients), hemochromatosis (1 patient), and alcoholic steatohepatitis (1 patient). Jaundice with elevated bilirubin, liver enzymes, and α-fetoprotein was common. Endoscopic retrograde cholangiopancreatography demonstrated bile duct dilatation, polypoid intraductal masses (5 samples), clots/debris (2 samples), or strictures (4 samples). All BDBs had single and clustered large cells with naked atypical nuclei, granular cytoplasm, high nuclear/cytoplasmic ratios, and nuclei with prominent macronucleoli. Less common findings included clear/microvesicular cytoplasm (35%), papillae (29%), and anisonucleosis (35%). Classic HCC features (widened trabeculae [35%], endothelial wrapping [24%], multinucleation [24%], and cytoplasmic bile pigment [35%]) were uncommon. A total of 11 BDBs were diagnosed as malignant (10 with HCC and 1 with cholangiocarcinoma), 2 were diagnosed as atypical, and 1 BDB was diagnosed as negative; approximately two-thirds were found to have polysomy on fluorescence in situ hybridization. Approximately 71% of patients died of disease at a median of 3.5 months. CONCLUSIONS: HCC may extend into the intrahepatic and/or extrahepatic biliary tree, causing masses and/or strictures that may be sampled on BDB. Although cytologically malignant, the classic features of HCC are uncommon, which can cause misdiagnosis. Cytopathologists should be mindful of this differential when evaluating BDBs, particularly when concomitant liver masses and/or HCC risk factors are present. Because of the associated high mortality and rapid rate of death, its presence should be conveyed clearly in pathology reports.

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.

Antiretroviral drug therapy (ART) effectively suppresses replication of both the immunodeficiency viruses, human (HIV) and simian (SIV); however, virus rebounds soon after ART is withdrawn. SIV-infected monkeys were treated with a 90-day course of ART initiated at 5 weeks post infection followed at 9 weeks post infection by infusions of a primatized monoclonal antibody against the α 4 β 7 integrin administered every 3 weeks until week 32. These animals subsequently maintained low to undetectable viral loads and normal CD4 + T cell counts in plasma and gastrointestinal tissues for more than 9 months, even after all treatment was withdrawn. This combination therapy allows macaques to effectively control viremia and reconstitute their immune systems without a need for further therapy.

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.