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Multifocal fibrosing thyroiditis (MFT) is an enigmatic entity, characterized by multiple fibrotic scar-like lesions with a paucicellular fibrotic center surrounded by a cellular peripheral area with reactive-appearing follicular cell atypia and variable chronic inflammation. Although poorly recognized and likely underreported in surgical pathology, the entity is considered rare with only 65 cases to date–including the current one reported to expand on the preoperative findings of this under-recognized entity. The average age of the patients is 46.8 years (range 15–71 years), 94% are female, with female to male ratio of 15:1. Individual MFT lesions typically have a superficial location. The average number of fibrotic lesions is 15.4 (range 2–51 per MFT case). Their average size is 3.1 mm (range 0.4–15.1). MFT is a disorder of diseased thyroids, typically found postoperatively in glands removed for other reasons, such as chronic lymphocytic/Hashimoto thyroiditis (32.3%), follicular nodular disease (nodular hyperplasia) (30.1%), hyperthyroidism/diffuse hyperplasia (Graves disease) (9.2%). Intriguing is the association with papillary thyroid carcinoma–present in 38.5% of MFT cases, and particularly with sub-centimetric and multifocal papillary thyroid carcinoma, with which MFT can be confused. Cases where MFT is the only thyroid pathology (7.7%) can be preoperatively mistaken for papillary thyroid carcinoma, due to worrisome ultrasound (US) and cytologic features, both of which are here documented for the first time as a component of this article. Wider recognition of MFT and of its cytologic and ultrasound features at preoperative evaluation may reduce unnecessary thyroidectomies.

Peritoneal carcinomatosis (PC) is defined as a metastatic involvement of the peritoneum by several other primary sites and it is characterized by a marked worsening of prognosis, with limited treatment opportunities. Subsequently, PC should be ruled out before any invasive treatment is administered. A new through-the-needle micro-biopsy forceps (MF) was recently introduced that permits micro-histology cores. In this case series, we evaluated the feasibility of MF in the assessment of PC to complete patient diagnostic work-ups. Five consecutive patients referred for endoscopic ultrasound staging were sampled using MF. Sampling was feasible in all patients with a technical success of 100%. No adverse events were reported in any cases. This technique was feasible and safe with a technical success rate of 100%. It permitted sampling of peritoneal irregularity, obtained high-quality tissue fragments in all cases, and enabled an additional assessment, i.e., immunohistochemical staining.

Background Standard suction and slow-pull techniques have been utilized during endoscopic ultrasound-guided fine needle aspiration of pancreatic solid lesions, but the correct sampling technique remains unclear. New needles designed to obtain samples suitable for histological evaluation have become available. We performed a study comparing the two sampling methods during endoscopic ultrasound-guided fine needle biopsy (EUS-FNB) in patients with pancreatic solid lesions. Methods We performed EUS-FNB with a 20 Gauge FNB needle using slow-pull or standard suction techniques in a prospective, randomized, multicenter study. The primary aim was bloodiness of the collected specimens. Secondary aims were technical success and performance of the two techniques. Results 110 patients were included (55 per group). No difference in blood contamination was observed (slow-pull 80% vs. suction 74%, p = 0.917). Technical success was 95% (96% vs. 94%, p = 0315). Sensitivity (96% vs. 93%), specificity (100% vs. 100%), positive likelihood ratio (NA), negative likelihood ratio (0.04 vs. 0.07), diagnostic accuracy (96 vs. 93%) did not differ between the two groups. Conclusion EUS-FNB with slow-pull and standard suction techniques are comparable in terms of blood contamination providing similar high diagnostic sensitivity and accuracy in pancreatic solid lesions. The use of the new generation FNB needle allows to reach such high level of diagnostic adequacy regardless of the technique utilized.

Endoscopic ultrasound-guided tissue acquisition (EUS-TA) of solid pancreatic tumors shows optimal specificity despite fair sensitivity, with an overall suboptimal diagnostic yield. We aim to quantify the adequacy and accuracy of EUS-TA and assess predictive factors for success, focusing on the presence and degree of specimen fibrosis. All consecutive EUS-TA procedures were retrieved, and the specimens were graded for sample adequacy and fibrosis. The results were evaluated according to patients’ and tumor characteristics and the EUS-TA technique. In total, 407 patients (59% male, 70 [63–77] year old) were included; sample adequacy and diagnostic accuracy were 90.2% and 94.7%, respectively. Fibrosis was significantly more represented in tumors located in the head/uncinate process (p = 0.001). Tumor location in the head/uncinate (OR 0.37 [0.14–0.99]), number of needle passes ≥ 3 (OR 4.53 [2.22–9.28]), and the use of cell block (OR 8.82 [3.23–23.8]) were independently related to adequacy. Severe fibrosis was independently related to false negative results (OR 8.37 [2.33–30.0]). Pancreatic tumors located in the head/uncinate process showed higher fibrosis, resulting in EUS-TA with lower sample adequacy and diagnostic accuracy. We maintain that three or more needle passes and cell block should be done to increase the diagnostic yield.

Inflammatory pseudotumor of the liver (IPTL) is a rare benign lesion that can mimic hepatic malignant neoplasms. A 79-year-old woman, in follow-up care for a left breast cancer, was referred to our Ultrasound Diagnostic Centre for a hepatic mass of unknown nature, displayed on PET-CT, CT and Abdominal Ultrasonography (US). The patient presented with abdominal pain and low-grade fever, increased values of C-Reactive Protein (CRP) and gamma-glutamyl transpeptidase (γGT). Abdominal US confirmed the presence of a heterogeneous polycyclic mass 4.0 × 3.7 cm in size, sub-capsular, localized in the segment VI, isoechoic in arterial phase and hypoechoic in portal and late phase on contrast-enhanced ultrasound (CEUS). A liver biopsy revealed the presence of chronic inflammatory cells without evidence of malignancy. As the patient did not respond to medical therapy, she underwent hepatic segmentectomy and cholecystectomy. At histology, the specimen showed acute and chronic inflammation with xanthogranulomatous features.

Pancreatic adenocarcinoma (PDAC) is the most frequent histological type of malignancy in the pancreas. Extracellular matrix (ECM), plays a critical role during the process of human carcinogenesis and the possible diversity in matricellular proteins composition of ECM may have a significant impact on the clinical course of PDAC. Aim of this paper was to evaluate the expression of three matricellular proteins, including Periostin (POSTN), Tenascin (TNS) and Osteopontin (OPN), in PDAC from long-survival (LS) and non-long survival (NLS) patients. A total of 30 PDAC were analyzed, 15 from patients that survived more than 60 months after surgery (LS) and 15 that died from the disease within 24 (NLS). RNA was extracted and OPN, TNS and POSTN mRNA levels were evaluated by qRT-PCR.LS and NLS samples showed the same type of POSTN and TN isoforms. On the contrary, OPN seems to be preferentially expressed in NLS PDAC. Moreover, OPNb and OPNc isoforms were expressed exclusively in NLS samples. In conclusion, Our data led to hypothesize a possible relationship between the expression of different isoforms of each of these proteins and the clinical outcome of patients with PDAC.

Carcinoma of the ampulla of Vater is an uncommon neoplasm and represents 0.5% of all gastrointestinal malignancies, being less common than carcinoma of the pancreas and bile ducts. The most common ampullary tumor is the adenocarcinoma with tubular growth pattern. Signet ring cell carcinoma is extremely rare. In this article, we report a case of signet ring cell carcinoma of the ampulla of Vater showing focal neuroendocrine amphicrine differentiation and intestinal phenotype, which occurred in a 49-year-old male who is still alive 7 years after surgery, without evidence of recurrence. This long-term survival might be attributed not only to the early stage of the disease but also to the neuroendocrine differentiation and the absence of genetic alterations.

Background and Objective: A new 20-gauge (G) biopsy needle with a core-trap technology has been developed with a large core size and enhanced flexibility. The aim of this multicenter study was to determine the feasibility, efficacy, and safety of EUS-guided fine-needle biopsy (EUS-FNB) with the new 20G needle in diagnosing subepithelial lesions (SELs). Materials and Methods: Retrospectively collected data from consecutive patients with SELs undergoing EUS-FNB with the 20G needle at five centers were analyzed. Results: A total of 50 SELs were included. The mean lesion size was 43.1 ± 17.5 mm. The lesion locations were esophagus (n = 1), stomach (n = 37), distal duodenum (n = 5), rectum (n = 6), and colon (n = 1). The procedure was technically feasible in all patients. Definitive diagnosis with full histological assessment including immunohistochemistry was obtained in 88% (44/50) of the patients. Considering malignant versus benign lesions, the sensitivity, specificity, positive predictive value, and negative predictive value were 85% (95% confidence interval [CI] 70.2–94.3), 100% (95% CI 58.7%–100%), 100% (95% CI 85.1%–100%), and 62.5 (95% CI 27.7–84.8), respectively. No major complications requiring additional care have been observed. Conclusions: In this multicenter study, we found that EUS-FNB with the new 20G core needle is an effective and safe method for the diagnosis of SELs with a high rate of producing adequate histological material and high diagnostic accuracy even from difficult-to-approach anatomical locations.

Background and Objective: EUS-guided fine-needle biopsy has become the standard for tissue sampling. A new 20G ProCore™ (PC) needle has been developed to overcome the limitations of tissue acquisition of the smaller needles (22G, 25G) and the rigidity of the larger one (19G). The aim of this study is to assess the performance of the 20G PC needle. Materials and Methods: Patients who underwent EUS-guided tissue acquisition with the 20G PC needle of pancreatic and extra-pancreatic mass lesions were retrospectively identified at three Italian centers (Bologna, Fermo, and Palermo). Diagnostic adequacy, accuracy, and tissue core acquisition were the outcome measures. All the cases were performed without rapid on-site evaluation. Results: A total of 384 patients with pancreatic (62.2%) and extra-pancreatic lesions were included in the study. For pancreatic lesions, adequacy, accuracy, sensitivity, and specificity were 92.4%, 91.5%, 90.8%, and 100%, respectively, with a number needed to misdiagnose (NNM) of 11.8. The tissue core was obtained in 72% of cases. Transduodenal approach was performed in 150 pancreatic lesions; adequacy, accuracy, and tissue core acquisition were 88.7%, 90%, and 66%, respectively (NNM 10). For extrapancreatic lesions, adequacy, accuracy, sensitivity, specificity, and tissue core sampling were 95.3%, 95.3%, 92.6%, 100%, and 84.5% (NNM 21.3). Conclusions: The 20G PC needle showed high diagnostic adequacy and accuracy, regardless the access route.

Background No study has compared the performance of light microscopy (LM) and whole slide imaging (WSI) for endoscopic ultrasound (EUS) histological acquired tissue samples from pancreatic solid lesions (PSLs). We evaluated the concordance between LM and WSI and the inter- and intra-observer agreements among pathologists on PSLs EUS acquired samples. Methods LM and WSI from 60 patients with PSLs were evaluated by five expert pathologists to define: diagnostic classification, presence of a core, number and percentage of lesional cells. Washout period between evaluations was 3 months. Time of the procedures was also assessed. Results Forty-eight cell-block and 12 biopsy samples were evaluated. A high concordance between LM and WSI was found. Inter- and intra-observer agreements for diagnostic classification were substantial and complete, respectively. For all the other parameters, the inter-observer agreement was usually higher for LM. For the intra-observer, a substantial agreement was reached regarding the presence of tissue core and the number and the percentage of malignant cells. Median time for performing LM was significantly shorter than for WSI (p Conclusions LM and WSI of cell-block and biopsy samples acquired by EUS in PSLs were highly concordant, with a substantial inter-observer and a complete intra-observer agreements regarding diagnostic classification.

Background A hallmark of pancreatic ductal adenocarcinoma is the desmoplastic reaction, but its impact on the tumor behavior remains controversial. Our aim was to introduce a computer -aided method to precisely quantify the amount of pancreatic collagenic extra-cellular matrix, its spatial distribution pattern, and the degradation process. Methods A series of normal, inflammatory and neoplastic pancreatic ductal adenocarcinoma formalin-fixed and paraffin-embedded Sirius red stained sections were automatically digitized and analyzed using a computer-aided method. Results We found a progressive increase of pancreatic collagenic extra-cellular matrix from normal to the inflammatory and pancreatic ductal adenocarcinoma. The two-dimensional fractal dimension showed a significant difference in the collagenic extra-cellular matrix spatial complexity between normal versus inflammatory and pancreatic ductal adenocarcinoma. A significant difference when comparing the number of cycles necessary to degrade the pancreatic collagenic extra-cellular matrix in normal versus inflammatory and pancreatic ductal adenocarcinoma was also found. The difference between inflammatory and pancreatic ductal adenocarcinoma was also significant. Furthermore, the mean velocity of collagenic extra-cellular matrix degradation was found to be faster in inflammatory and pancreatic ductal adenocarcinoma than in normal. Conclusion These findings demonstrate that inflammatory and pancreatic ductal adenocarcinomas are characterized by an increased amount of pancreatic collagenic extra-cellular matrix and by changes in their spatial complexity and degradation. Our study defines new features about the pancreatic collagenic extra-cellular matrix, and represents a basis for further investigations into the clinical behavior of pancreatic ductal adenocarcinoma and the development of therapeutic strategies.

Context.—Integration of the analysis of genetic markers with endoscopic ultrasound–guided fine-needle aspiration and cytologic evaluation has increased the accuracy of the preoperative diagnosis of pancreatic lesions. The application of high-throughput gene panel analysis using next-generation sequencing platforms is now offering a great opportunity for further improvements.Objective.—To review the application of next-generation sequencing to the preoperative diagnosis of pancreatic lesions.Data Sources.—For data acquisition, a PubMed search using the terms next-generation sequencing, pancreas, pancreatic lesions, pancreatic tumors, and EUS-FNA was performed covering the years 2000–2017.Conclusions.—KRAS remains the gene most widely studied for preoperative single-gene tests. Next-generation sequencing reliably allows analysis of multiple gene markers starting from limited amounts of DNA. The study of multigene panels has become a very attractive option for the management and preoperative risk stratification of patients with pancreatic cancer.

Extracellular matrix (ECM) plays a fundamental role in tissue architecture and homeostasis and modulates cell functions through a complex interaction between cell surface receptors, hormones, several bioeffector molecules, and structural proteins like collagen. These components are secreted into ECM and all together contribute to regulate several cellular activities including differentiation, apoptosis, proliferation, and migration. The so-called "matricellular" proteins (MPs) have recently emerged as important regulators of ECM functions. The aim of our review is to consider all different types of MPs family assessing the potential relationship between MPs and survival in patients with pancreatic ductal adenocarcinoma (PDAC). A systematic computer-based search of published articles, according to the Preferred Reporting Items for Systematic reviews and Meta-Analysis (PRISMA) Statement issued in 2009 was conducted through Ovid interface, and literature review was performed in May 2017. The search text words were identified by means of controlled vocabulary, such as the National Library of Medicine's MESH (Medical Subject Headings) and Keywords. Collected data showed an important role of MPs in carcinogenesis and in PDAC prognosis even though the underlying mechanisms are still largely unknown and data are not univocal. Therefore, a better understanding of MPs role in regulation of ECM homeostasis and remodeling of specific organ niches may suggest potential novel extracellular targets for the development of efficacious therapeutic strategies.

Background Pancreatic adenocarcinoma (PDAC) is one of the deadliest human malignancies. Although surgery is currently the only effective treatment for PDAC, most patients survive less than 20 months after tumor resection. Objective The primary goal was to investigate alterations in KRAS, TP53, SMAD4 and CDKN2A/p16 in tumors from patients with exceptionally long survival after surgery. Methods Tumors from 15 patients with PDAC that survived more than 55 months after surgery ("LS") were analyzed for KRAS, TP53, IDH1, NRAS and BRAF using next-generation sequencing. SMAD4 and CDKN2A/p16 was tested using immunohistochemistry. MGMT promoter methylation was investigated. Results Tumors from "LS" have a lower prevalence of KRAS and TP53 mutations and had more frequently SMAD4 retained expression, if compared with that of patients died within 24 months from surgery. The survival of patients with wild-type KRAS and TP53 tumors was more than twice longer than that of patients bearing KRAS and TP53 mutations (90.2 vs. 41.1 months). Patients with KRAS wild-type tumors and that retained SMAD4 expression had a survival twice longer than cases with alterations in both genes (83.8 vs. 36.7 months). Eleven tumors (39.3%) showed MGMT methylation. Conclusions Our data indicate that absence of KRAS, TP53 and SMAD4 genetic alterations may identify a subset of pancreatic carcinomas with better outcome.

Background: Rapid on-site evaluation (ROSE) improves the adequacy and accuracy of EUS-guided tissue acquisition, although it is not routinely widely available. Evidence suggested that core needles might overcome the absence of ROSE. The aim of this study was to evaluate the influence of ROSE on the adequacy and accuracy of EUS-guided tissue acquisition with core needles in patients with pancreatic solid lesions. Methods: Patients who underwent EUS-guided tissue acquisition of pancreatic mass lesions were retrospectively identified at three tertiary referral centers and those performed with the core needle were included. Adequacy, defined as the rate of cases in which a tissue specimen for proper examination was achieved, with and without ROSE was the primary outcome measure. The diagnostic accuracy and tissue core acquisition were the secondary outcome measures. Results: A total of 333 patients with pancreatic solid mass lesions were included in the study; 140 cases sampled with ROSE and 193 cases without ROSE. The adequacy was 92.1 % in the group sampled with ROSE and 88.1 % in the group without ROSE (p = 0.227). In the ROSE group sensitivity, specificity, and accuracy were 90.7, 100 and 92.1 %, respectively. In the group without ROSE, sensitivity, specificity, and accuracy were 87.2, 100, and 88.1 %, respectively. No difference for all these figures was observed between the two groups. The tissue core was available in 61.4 and 53.4 % of cases with and without ROSE, respectively (p = 0.143). Conclusion: In the absence of ROSE, EUS-based tissue acquisition with Core needle should be considered since it achieves comparable tissue sampling adequacy and accuracy.

Pancreatic ductal adenocarcinoma (PDAC) is expected to become the second leading cause of cancer-associated death in the next decade or so. It is widely accepted that tumorigenesis is linked to specific alterations in key genes and pancreatic neoplasms are some of the best characterized at the genomic level. Recent whole-exome and whole-genome sequencing analyses confirmed that PDAC is frequently characterized by mutations in a set of four genes among others: KRAS, TP53, CDKN2A/p16, and SMAD4. Sequencing, for example, is the preferable technique available for detecting KRAS mutations, whereas in situ immunochemistry is the main approach for detecting TP53 gene alteration. Nevertheless, the diagnosis of PDAC is still a clinical challenge, involving adequate acquisition of endoscopic ultrasound (EUS)-guided fine-needle aspiration (FNA) and specific pathological assessment from tissue architecture to specific biomolecular tests. The aim of the present review is to provide a complete overview of the current knowledge of the biology of pancreatic cancer as detected by the latest biomolecular techniques and, moreover, to propose a paradigm for strict teamwork collaboration in order to improve the correct use of diagnostic sources.

RECOMMENDATIONSFor routine EUS-guided sampling of solid masses and lymph nodes (LNs) ESGE recommends 25G or 22G needles (high quality evidence, strong recommendation); fine needle aspiration (FNA) and fine needle biopsy (FNB) needles are equally recommended (high quality evidence, strong recommendation).When the primary aim of sampling is to obtain a core tissue specimen, ESGE suggests using 19G FNA or FNB needles or 22G FNB needles (low quality evidence, weak recommendation).ESGE recommends using 10-mL syringe suction for EUS-guided sampling of solid masses and LNs with 25G or 22G FNA needles (high quality evidence, strong recommendation) and other types of needles (low quality evidence, weak recommendation). ESGE suggests neutralizing residual negative pressure in the needle before withdrawing the needle from the target lesion (moderate quality evidence, weak recommendation).ESGE does not recommend for or against using the needle stylet for EUS-guided sampling of solid masses and LNs with FNA needles (high quality evidence, strong recommendation) and suggests using the needle stylet for EUS-guided sampling with FNB needles (low quality evidence, weak recommendation).ESGE suggests fanning the needle throughout the lesion when sampling solid masses and LNs (moderate quality evidence, weak recommendation).ESGE equally recommends EUS-guided sampling with or without on-site cytologic evaluation (moderate quality evidence, strong recommendation). When on-site cytologic evaluation is unavailable, ESGE suggests performance of three to four needle passes with an FNA needle or two to three passes with an FNB needle (low quality evidence, weak recommendation).For diagnostic sampling of pancreatic cystic lesions without a solid component, ESGE suggests emptying the cyst with a single pass of a 22G or 19G needle (low quality evidence, weak recommendation). For pancreatic cystic lesions with a solid component, ESGE suggests sampling of the solid component using the same technique as in the case of other solid lesions (low quality evidence, weak recommendation).ESGE does not recommend antibiotic prophylaxis for EUS-guided sampling of solid masses or LNs (low quality evidence, strong recommendation), and suggests antibiotic prophylaxis with fluoroquinolones or beta-lactam antibiotics for EUS-guided sampling of cystic lesions (low quality evidence, weak recommendation). ESGE suggests that evaluation of tissue obtained by EUS-guided sampling should include histologic preparations (e. g., cell blocks and/or formalin-fixed and paraffin-embedded tissue fragments) and should not be limited to smear cytology (low quality evidence, weak recommendation).

Background Cytologic diagnosis by endoscopic ultrasound-guided fine needle aspiration is associated with low sensitivity and adequacy. A newly designed endoscopic ultrasound-guided fine needle biopsy device, endowed with a side fenestration, is now available. Aims We carried out a study with the aim of evaluating the feasibility, safety, and diagnostic yield of the 22-gauge needle with side fenestration for endoscopic ultrasound fine needle aspiration and biopsy of pancreatic cystic lesions. Methods 58 patients with 60 pancreatic cystic lesions consecutively referred for endoscopic ultrasound guided-fine needle aspiration were enrolled in a prospective, dual centre study, and underwent fine needle aspiration and biopsy with the 22-gauge needle with side fenestration. Results Fine needle aspiration and biopsy was technically feasible in all cases. In 39/60 (65%) pancreatic cystic lesions, the specimens were adequate for cyto-histologic assessment. In lesions with solid components, and in malignant lesions, adequacy was 94.4% ( p = 0.0149) and 100% ( p = 0.0069), respectively. Samples were adequate for histologic evaluation in 18/39 (46.1%) cases. There were only 2 (3.3%) mild complications. Conclusions Fine needle aspiration and biopsy with the 22-gauge needle with side fenestration is feasible, and superior to conventional endoscopic ultrasound-guided fine needle aspiration cytology from cystic fluid, particularly in pancreatic cystic lesions with solid component or malignancy, with a higher diagnostic yield and with no increase in complication rate.

Background and Aims The recent development of microforceps for EUS through-the-needle biopsy (TTNB) sampling of the wall of pancreatic cystic lesions (PCLs) allows the collection of histologic specimens never handled and evaluated before by pathologists. We aimed to estimate the interobserver agreement among pathologists in evaluating such samples. Methods TTNB specimen slides from 40 PCLs with worrisome features were retrieved and independently evaluated for specimen adequacy, presence of lining epithelium, grade of epithelial dysplasia, presence of ovarian type stroma, and specific diagnosis by 6 expert pathologists from 6 different tertiary care centers. The Gwet's AC1 was used to assess interobserver agreement. Results An almost perfect agreement was observed for specimen adequacy (AC1, .82; 95% confidence interval [CI], .79-.98), presence of lesional epithelium (AC1, .90; 95% CI, .86-.92), epithelial dysplasia (AC1, .97; 95% CI, .95-.99), and ovarian-like stroma (AC1, .90; 95% CI, .86-.93). When considering all diagnoses separately, a moderate to substantial agreement was observed (AC1, .62; 95% CI, .57-.67), similarly to mucinous cysts versus serous adenoma versus other diagnoses (AC1, .65; 95% CI, .59-.70) and for mucinous cysts versus all other diagnoses (AC1,.74; 95% CI, .68-.84). The agreement for diagnosis of mucinous cystic neoplasm versus intraductal mucinous papillary neoplasm was almost perfect (AC1, .88; 95% CI, .81-.95). Conclusions Interobserver agreement between expert pathologists in the evaluation of TTNB samples from PCLs with worrisome features was close to perfection for all evaluated parameters, except definitive diagnosis. When mucinous cystic lesions were compared versus all other diagnoses, the agreement became substantial, thus indicating that TTNB specimens can provide important information for PCL management decisions.

Objectives: PEComas (perivascular epithelioid cell tumors) are a family of neoplastic lesions that share overlapping ultrastructure and morphological and immunohistochemical appearance and include angiomyolipoma, lymphangioleiomyomatosis, and clear cell “sugar” tumor of the lung, as well as similar tumors that occur in a variety of visceral, cutaneous, and soft tissue sites throughout the body. Methods: A 40-year-old woman came to medical attention because of epistaxis and because of unilateral nasal obstruction of 3 months' duration. Endoscopic examination revealed a well-demarcated exophytic lesion attached to the anterior portion of the middle turbinate. Results: The lesion was superficially located, and therefore amenable to complete surgical excision. Seven years after surgery, the patient is alive and well, without evidence of local recurrence or metastastic disease. Based on morphological and immunohistochemical appearance, a diagnosis of PEComa with worrisome histologic features was rendered. Conclusions: In the present study, we describe a PEComa that occurred in the nasal cavity and discuss the behavior of this entity. The importance of recognizing this disease will ensure its consideration in the differential diagnosis of tumors of the head that have similar morphological features. The histogenesis of PEComa still remains elusive, and collection of additional cases with a prolonged follow-up will be important in accurately determining the behavior of these distinctive tumors.

The use of endoscopic ultrasonography has allowed for improved detection and pathologic analysis of fine needle aspirate material for pancreatic lesion diagnosis. The molecular analysis of KRAS has further improved the clinical sensitivity of preoperative analysis. For this reason, the use of highly analytical sensitive and specific molecular tests in the analysis of material from fine needle aspirate specimens has become of great importance. In the present study, 60 specimens from endoscopic ultrasonography fine needle aspirate were analyzed for KRAS exon 2 and exon 3 mutations, using three different techniques: Sanger sequencing, allele specific locked nucleic acid PCR and Next Generation sequencing (454 GS-Junior, Roche). Moreover, KRAS was also tested in wild-type samples, starting from DNA obtained from cytological smears after pathological evaluation. Sanger sequencing showed a clinical sensitivity for the detection of the KRAS mutation of 42.1%, allele specific locked nucleic acid of 52.8% and Next Generation of 73.7%. In two wild-type cases the re-sequencing starting from selected material allowed to detect a KRAS mutation, increasing the clinical sensitivity of next generation sequencing to 78.95%. The present study demonstrated that the performance of molecular analysis could be improved by using highly analytical sensitive techniques. The Next Generation Sequencing allowed to increase the clinical sensitivity of the test without decreasing the specificity of the analysis. Moreover we observed that it could be useful to repeat the analysis starting from selectable material, such as cytological smears to avoid false negative results.

Pancreatic metastases are rare. The role of surgery is poorly defined, and data on long-term survival are lacking.Data from patients with pancreatic metastases observed in our division from 2003 to 2008 were retrospectively analyzed. In addition, the recent English medical literature was reviewed regarding series of patients with pancreatic secondary tumors.Data from 234 patients including 9 consecutive patients observed in our division were retrieved. Metastasis from renal cell carcinoma accounted for 67.9% of all cases. Factors predictive of worse survival, as determined by multivariate analysis, were symptoms at diagnosis, synchronous tumors, radical-intent surgery not performed, and pathologic diagnosis of the primary tumor. Compared with pancreatic metastases from renal cell cancer, metastases from melanoma (P0.001) and lung cancer (P = 0.002) were associated with worse survival. The differences in survival of patients with renal cell cancer metastases and those with breast cancer, colorectal, or sarcoma metastases did not reach statistical significance.There may be a subset of patients with pancreatic metastases who are able to benefit from surgery with respect to improved long-term survival. Symptoms at diagnosis, presentation with primary tumor, surgical resection, and pathologic diagnosis seem to be important prognostic factors.

The first case of well-differentiated intrahepatic cholangiocarcinoma with remarkable follicular architecture resembling a follicular neoplasm of thyroid is described in a 52-year-old man. The follicles contained homogenous eosinophilic material akin to colloid and were lined by benign-looking cuboidal cells. Immunohistochemically, thyroid transcription factor-1 (TTF-1) and thyroglobulin were negative and the patient had no evidence of a previous or concomitant thyroid tumour. This case can be added to the list of extrathyroid primary tumours that resemble thyroid neoplasms.

AIM: To summarize the current knowledge about the potential relationship between hepatitis C virus (HCV) infection and the risk of several extra-liver cancers. METHODS: We performed a systematic review of the literature, according to the Preferred Reporting Items for Systematic reviews and Meta-Analysis (PRISMA) Statement. We extracted the pertinent articles, published in MEDLINE and the Cochrane Library, using the following search terms: neoplasm/cancer/malignancy/tumor/carcinoma/adeno-carcinoma and non-Hodgkin lymphomas, kidney/renal-, cholangio-, pancreatic-, thyroid-, breast-,oral-, skin-, prostate-, lung-, colon-, stomach-, haematologic. Case series, case-series with control-group, case-control, cohort-studies as well as meta-analyses, written in English were collected. Some of the main characteristics of retrieved trials, which were designed to investigate the prevalence of HCV infection in each type of the above-mentioned human malignancies were summarised. A main table was defined and included a short description in the text for each of these tumours, whether at least five studies about a specific neoplasm, meeting inclusion criteria, were available in literature. According to these criteria, we created the following sections and the corresponding tables and we indicated the number of included or excluded articles, as well as of meta-analyses and reviews: (1) HCV and haematopoietic malignancies; (2) HCV and cholangiocarcinoma; (3) HCV and pancreatic cancer; (4) HCV and breast cancer; (5) HCV and kidney cancer; (6) HCV and skin or oral cancer; and (7) HCV and thyroid cancer. RESULTS: According to available data, a clear correlation between regions of HCV prevalence and risk of extra-liver cancers has emerged only for a very small group of types and histological subtypes of malignancies. In particular, HCV infection has been associated with: (1) a higher incidence of some B-cell Non-Hodgkin-Lymphoma types, in countries, where an elevated prevalence of this pathogen is detectable, accounting to a percentage of about 10%; (2) an increased risk of intra-hepatic cholangiocarcinoma; and (3) a correlation between HCV prevalence and pancreatic cancer (PAC) incidence. CONCLUSION: To date no definitive conclusions may be obtained from the analysis of relationship between HCV and extra-hepatic cancers. Further studies, recruiting an adequate number of patients are required to confirm or deny this association.

Five cases of mucoepidermoid carcinoma (MEC) of the breast are reported. All patients were women ranging in age from 29 years to 80 years. As histological grading is one of the most important prognostic factors in breast invasive carcinomas, MEC was graded using the Auclair et al. [1] grading system specific for MEC of salivary glands and the Elston and Ellis [4] grading method, a widely employed grading system in breast cancer. It was found that the two different grading systems appear to be interchangeable in assessing the grade of MEC of the breast. Accordingly, three cases were regarded low grade (G. 1), one intermediate (G. 2) and one high grade (G. 3). The cases were studied with immunohistochemistry and were found to have the same keratin pattern shown by their salivary gland counterpart. It was found that there are more similarities than differences between MEC of the breast and of salivary glands.

Background Pancreatic mucinous cystic lesions might develop malignancy if untreated, or could harbor malignancy at the time of the diagnosis. Many reports stated that cyst fluid carcinoembryonic antigen is an accurate diagnostic marker of pancreatic mucinous cysts. Methods A man with a incidental pancretic cystic lesion of 35 mm in diameter was admitted to our Department. CT and EUS did not reveal solid components, main duct was not dilated and cyst fluid CEA was very high (1445 ng/ml). Results The patient underwent a pancreatoduodenectomy and the surgical specimen showed a pseudocyst with columnar mucinous epithelium, consistent with low-grade PanIN. Conclusions Is it possible that the mucinous epithelium of panIN was responsible for the unexpectedly high CEA value?Clinicians should be aware of the usefulness of the CEA level in cystic fluid but even a very high CEA value should not be considered by itself to be evidence of a mucinous lesion.

Early detection of small pancreatic cancer is important because expected survival is markedly better for tumors ≤2 cm. A new endoscopic ultrasound-(EUS) guided biopsy needle with side fenestration has been recently developed to enable fine-needle biopsy (FNB) under EUS guidance. The aim of this study was to evaluate the outcome of EUS–FNB using a 22-gauge ProCore needle in solid pancreatic lesions ≤2 cm, in terms of diagnostic accuracy and yield. From January 2011 to December 2012, all consecutive EUS-guided tissue sampling of small pancreatic lesions (≤2 cm) were performed using 22-gauge ProCore needles; the data of these patients were analyzed retrospectively. Sixty-eight patients with a mean age of 65.7 years were included. The mean lesion size was 16.5 mm (range 5–20). None of the patients developed complications. On pathological examination, the tissue retrieved was judged adequate in 58 out of 68 cases (85.3 %) and the presence of a tissue core was recorded in 36 out of 68 cases (52.9 %). The overall sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were 80, 100, 100, 40, and 82 %, respectively. Our results suggested that EUS–FNB of small pancreatic lesions using a 22-gauge ProCore needle is effective and safe, and supports our hypothesis that EUS–FNB is highly useful in establishing the nature of small pancreatic lesions.

Context Hepatitis B (HBV) and hepatitis C virus (HCV) possess well-known oncogenic properties and may promote carcinogenesis in liver. However antigens and replicative sequences of HBV/HCV have been also detected in different extra-hepatic tissues, including the pancreas. Although epidemiological studies and meta-analyses have recently suggested that HBV/HCV may be also risk factors for pancreatic cancer and several researches have investigated the possible mechanisms and intra-/extra-cellular paths involved in pancreatic and hepatic carcinogenesis, to date, these complex processes remain largely unexplained. Objectives In our paper, we aimed to propose a comprehensive and qualitative hypothetical model, describing how HBV/HCV may exert their oncogenic role. Methods We performed a systematic research of scientific literature, by searching MEDLINE, the Cochrane Library and EMBASE databases. The used keywords were: “chronic HBV/HCV”, “pancreatic cancer”, “liver carcinoma”, “carcinogenesis mechanisms”, “tensional integrity”, “cytoskeleton”, and “extracellular matrix”. Results Taking advantage from available studies, we suggest an unifying hypothesis based on results and data, obtained from different areas of research. In particular we considered the well-defined model of tensional integrity and correlated it to changes induced by HBV/HCV in viscoelastic properties/stiffness of cellular/extracellular microenvironments. These events perturb the tightly-regulated feedback loop, which usually couples the intracellular-generated forces to substrate rigidity of extracellular compartments. Therefore, such a change strongly affects intracellular functions and cellular fate, by promoting a substantial deregulation of critical intracellular biochemical activities and genome expression. Conclusions Our hypothesis might provide for the first time a reliable system, which correlates tensional integrity model with intra-/extra-cellular modifications, occurring in liver and pancreas during HBV/HCV-induced carcinogenesis. This approach might improve our understanding of pathogenetic mechanisms involved in the development of pancreatic and hepatic carcinogenesis , enhancing the possibility of their treatment. Furthermore, should the usefulness of this model be definitively confirmed, it might be also helpful to extend its field of application to other viruses-related cancers.Image: Signaling pathways (Figure 1), JOP. Journal of the Pancreas, Vol 15, No 2 (2014): March - p. 84-218

The Ki-67 labeling index has been found to bear prognostic significance in gastrointestinal neuroendocrine tumors (NETs), and it was recently incorporated in NET histological grading. Nevertheless, a reliable preoperative determination of NET grading could be useful in clinical practice. The aim of this study is to compare the results of Ki-67 labeling index, as measured on cytological samples and on surgical specimens of patients with pancreatic NETs (P-NETs). We also investigated whether concordance might be improved, using a 5 % (instead of 2 %) cutoff value for defining G2 tumors. We retrospectively identified 48 consecutive patients with 53 P-NETs, from our five institutions, and we measured Ki-67 labeling index on their cytological samples and surgical specimens. The traditional 2 % and the alternative 5 % cutoff values were used to classify G2 tumors. The concordance rate between cytological and histological grading was 46/53 (86.8 %; weighted κ statistic 0.77; 95 % confidence interval (95 % CI) 0.60-0.94). No cases of cytological G1-G2 NETs were upgraded to G3 neuroendocrine carcinoma (NEC) at histological grading. Cytology was found to be highly specific in the diagnosis of both G2 (94.1 %; 95 % CI 80.3-99.3) and G3 tumors (100.0 %; 95 % CI 92.8-100), but the sensitivity was poor for G2 NETs (66.7 %; 95 % CI 38.4-88.2) and high for the prediction of G3 NECs (100 %; 95 % CI 39.8-100.0). When the 5 % cutoff value was adopted, concordance rate was 49/53 (92.4 %; weighted κ 0.82; 95 % CI 0.64-1.00). In conclusion, Ki-67 cytological expression can distinguish well-differentiated (both G1 and G2) from poorly differentiated P-NETs, and it may be useful for their preoperative classification. © 2014 Springer-Verlag.

Merkel cell carcinoma of the parotid gland associated with Warthin tumour: report of two cases Aims: Two cases of Merkel cell carcinoma occurring simultaneously and in close association with a Warthin tumour of the parotid gland are reported Methods and results: The patients were a 65-year-old man and a 70-year-old man, respectively. The Merkel cell carcinoma component was immunoreactive for chromogranin and keratin 20 and contained neuroendocrine-type granules at the ultrastructural level. Conclusions: The histogenesis of this heretofore undescribed combination is discussed.

A case of uterine leiomyoma with skeletal muscle differentiation is described. The patient is a 40-year-old woman who underwent abdominal hysterectomy and left salpingo-oophorectomy for fibroids. Evidence of skeletal muscle differentiation was evident at light and electron microscopy in one out of three "ordinary" leiomyomas. This was also shown by positive immunoreactions with antiskeletal muscle actin and myoglobin antisera. To our knowledge, this is the second case reported of the occurrence of skeletal muscle differentiation within a uterine leiomyoma and highlights the divergent differentiating potential of smooth muscle cells.