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Introduction Hurthle cells are modified follicular thyroid cells, whose development and proliferation have been related to different stimuli inducing cellular stress. Most thyroid aspirates containing Hurthle cells are classified as indeterminate, although the specific risk of malignancy for this subtype of atypia remains unclear. The aim of our study was to assess if the presence of Hurthle cells in indeterminate thyroid nodules correlates with the risk of malignancy. We further evaluated if this risk can be modified by the presence of an underlying Hashimoto's thyroiditis. Materials and methods We retrospectively analyzed all indeterminate thyroid nodules that were surgically treated at our institution between January 2010 and March 2019. For each nodule, we inferred the presence of Hurthle cells in the cytological report. Cytological findings were then correlated with histological reports. Results 354 indeterminate thyroid nodules were included in the study. The rate of malignancy resulted significantly lower in nodules exhibiting Hurthle cells compared to those negative for this cellular pattern (11.4% vs 22.5%, p = 0.01). Although there was no difference in the rate of malignancy in the whole population according to the presence or absence of Hashimoto's thyroiditis (21.5 vs 18.5%, p = 0.63), the significantly lower prevalence of malignant lesions in nodules with Hurthle cells was confirmed only in the presence of a histologically documented Hashimoto's thyroiditis (6.2% vs 32%, p = 0.005). Conclusions The finding of Hurthle cells in indeterminate thyroid nodules is associated with a low risk of malignancy in patients with an underlying Hashimoto's thyroiditis. The clinical management of these lesions may therefore be more conservative.

Background The possible benefit of frozen section (FS) analysis during (PD) for pancreatic ductal adenocarcinoma (PDAC) and of additional resection up to total pancreatectomy (TP) is debated. Aim of this work is to evaluate the prognostic role of positive FS analysis after PD for PDAC. Methods Multicentric retrospective analysis on prospective databases of three institutions. Based on FS analysis patients were classified as FS negative/FS positive. All positive FS patients underwent extended PD (EPD) or TP. Postoperative outcomes, disease-free (DFS) and disease-specific survival (DSS) were evaluated. Results Of 371 patients, 58 (16%) had positive FS. This resulted in 313 (84%) SPD (standard pancreatoduodenectomy), 22 (6%) EPD and 36 (10%) TP. Postoperative mortality was higher in patients undergoing TP (11% compared to 4.5% in EPD and 1% in SPD; p = 0.01). 26% of patients underwent neoadjuvant therapy, and it did not decrease the rate of positive FS. Systemic/local relapse rates were 59% and 41% in negative FS group, and 78% and 22% in positive FS group (p = 0.031). Median DFS and DSS were 20 and 37 months in negative FS group, and 12 and 23 months in positive FS patients (p = 0.001). Independent predictors of recurrence were G3, N1/N2 status and positive FS. R1 resection, G3, N1/N2 status, perineural invasion and positive FS were independent predictors of DSS. Conclusions Positive FS analysis is a poor prognostic factor after PD for PDAC. It is significantly associated with a high rate of R1 resection at final histology, PDAC recurrence and poor survival.

Background: Surgery remains the only treatment for the cure of pancreatic neuroendocrine tumors (PanNETs). Biomarkers to identify the completeness of resection and predict recurrence are lacking. Objective: The aims of this study were to evaluate if the blood measurement of neuroendocrine gene transcripts (NETest) was diagnostic of PanNETs, and whether NETest blood levels could identify complete resection. We compared transcript analysis with the biomarker chromogranin A (CgA). Methods: This was a prospective, longitudinal, single-center study including 30 patients with a postoperative histological confirmation of PanNET. Blood for NETest and CgA was collected preoperatively and on postoperative day (POD)1, POD5, and POD30. Transcripts were measured by real-time quantitative reverse transcription polymerase chain reaction and multianalyte algorithmic analysis (NETest; normal < 20), and CgA was measured by enzyme-linked immunosorbent assay (ELISA; normal < 109ng/mL). Data are expressed as mean ± standard deviation (SD). Results: Pancreatic surgical resections (n = 30) were R0, 26; R1, 2; and R2, 2. Preoperatively, NETest score was elevated in all 30 patients (44.7 ± 27), but postoperatively, NETest scores significantly decreased (p = 0.006) to POD30 (24.7 ± 24). The proportion of patients (15/30) with an elevated score significantly decreased by POD30 (p < 0.0001). CgA levels were elevated preoperatively (184 ± 360ng/mL) in only 9/30 patients, but did not decrease significantly postoperatively at POD30 (260 ± 589ng/mL, p = 0.398). The number of patients with elevated CgA levels remained unchanged (9/30). Conclusions: The NETest is an accurate diagnostic biomarker for PanNETs (100%). A decrease in NETest levels after radical resection suggests this blood test provides early assessment of surgical efficacy. CgA had no clinical utility.

Background & Aims The risk of malignancy is uncertain for intraductal papillary mucinous neoplasms (IPMNs) with main pancreatic duct (MPD) of 5-9 mm. No study has correlated MPD size and malignancy considering the anatomic site of the gland (head versus body-tail). Our aim was to analyze the significance of MPD in pancreatic head/body-tail as a predictor of malignancy in main-duct/mixed IPMNs. Methods Retrospective analysis of resected patients between 2009-2018 was performed. Malignancy was defined as high-grade dysplasia and invasive carcinoma. MPD diameter was measured with magnetic resonance imaging. Receiver operating characteristic curve (ROC) analysis was utilized to identify optimal MPD cut-off for malignancy. Independent predictors of malignancy were searched. Results Malignancy was detected in 74% of 312 identified patients. 213 patients (68.3%) had IPMNs of the pancreatic head and 99 (31.7%) of the body-tail. ROC analysis identified 9 and 7 mm as the optimal MPD cut-offs for malignancy in IPMNs of head and body-tail of the pancreas, respectively. Multivariate analysis confirmed that MPD ≥9 mm (pancreatic head) and ≥7 mm (body-tail) were independent predictors of malignancy along with macroscopic solid components, positive cytology and elevated CA 19-9. The risk of malignancy was low for IPMNs with MPD ≤8 mm (pancreatic head) or ≤6 mm (pancreatic body-tail) unless high-risk stigmata or multiple worrisome features were present. Conclusions Different thresholds of MPD dilation are associated with malignancy in IPMNs of the head and body-tail of the pancreas. The risk of malignancy for IPMNs with MPD ≤8 mm (pancreatic head) or ≤6 mm (pancreatic body-tail) lacking high-risk stigmata or multiple worrisome features is low.

Intraductal carcinoma (IC) is the new WHO designation for tumors previously encompassed by "low-grade cribriform cystadenocarcinoma" and "low-grade salivary duct carcinoma." The relationship of IC to salivary duct carcinoma (SDC) is controversial, even though they are considered to be distinct entities. IC is a rare low-grade malignant salivary gland neoplasm with histopathological features reminiscent of atypical ductal hyperplasia or ductal carcinoma in situ of the breast, showing diffuse S100 protein and mammaglobin positivity, while it is partially defined genetically. Recently, RET rearrangements including NCOA4-RET and TRIM27-RET have been described in IC. Here, we genetically characterize the largest cohort of IC to date (33 cases) including 8 cases with focal or widespread invasive growth and 1 case with lymph node metastasis. Thirty-three cases of IC were analyzed by next-generation sequencing (NGS) using the FusionPlex Solid Tumor kit (ArcherDX). Identified gene fusions were confirmed using fluorescence in situ hybridization break-apart and fusion probes and an reverse transcription polymerase chain reaction designed specifically for the detected breakpoints. Ten cases of SDC were analyzed for comparison using NGS panels that detect mutations and fusion transcripts. NGS analysis detected an NCOA4-RET fusion transcript in 11 cases of intercalated duct-type IC joining exon 7 or 8 of NCOA4 gene and exon 12 of the RET gene. Eight cases of IC had an invasive growth pattern, including one with widespread invasion and lymph node metastasis. Three invasive ICs harbored an NCOA4-RET fusion transcript, while 1 case was negative, and 2 cases were not analyzable. In addition, a novel TRIM27-RET fusion transcript between exon 3 of TRIM27 and exon 12 of RET was identified in 2 cases of IC with apocrine features, and one of them displayed invasive growth. Two IC cases with invasive growth harbored novel fusions TUT1-ETV5 and KIAA1217-RET, respectively. A total of 42.4% of the cases in this series of IC harbored fusions involving RET. Such fusion transcripts were not detected in any of the 10 SDC cases. We have confirmed NCOA4-RET as a predominant fusion in intercalated duct-type IC, including 3 cases with invasive growth pattern. A novel finding in our series was a case of widely invasive intercalated duct-type IC, with a single lymph node metastasis that revealed an NCOA4-RET fusion transcript. We also demonstrated that a subset of apocrine ICs harbored a TRIM27-RET gene fusion, including one case with invasive growth. In contrast, neither NCOA4-RET nor TRIM27-RET fusions were detected in any tested SDCs. Thus, the distinct molecular findings in IC and SDC support that the tumors are separate malignant salivary tumor entities. The presence of tumor-type-specific NCOA4-RET or TRIM27-RET translocations in a subset of widely invasive carcinomas with intercalated duct-like immunoprofiles suggests that a recharacterization of IC including its redesignation as "intercalated duct carcinoma, invasive or noninvasive" may be appropriate.

Intraductal carcinoma (IC) is the new World Health Organization designation for tumors previously called "low-grade cribriform cystadenocarcinoma" and "low-grade salivary duct carcinoma." The relationship of IC to salivary duct carcinoma is controversial, but they now are considered to be distinct entities. IC is a rare low-grade malignant salivary gland neoplasm with features similar to mammary atypical ductal hyperplasia or ductal carcinoma in situ, that shows diffuse S100 protein and mammaglobin positivity and is only partially defined genetically. (Mammary analogue) secretory carcinoma harboring ETV6-NTRK3, and in rare cases ETV6-RET fusion, shares histomorphologic and immunophenotypical features with IC. Recently, RET rearrangements and NCOA4-RET have been described in IC, suggesting a partial genetic overlap with mammary analogue secretory carcinoma. Here, we genetically characterize the largest cohort of IC to date to further explore this relationship. Seventeen cases of IC were analyzed by next-generation sequencing using the FusionPlex Solid Tumor kit (ArcherDX). Identified fusions were confirmed using fluorescence in situ hybridization break apart and, in some cases, fusion probes, and a reverse transcription polymerase chain reaction designed specifically to the detected breakpoints. All analyzed cases were known to be negative for ETV6 rearrangement by fluorescence in situ hybridization and for ETV6-NTRK3 fusion by reverse transcription polymerase chain reaction. Next-generation sequencing analysis detected a NCOA4-RET fusion transcript joining exon 7 or 8 of NCOA4 gene and exon 12 of RET gene in 6 cases of intercalated duct type IC; and a novel TRIM27-RET fusion transcript between exons 3 and 12 in 2 cases of salivary gland tumors displaying histologic and immunohistochemical features typical of apocrine IC. A total of 47% of IC harbored a fusion involving RET. In conclusion, we have confirmed the presence of NCOA4-RET as the dominant fusion in intercalated duct type IC. A novel finding in our study has been a discovery of a subset of IC patients with apocrine variant IC harboring a novel TRIM27-RET.

Peptide Receptor Radionuclide Therapy (PRRT) is an emerging therapeutic option for pancreatic neuroendocrine tumors (PanNETs). A possible role for PRRT as a neoadjuvant agent is still largely undetermined, explored only in case reports or small case series. Likewise, the histopathological and immunophenotypic changes induced by PRRT are poorly characterized. In the present study, 24 patients who underwent neoadjuvant PRRT on the basis of their disease’s characteristics were retrospectively matched with 24 patients who underwent upfront surgery. A comprehensive morphological and immunohistochemical evaluation was conducted to identify the differences in the two groups. The most significant findings were that the total percentage of stroma increased significantly in patients who underwent PRRT (p < 0.0001) and the characteristics of the stroma were different in the two groups. The somatostatin receptors type 2A (SSTR2A) were retained in most patients (87%) after PRRT. The density of CD163+ M2-polarized macrophages was greater in the PRRT group (p = 0.022), and M2-polarized macrophages tended to assume an epithelioid morphology (p = 0.043). In the neoadjuvant PRRT group, none of the histological parameters considered were associated with progression-free survival (PFS). Neoadjuvant PRRT in PanNETs is associated with reduced tumor diameter, an increased percentage of stroma, preserved SSTR2A expression in most of the cases, and an increased CD163+ M2-polarized macrophages density.

Recently, the term mixed neuroendocrine non-neuroendocrine neoplasms (MiNEN) has been proposed as an umbrella definition covering different possible combinations of mixed neuroendocrine-exocrine neoplasms. Among these, the adenoma plus neuroendocrine tumor (NET) combination is among the rarest and not formally recognized by the 2019 WHO Classification. In this setting, the debate between either collision tumors or true mixed neoplasms is still unsolved. In this report, a pancreatic intraductal papillary mucinous neoplasm (IPMN) plus a NET is described, and the molecular investigations showed the presence in both populations of the same KRAS, GNAS, and CDKN2A mutations and the amplification of the CCND1 gene. These data prove clonality and support a common origin of both components, therefore confirming the true mixed nature. For this reason, mixed neuroendocrine-exocrine neoplasms, in which the exocrine component is represented by a glandular precursor lesion (adenoma/IPMN) only, should be included into the MiNEN family.

Perineural invasion (PNI) is defined as the presence of neoplastic cells along nerves and/or within the different layers of nervous fibers: epineural, perineural and endoneural spaces. In pancreatic cancer—particularly in pancreatic ductal adenocarcinoma (PDAC)—PNI has a prevalence between 70 and 100%, surpassing any other solid tumor. PNI has been detected in the early stages of pancreatic cancer and has been associated with pain, increased tumor recurrence and diminished overall survival. Such an early, invasive and recurrent phenomenon is probably crucial for tumor growth and metastasis. PNI is a still not a uniformly characterized event; usually it is described only dichotomously (“present” or “absent”). Recently, a more detailed scoring system for PNI has been proposed, though not specific for pancreatic cancer. Previous studies have implicated several molecules and pathways in PNI, among which are secreted neurotrophins, chemokines and inflammatory cells. However, the mechanisms underlying PNI are poorly understood and several aspects are actively being investigated. In this review, we will discuss the main molecules and signaling pathways implicated in PNI and their roles in the PDAC.

Background/Aims: The annual incidence of pancreatic neuroendocrine tumors (PanNET) has been estimated to be around 0.8/100,000 inhabitants. The aim of this study was to determine the frequency of incidental histological diagnosis of PanNET in pancreatic specimen evaluation for a purpose other other than PanNET diagnosis. Methods: One thousand seventy-four histopathological examinations of pancreatic specimens performed in 3 centers in Italy were retrospectively reviewed. All cases with a main pathological diagnosis of PanNET were excluded. Results: An incidental associated diagnosis of PanNET was made in 41 specimens (4%). Among those 41 cases, 29 (71%) had a largest diameter p = 0.048). There was no association between incidental diagnosis of PanNET and age, gender, BMI, smoking habit, diabetes, and type of operation. Conclusions: The frequency of incidental histological diagnosis of PanNET is considerably high, suggesting that their real prevalence is probably underestimated. The present study suggests a possible correlation between the incidental occurrence of PanNET and IPMN.

Background: A fatty infiltration of the pancreas has been traditionally regarded as the main histological risk factor for postoperative pancreatic fistula, whereas the role of the secreting acinar compartment has been poorly investigated. The aim of this study was to evaluate the role of acinar content at pancreatic resection margin in the development of clinically relevant postoperative pancreatic fistula and clinically relevant postoperative acute pancreatitis after pancreaticoduodenectomy. Methods: Data from 388 consecutive patients who underwent pancreaticoduodenectomy (2018–2019) were analyzed. Pancreatic section margins were histologically assessed for acinar, fibrosis, and fat content. Acinar content was categorized using median and third quartile as cut-offs. Univariate and multivariable analysis of possible predictors of clinically relevant postoperative pancreatic fistula and clinically relevant postoperative acute pancreatitis were performed. Results: Acinar content was 80% in 66 patients (17.0%). The rate of clinically relevant postoperative pancreatic fistula and clinically relevant postoperative acute pancreatitis was significantly higher in patients with acinar content >80% (39.4% and 33.3%, respectively) as well as in those with acinar content ≥60% and ≤80% (36.5% and 35.3%, respectively), compared with patients with acinar content 80%, odds ratio 2.93, P = .010) and clinically relevant postoperative acute pancreatitis (≥60% and ≤80%, odds ratio 9.42, P < .001; >80%, odds ratio 10.16, P < .001). Conclusion: An acinar content at pancreatic resection margin ≥60% is associated to an increased risk of clinically relevant postoperative pancreatic fistula and clinically relevant postoperative acute pancreatitis. Fat content was associated neither with clinically relevant postoperative pancreatic fistula nor with clinically relevant postoperative acute pancreatitis.

Wilms tumors growing in a botryoid fashion into the renal pelvis have been reported since the 1960s as a rare tumor type usually associated with stromal histology and a good prognosis. However, the true frequency, association with Wilms tumor subtypes, and stage have never been comprehensively studied. We analyzed all Wilms tumors enrolled into the International Society of Paediatric Oncology (SIOP) United Kingdom 2001 Trial (2001-2011), which showed botryoid growth. In addition, we reviewed published series reporting papers on botryoid Wilms tumors. 77/739 patients (10.4%) showed at least one Wilms tumor with a botryoid pattern, and they were sub-classified according to the SIOP criteria as follows: 28 stromal, 21 mixed, 7 regressive, 3 completely necrotic, 4 blastemal, 2 epithelial, 3 diffuse anaplasia, 1 focal anaplasia, and 10 non-anaplastic type (treated with primary surgery). Stage was as follows: 25 stage I, 21 stage II, 12 stage III, 11 stage IV, and 8 stage V. In six cases, local pathologists incorrectly upstaged the tumor from stage I to stage II based on botryoid growth. The event-free and overall survivals were 90 and 96%, respectively. We concluded that botryoid growth pattern is a common finding in Wilms tumor and that all histological types and stages can share this feature. The botryoid growth itself is not a criterion for stage II. Botryoid Wilms tumor is not an entity but merely represents a pattern of tumor growth; such tumors should be sub-classified according to their overall histological features, which will determine treatment and prognosis.

Background: Peptide receptor radionuclide therapy is a valid therapeutic option for pancreatic neuroendocrine neoplasms. The aim of this study was to describe an initial experience with the use of peptide receptor radionuclide therapy as a neoadjuvant agent for resectable or potentially resectable pancreatic neuroendocrine neoplasms. Methods: The postoperative outcomes of 23 patients with resectable or potentially resectable pancreatic neuroendocrine neoplasms at high risk of recurrence who underwent neoadjuvant peptide receptor radionuclide therapy (peptide receptor radionuclide therapy group) were compared with 23 patients who underwent upfront surgical operation (upfront surgery group). Patients were matched for tumor size, grade, and stage. Median follow-up was 61 months. Results: The size (median greatest width) of the primary pancreatic neuroendocrine neoplasms decreased after neoadjuvant peptide receptor radionuclide therapy (59 to 50 mm; P =.047). There were no differences in intraoperative and postoperative outcomes and there were no operative deaths, but the risk of developing a pancreatic fistula tended to be less in the peptide receptor radionuclide therapy group when compared to the upfront surgery group (0/23 vs 4/23; P .2) differed between groups, but progression-free survival in the 31 patients who had an R0 resection seemed to be greater in the 15 patients in the peptide receptor radionuclide therapy group versus 16 patients the upfront group (median progression-free survival not reached vs 36 months; P

Nephrogenic adenoma is a benign condition of the urinary tract resulting from the displacement and seeding of renal tubular cells from the renal pelvis to the urethra. A retrospective series of 134 cases collected from four hospitals in three different countries was analyzed in this study. Recorded clinical data included age and sex, topography, urological antecedents, coexistent lesions, and follow-up. Cytonuclear and architectural features were reviewed, and PAX-8, p63, PSMA, S100A1, CEA, EMA, CD117, cannabinoid receptor CB1, AMACR, E-cadherin, and CD10 antibodies were included in an immunohistochemical panel. Males predominated (105 M/29 F) with an average age of 66 years (range, 14-96). Urothelial carcinoma was the most frequent clinical antecedent (43.2 %) and also the most common coexisting lesion (14 %). Tubular architecture was the most frequent pattern detected (40 %) although most cases showed a mixed pattern (45.5 %). Deep infiltrative growth into the muscularis propria occurred in two cases. EMA and PAX-8 were expressed in 100 % of nephrogenic adenomas, while E-cadherin reactivity was observed in 66.6 % of cases, cannabinoid receptor CB1 in 25 %, CD10 in 13.6 %, CD117 in 4.1 %, and AMACR in 2.7 %. For the rest of the antigens, no reactivity was found. The average time lapse between the pathological antecedent and the discovery of a nephrogenic adenoma was 32 months. We conclude that nephrogenic adenoma displays a broad spectrum of histological features that may mimic malignancy. In our experience, CB1 immunostaining adds a further argument in favor of a renal origin of this lesion. The combination of PAX-8+, p63-, and EMA + distinguishes nephrogenic adenoma from urothelial and prostate carcinoma, its most frequent malignant look-alikes.

An 81-year-old man affected by renal failure, underwent 18F-FDG PET/CT for detecting primary lesion because of multiple lung nodules consistent with secondary lesions revealed by computed tomography without contrast. PET study documented high pathologic uptake at anterior and upper wall of urinary bladder, and a primary urinary bladder cancer was suspected. Biopsy confirmed the presence of a high-grade transitional cell carcinoma.

Drug-induced damage to the gastrointestinal mucosa has been mainly focused on damage in the upper tract. However, increasing evidence suggests that commonly used drugs may also affect the mucosa of the lower gut, and particularly in the colon. The aim of this study was to report that fairly homogeneous colonoscopic findings, correlate with histological evidence of drug-induced mucosal injury. Charts of patients with the “cherry tree” colonoscopic aspect were reviewed to correlate the endoscopic and histological findings for a possible association with the use of drugs. Data from 29 patients (5 men, 24 women, age range 16–76 years) with the “cherry tree” colonoscopic findings were analyzed. Histology revealed an increase in eosinophils in the left colon in 23 patients, pseudomelanosis coli in 3, and microscopic colitis in 3. The findings were associated with proton pump inhibitors in 19 (65.5 %), non-steroidal anti-inflammatory drugs or statins (3 cases each), and other drugs [4 cases, including estroprogestinics (1), antidepressants (2), and thyroxin (1)]. The “cherry tree” colonoscopic appearance suggests drug-induced colonic damage. Awareness of this association may prevent unnecessary, expensive and time-consuming procedures.

An 83-year-old woman with multiple autoimmune disorders treated with corticosteroids was admitted to emergency department for heart failure and fever, after 1 year from implantation of trans-aortic valve (23-mm-Edward-Sapien-3). Diagnosis of definitive infective endocarditis was achieved: positive blood cultures for Streptococcus Gallolyticus and transoesophageal echocardiography (TEE) showing high trans-prosthesis gradients (mean-gradient 60 mmHg) and 15-mm-fluctuating vegetation on prosthetic leaflets ( Panels …