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Neuroendocrine neoplasms of the gut are a heterogeneous group of tumors showing different morphological, clinical, prognostic, and molecular features. Currently, these proliferations are classified as “neuroendocrine neoplasms” (NENs), which include two main entities: well-differentiated neuroendocrine tumor (NET) and poorly differentiated neuroendocrine carcinoma (NEC). It is worth noting that a growing burden of evidence has been accumulating in the last years showing that NET and NEC, despite sharing neuroendocrine differentiation, are, in fact, two different diseases with different morphology, clinical presentation, outcome, and molecular background. NETs are graded with a three-tiered system (NET G1, NET G2, NET G3) based on the proliferation assessment, using both mitotic count and Ki67 proliferation index. NECs, which show a poorly differentiated morphology, are high grade by definition. In addition to pure NENs, mixed epithelial neoplasms composed of a neuroendocrine and a non-neuroendocrine component can be found in the digestive system. When each of the two components is malignant and reaches at least 30% of the tumor mass, these neoplasms are defined as mixed neuroendocrine–non-neuroendocrine neoplasms (MiNENs). There are different MiNEN types which show different morphology and prognosis mainly based on the clinicopathological characteristics of each component. While the global incidence of malignant neoplasms is more or less stable over the last 40 years, the incidence and prevalence of NENs has increased over the same period, probably reflecting the effectiveness of modern diagnostic tools with consequent frequent detection of early-stage cases. Due to the early detection and the use of more effective personalized therapeutic approaches, survival of patients with NETs has been improving over time.

Neuroendocrine neoplasms (NENs) of the genitourinary tract are uncommon, but the pathologist has to be prepared to recognize them and to assess the morphophenotypic factors that can drive their treatment and prognosis. NENs have been described in the kidney, urinary bladder, prostate, testes, uterine cervix, uterine corpus, and ovaries. The clinico-pathological features and the nomenclature of these neoplasms may vary from site to site. This chapter systematically reviews the spectrum of genitourinary NEN within the context of a unitary vision of the diagnostic criteria and classification, paralleling the scheme recently proposed by the World Health Organization and the International Agency for Research on Cancer (IARC).

Mixed neuroendocrine and non-neuroendocrine neoplasms (MiNENs) of the digestive system represent a challenging task for both pathologists and clinicians. Their nomenclature has changed several times and their diagnostic criteria, classification, and clinical behaviour have been matter of debate over the past years. Although several attempts have been made to elucidate the pathogenesis and biology of MiNENs, some issues remain still open. This review will provide: a historical background that helps to understand the evolution of the concept and nomenclature of mixed neoplasms a revision of the knowledge on this topic, including molecular aspects, to give the reader a comprehensive and practical overview on this challenging field of pathology a focus on the diagnostic criteria and on the determination of prognostic and predictive factors a description of the different tumour types in the different sites of origin.

Abstract Introduction The incidence of neuroendocrine neoplasms (NENs) seems to increase worldwide. However, long-term, population-based data that consider differentiation levels are sparse. Objective To evaluate the incidence trend of lung and gastroenteropancreatic (GEP) NENs according to the latest International Agency for Research on Cancer/World Health Organization classification over a 41-year time period in two Swiss regions. Methods All cases of lung and GEP NENs recorded in the Vaud and Neuchâtel Cancer Registries from 1976–2016 were included. NENs were stratified into well-differentiated neuroendocrine tumors (NETs) and poorly differentiated neuroendocrine carcinomas (NECs). Changes in annual age-standardized incidence rates were calculated for lung and GEP NETs and NECs by sex. Results There were 4141 patients diagnosed with NENs, of which 65% were men. The incidence of lung NETs did not reveal any statistically significant trend in men, but increased in women by 4.9%/year between 1976–2016. The incidence of lung NECs in men decreased significantly by 2.6%/year from 1985–2016 whereas the incidence of lung NECs in women increased significantly between 1976–1998 by 6%/year. For GEP NETs, a steady annual increase in incidence occurred between 1976–2016 with a magnitude of 1.7% in men and 1.3% in women. No trend in incidence of GEP NECs was found for both sexes. Conclusions The incidence trends of lung NECs in men and women parallel changes in smoking prevalence in the population whereas causes of the increase in incidence of GEP NETs are not fully understood. Our study supports the importance of evaluating the epidemiology of NENs by their differentiation level.

Mixed neuroendocrine-non-neuroendocrine neoplasms (MiNENs) of the gallbladder are generally composed of adenocarcinoma and neuroendocrine carcinoma (NEC). Rare cases associated with intracholecystic papillary neoplasm (ICPN) have been reported. Although recent molecular data suggest that the different components of digestive MiNENs originate from a common precursor stem cell, this aspect has been poorly investigated in gallbladder MiNENs. We describe the clinicopathologic and molecular features of a MiNEN composed of ICPN, adenocarcinoma, and NEC. A 66-year-old woman presented with severe abdominal pain. She underwent radical cholecystectomy and an intracholecystic mass was found. Histologically, it was composed of ICPN associated with adenocarcinoma and large cell neuroendocrine carcinoma (LCNEC). The three components were positive for DNA repair proteins and p53. EMA was positive in the ICPN and adenocarcinoma components, while it was negative in the LCNEC. Heterogeneous expression of Muc5AC, cytokeratin 20, and CDX2 was only observed in the ICPN component. Cytokeratin 7 was diffusely positive in both adenocarcinoma and LCNEC components, while it was heterogeneously expressed in the ICPN. The copy number variation analysis showed overlapping results between the adenocarcinoma and LCNEC components with some minor differences with the ICPN component. The three tumor components showed the same mutation profile including TP53 mutation c.700T > C (p. Tyr234His), without mutations in other 51 genes known to be frequently altered in cancer pathogenesis and growth. This finding may support the hypothesis of a monoclonal origin of the different tumor components. We have also performed a review of the literature on gallbladder MiNENs.

Mixed neuroendocrine-nonneuroendocrine neoplasm (MiNEN) consisting of adenoma and well-differentiated neuroendocrine tumor (NET) has been recently defined as "MANET." However, the clinico-pathologic and pathogenetic features of this entity are not thoroughly studied. We examined the clinico-pathologic features of 12 MANETs by expanding their p53 and β-catenin expression profiles as well as the presence of microsatellite instability and KRAS, BRAF, and PIK3CA mutations in the 2 tumor components. In all cases, the adenomatous component represented the larger part of the lesions and the NET was localized in the deep central portion of polyps. In 9 cases the latter was represented by NET G1, in 2 by NET G2, and in 1 by NET G3. In all cases, the glandular and NET components were intimately admixed, with zone of transition between the tumor components. The NET component was p53 negative in all cases and 3 of 8 cases showed variable nuclear positivity for β-catenin. All patients with follow-up data were alive and free of disease after a mean follow-up time of 9 years. No mutations in KRAS, BRAF, and PIK3CA genes and no microsatellite instability were found in both tumor components. Review of the literature also identified 59 previously reported MANETs and no tumor-related death has been found. Like mixed adenoneuroendocrine carcinomas, a high-grade malignant form of MiNENs with a poorly differentiated neuroendocrine carcinoma component, a common origin for both tumor constituents may be hypothesized. Moreover, the current series provides evidence that MANET is an indolent disease that needs to be distinguished from aggressive high-grade MiNENs.

Background: The most appropriate nodal staging for pancreatic neuroendocrine neoplasms (PanNENs) is unclear. Aim of the study was to evaluate the effect of the number of positive lymph nodes on prognosis after pancreaticoduodenectomy for PanNENs. Methods: A retrospective analysis of pancreaticoduodenectomies for nonfunctioning PanNENs was performed. PanNENs with nodal metastases (N+) were classified into N1 (1 to 3 positive lymph nodes) and N2 (4 or more positive lymph nodes). Univariate and multivariate analyses of disease-free survival were performed. Results: 157 patients were included. 99 patients (63%) had N0 PanNENs whereas 58 patients (37%) had nodal involvement (N+). Patients with N0 PanNENs had a 3-year disease-free survival rate of 89% compared with 83% and 75% in patients with N1 and N2 PanNENs, respectively (P < 0.0001). Independent predictors of disease-free survival were the presence of necrosis, lymph node ratio and nodal status. Factors positively correlated with the number of positive lymph nodes were the Ki67 value, the T stage and the number of examined lymph nodes. Similar percentage of N0 and N+ PanNENs was demonstrated for a cut-off of 13 examined lymph nodes. Conclusions: The number of positive lymph nodes is accurate in predicting recurrence for PanNENs. Thirteen examined lymph nodes seems to be the minimum number of lymph nodes to be resected/examined in patients who undergo pancreaticoduodenectomy for PanNENs.

Neuroendocrine neoplasms (NENs) are a heterogeneous group of epithelial neoplastic proliferations that irrespective of their primary site share features of neural and endocrine differentiation including the presence of secretory granules, synaptic-like vesicles, and the ability to produce amine and/or peptide hormones. NENs encompass a wide spectrum of neoplasms ranging from well-differentiated indolent tumors to highly aggressive poorly differentiated neuroendocrine carcinomas. Most cases arise in the digestive system and in thoracic organs, i.e., the lung and thymus. A correct diagnostic approach is crucial for the management of patients with both digestive and thoracic NENs, because their high clinical and biological heterogeneity is related to their prognosis and response to therapy. In this context, immunohistochemistry represents an indispensable diagnostic tool that pathologists need to use for the correct diagnosis and classification of such neoplasms. In addition, immunohistochemistry is also useful in identifying prognostic and theranostic markers. In the present article, the authors will review the role of immunohistochemistry in the routine workup of digestive and thoracic NENs.

Combined neoplasms of the lung are defined by the WHO classification as an admixture of a small or large cell neuroendocrine carcinoma and a non-neuroendocrine component. However, rare cases of carcinoids combined with a non-neuroendocrine component have been described. These tumor types are not included as a specific entity in the WHO classification of pulmonary neoplasms and their pathogenesis is still unknown. We describe the clinico-pathologic and molecular features of a mixed (combined) lung neoplasm composed of adenocarcinoma and atypical carcinoid. The NGS analysis of the two different tumor components shows a similar molecular profile suggesting their monoclonal origin from a transformed stem/progenitor tumor cell which acquires a divergent differentiation during its development and progression. We also suggest the use of the recently proposed term of mixed neuroendocrine/non-neuroendocrine neoplasm (MiNEN) to define mixed (combined) neoplasms of the lung, because it seems to better cover the wide spectrum of different possible combinations of neuroendocrine and non-neuroendocrine components.

Hyalinizing trabecular tumour (HTT) is a rare thyroid neoplasm of follicular cell origin characterised by a trabecular growth pattern and prominent intratrabecular and intertrabecular hyalinisation. These peculiar histological features allow the prompt recognition of this neoplasm in surgical specimens. However, cytological diagnosis of HTT remains elusive and misleading because of overlapping characteristics with other thyroid tumours, particularly papillary thyroid carcinoma (PTC), medullary thyroid carcinoma (MTC) and the newly described non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP). Nevertheless, the proper recognition of this neoplasm on preoperative cytological preparations is important to avoid unnecessary overtreatment of this indolent lesion. A thorough review of the literature has revealed that the correct diagnosis of HTT in cytological smears is achieved in only 8% of cases. In a further 6% of cases, diagnostic doubt has been indicated. Sixty percent of published cases of HTT have been misdiagnosed as suggestive, suspicious or positive for PTC. These findings underline the difficulties of a cytological-based diagnosis of such entity. In this article we review the cytomorphological features of HTT and their correlation to histological features to provide the reader with the tools to improve diagnostic performance in the identification of HTT on preoperative cytology.

Objective: The aim of this study was to evaluate clinical and morphological features related to nodal involvement in appendiceal neuroendocrine tumors (NETs), to identify patients who should be referred for oncological radicalization with hemicolectomy. Background: Appendiceal NETs are usually diagnosed accidentally after appendectomy; the indications for right hemicolectomy are currently based on several parameters (ie, tumor size, grading, proliferative index, localization, mesoappendiceal invasion, lymphovascular infiltration). Available guidelines are based on scarce evidence inferred by small, retrospective, single-institution studies, resulting in discordant recommendations. Methods: A retrospective analysis of a prospectively collected database was performed. Patients who underwent surgical resection of appendiceal NETs at 11 tertiary Italian centers, from January 1990 to December 2015, were included. Clinical and morphological data were analyzed to identify factors related to nodal involvement. Results: Four-hundred fifty-seven patients were evaluated, and 435 were finally included and analyzed. Of them, 21 had nodal involvement. Grading G2 [odds ratio (OR) 6.04], lymphovascular infiltration (OR 10.17), size (OR 18.50), and mesoappendiceal invasion (OR 3.63) were related to nodal disease. Receiver operating characteristic curve identified >15.5mm as the best size cutoff value (area under the curve 0.747). On multivariate analysis, grading G2 (OR 6.98), lymphovascular infiltration (OR 8.63), and size >15.5mm (OR 35.28) were independently related to nodal involvement. Conclusions: Tumor size >15.5mm, grading G2, and presence of lymphovascular infiltration are factors independently related to nodal metastases in appendiceal NETs. Presence of 1 of these features should be considered an indication for oncological radicalization. Although these results represent the largest study currently available, prospective validation is needed.

Neuroendocrine differentiation in breast neoplasms has been a matter of discussion since the first description of a neuroendocrine neoplasm (NEN) in this site. In fact, NENs of the breast (Br-NENs) represent a less well-defined group of neoplasms than analogous entities in other organs, such as the lung and the gastroenteropancreatic tract. Pure neuroendocrine phenotype is extremely rare, both for the well- and for the poorly differentiated morphology. In contrast, the expression of neuroendocrine markers in otherwise typical breast carcinomas, both of special and of non-special type, without morphologically evident neuroendocrine differentiation is more common. Consequently, the diagnostic criteria and the classification scheme for Br-NENs have been continuously changing over time, and real consensus on this topic is still lacking. In this chapter, we recapitulate the evolution of the concept of Br-NEN; review the available knowledge on their morphological, molecular, and clinical features; and critically discuss the current classification scheme.

The incidence of neuroendocrine neoplasms (NENs) seems to increase worldwide. Long‐term, population‐based series that consider tumor differentiation are, however, sparse. We assessed the incidence trend of lung and gastroenteropancreatic (GEP) NENs according to the latest International Agency for Research on Cancer/World Health Organization classification over a 41‐year time period in two Swiss regions. All cases of lung and GEP NENs recorded in the Vaud and Neuchâtel Cancer Registries from 1976 to 2016 were included. NENs were stratified into well‐differentiated neuroendocrine tumors (NETs) and poorly differentiated neuroendocrine carcinomas (NECs). Changes in annual age‐standardized incidence rates were calculated for lung and GEP NETs and NECs by sex. Of 4,141 patients diagnosed with NENs, 65% were men. The incidence of lung NETs among men and women increased by 3.9%/year (95% CI: −5.3, 14.1%) and 4.9%/year (0.1, 9.9%), respectively, between 1976 and 2016. The incidence of lung NECs decreased by 2.6%/year (−3.1,‐1.8%) in men from 1985 to 2016 whereas it increased in women between 1976 and 1998 by 6%/year (4.2, 7.9%). For GEP NETs, a steady annual increase in incidence occurred between 1976 and 2016 with a magnitude of 1.7% (0.7, 2.7%) in men and 1.3% (0.5, 2.1%) in women. No significant trend in incidence of GEP NECs was found for both sexes. The incidence trends of lung NECs in men and women parallel changes in smoking prevalence in the population. Causes of the increase in incidence of GEP NETs are likely multifactorial. Our study supports the importance of evaluating the epidemiology of NENs by tumor differentiation., Over the last four decades, the incidence trends of neuroendocrine lung neoplasms (NENs) parallel, in men and women, changes in smoking prevalence in the population. The steady increase in gastroenteropancreatic (GEP) NENs in both sexes is likely multifactorial but has not yet been fully elucidated.

Background: Follicular-patterned thyroid nodules predominantly composed of macrofollicular structures without nuclear atypia are generally regarded as benign (i.e., hyperplastic nodules or follicular adenomas). In line with this concept, fine-needle aspiration cytology (FNAC) also assigns a benign connotation to the presence of macrofollicular structures, unless thyrocytes present papillary thyroid carcinoma (PTC)-related nuclear features that raise the possibility of a macrofollicular variant of PTC. However, cases showing macrofollicular architecture, capsular invasion, and no PTC features can also be observed. Methods: We describe the clinical, cytological, histological, and molecular genetic features of four cases of encapsulated follicular neoplasms that presented histologically with a predominant (>70%) macrofollicular architecture, but which also showed clear signs of capsular invasion, and thus were classified as macrofollicular variant of follicular thyroid carcinoma (MV-FTC). Results: Cytologically, macrofollicular structures were identified in all cases, leading to a benign FNAC diagnosis in three of the four cases. Due to increasing nodule size, thyroidectomy was performed in all cases. Histology showed focal and limited capsular invasion, without vascular invasion. Next-generation sequencing (custom 394 gene panel) of each tumor compared with matched normal DNA revealed a total of 7 somatic variants, including dual (likely biallelic) mutations in the DICER1 gene in 2 patients. The clinical outcome was excellent in all cases. Conclusions: Similar to the classical minimally invasive follicular thyroid carcinoma, MV-FTC appears to behave indolently. MV-FTC has a high rate of false-negative FNAC results, but MV-FTC is very rare (

Pituitary neuroendocrine tumors (PitNETs) : nomenclature evolution, not clinical revolution

Adrenocorticotropic hormone (ACTH)-secreting lung carcinoids represent the principal cause of ectopic Cushing syndrome, but the prevalence of ACTH expression and the association between ACTH production and Cushing syndrome in lung carcinoids have scarcely been investigated. In addition, available information on the prognostic meaning of ACTH production is controversial. The aims of this multicentric retrospective study, also including a review of the literature, were to describe the clinico-pathologic features of ACTH-producing lung carcinoids, to assess recurrence and specific survival rates, and to evaluate potential prognostic factors. To identify ACTH production in 254 unselected and radically resected lung carcinoids, we used a double approach including RT-PCR (mRNA encoding for pro-opiomelanocortin) and immunohistochemistry (antibodies against ACTH and β-endorphin). Sixty-three (24.8%) tumors produced ACTH and 11 of them (17.4%), representing 4.3% of the whole series, were associated with Cushing syndrome. The median follow-up time was 71 months. The 10-year overall and specific survival rates were 88.5% and 98.2%, respectively, with difference neither between functioning and nonfunctioning tumors nor between ACTH-positive and ACTH-negative carcinoids. At univariate analysis, histological type (typical or atypical) and Ki67 index significantly correlated with tumor recurrence. The literature review identified 172 previously reported patients with functioning ACTH-secreting lung carcinoids, and the meta-analysis of survival showed that 92% of them were alive after a mean follow-up time of 50 months. Our results demonstrate that ACTH-producing lung carcinoids are not rare, are not always associated with Cushing syndrome, and do not represent an aggressive variant of lung carcinoid.

The glucagon-like peptide-1 receptor agonist exenatide improves glycemic control by several and not completely understood mechanisms. Herein, we examined the effects of chronic intravenous exenatide infusion on insulin sensitivity, β cell and α cell function and relative volumes, and islet cell apoptosis and replication in nondiabetic nonhuman primates (baboons). At baseline, baboons received a 2-step hyperglycemic clamp followed by an l-arginine bolus (HC/A). After HC/A, baboons underwent a partial pancreatectomy (tail removal) and received a continuous exenatide (n = 12) or saline (n = 12) infusion for 13 weeks. At the end of treatment, HC/A was repeated, and the remnant pancreas (head-body) was harvested. Insulin sensitivity increased dramatically after exenatide treatment and was accompanied by a decrease in insulin and C-peptide secretion, while the insulin secretion/insulin resistance (disposition) index increased by about 2-fold. β, α, and δ cell relative volumes in exenatide-treated baboons were significantly increased compared with saline-treated controls, primarily as the result of increased islet cell replication. Features of cellular stress and secretory dysfunction were present in islets of saline-treated baboons and absent in islets of exenatide-treated baboons. In conclusion, chronic administration of exenatide exerts proliferative and cytoprotective effects on β, α, and δ cells and produces a robust increase in insulin sensitivity in nonhuman primates.

The 2017 World Health Organization classification of central nervous system and endocrine tumors have introduced significant changes in the diagnostic criteria for pituitary lesions. The aim of our paper is to describe the epidemiological, clinico-pathological, and radiological features of a single consecutive institutional surgical series of rare pituitary lesions, using these new criteria. Of the 316 endoscopic endonasal trans-sphenoidal approaches performed for pituitary lesions between 2010 and 2018, 15 rare lesions were encountered. These included metastases, pituitary carcinomas, pituicytomas, granular cell tumor, primary pituitary lymphomas, germinoma, mixed gangliocytoma-adenoma, hypophysitis, and pituitary hyperplasia. Their clinical, radiological, and pathological features are herewith presented along with a literature review that enabled us to propose an algorithm to facilitate a diagnosis for rare pituitary lesions.

Preclinical data show that intravesical instillation of Ty21a/Vivotif, a commercial vaccine against typhoid fever, is an effective alternative option to standard Bacillus Calmette-Guérin (BCG) immunotherapy for non-muscle-invasive bladder cancer (NMIBC). Here, we characterized the inflammatory effects of Ty21a on the bladder and investigated the immune mechanisms underlying tumor regression toward the use of this bacterial vaccine in NMIBC patients. MB49 bladder tumor-bearing mice had significantly improved survival after intravesical instillations of Ty21a doses of 10 6 to 10 8 colony-forming units. By IHC and morphology, both BCG and Ty21a instillations were associated with bladder inflammation, which was decreased with the use of low, but effective doses of Ty21a. Flow-cytometry analysis showed a significant infiltration of T cells, natural killer (NK) cells, and myeloid cells, compared with controls, after a single dose of Ty21a, whereas this was only observed after multiple doses of BCG. The induced myeloid cells were predominantly neutrophils and Ly6C + CD103 + dendritic cells (DC), the latter being significantly more numerous after instillation of Ty21a than BCG. Ex vivo infection of human leukocytes with Ty21a, but not BCG, similarly significantly increased DC frequency. CD4 + and CD8 + T cells, but not NK cells nor neutrophils, were required for effective bladder tumor regression upon Ty21a treatment. Thus, the generation of antitumor adaptive immunity was identified as a key process underlying Ty21a-mediated treatment efficacy. Altogether, these results demonstrate mechanisms behind intravesical Ty21a therapy and suggest its potential as a safe and effective treatment for NMIBC patients.

International audience; Background: The tumor-expressed CD73 ectonucleotidase generates immune tolerance and promotes invasiveness via adenosine production from degradation of AMP. While anti-CD73 blockade treatment is a promising tool in cancer immunotherapy, a characterization of CD73 expression in human hepatobiliopancreatic system is lacking.Patients and methods: CD73 expression was investigated by immunohistochemistry in a variety of non-neoplastic and neoplastic conditions of the liver, pancreas, and biliary tract.Results: CD73 was expressed in normal hepatobiliopancreatic tissues with subcellular-specific patterns of staining: canalicular in hepatocytes, and apical in cholangiocytes and pancreatic ducts. CD73 was present in all hepatocellular carcinoma (HCC), in all pancreatic ductal adenocarcinoma (PDAC), and in the majority of intra and extrahepatic cholangiocellular carcinomas, whereas it was detected only in a subset of pancreatic neuroendocrine neoplasms and almost absent in acinar cell carcinoma. In addition to the canonical pattern of staining, an aberrant membranous and/or cytoplasmic expression was observed in invasive lesions, especially in HCC and PDAC. These two entities were also characterized by a higher extent and intensity of staining as compared to other hepatobiliopancreatic neoplasms. In PDAC, aberrant CD73 expression was inversely correlated with differentiation (p < 0.01) and was helpful to identify isolated discohesive tumor cells. In addition, increased CD73 expression was associated with reduced overall survival (HR 1.013) and loss of E-Cadherin.Conclusions: Consistent CD73 expression supports the rationale for testing anti-CD73 therapies in patients with hepatobiliopancreatic malignancies. Specific patterns of expression could also be of help in the routine diagnostic workup.

We review the clinical and pathologic features of seven cases of papillary carcinoma of the thyroid that invaded the trachea and were treated by thyroidectomy, airway resection with reconstructive surgery over an interval of 15 years. We depicted the peculiarity of invasion of well differentiated papillary thyroid carcinoma (PTC) cells is perpendicularly oriented to the tracheal lumen, in between cartilaginous rings, along blood vessels and collagen fibers. Tracheal rings appear non-infiltrated in all histological sections of well differentiated PTC infiltrating the trachea. Similar description of inter-cartilage PTC infiltration into the trachea was first provided by Shin et al. in 1993. Interestingly, our pathological revision support the estimation by Shin et al., though that cartilage rings infiltration did occur in poorly differentiated thyroid cancers with exiguous prognosis.

Thyroid implants in the soft tissue of the neck are very rare findings of traumatic, iatrogenic, or neoplastic origins. We describe the clinico-pathological and molecular analysis of three cases with an initial diagnosis of follicular adenoma, Hürthle cell variant (FA-HCT), which developed cervical thyroid implants at 60, 59, and 36 months after thyroid surgery, followed by further neck recurrences, and, eventually, by distant metastases. A systematic review of all histopathological samples of both the primary lesions and the neck implants was performed. Molecular study included the analysis of pan-RAS and BRAF mutations and RET/PTC1, RET/PTC3, and PAX8/PPARγ rearrangements. The review of the original slides and of additional re-cuts of each block of the thyroid lesions did not show any sign of capsular and/or vascular invasion; thus, the original diagnoses of FA-HCT were confirmed. When sampling adequacy was considered, it turned out that the capsule was completely evaluable in case #3, whereas 85 % was evaluable for case #1 and less than 50 % for case #2. We cannot exclude that cases #1 and #2 were carcinomas that had not been completely sampled. The first occurring neck implants showed neither histological signs of malignancy nor the presence of lymphoid tissue. However, further neck recurrences had different histological aspects, with a clear infiltrative growth. Moreover, a mesenchymal reaction forming a sort of capsule was observed around oncocytic cells along with signs of vascular invasion. Molecular analysis revealed no alterations in the genes and rearrangements studied. Oncocytic thyroid implants in the neck soft tissue should be regarded as metastasis, even in the absence of clear-cut signs of malignancy and in the case of a bona fide diagnosis of Hürthle cells adenoma of the thyroid.

IgG4-related hypophysitis (IgG4-RH) is a rare disease, which can occur singularly or as manifestation of a systemic IgG4-related disease (IgG4-RD). Less than one hundred cases have been reported in the literature, very few of which were histopathologically documented. We analyzed the clinical, radiological, and histopathological features of two cases of IgG4-RH, the former observed in a 66-year-old man in the context of an IgG4-RD, and the latter affecting a 21-year-old woman, as an isolated lesion. In addition, we performed a comprehensive review of the previously published histopathologically documented cases of IgG4-RH. Pituitary samples from both patients showed dense lymphoplasmacytic infiltration, interstitial and storiform fibrosis, and high numbers of IgG4-positive plasma cells, consistent with IgG4-RH. From the literature review, we retrieved 18 papers reporting a total of 22 cases of histopathologically documented IgG4-RH. The revision of these cases, also including the two reported herein, showed an equal distribution of IgG4-RH in the two sexes, albeit significant clinico-pathological variation was found between cases arisen in female and male patients, respectively. In detail, IgG4-RH females were affected in their second-third decade of life, with a solitary pituitary lesion, low IgG4 serum level, and frequent association with autoimmune disorders. By contrast, IgG4-RH in men was a disease of the elderly, often in the context of a systemic IgG4-RD, with high IgG4 serum levels. Our study shows that IgG4-RH, as currently defined, is a clinically heterogenous disease, with different features in the two sexes. Indeed, cases diagnosed in young women, as our case 2, mostly do not present other evidence of IgG4-RD and might be better classified as lymphocytic hypophysitis with abundant IgG4+ plasma cells. For this reason, the histopathological examination of the pituitary lesion, particularly in female patients, may still be useful for a correct differential diagnosis with other variants of primary hypophysitis.

Tumors of the pituitary gland are frequent intracranial neoplasms. They can affect all ages and show a slight prevalence in females. Clinically, they can present either with signs and symptoms of pituitary hormone hypersecretion, or as space-occupying intracranial masses, with visual defects and headaches as the main symptoms. Rarely, neoplasms in this site may cause hypopituitarism.

Merkel cell carcinoma is an aggressive neuroendocrine skin tumor, for which several non-conclusive prognostic factors of adverse clinical behavior have been reported. As promoter methylation of the immune checkpoint receptor CD279/PD-1/PDCD1(mPDCD1) has been shown to be a prognostic factor in different cancers, we investigated its role in Merkel cell carcinoma. mPDCD1was assessed retrospectively in a cohort of 69 Merkel cell carcinoma patients from the University of Bologna, University of Turin and University of Insubria. Kaplan-Meier curves and log-rank tests were calculated for all variables. To assess the influence of mPDCD1, the Cox proportional hazards model and different Royston-Parmar models were evaluated. High PDCD1 methylation (mPDCD1 high ) was associated with a higher overall mortality at both the univariate analysis (log rank test: χ 2 = 5.17, p = 0.023; permutation test: p = 0.023) and the multivariate analysis (HR = 2.111, p = 0.042). The other variables associated with a higher overall mortality at the multivariate analysis were clinical stage III-IV (HR = 2.357, p = 0.008), size > 2 cm (HR = 2.248, p = 0.031) and Merkel cell polyomavirus (HR = 0.397, p = 0.015). Further, mPDCD1 high was strongly associated with older age (81 vs 76 years, p = 0.042), absence of immune cells (92.6%, p < 0.001), no expression of PD-L1 by immune cells (70.4%, p = 0.041) and by both immune and tumor cells (70.4%, p = 0.001). mPDCD1 is a valid prognostic parameter in patients affected by Merkel cell carcinoma. In addition, it could provide an estimate of the global PD-1/PD-L1 expression with potentially relevant implications from a therapeutic point of view.

Lymphoproliferative disorders (LPDs) rarely involve the endocrine system, either as dissemination of a systemic condition, or as primary diseases. Due to their rarity, LPDs of endocrine organs can represent a diagnostic challenge for both pathologists and clinicians. Nevertheless, a comprehensive review of LPDs arising in endocrine organs reveals several specific clinico-pathological features that can be helpful in the correct management of the cases, from both a diagnostic and a therapeutic point of view. We designed this review with the aim of systematically addressing the morphological, immunohistochemical and genetic characteristic of LPDs of the different endocrine organs. Both lymphomas and mass forming immune cell-based inflammatory diseases, such as IgG4-related lesions, are included in the discussion. In addition, for each primary site, we propose a step-wise diagnostic approach and provide the reader with practical tools to address differential diagnostic and prognostic issues that can be useful to manage such unexpected lesions in daily practice. Finally, endocrine function in lymphoma is discussed.

Angiosarcoma and anaplastic carcinoma are the most lethal neoplasms of the thyroid worldwide and share some similarities, which have led to a longstanding controversy on their etiopathological relationship. Thyroid angiosarcomas are characterized by vessel formation and an immunophenotype common to endothelial cells, while anaplastic carcinomas are partially or wholly composed of mesenchymal-like cells that have lost the morphologic and functional features of normal thyroid follicular cells. To investigate whether angiosarcomas represent the endothelial extreme of the differentiation spectrum of carcinomas or they are bona fide vascular neoplasms, we studied the clinico-morphologic and genetic characteristics of a series of 10 angiosarcomas and 22 anaplastic carcinomas. Immunohistochemically, among the endothelial markers, CD31 and ERG were the most consistently expressed in angiosarcomas. Among the markers of thyroid origin, PAX8 was the most reliable in anaplastic carcinomas, while TTF-1 reactivity was found in only 5% of anaplastic carcinomas and thyroglobulin was always negative. Pankeratin reacted with most angiosarcomas and anaplastic carcinomas and is therefore not useful in the differential diagnosis. Interestingly a mutated pattern of p53 immunostaining prompted a diagnosis of anaplastic carcinoma. To compare the genetic profile, we used the NGS approach to sequence hotspot regions within a panel of 57 genes. As a result, only a few mutations were found in angiosarcomas and all of them were single events (no TP53 or TERT mutation). On the other hand, anaplastic carcinomas were characterized by a higher number of mutations, and TP53 and TERT promoter mutations were the most frequent genetic alterations. The lack in angiosarcomas of the common mutations identified in anaplastic carcinomas supports a different genetic origin and strongly suggests that, in spite of a shared sarcomatous morphology and a similar clinical aggressiveness, angiosarcomas and anaplastic carcinomas rely on a completely different set of genetic alterations during their evolution.

While a number of structural and cellular abnormalities occur in the islet of Langerhans in diabetes, and in particular in type 2 diabetes, the focus has been mostly on the insulin producing β-cells and only more recently on glucagon producing α- and δ-cells. There is ample evidence that in type 2 diabetes mellitus (T2DM), in addition to a progressive decline in β-cell function and associated insulin resistance in a number of insulin-sensitive tissues, alterations in glucagon secretion are also present and may play an important role in the pathogenesis of hyperglycemia both in the fasting and in the postprandial state. Recently, a number of studies have showed that there are also functional and structural alterations in glucagon-producing α-cells and somatostatin-producing δ-cells. Thus, it is becoming increasingly clear that multiple cellular alterations of multiple cell types occur, which adds even more complexity to our understanding of the pathophysiology of this common and severe disease. We believe that persistent efforts to increase the understanding of the pathophysiology of hormone secretion in the islets of Langerhans will also improve our capability to better prevent and treat diabetes mellitus.

We report a case of tumour in the head of the pancreas observed in a 57-year-old man with a history of worsening jaundice and elevated alpha-fetoprotein (AFP) serum level, who underwent Whipple pancreatoduodenectomy. Histologically, the tumour was predominantly composed of solid sheets of large eosinophilic cells with a prominent lymphoid infiltration without association neither with DNA microsatellite instability nor Epstein-Barr virus infection. The tumour was diffusely and strongly positive for hepatocyte paraffin-1 (Hep Par-1) and glypican-3 leading to the diagnosis of hepatoid carcinoma. Strong cytoplasmic staining for AFP was focally observed. Moreover, tumour cells showed countless cytoplasmic eosinophilic globules immunoreactive for the stress protein p62. A primary hepatocellular carcinoma of the liver was ruled out by careful clinical analysis. Hepatoid carcinoma is an extremely rare pancreatic neoplasm, and here, we describe the first case of such variant associated with lymphoid stroma. The characteristic histologic features and the immunophenotypic profile help in distinguishing this carcinoma from other pancreatic tumours, notably from medullary carcinoma.

Ribonuclease T2 (RNASET2) is a pleiotropic and polyfunctional protein, which exerts several different activities in neoplastic cells since the early steps of tumor development. Besides having an antitumorigenic activity, RNASET2 inhibits both bFGF-induced and VEGF-induced angiogenesis and has a role as a stress-response, alarmin-like, protein. In this study, we investigated RNASET2 expression in well-differentiated and poorly differentiated neuroendocrine neoplasms of the lung (Lu-NENs), which are known to show clear-cut differences in morphology, biology and clinical behavior. In addition, we explored possible relationships between RNASET2 expression and a series of immunohistochemical markers related to hypoxic stress, apoptosis, proliferation and angiogenesis. Our results showed a significantly higher expression of RNASET2, HIF-1α, and its target CA IX in poorly differentiated than in well-differentiated Lu-NENs, the former also showing higher proliferation and apoptotic rates, as well as a lower microvessel density (MVD) than the latter. Moreover, we were able to demonstrate in vitro an overexpression of RNASET2 in consequence of the activation of HIF-1α. In conclusion, we suggest that in poorly differentiated Lu-NENs, RNASET2 expression may be induced by HIF-1α, behaving as an alarmin-like molecule. In this aggressive group of cancers, which have highly deregulated proliferation pathways, RNASET2 fails to exert the growth-inhibiting effects described in other types of neoplasms. Its increased expression, however, may contribute to the typical phenotypic alterations seen in poorly differentiated Lu-NENs, such as the high apoptotic rate and the extensive necrosis, and may also enhance the low MVD observed in these neoplasms.

Background: Gastric neuroendocrine neoplasms (NENs) are very heterogeneous, ranging from mostly indolent, atrophic gastritis-associated, type I neuroendocrine tumors (NETs), through highly malignant, poorly differentiated neuroendocrine carcinomas (pdNECs), to sporadic type III NETs with intermediate prognosis, and various rare tumor types. Histologic differentiation, proliferative grade, size, level of gastric wall invasion, and local or distant metastases are used as prognostic markers. However, their value remains to be tailored to specific gastric NENs. Methods: Series of type I NETs (n = 123 cases), type III NETs (n = 34 cases), and pdNECs (n = 43 cases) were retrospectively collected from four pathology centers specializing in endocrine pathology. All cases were characterized clinically and histopathologically. During follow-up (median 93 months) data were recorded to assess disease-specific patient survival. Results: Type I NETs, type III NETs, and pdNECs differed markedly in terms of tumor size, grade, invasive and metastatic power, as well as patient outcome. Size was used to stratify type I NETs into subgroups with significantly different invasive and metastatic behavior. All 70 type I NETs < 0.5 cm (micro-NETs) were uneventful. Ki67-based grading proved efficient for the prognostic stratification of type III NETs; however, grade 2 (G2) was not associated with tumor behavior in type I NETs. Although G3 NETs (2 type I and 9 type III) had a very poor prognosis, it was found that patient survival was longer with type III G3 NETs compared to pdNECs. Conclusions: Given the marked, tumor type-related behavior differences, evaluation of gastric NEN prognostic parameters should be tailored to the type of neoplastic disease.

Background: The World Health Organization (WHO) and the American Joint Cancer Committee (AJCC) modified the grading of pancreatic neuroendocrine neoplasms from a three-tier (WHO-AJCC 2010) to a four-tier system by introducing the novel category of NET G3 (WHO-AJCC 2017). Objectives: This study aims at validating the WHO-AJCC 2017 and identifying the most effective grading system. Method: A total of 2,102 patients were enrolled; entry criteria were: (i) patient underwent surgery; (ii) at least 2 years of follow-up; (iii) observation time up to 2015. Data from 34 variables were collected; grading was assessed and compared for efficacy by statistical means including Kaplan-Meier method, Cox regression analysis, Harrell’s C statistics, and Royston’s explained variation in univariable and multivariable analyses. Results: In descriptive analysis, the two grading systems demonstrated statistically significant differences for the major category sex but not for age groups. In Cox regression analysis, both grading systems showed statistically significant differences between grades for OS and EFS; however, no statistically significant difference was observed between the two G3 classes of WHO-AJCC 2017. In multivariable analysis for the two models fitted to compare efficacy, the two grading systems performed equally well with substantially similar optimal discrimination and well-explained variation for both OS and EFS. The WHO-AJCC 2017 grading system retained statistically significant difference between the two G3 classes for OS but not for EFS. Conclusions: The WHO-AJCC 2017 grading system is at least equally performing as the WHO-AJCC 2010 but allows the successful identification of the most aggressive PanNET subgroup. Grading is confirmed as probably the most powerful tool for predicting patient survival.

Olfactory neuroblastoma (ONB) is a malignant neuroendocrine neoplasm with a usually slow course, but with considerable recurrence rate. Many neuroendocrine tumors have shown good response to the treatment with somatostatin analogs and somatostatin radioreceptor therapy. In ONBs, there are scarce data on somatostatin-based treatment and the cellular expression of somatostatin receptors (SSTR), the prerequisite for binding and effect of somatostatin on normal and tumor cells. The aim of our study was to investigate the immunohistochemical expression of SSTR2A and SSTR5 in a cohort of 40 ONBs. In addition, tissue microarrays containing 40 high-grade sinonasal carcinomas as well as 6 sinonasal lymphomas, 3 rhabdomyosarcomas, and 3 Ewing sarcomas were evaluated. Volante system was applied for staining evaluation. Thirty cases (75%) were immunopositive for SSTR2A and 3 (7.5%) for SSTR5. Among the 30 SSTR2A-positive ONBs, 19 tumors (63.3%) scored 2+ and 11 (36.7%) scored 3+. All SSTR5-positive ONBs scored 2+. Neither sinonasal carcinomas nor sinonasal small round blue cell neoplasms expressed SSTR2A or SSTR5. The frequent expression of SSTR2A provides a rationale for radioreceptor diagnosis and therapy with SST analogs in ONBs. SSTR2A expression in ONBs is a helpful adjunct in the differential diagnosis of ONBs.

Neuroendocrine neoplasms (NENs) are a heterogeneous group of epithelial neoplastic proliferations arising in a large number of body organs, although most cases arise in the bronchopulmonary and gastroenteropancreatic (GEP) systems. Irrespective of their primary site, neoplastic cells share features of neural and endocrine differentiation and neoplasms encompass a wide spectrum of entities, from very indolent well-differentiated neuroendocrine tumors (NETs) to highly aggressive neuroendocrine carcinomas (NECs). They represent a challenge for oncologists and pathologists and a correct diagnostic approach is crucial for the management of patients. Indeed, although the diagnosis of GEP and lung NENs is generally simple in routine practice, there are critical aspects that need to be taken into account during the diagnostic workup. The most challenging tasks include the difficulty in achieving the correct prognostic evaluation of NETs by recognizing their metastatic/aggressive potential and the identification of NECs. To this aim, a comprehensive clinical, morphological, immunohistochemical, and molecular investigation represents the most reliable tool for pathologists. The present chapter examines current approaches to the diagnosis and prognostic classification of GEP and lung NENs, focusing on the classification and the critical use of morphological parameters, immunohistochemical stainings, and molecular markers in the pathology workup.

In 1983, a monoclonal antibody, Ki67, was generated, that labeled the nuclei of proliferating non-neoplastic and neoplastic cells. The name Ki67 derived from the city of Kiel (Ki) where the antibody was produced in the university department of pathology and refers to the number of the original clone (67). Systematic assessment of the proliferative activity of tumors using Ki67 started in the 1990s, when Ki67, which only worked on frozen tissue, was complemented by the antibody MIB-1 that also worked in formalin-fixed tissues. Pancreatic neuroendocrine neoplasms (PanNENs) were the first endocrine tumors whose proliferative activity was assessed with Ki67. This approach was so successful that Ki67 was included as prognostic marker in the 2000 and 2004 WHO classifications of gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs). In 2010, the WHO classification of GEP-NENs introduced a three-tiered grading, originally proposed by ENETS in 2006 that was mainly based on the Ki67 index. As it has subsequently been shown that the Ki67 index is the most reliable factor in the prognostic evaluation of GEP-NENs, especially of PanNENs, the 2017 WHO classification of PanNENs requires its use and strongly recommends exact assessment of the proportion Ki67-labeled cells as basis for the calculation of the Ki67 index. Problems in assessing the Ki67 index include intertumoral and intratumoral staining heterogeneity and counting methods. Despite such problems, the Ki67 index has emerged as indispensable for the prognostic and therapeutic stratification of the majority of GEP-NENs and can barely be replaced by counting mitoses. In future, however, it can be anticipated that the Ki67 cut-offs experience refinement in relation to the type of tumor, its location, and its response to therapy. It is also possible that the prognostic risk of an individual tumor is calculated for each Ki67 unit and not for an "a priori" fixed Ki67 class.

A 37-year-old male with long-standing and extensive ulcerative pancolitis developed a rapidly lethal poorly differentiated neuroendocrine carcinoma (NEC) in the sigmoid colon. Prior biopsies obtained from multiple sites of the colon during endoscopic surveillance showed minimal inflammatory changes and no sign of dysplasia. Patients with inflammatory bowel disease (IBD) are at increased risk of colorectal malignancies, and adenocarcinoma is the most common type of colorectal neoplasm associated with ulcerative colitis and Crohn’s disease, but other types of epithelial and nonepithelial tumors have also been described in IBD. NECs arising in the setting of ulcerative colitis are very rare and are reported as anecdotic findings. We describe the clinicopathological features of an IBD-related NEC and review the previously reported cases.

Background: Mixed neuroendocrine/nonneuroendocrine carcinomas are heterogeneous tumors with poorly defined diagnostic and clinical features and without pathological or molecular markers of prognosis or markers predicting their response to therapy. We aimed at analyzing the pathological features and the expression of genes involved in DNA repair or synthesis in a cohort of patients with mixed carcinomas from different sites as compared to the patients' outcome. Methods: Relative cDNA quantification of ribonucleotide reductase, large subunit 1, excision repair cross-complementation group 1, thymidylate synthase and topoisomerase IIa genes was tested using real-time PCR on microdissected neuroendocrine and nonneuroendocrine tumor components of 42 mixed cases (from the lung as well as the gastrointestinal and genitourinary tracts) and on 45 control cases of pure neuroendocrine and nonneuroendocrine carcinomas. Results: The expression levels of all genes were stable comparing nonneuroendocrine and neuroendocrine components of mixed cases (except for topoisomerase IIa in lung samples) but significantly different as compared to control nonneuroendocrine and neuroendocrine tumors. In the multivariate analysis including all clinical and pathological parameters and gene expression levels available, a predominant nonneuroendocrine component, the administration of additional therapy other than surgery and a high thymidylate synthase expression in nonneuroendocrine tumor tissue were significantly associated with a lower risk of a patient's death. Conclusions: Our data show that mixed neuroendocrine/nonneuroendocrine carcinomas are different at the molecular level from their pure neuroendocrine and nonneuroendocrine counterparts, and detailed analyses of their clinical, pathological and molecular features may improve the clinical strategies for the treatment of these rare and underestimated tumors.

Gastroenteropancreatic (GEP) neuroendocrine carcinomas (NECs) and mixed adenoneuroendocrine carcinomas (MANECs) are heterogeneous neoplasms characterized by poor outcome. Microsatellite instability (MSI) has recently been found in colorectal NECs showing a better prognosis than expected. However, the frequency of MSI in a large series of GEP-NEC/MANECs is still unknown. In this work, we investigated the incidence of MSI in GEP-NEC/MANECs and characterized their clinicopathologic and molecular features. MSI analysis and immunohistochemistry for mismatch repair proteins (MLH1, MSH2, MSH6 and PMS2) were performed in 89 GEP-NEC/MANECs (six esophageal, 77 gastrointestinal, three pancreatic, and three of the gallbladder). Methylation of 34 genes was studied by methylation-specific multiplex ligation probe amplification. Mutation analysis of BRAF and KRAS was assessed by PCR-pyrosequencing analysis. MSI was observed in 11 NEC/MANECs (12.4%): seven intestinal and four gastric. All but two MSI-cases showed MLH1 methylation and loss of MLH1 protein. The remaining two MSI-cancers showed lack of MSH2 or PMS2 immunohistochemical expression. MSI-NEC/MANECs showed higher methylation levels than microsatellite stable NEC/MANECs (40.6% vs 20.2% methylated genes respectively, PBRAF mutation was detected in six out of 88 cases (7%) and KRAS mutation was identified in 15 cases (17%). BRAF mutation was associated with MSI (PKRAS status did not correlate with any clinicopathologic or molecular feature. Vascular invasion (P=0.0003) and MSI (P=0.0084) were identified as the only independent prognostic factors in multivariate analysis. We conclude that MSI identifies a subset of gastric and intestinal NEC/MANECs with distinct biology and better prognosis. MSI-NEC/MANECs resemble MSI-gastrointestinal adenocarcinomas for frequency, molecular profile and pathogenetic mechanisms.

Podocyte injury and resulting albuminuria are hallmarks of diabetic nephropathy, but targeted therapies to halt or prevent these complications are currently not available. Here, we show that the immune-related molecule B7-1/CD80 is a critical mediator of podocyte injury in type 2 diabetic nephropathy. We report the induction of podocyte B7-1 in kidney biopsy specimens from patients with type 2 diabetes. Genetic and epidemiologic studies revealed the association of two single nucleotide polymorphisms at the B7-1 gene with diabetic nephropathy. Furthermore, increased levels of the soluble isoform of the B7-1 ligand CD28 correlated with the progression to ESRD in individuals with type 2 diabetes. In vitro, high glucose conditions prompted the phosphatidylinositol 3 kinase–dependent upregulation of B7-1 in podocytes, and the ectopic expression of B7-1 in podocytes increased apoptosis and induced disruption of the cytoskeleton that were reversed by the B7-1 inhibitor CTLA4-Ig. Podocyte expression of B7-1 was also induced in vivo in two murine models of diabetic nephropathy, and treatment with CTLA4-Ig prevented increased urinary albumin excretion and improved kidney pathology in these animals. Taken together, these results identify B7-1 inhibition as a potential therapeutic strategy for the prevention or treatment of diabetic nephropathy.