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The tumor microenvironment is considered to play a pivotal role in various human malignancies. Neuroendocrine and non-neuroendocrine neoplasms are considered to have different tumor microenvironments. However, owing to differences in the systemic and/or local immune statuses, tumor microenvironments in different patients may be difficult to compare. Mixed neuroendocrine non-neuroendocrine neoplasms (MiNENs), although rare, could be useful for exploring the effects of neuroendocrine differentiation on the tumor microenvironment, because both neuroendocrine and non-neuroendocrine components are present in the same tumor. Here, we examined 33 cases of histologically confirmed MiNENs and evaluated the influence of neuroendocrine differentiation on the tumor microenvironment by comparing tumor-infiltrating lymphocytes, tumor-associated macrophages, and other relevant factors in the two components the same tumor. The immunoreactivity of those examined above was evaluated quantitatively. The values of vasohibin-1-positive density (p < 0.0001) and immunoreactivity (p < 0.0001) (representing the neoangiogenesis status) were significantly higher in neuroendocrine as compared to non-neuroendocrine areas of the same tumors. In addition, the Foxp3/CD8 (p = 0.0717) and the PD-1/CD8 ratios (p = 0.0176) (representing tumor immunity suppression) tend to increase in neuroendocrine carcinomas. Immunoreactivity of CD163, a marker of M2-like macrophages, was also higher in the neuroendocrine areas. Our findings indicate that neuroendocrine and non-neuroendocrine tumors differ from each other with respect to the characteristics of both tumor cells and the tumor microenvironment.

Insulinoma-associated protein 1 (INSM1) and orthopedia homeobox (OTP) are transcription factors that play a critical role in neuroendocrine (NE) and neuroepithelial cell development. INSM1 has been identified in multiple tumors of NE or neuroepithelial origin, whereas OTP expression has been mainly studied in NE tumors of pulmonary origin. Expression of OTP appears to correlate with poorer prognosis in pulmonary carcinoids; however, its expression patterns in other NE/neuroepithelial tumors need further investigation. Here, we assessed the diagnostic utility of INSM1 and OTP in tumors with NE differentiation at relatively uncommon sites including prostate, breast, and tumors of gynecologic origin. Thirty-two formalin-fixed, paraffin-embedded cases were used to construct a tissue microarray. Immunohistochemistry for INSM1 and OTP was performed and scored semi-quantitatively. INSM1 was diffusely expressed in 60% of gynecologic tumors, 71.4% of mammary carcinoma, and 25% of prostate adenocarcinoma with NE differentiation. Diffuse expression of OTP was detected in 50% of prostate adenocarcinoma with NE differentiation and 100% neuroendocrine carcinoma of the ovary. Immunostain for achaete-scute homolog 1, chromogranin, synaptophysin, and CD56 supported the NE and/or neuroepithelial differentiation of the tumors. In summary, INSM1 is expressed in most of the tumors with NE and neuroepithelial differentiation in this study, confirming the diagnostic utility of INSM1 as a novel and sensitive marker of NE/neuroepithelial differentiation. The expression of OTP in some NE tumors outside of lung expands the spectrum of tumors that may express this biomarker and should be considered when working up a NE tumor of unknown primary site.

Introduction Treatment strategy for castration‐resistant prostate cancer with neuroendocrine differentiation after radiation therapy has not been established. Case presentation We described a case of castration‐resistant prostate cancer with neuroendocrine differentiation after initial external beam radiotherapy followed by salvage androgen deprivation therapy. Magnetic resonance imaging detected recurrence of a suspicious lesion in the left lobe of the prostate, although the prostate‐specific antigen level was <0.2 ng/mL. Transperineal prostate saturation needle biopsy detected adenocarcinoma with neuroendocrine differentiation. The patient underwent salvage focal brachytherapy and had a prostate‐specific antigen progression‐free survival of 20 months with no obvious adverse events. No recurrence has been detected on magnetic resonance imaging for 18 months. Conclusion Salvage focal brachytherapy for prostate cancer after external beam radiotherapy can be one of the treatment strategies for local recurrence of castration‐resistant prostate cancer with neuroendocrine differentiation.

YAP1, the main Hippo pathway effector, is a potent oncogene and is overexpressed in non‐small‐cell lung cancer (NSCLC); however, the YAP1 expression pattern in small‐cell lung cancer (SCLC) has not yet been elucidated in detail. We report that the loss of YAP1 is a special feature of high‐grade neuroendocrine lung tumors. A hierarchical cluster analysis of 15 high‐grade neuroendocrine tumor cell lines containing 14 SCLC cell lines that depended on the genes of Hippo pathway molecules and neuroendocrine markers clearly classified these lines into two groups: the YAP1‐negative and neuroendocrine marker‐positive group (n = 11), and the YAP1‐positive and neuroendocrine marker‐negative group (n = 4). Among the 41 NSCLC cell lines examined, the loss of YAP1 was only observed in one cell line showing the strong expression of neuroendocrine markers. Immunostaining for YAP1, using the sections of 189 NSCLC, 41 SCLC, and 30 large cell neuroendocrine carcinoma (LCNEC) cases, revealed that the loss of YAP1 was common in SCLC (40/41, 98%) and LCNEC (18/30, 60%), but was rare in NSCLC (6/189, 3%). Among the SCLC and LCNEC cases tested, the loss of YAP1 correlated with the expression of neuroendocrine markers, and a survival analysis revealed that YAP1‐negative cases were more chemosensitive than YAP1‐positive cases. Chemosensitivity test for cisplatin using YAP1‐positive/YAP1‐negative SCLC cell lines also showed compatible results. YAP1‐sh‐mediated knockdown induced the neuroendocrine marker RAB3a, which suggested the possible involvement of YAP1 in the regulation of neuroendocrine differentiation. Thus, we showed that the loss of YAP1 has potential as a clinical marker for predicting neuroendocrine features and chemosensitivity. YAP1 is possibly involved in the regulation of neuroendocrine differentiation of lung tumors. Loss of YAP1 correlated with strong expression of neuroendocrine markers. Loss of YAP1 is a predictor of chemothensitivity in high‐grade neuroendocrine tumors.

Breast carcinoma with neuroendocrine differentiation, also known as neuroendocrine breast carcinoma (NEBC), includes a heterogeneous group of rare tumors, which account for 2–5% of all invasive breast carcinomas. Because of their low incidence, most of the current limited knowledge of these tumors derives from anecdotal case reports or small retrospective series. The diagnosis of NEBC is based on the presence of morphological features similar to gastrointestinal and lung NETs and neuroendocrine markers. NEBCs are usually hormone receptors positive and HER2 negative, but despite this luminal phenotype, most recent studies suggested that NEBC could be associated with worse prognosis compared to invasive breast cancer without neuroendocrine differentiation. Due to its rarity and lack of randomized data, there is little evidence to guide the choice of treatment, so NEBC is currently treated as any invasive breast carcinoma not-otherwise specified. Recently, attempts to molecularly characterize NEBC have been made, in order to provide new targets for a more personalized treatment of this uncommon entity.

Abstract Objectives Laryngeal neuroendocrine carcinomas are heterogeneous neoplasms characterized by neuroendocrine differentiation. Their prognoses are dependent on tumor type, therefore different classifications have been developed. Moreover, other tumors have overlapping pathologic features posing a range of diagnostic possibilities. Methods A review of the literature was performed to comprehensively understand the classification and diagnosis of these tumors. Results We review the past and present classification systems, with emphasis to the latest 2017 World Health Organization Classification of Head and Neck Tumors. We highlight salient clinicopathologic features and discuss the presumptive etiologic role of human papilloma virus. We share a practical algorithmic approach to the diagnosis of suspected neuroendocrine neoplasms of the larynx including a novel marker for neuroendocrine differentiation, insulinoma-associated protein 1. Conclusions Accurate diagnosis and grading of laryngeal neuroendocrine carcinomas is critical for prognostication and therapeutic decision making. The use of an algorithm is instrumental in assuring the exclusion of mimickers.

Abstract Human epididymis protein 4 (HE4) is originally described as an epididymis specific protein and now clinically used as a serum marker for ovarian carcinoma. However, the expression of HE4 in neuroendocrine neoplasms (NENs) has not been studied. By immunohistochemistry, the expressions of HE4 in 94 normal tissues and 484 NENs which included 242 well-differentiated NENs and 242 poorly differentiated NENs were studied. HE4 was positive in 90/94 (95.7%) of the neuroendocrine cells in normal tissues, 228/242 (94.2%) of well-differentiated NENs, and 206/242 (85.1%) of poorly differentiated NENs, and the expression of HE4 decreased progressively with loss of histological differentiation, with the positive rate of 96.2%, 92.7%, 92.3%, 85.4%, and 84.4% in NET-G1/carcinoid, NET-G2/atypical carcinoid, NET-G3, NEC-LC, and NEC-SC respectively. In NET-G1 and NET-G2, HE4 staining showed a peculiar polarized distribution, with an extraordinarily strong granular staining in subnuclear cytoplasm. A diffuse and uniform cytoplastic HE4 staining was observed in NET-G3 and poorly differentiated NENs. The positive rate of HE4 in primary tumors (91.1%, 387/425) was significantly higher than that of metastases (79.7%, 47/59) (p < 0.05). In a series of 70 pure non-NENs poorly differentiated carcinomas, the specificity rate of HE4 was 92.9% (65/70), which was in line with that of Syn. The negative rate of HE4 was 87.0% (40/46) in the non-neuroendocrine components of the MiNEN cases, which was lower than that of the pure non-neuroendocrine carcinomas (92.9%, 65/70) but without statistical significance (p > 0.05). HE4 may prove to be a useful immunohistochemical marker of neuroendocrine differentiation, although comparative studies and a more extensive analysis of other tissue types are necessary.

Our understanding of neuroendocrine prostate cancer (NEPC) has assumed a new perspective in light of the recent advances in research. Although classical NEPC is rarely seen in the clinic, focal neuroendocrine trans-differentiation of prostate adenocarcinoma occurs in about 30% of advanced prostate cancer (PCa) cases, and represents a therapeutic challenge. Even though our knowledge of the mechanisms that mediate neuroendocrine differentiation (NED) is still evolving, the role of androgen deprivation therapy (ADT) as a key driver of this phenomenon is increasingly becoming evident. In this review, we discuss the molecular, cellular, and therapeutic mediators of NED, and emphasize the role of the tumor microenvironment (TME) in orchestrating the phenotype. Understanding the role of the TME in mediating NED could provide us with valuable insights into the plasticity associated with the phenotype, and reveal potential therapeutic targets against this aggressive form of PCa.

Neuroendocrine prostate cancer (NEPC) is an aggressive and lethal variant of prostate cancer (PCa), and it remains a diagnostic challenge. Herein we report our findings of using synaptic vesicle glycoprotein 2 isoform A (SV2A) as a promising marker for positron emission tomography (PET) imaging of neuroendocrine differentiation (NED). The bioinformatic analyses revealed an amplified SV2A gene expression in clinical samples of NEPC versus castration-resistant PCa with adenocarcinoma characteristics (CRPC-Adeno). Importantly, significantly upregulated SV2A protein levels were found in both NEPC cell lines and tumor tissues. PET imaging studies were carried out in NEPC xenograft models with 18F-SynVesT-1. Although 18F-SynVesT-1 is not a cancer imaging agent, it showed a significant uptake level in the SV2A+ tumor (NCI-H660: 0.70 ± 0.14 %ID/g at 50–60 min p.i.). The SV2A blockade resulted in a significant reduction of tumor uptake (0.25 ± 0.03 %ID/g, p = 0.025), indicating the desired SV2A imaging specificity. Moreover, the comparative PET imaging study showed that the DU145 tumors could be clearly visualized by 18F-SynVesT-1 but not 68Ga-PSMA-11 nor 68Ga-DOTATATE, further validating the role of SV2A-targeted imaging for noninvasive assessment of NED in PCa. In conclusion, we demonstrated that SV2A, highly expressed in NEPC, can serve as a promising target for noninvasive imaging evaluation of NED.

Neuroendocrine differentiation in breast carcinomas has been a matter of discussion since it was first described almost 60 years ago. Indeed, so-called neuroendocrine neoplasms of the breast (Br-NENs) are a less well-defined group of neoplasms than analogous entities in other anatomic sites, such as the lung and the gastroenteropancreatic (GEP) tract. Pure neuroendocrine phenotype is extremely rare, whereas the expression of neuroendocrine markers in usual breast carcinomas, both of special and of non-special type, without evident neuroendocrine morphology, is more common. In this context, 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, despite the recent publication of the 5th edition of the WHO classification of breast tumors. In this review, we will recapitulate the evolution of the concept of Br-NEN; revise the available knowledge on their morphological, molecular, and clinical features; and critically discuss the current classification scheme.