Perspectives for immunotherapy in endocrine cancer.

The fight against cancer has seen major breakthroughs in recent years. More than a decade ago, tyrosine kinase inhibitors targeting constitutively activated signaling cascades within the tumor inaugurated a new era of oncological therapy. Recently, immunotherapy with immune checkpoint inhibitors has started to revolutionize the treatment of several malignancies, most notably malignant melanoma, leading to the renaissance and the long-awaited breakthrough of immunooncology. This review provides an overview of the basis of immunotherapy from its initial concepts of anti-tumor immunity and cell-based therapy to the development of immune checkpoint inhibitors and discusses published studies and the perspectives of immunooncology for the treatment of endocrine malignancies.

Diffuse endocrine system, neuroendocrine tumors and immunity: what's new?

During the last two decades, research into the modulation of immunity by the neuroendocrine system has flourished, unravelling significant effects of several neuropeptides, including somatostatin (SRIH), and especially cortistatin (CST), on immune cells. Scientists have learnt that the diffuse neuroendocrine system can regulate the immune system at all its levels: innate immunity, adaptive immunity, and maintenance of immune tolerance. Compelling studies with animal models have demonstrated that some neuropeptides may be effective in treating inflammatory disorders, such as sepsis, and T helper 1-driven autoimmune diseases, like Crohn's disease and rheumatoid arthritis. Here, the latest findings concerning the neuroendocrine control of the immune system are discussed, with emphasis on SRIH and CST. The second part of the review deals with the immune response to neuroendocrine tumors (NETs). The anti-NET immune response has been described in the last years and it is still being characterized, similarly to what is happening for several other types of cancer. In parallel with investigations addressing the mechanisms by which the immune system contrasts NET growth and spreading, ground-breaking clinical trials of dendritic cell vaccination as immunotherapy for metastatic NETs have shown in principle that the immune reaction to NETs can be exploited for treatment.

Dendritic cell based immunotherapy--a promising therapeutic approach for endocrine malignancies.

Dendritic cells (DCs) are the most potent antigen presenting cells in the human organism. Ever since the discovery of their function in the self/nonself discrimination, DCs have been seen as potential candidates for therapy in malignant tumors. With the exception of differentiated thyroid cancer, endocrine malignancies are rare tumors and apart from surgical intervention there is no truly established method for their treatment. Therefore, the prognosis of many endocrine carcinomas is still poor and new therapeutic options are needed. In the last decade, different immunotherapeutic approaches have shown promising results in other solid tumors. In recent studies, immunotherapy using DCs has been proven to be safe and effective to induce antitumor immune responses leading to tumor regression and even rejection of cancer in some cases. This review will summarize the latest progress in DCs based immunotherapy with special focus on the limited experience in endocrine malignancies. With regard to these tumors, it is of special interest which antigens could serve as potential target antigens for future trials. We also discuss what steps have to be taken to develop a better immunotherapy in endocrine tumors.

Immunesurveillance by dendritic cells: potential implication for immunotherapy of endocrine cancers.

Dendritic cells (DCs) are highly efficient antigen-presenting cells in the immune system with the potential to regulate the system and induce a cytotoxic T-cell response. As a proof of principle, a multitude of animal and human studies has demonstrated that immunization with antigen-loaded DCs may lead to anti-tumour immune responses with tumour regression and rejection of cancer. The identification of tumour antigens that can be recognized by T lymphocytes has facilitated the development of new protocols and enabled immunologists to monitor immune responses. However, to date, long-term clinical effects on larger numbers of cancer patients are missing, and there is no generally accepted DC generation or activation protocol. This review will focus on the most important findings on the role of DCs within the immune system and how to generate and activate these cells in order to induce cytotoxic immunity in non-endocrine and endocrine malignancies. Recently, we and other researchers reported on DC vaccinations in patients with endocrine malignancies mainly in metastasized medullary thyroid carcinoma resulting in tumour-specific immunity and partial clinical responses in some cases. Based on these and other in vitro data, new DC vaccination protocols for the treatment of patients with endocrine tumours have now been conducted.

Fine needle aspiration cytology of endocrine neoplasms of the pancreas. Morphologic and immunocytochemical findings in 20 cases.

OBJECTIVE: To analyze the role of fine needle aspiration (FNA) cytology in the preoperative diagnosis of pancreatic endocrine neoplasms. METHODS: Cytologic and histologic diagnoses of pancreatic endocrine tumors were reviewed. A total of 20 FNA cytologic procedures from 20 patients were selected. A false positive case, a retroperitoneal paraganglioma, was also reviewed. Two groups of patients were established: (1) those in whom a surgical biopsy with an immunohistochemical study was available (n = 13), and (2) those with a pancreatic tumor in which the diagnosis was confirmed by immunocytochemical studies (n = 7). In 13 cases the pancreatic tumor was aspirated, while in 7, liver metastases were studied. The immunoexpression of chromogranin and synaptophysin was evaluated in alcohol-fixed smears from 12 and 11 cases, respectively. RESULTS: One false negative and 1 false positive diagnosis were present. In the remaining 19 cases a cytologic diagnosis of pancreatic endocrine tumor was given. Main cytologic features were: (1) a prominent cellular dissociation with many single cells and small, poorly cohesive groups; (2) intermediate to large size cells with ill-defined cytoplasm, naked or eccentric nuclei, and frequent binucleation; and (3) variable nuclear pleomorphism with the characteristic finely granular distribution of the chromatin. Immunocytochemical evidence of endocrine differentiation (chromogranin or synaptophysin) was present in the 12 cases analyzed. CONCLUSION: FNA cytology offers the possibility of a precise preoperative, noninvasive diagnosis of pancreatic endocrine tumors. Cytologic features differ considerably from those of pancreatic adenocarcinoma, allowing differentiation from nonfunctioning endocrine neoplasms. In difficult cases immunocytologic studies are very helpful.

Dendritic cell vaccination: new hope for the treatment of metastasized endocrine malignancies.

Dendritic cells (DCs) are antigen-presenting cells that are involved in the induction of primary immune responses. The unique ability of DCs to activate naive and memory CD4+ and CD8+ T cells suggests that they could be used for the induction of a specific antitumour immunity. In the past few years, several in vitro and in vivo studies in rodents and humans have demonstrated that immunizations with DCs pulsed with tumour antigens result in protective immunity and rejection of established tumours in various malignancies. Here, we focus on recent results of how DCs regulate immune responses that are important for generating antitumour cytotoxic T cells, and summarize clinical vaccination trials for the treatment of endocrine and nonendocrine carcinomas. Preliminary results suggest that DC vaccines might be novel tools for antitumour immunotherapies to treat chemotherapy-resistant and radioresistant endocrine cancers, such as metastasized medullary thyroid carcinomas and other neuroendocrine carcinomas.

Classic and recent special stains used in differential diagnosis of endocrine tumors.

During the twentieth century, stains for endocrine cells and tumors were developed from empiric cytologic procedures aimed at modern cytochemical methods. Before the 1970s, endocrine stains were mainly based on silver reaction, although other reactions were also proposed; however, the chemical basis of most of these reactions is still unclear. The development of fluorescence procedures for detecting biogenic amines at the cellular level provided information about endocrine cell function of normal cells and related tumors. However, the application of immunocytochemical reactions brought greater and more definitive insights. Several immunocytochemical markers are now available. Some are specific for a definite cell type, while others detect endocrine differentiation in general. Some of these "pan-endocrine" markers are highly specific, and others are highly sensitive but less specific. They all play a definite role in diagnostic pathology. The use of molecular procedures to detect specific mRNA or genetic mutations of diagnostic interest in endocrine pathology should complement immunophenotyping, especially in some problematic fields, such as that of "poorly differentiated" tumors.

Immunoreactivity and expression of amylin in gastroenteropancreatic endocrine tumors.

Amylin was isolated from human insulinomas, but there has been only preliminary data regarding whether this peptide can also be detected in other types of gastroenteropancreatic endocrine tumors. In the present study, immunohistochemical staining of 87 gastroenteropancreatic endocrine tumors demonstrated amylin immunoreactivity in 21.8% of the neoplasmas. Thirteen of 15 insulinomas, three of 21 gastrinomas, two of 29 nonfunctioning tumors, and one of 18 carcinoids were amylin-immunoreactive. Seventeen of the 19 amylin-immunoreactive tumors were primarily located in the pancreas, but two tumors were found in the intestine. Measurements of amylin messenger RNA expression in a few tumors revealed amylin synthesis in these tumors. Amylin immunoreactivity did not correlate with invasion and metastasis. However, the rate of curative resections was significantly higher in amylin-immunoreactive tumors. These results demonstrate for the first time that amylin immunoreactivity is not restricted to insulinomas and can also occur rarely in endocrine tumors of the intestine.

Tissue reactivity of anti-Leu19.

Monoclonal antibody anti-Leu19, is a marker of natural killer cells. Since reactivity between anti-Leu7, another natural killer cell marker, and small cell neuroendocrine carcinomas has been described, we evaluated the reactivity of anti-Leu19 in 92 neuroendocrine tumours. Frozen sections in each case were immunostained using the avidin-biotin-peroxidase complex method with monoclonal anti-Leu19. We found Leu19 expression in 93% of the cases. We also evaluated 149 other tumours, including adenocarcinomas, undifferentiated large cell carcinomas, lymphomas, melanomas and soft tissue tumours. We found Leu19 expression in 36% (by liberal interpretative criteria), or 29% (by conservative interpretative criteria) of these cases. Thus, while anti-Leu19 appears to be a sensitive marker for neuroendocrine tumours, a lack of specificity limits its practical application in diagnostic histopathology.