Classification of neuroendocrine neoplasms: lights and shadows.

Neuroendocrine neoplasms (NENs) are a heterogeneous group of neoplastic proliferations showing different morphological features, immunophenotype, molecular background, clinical presentation, and outcome. They can virtually originate in every organ of the human body and their classification is not uniform among different sites. Indeed, as they have historically been classified according to the organ in which they primarily arise, the different nomenclature that has resulted have created some confusion among pathologists and clinicians. Although a uniform terminology to classify neuroendocrine neoplasms arising in different systems has recently been proposed by WHO/IARC, some issues remain unsolved or need to be clarified. In this review, we discuss the lights and shadows of the current WHO classifications used to define and characterize NENs of the pituitary gland, lung, breast and those of the head and neck region, and digestive and urogenital systems

Localization of inhibin-activin subunits in normal pituitary and pituitary adenomas

The localization of inhibin/activin (I/A) subunits was investigated in human normal adenohypophysial cells and in 87 pituitary adenomas of different types, using immunohistochemistry. Monoclonal antibodies directed against alpha, beta A and beta B subunits of I/A were employed. In normal pituitary, alpha subunit of inhibin was detected only in FSH-positive gonadotrophs, while beta A subunit of I/A was expressed in FSH-positive gonadotrophs, GH-cells and in a few PRL-cells. beta B subunit was found in FSH-positive gonadotrophs, TSH-cells and a few LH-positive gonadotrophs. The three subunits of I/A were detected in the majority of nonfunctioning tumors, while functioning adenomas showed a significantly lower expression. This study shows that alpha, beta A and beta B subunits of I/A are expressed by specific adenohypophysial cell types and that they are characteristically present in nonfunctioning adenomas. These results suggest that inhibins and activins may play a role in the local regulation of pituitary hormonal secretion both in normal adenohypophysial cells and in pituitary adenoma

Detection of gonadotropin-releasing hormone receptor in normal human pituitary cells and pituitary adenomas using immunohistochemistry

Gonadotropin-releasing hormone (GnRH), which is a well-known regulator of gonadotroph function, has recently been considered to be a paracrine factor involved in the control of somatotroph, lactotroph, and corticotroph cells. GnRH action is initiated by binding to a specific cell surface receptor, the gonadotropin-releasing hormone receptor (GnRHR), which is expressed by follicle-stimulating hormone/luteinizing hormone (FSH/LH) cells. Using in situ hybridization techniques, GnRHR messenger ribonucleic acid (mRNA) has recently been detected in normal human anterior pituitary gland and in various pituitary adenomas, including FSH/LH-cell, growth hormone (GH)-cell, adrenocorticotropic hormone (ACTH)-cell, and null-cell adenomas. However, immunohistochemical studies indicating the specific cell distribution of GnRHR in normal pituitary cells have never been reported. The aim of the present investigation was to evaluate the immunohistochemical expression of GnRHR in different types of normal pituitary cells and related tumors. Using double-label immunohistochemical techniques on formalin-fixed and paraffin-embedded tissues and specific antibodies directed against pituitary hormones and GnRHR, we found GnRHR immunoreactivity not only in FSH/LH cells, but also in GH- and thyroid-stimulating hormone (TSH) cells. GnRHR was detected in FSH/LH-cell, GH-cell, mixed GH- and prolactin (PRL)-cell, and alpha-subunit (alpha-SU)/null-cell adenomas. The findings of this study suggest that the interaction between GnRH and GnRHR may play a role in paracrine/autocrine regulation of different types of normal pituitary cells and pituitary adenoma

Localization of inhibins and activins in normal endocrine cells and endocrine tumors of the gut and pancreas: an immunohistochemical and in situ hybridization study

Activins and inhibins, which belong to the TGF beta family, are composed of different combinations of alpha-, betaA-, and betaB-subunits, resulting in inhibin A (alphabetaA), inhibin B (alphabetaB), activin A (betaAbetaA), activin B (betaBbetaB), and activin AB (betaAbetaB). They regulate several cell functions, acting as paracrine/autocrine factors. Their actions, which depend on binding to specific receptors, are also modulated by follistatin. Gastroenteropancreatic (GEP) endocrine cells and endocrine tumors (ETs) produce several growth factors, but it is not well known whether they express follistatin and the various inhibin/activin subunits. We studied their expression in 65 GEP ETs using immunohistochemistry (IHC) and in situ hybridization (ISH). The alpha-subunit and follistatin were not identified in normal GEP endocrine cells and were poorly expressed in ETs. A betaA-subunit immunoreactivity (IR) was detected in A-, G-, EC-, and GIP-cells, while betaB-chain IR was present only in D-cells. The mRNAs encoding for these molecules were poorly expressed in normal tissues. BetaA- and betaB-subunits were identified in several ETs by both IHC and ISH: betaA-subunit mainly in G-cell and A-cell ETs, and betaB-subunit in D-cell, A-cell, and EC-cell ETs. Our results demonstrate a differential expression of activin/inhibin subunits among different types of GEP endocrine cells and related tumors, suggesting a role in modulation of biological functions of these normal and neoplastic endocrine cell

Mixed mucus-secreting and oncocytic carcinoma of the thyroid - Pathologic, histochemical, immunohistochemical, and ultrastructural study of a case

We report a carcinoma that is, to the best of our knowledge, the first case of a mixed mucus-secreting and oncocytic carcinoma of the thyroid. We also describe the histochemical, immunohistochemical, and ultrastructural features of this tumor. A 59-year-old man complaining of severe bone pain and weight loss underwent clinical and radiologic investigations. The studies revealed a nodule in the left thyroid lobe that was "cold" by (131)I scintiscan and multiple lytic lesions of the skeleton that showed increased uptake by (99m)Tc-Sestamibi scintiscan. Left hemithyroidectomy was performed and the surgical specimen contained a well-circumscribed nodule of 3 cm in the greatest diameter. Light microscopy showed an oncocytic carcinoma with an area of glandular and papillary proliferation of mucin-producing cells. A double histochemical approach (Alcian blue-periodic acid-Schiff and Alcian blue-high-iron diamine) combined with ultrastructural investigation confirmed the presence of true mucus, ruling out the presence of breakdown products of thyroglobulin. Ultrastructural and immunohistochemical studies, together with clinical findings, excluded a possible metastatic origin of the mucin-producing componen

Localization of hepatocyte growth factor and Its receptor met in endocrine cells and related tumors of the gut and pancreas: an immunohistochemical study

Hepatocyte growth factor (HGF), a stimulator of angiogenesis and cell migration, regulates the growth of a wide variety of cells by binding to its high-affinity receptor met and is involved in the growth and aggressiveness of several tumors. In this study we investigated the expression of HGF and met in normal endocrine cells and related neoplasms of the gut and pancreas to verify their possible role in tumor pathogenesis, growth, and aggressiveness. Normal tissues and 60 different endocrine tumors were immunostained using specific antibodies directed against HGF, met, and various hormones. HGF immunoreactivity (IR) was found in antroduodenal G cells, rectal enterochromaffin (EC) cells, and pancreatic A and B cells, whereas met IR was detected in antral EC and C cells, and in pancreatic B cells; 46 of 60 tumors examined were positive for HGF, and they were mainly represented by ECL-, EC-, and L-cell neoplasms. met IR was identified in 50/60 tumors of various phenotypes. HGF and met coexpression was found in 42/60 cases, most of which were represented by EC-cell tumors. HGF/met coexpression was significantly more frequent in ileocolonic EC-cell tumors, which in the majority of cases were malignant, than in appendiceal EC-cell tumors, which were all benign. Our results demonstrated, for the first time, that HGF and met are specifically distributed in normal gut and pancreatic endocrine cells and, in addition, suggest that HGF and met may be implicated as autocrine/paracrine factors regulating the growth of gastroenteropancreatic endocrine tumors, mainly of ileocolonic EC-cell carcinoid

Immunohistochemical localization of acidic fibroblastic growth factor in normal human enterocromaffin cells and related gastrointestinal tumors

Acidic fibroblast growth factor (aFGF) is a member of the structurally related heparin-binding growth factor family. The best studied members of this family are aFGF and basic FGF (bFGF), which are potent mitogens and differentiation factors for mesoderm-derived cells, including fibroblasts. This study was designed to verify the immunohistochemical expression of aFGF in normal human endocrine cells of the gut and in related endocrine tumours. We examined normal gastrointestinal mucosa from seven different subjects and 41 gut endocrine tumours from different sites, including stomach, duodenum, and small and large intestine, using an aFGF polyclonal antibody with no cross-reactivity for bFGF. We localized aFGF in a fraction of serotonin-producing enterochromaffin (EC) cells of the normal gut, while it was absent in gastrin (G), CCK, secretion (S), somatostatin (D) and glicentin (L) cells. aFGF immunoreactivity was also expressed in serotonin producing EC cell tumours, but not in other functional types of gut endocrine neoplasms investigated, including gastric ECL cell, duodenal somatostatin and gastrin cell, and rectal L cell tumours. A positive correlation was found between expression of aFGF and the amount of tumour fibrous stroma, suggesting that aFGF may be involved in proliferation and activity of stromal fibroblast

AKAP2-anchored protein phosphatase 1 controls prostatic neuroendocrine carcinoma cell migration and invasion.

Prostate cancer (PC) is the second leading cause of cancer-related death in men. The growth of primary prostate cancer cells relies on circulating androgens and thus the standard therapy for the treatment of localized and advanced PC is the androgen deprivation therapy. Prostatic neuroendocrine carcinoma (PNEC) is an aggressive and highly metastatic subtype of prostate cancer, which displays poor prognosis and high lethality. Most of PNECs develop from prostate adenocarcinoma in response to androgen deprivation therapy, however the mechanisms involved in this transition and in the elevated biological aggressiveness of PNECs are poorly defined. Our current findings indicate that AKAP2 expression is dramatically upregulated in PNECs as compared to non-cancerous prostate tissues. Using a PNEC cell model, we could show that AKAP2 is localized both intracellularly and at the cell periphery where it colocalizes with F-actin. AKAP2 and F-actin interact directly through a newly identified actin-binding domain located on AKAP2. RNAi-mediated silencing of AKAP2 promotes the phosphorylation and deactivation of cofilin, a protein involved in actin turnover. This effect correlates with a significant reduction in cell migration and invasion. Co-immunoprecipitation experiments and proximity ligation assays revealed that AKAP2 forms a complex with the catalytic subunit of protein phosphatase 1 (PP1) in PNECs. Importantly, AKAP2-mediated anchoring of PP1 to the actin cytoskeleton regulates cofilin dephosphorylation and activation, which, in turn, enhances F-actin dynamics and favors migration and invasion. In conclusion, this study identified AKAP2 as an anchoring protein overexpressed in PNECs that controls cancer cell invasive properties by regulating cofilin phosphorylation

Consumptive hypothyroidism in a patient with malignant rhabdoid tumor of the kidney: case report on a newly found association

Introduction: Consumptive hypothyroidism is a rare paraneoplastic condition most commonly associated with infantile hemangiomas. It is caused by overexpression of deiodinase type 3 (D3), which leads to preferential conversion of thyroxine to the metabolically inactive reverse triiodothyronine (rT3), paralleled by a decrease of the biologically active T3. Case presentation: A 46-year-old male patient with previously normal thyroid function was diagnosed with a renal carcinoma with rhabdoid differentiation. He was treated with sunitinib, followed by the immune checkpoint inhibitors ipilimumab and nivolumab, and he developed primary hypothyroidism secondary to thyroiditis. Substitution with unusually high doses of levothyroxine as high as 4.3 mu g/kg/day did not normalize his thyroid function. Poor compliance was refuted because there was no improvement after observed administration. He had no malabsorption. Although tyrosine kinase inhibitors can increase the expression of D3, this effect tends to be modest. Therefore, the suspicion of tumor-related consumptive hypothyroidism was raised and supported by low free T3 and elevated rT3 levels. The therapy could not be further modified because the patient opted for palliative care and passed away 12 days later.Immunohistochemistry of the tumor from a sample obtained prior to systemic therapy documented abundant expression of D3, corroborating the diagnosis of consumptive hypothyroidism. Conclusions: This observation extends the spectrum of malignancies overexpressing D3. Although rare, increased awareness of this paraneoplastic syndrome is key, if persistent hypothyroidism cannot be explained by compliance issues or malabsorption. Substitution with high doses of levothyroxine, and combination therapy with liothyronine, can correct hypothyroidism in these patients