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Pancreatic neuroendocrine neoplasms (pNENs) are rare, representing only a small percentage of all pancreatic tumors. We report the clinical and radiological features of pNENs. Intraoperative pathology confirmed pNENs with clear margins and the patient did not require adjuvant chemoradiation. The patient is currently doing well and being closely monitored due to the high risk of relapse.

Papillary thyroid carcinoma (PTC) is the most common histological form of thyroid cancer in children and is characterized by a very good prognosis. However lymph node and lung metastases in PTC occur more frequently in pediatric patients than in adults. Ultrasound together with fine needle aspiration biopsy (FNAB) are the gold standard in the diagnosis of thyroid nodules in children. A new valuable diagnostic method became also elastography. The gold treatment standard remains thyroidectomy. In young patients with lymph node and/or distant metastases, there is abundant evidence to show that disease-free survival is improved by radioactive iodine (RAI) therapy. We present three patients diagnosed with PTC in Department of Paediatrics, Endocrinology, Diabetology with Cardiology Division, Medical University of Bialystok, Poland treated with the cooperation of the Department of Nuclear Medicine and Endocrine Oncology at M. Sklodowska-Curie National Research Institute in Gliwice, Poland.

An adrenal oncocytic neoplasm is an extremely rare tumour arising from the adrenal gland and it should be considered in the differential diagnosis of an adrenal incidentaloma, since it is frequently non-functioning. The suspicion for malignancy is high when an adrenal incidentaloma is >4 cm in size; however, adrenal oncocytomas are large, measuring an average of 8 cm, are round and encapsulated, and normally have a benign behaviour. We present a case of a 55-year-old male patient with dyslipidaemia, medicated with simvastatin. Upon complaints of abdominal pain, the general physician asked for an abdominal ultrasound that revealed an adrenal lesion, further characterized with a computed tomography scan, which showed an adrenal lesion measuring 49 × 64 × 56 mm and a calcification focus. The patient was referred to the general surgery and endocrinology department. The analytical study was negative for pheochromocytoma or Cushing's syndrome, which allowed surgery to be conducted, as is recommended. The aim of this case report is to contribute to the knowledge on adrenal oncocytomas, since there is scarce information based on singular experiences.

Immune checkpoint inhibitors are potent and promising immunotherapeutic agents that are increasingly used for the management of various types of advanced cancers. The widespread approval of this group of drugs simultaneously revealed immune-related adverse events as unique side-effects. Endocrinopathies are one of the most common immune-related adverse events. The precise pathogenic mechanisms for these endocrinopathies are still unclear. Though few of the endocrinopathies are reversible, calling for only symptom control, most are irreversible, requiring multiple long-term hormone replacement therapies. However, in contrast to other organ-specific immune-related adverse events, patients with endocrinopathies can continue their immune checkpoint therapy, provided the hormone replacement therapy is adequate and the symptoms are controlled. Though patients who have developed immune-related adverse events demonstrate superior antitumor activity and overall survival, due to the high morbidity associated with the immune-related adverse events, researchers are trying to uncouple the antitumour activity associated with immune checkpoint inhibitor therapy from the immune-related adverse events, to preserve antitumour activity without adverse events.

Pheochromocytoma (PHEO) is a rare tumour that arises from adreno-medullary chromaffin cells and secretes catecholamines. These hormones are also secreted by paragangliomas, which derive from extra-adrenal cells of the sympathetic paravertebral ganglia. At least one-third of PHEOs are familial. Neurofibromatosis type 1 (NF1), or von Recklinghausen's disease, is diagnosed upon clinical criteria, and the study of PHEO is advised if hypertension is present. The incidence of PHEO in NF1 is 0.1–5.7% and explains hypertension in 20–50% of these patients. Recent advances in the treatment of this condition and preoperative preparation allow us to reduce its high cardiovascular morbimortality. Here we present the case of a 31-year-old female with known NF1 who presented with 5 months' history of non-specific symptoms and an episode of intraoperative hypertensive crisis. The workup detected a left sided PHEO, which was treated surgically. Our case illustrates the high prevalence of hereditary PHEO and how its presentation can go unnoticed. It reinforces the significance of screening for PHEO in patients with NF1.

In this issue of Endocrine-Related Cancer we celebrate the 80th anniversary of the first reported therapeutic use of radioiodine with a special issue dedicated to the history, current uses, and future research for this cornerstone of thyroid cancer therapy. Edited by Professor Christopher McCabe, one of our outstanding Associate Editors and an expert in thyroid cancer biology, a panel of expert authors provide six comprehensive and up-to-date reviews covering important topics for endocrine oncology researchers and clinicians.

Cytology is a modern, fast, secure, and cost-effective method to render a diagnosis of neoplastic processes throughout the body, including neuroendocrine neoplasms. Fine-needle aspiration and exfoliative cytology specimens show a good sensitivity and specificity in detecting neuroendocrine neoplasms. Increased imaging has led to an increased and earlier detection of neuroendocrine neoplasms. In addition, the easy accessibility of both endoscopic procedures and a fast-diagnostic workup by cytology allow for earlier diagnoses on less invasively obtained material, increasingly in an outpatient setting. Thus, cytology has contributed to the decrease in the mortality of neuroendocrine neoplasms. This chapter focuses on general and site-specific cytology of neuroendocrine neoplasms to make the reader familiar with the spectrum of the cytology of neuroendocrine neoplasms. In addition, differential diagnoses and the use of ancillary techniques such as immunocytochemisty and immunohistochemistry are discussed. Finally, the widely accepted organ system-based, specific classification systems to facilitate the conversation among members of multidisciplinary endocrine oncology team are discussed.

Therapeutic advances have revolutionised cancer treatment over the last two decades, but despite improved survival and outcomes, adverse effects to anticancer therapy such as dyselectrolytaemias do occur and need to be managed appropriately. This review explores essential aspects of sodium homeostasis in cancer with a focus on alterations arising from anticancer medications. Sodium and water balance are tightly regulated by close interplay of stimuli arising from hypothalamic osmoreceptors, arterial and atrial baroreceptors and the renal juxtaglomerular apparatus. This delicate balance can be disrupted by cancer itself, as well as the medications used to treat it. Some of the conventional chemotherapeutics, such as alkylating agents and platinum-based drugs, can cause hyponatraemia and, on rare occasions, hypernatraemia. Other conventional agents such as vinca alkaloids, as well as newer targeted cancer therapies including small molecule inhibitors and monoclonal antibodies, can cause hyponatraemia, usually as a result of inappropriate antidiuretic hormone secretion. Hyponatraemia can also sometimes occur secondarily to drug-induced hypocortisolism or salt-wasting syndromes. Another atypical but distinct mechanism for hyponatraemia is via pituitary dysfunction induced by immune checkpoint inhibitors. Hypernatraemia is uncommon and occasionally ensues as a result of drug-induced nephrogenic diabetes insipidus. Identification of the aetiology and appropriate management of these conditions, in addition to averting treatment-related problems, can be lifesaving in critical situations.

About 3000 thousand years ago Marcus Aurelius said: “Time is a sort of river of passing events, and strong is its current; no sooner is a thing brought to sight than it is swept by and another takes its place, and this too will be swept away…” 1.

Lack of routine fresh or frozen tissue is a barrier to widespread transcriptomic analysis of adrenal cortical tumors and an impediment to translational research in endocrinology and endocrine oncology. Our group has previously pioneered the use of targeted amplicon-based next-generation sequencing for archival formalin-fixed paraffin-embedded (FFPE) adrenal tissue specimens to characterize the spectrum of somatic mutations in various forms of primary aldosteronism. Herein, we developed and validated a novel 194-amplicon targeted next-generation RNA sequencing (RNAseq) assay for transcriptomic analysis of adrenal tumors using clinical-grade FFPE specimens. Targeted RNAseq-derived expression values for 27 adrenal cortical tumors, including aldosterone-producing adenomas (APA; n=8), cortisol-producing adenomas (CPA; n=11), and adrenal cortical carcinomas (ACC; n=8), highlighted known differentially-expressed genes (DEGs; i. e., CYP11B2, IGF2, etc.) and tumor type-specific transcriptional modules (i. e., high cell cycle/proliferation transcript expression in ACC, etc.), and a subset of DEGs was validated orthogonally using quantitative reverse transcription PCR (qRT-PCR). Finally, unsupervised hierarchical clustering using a subset of high-confidence DEGs revealed three discrete clusters representing APA, CPA, and ACC tumors with corresponding unique gene expression signatures, suggesting potential clinical utility for a transcriptomic-based approach to tumor classification. Overall, these data support the use of targeted amplicon-based RNAseq for comprehensive transcriptomic profiling of archival FFPE adrenal tumor material and indicate that this approach may facilitate important translational research opportunities for the study of these tumors.

Neuroendocrine tumours are a heterogeneous group of neoplasms with a variety of treatment options, but studies suggest they should in most cases, if they are not curable surgically, be treated initially with monthly long-acting somatostatin analogues. New data recently published suggest that if patients show progression on the current analogues at the recommended doses, increasing the dose or frequency of these analogues may provide a further therapeutic effect, although proper randomised trials will be necessary to confirm this effect.

Apreviously healthy 53-year-old woman presented with new onset arterial hypertension diagnosed during workup for daily pulsatile bilateral frontal headaches and paroxysmal episodes of fatigue, palpitations and sweating. High urinary metanephrines were detected and an abdominal magnetic resonance image evidenced two nodular bilateral adrenal lesions and a left iliac focal lesion. (18)F-FDG-PET/CT (fluorodeoxyglucose-positron emission tomography/computed tomography) scanning revealed mild-to-moderate uptake in both adrenal lesions and mild uptake in the iliac bone, whereas (123)I-metaiodobenzylguanide scintigraphy revealed uptake only in the right adrenal. CT-scan confirmed the heterogeneous nodular lesion on the right adrenal gland as suspicious for pheochromocytoma and a non-specific sclerotic lesion in the iliac. A right adrenalectomy was performed with posterior resolution of symptoms and normalisation of urinary metanephrines. Histology confirmed a pheochromocytoma and later a mutation of the TMEM127 gene was detected. The present case highlights the importance of genetic testing for pheochromocytoma in order to better guide the management of these patients.

Perioperative nursing care is the key to success for every surgical procedure, especially for elective surgery, such as endocrine surgery of the thyroid, parathyroid, and adrenal glands. Patient positioning, preoperative deep venous thrombosis prophylaxis, and consideration for preoperative antibiotics are discussed in this chapter. This chapter also discusses anesthesia considerations including approach during intraoperative recurrent laryngeal nerve monitoring. The role of nurse navigator for preoperative and postoperative coordination of patient care is outlined. Having an endocrine oncology nurse navigator allows the patient to have a coordinated care experience, with timely access to specialists, before and after the surgical intervention.

Purpose Papillary thyroid carcinoma (PTC) is the most frequent endocrine tumor. BRAFV600E represents the PTC hallmark and is targeted with selective inhibitors (e.g. vemurafenib). Although there have been promising results in clinical trials using these inhibitors, most patients develop resistance and progress. Tumor clonal diversity is proposed as one mechanism underlying drug resistance. Here we have investigated mechanisms of primary and secondary resistance to vemurafenib in BRAFWT/V600E–positive PTC patient-derived cells with P16-/- (CDKN2A-/-). Experimental Design Following treatment with vemurafenib, we expanded a sub-population of cells with primary resistance and characterized them genetically and cytogenetically. We have used exome sequencing, metaphase chromosome analysis, FISH and oligonucleotide SNP-microarray assays to assess clonal evolution of vemurafenib-resistant cells. Furthermore, we have validated our findings by networks and pathways analyses using PTC clinical samples. Results Vemurafenib-resistant cells grow similarly to naïve cells but are refractory to apoptosis upon treatment with vemurafenib, and accumulate in G2-M phase. We find that vemurafenib-resistant cells show amplification of chromosome 5 and de novo mutations in the RBM (RNA-binding motifs) genes family (i.e. RBMX, RBM10). RBMX knockdown in naïve-cells contributes to tetraploidization, including expansion of clones with chromosome 5 aberrations (e.g. isochromosome 5p). RBMX elicits gene regulatory networks with chromosome 5q cancer-associated genes and pathways for G2-M and DNA damage-response checkpoint regulation in BRAFWT/V600E-PTC. Importantly, combined therapy with vemurafenib plus palbociclib (inhibitor of CDK4/6, mimicking P16 functions) synergistically induces stronger apoptosis than single agents in resistant-cells and in anaplastic thyroid tumor cells harboring the heterozygous BRAFWT/V600E mutation. Conclusions Critically, our findings suggest for the first time that targeting BRAFWT/V600E and CDK4/6 represents a novel therapeutic strategy to treat vemurafenib-resistant or vemurafenib-naïve radioiodine-refractory BRAFWT/V600E-PTC. This combined therapy could prevent selection and expansion of aggressive PTC cell sub-clones with intrinsic resistance, targeting tumor cells either with primary or secondary resistance to BRAFV600E inhibitor.

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant endocrine tumour syndrome characterised by three main manifestations: primary hyperparathyroidism (78–94%), gastroenteropancreatic neuroendocrine tumours (GEP-NETs) (35–78%) and pituitary adenomas (20–65%). For metastatic and inoperable GEP-NETs, there are some interventional and medical therapies. Peptide receptor radionuclide therapy (PRRT) with Yttrium-90 (90Y) and Lutetium-177 (177Lu) is one of the important radiotherapies. Herein we describe a case of MEN1 syndrome with inoperable metastatic GEP-NETs who had excellent response to the treatment with six cycles of 177Lu-DOTATATE. The patient was admitted to our clinic with widening of hands and feet, polyuria, polydipsia, nausea, vomiting and constipation. His laboratory and screening findings were consistent with primary hyperparathyroidism, acromegaly, secondary hypogonadism and central diabetes insipidus. He underwent 3.5 parathyroidectomy and hypophysis adenomectomy. Under treatment with lanreotide and cabergoline, he developed metastatic duodenal NET. PRRT with 177Lu-DOTATATE was administered in six cycles and an excellent response was displayed without any side effect. In conclusion, the dramatic response of the patient to PRRT with 177Lu-DOTATATE, described in our case report and recent published articles indicating the beneficial efficacy and limited adverse effects of 177Lu-DOTATATE, should encourage clinicians to use PRRT for inoperable or metastatic NETs.

Background: Parathyroid carcinoma is rare, representing

In the last few years, the role and use of medical technologies in (neuro)endocrine oncology has greatly evolved allowing not only important diagnostic information but also prognostic stratification in different clinical situations. The terms “prognostic” and “predictive” are commonly used to describe the relationships between biomarkers and patients’ clinical outcomes but have quite different meaning. The present work discusses the prognostic and predictive value of nuclear medicine imaging. It critically reviews the clinical significance and potential impact of molecular examinations on follow-up and therapeutic strategies in patients with neuroendocrine neoplasms, thyroid tumors, and adrenal malignancies.

Pituitary carcinoma is a rare disease, defined by the presence of cerebrospinal or distant metastasis of a pituitary neuroendocrine tumor (PitNET). To review our institutional experience of pituitary carcinoma, we searched the database of the UHN Endocrine Oncology Site group and the University Health Network pathology laboratory information system from 2001 to 2016. Among 1055 PitNETs from 1169 transsphenoidal resections, we identified 4 cases of pituitary carcinoma, indicating that pituitary carcinoma represents around 0.4% of PitNETs. All four patients were women. The age at initial presentation ranged from 23 to 54 years. Two patients had Cushing disease with corticotroph tumors; one was initially a densely granulated corticotroph tumor that evolved to become sparsely granulated, while the other was a Crooke cell tumor. One patient had a functioning sparsely granulated lactotroph tumor and one had a clinically silent poorly differentiated PIT1 lineage tumor. Apart from a relatively high Ki67 labeling index (≥ 10%) in three tumors, there were no cytomorphologic features at the time of initial presentation that could predict subsequent metastatic behavior. The time from diagnosis of the pituitary neuroendocrine tumor to the diagnosis of malignancy was 3 to 14 years. Therapies included somatostatin analogs, external beam radiotherapy, chemotherapies including capecitabine/temozolomide, everolimus, sunitinib, bevacizumab, and peptide receptor radionuclide therapy (PRRT). One patient died of disease 18 years after initial diagnosis, underscoring the protracted course of this ultimately fatal neuroendocrine malignancy.

Progressive hirsutism and moderate to severe male-pattern balding in women requires exclusion of an adrenal or ovarian tumour, especially in the presence of significantly elevated androgen levels. We present the case of a 68-year-old woman who was referred to an endocrinology clinic with insidious onset excessive facial hair growth and loss of scalp hair. Her testosterone levels were significantly elevated at 13 nmol/L (normal range: 0.1–1.4 nmol/L), although dehydroepiandrosterone sulphate and 17-hydroxyprogesterone levels were normal, suggestive of an ovarian source of androgens. Repeated radiologic investigations, including pelvic ultrasound, and abdominal and pelvic computed tomography, could not identify the obvious source of androgens. Based on strong clinical suspicion of an ovarian tumour, she underwent an elective salpingo-oophorectomy, which detected an occult Leydig cell tumour on histopathological analysis. Post-operatively, her hyperandrogenic features significantly improved and testosterone levels normalized.

The presentation of adrenocortical carcinoma (ACC) with bilateral adrenal masses and acute adrenal insufficiency is exceedingly rare and has only been seen in anecdotal case reports. Herein, we describe the case of a 50-year-old male who presented with a painful abdominal lump, loss of weight and appetite, several episodes of vomiting, and hypotension. Imaging studies were suggestive of bilateral adrenal masses and a lung mass. Hormonal work-up was suggestive of acute adrenal insufficiency, with the adrenal masses being non-secretory. An ultrasound-guided biopsy from one of the adrenal masses was suggestive of ACC, thus confirming the diagnosis as bilateral ACC with distant metastases. Bilateral adrenalectomy was planned for the patient, but unfortunately, he succumbed to his disease before the surgery.

BACKGROUND: Skin, nervous tissue, dopamine and melanoma share a common neuroectodermal origin. Hence, processes that modulate nervous tissue formation, patient mental status, motor regulation of individuals, and skin cancerogenesis are inextricably linked. Psycho-neuro-endocrine oncology (or dermato-oncology), i.e. P.N.E.O., is a new model or trend in medicine and science presented for the first time in the world literature by us, that aims to examine the relationship between the mental state, the hormones and the malignant transformation. Schizophrenia and Parkinson’s disease are the two main patterns of disease where the main symptoms are related to dopamine levels in the human body. According to our analyses of the available literature, the amount of dopamine is related to the incidence of melanocytic or non-melanocytic cutaneous tumours in patients with central nervous system diseases and those affecting the motor function and coordination. Such patterns of interaction are extremely indicative of the elucidation of the ubiquitous hypothesis or statement: “My illness is on a mental basis, caused by stress ...”CASE PRESENTATION: We present a 44-year-old patient with untreated schizophrenia for approximately 25 years, associated with advanced acral localised melanoma. Schizophrenia is generally associated with a higher level of dopamine, which is also a key precursor to melanin synthesis. After a careful analysis of all literature on melanoma in patients with 1) treated and untreated schizophrenia, 2) those with untreated and untreated forms of Parkinson’s disease, it would be logical to conclude that the high level of dopamine in the described patient groups is a risk factor for the development of melanoma.CONCLUSIONS: The possible mechanisms for the occurrence of malignant melanoma within the so-called psycho/neuro/endocrine oncology (P.N.E.O.), as well as the effective methods of prevention, are under discussion.

We sought to assess participation of underrepresented minorities with endocrine neoplasms in clinical trials conducted in the National Cancer Institute's (NCI) Intramural Research Program.We performed a retrospective analysis of patients enrolled in Endocrine Oncology Branch (EOB) clinical trials, comparing demographics to regional and national demographics. We compared specific endocrine cancer patient data to data from NCI's Surveillance, Epidemiology, and End Results (SEER) program.Comparing EOB patients to national demographics, we found more white (77% vs 74%, P 0.001) and black patients (14% vs 12%, P 0.001). For thyroid cancer, there were more black (16% vs 7%, P 0.0001) and other minority patients (17% vs 11%, P 0.0001) compared to SEER. For gastroenteropancreatic neuroendocrine tumors (GEPNETs), there were fewer black (6% vs 19%, P 0.0001) and other minority patients (6% vs 8%, P 0.0001).Enrollment parity of underrepresented minorities into clinical trials is achievable, although possibly cancer type-specific.

This chapter discusses oncological disorders of the endocrine system, including markers for diagnosis, such as chromogranin A, serum neuron-specific enolase, and pancreatic polypeptide (PP). It also describes imaging techniques such as CT and endoscopy, which are matched to neuroendocrine tumour (NET) type. The chapter outlines pathogenesis, symptoms, and management options for NETs such as gastro-entero-pancreatic tumours, insulinomas, gastinomas, glucagonomas, vasoactive intestinal polypeptide (VIP)-secreting tumours or ‘VIPomas’, and somatostatinomas. Ectopic hormone production is described along with disorders such as syndrome of inappropriate anti-diuretic hormone secretion (SIADH), parathyroid hormone-related protein (PTHrP) tumours, ectopic adrenocorticotropic hormone tumours, and human chorionic gonadotrophin (hCG) tumours, as well as their pathophysiology and respective medical management strategies. The chapter details endocrine function following chemotherapy and radiotherapy, listing associated anatomical structures and the biochemical effects of such treatments.

Background: We aimed to determine training levels and utilization of surgeon-performed ultrasound (SPUS) among endocrine surgeons. Methods: Survey of American Association of Endocrine Surgeons members and recent endocrine surgery fellowship graduates. Results: Thirty-four percent (165/481) recipients completed the survey. Of 60% endocrine surgery fellowship-trained surgeons, 58% performed ultrasound during fellowship and 18% during residency. Currently, 65% employ SPUS, with significant variability: 31% without biopsy; 60% not in the operating room; 39% for lymph node mapping; 22% for long-term thyroid cancer surveillance. SPUS altered surgical decision making ‘sometimes’ (>50%) or ‘most of the time’ (31%). Support for ‘rich ultrasound exposure’ was nearly universal. Although 76% felt comfortable with SPUS interpretation, 43% nevertheless obtained additional radiology-performed ultrasound. The majority (53%) rated SPUS as ‘indispensable’. Conclusion: Ultrasound is employed by a growing number of endocrine surgeons, who view it as necessary for clinical practice though usage patterns differ. Formal SPUS education during fellowship training appears advantageous.

Medullary thyroid cancer (MTC) can be caused by germline mutations of the RET proto-oncogene or occurs as a sporadic form. It is well known that RET mutations affecting the cysteine-rich region of the protein (MEN2A-like mutations) are correlated with different phenotypes than those in the kinase domain (MEN2B-like mutations). Our aim was to analyse the whole-gene expression profile of MTC with regard to the type of RET gene mutation and the cancer genetic background (hereditary vs sporadic). We studied 86 MTC samples. We demonstrated that there were no distinct differences in the gene expression profiles of hereditary and sporadic MTCs. This suggests a homogeneous nature of MTC. We also noticed that the site of the RET gene mutation slightly influenced the gene expression profile of MTC. We found a significant association between the localization of RET mutations and the expression of three genes: NNAT (suggested to be a tumour suppressor gene), CDC14B (involved in cell cycle control) and NTRK3 (tyrosine receptor kinase that undergoes rearrangement in papillary thyroid cancer). This study suggests that these genes are significantly deregulated in tumours with MEN2A-like and MEN2B-like mutations; however, further investigations are necessary to demonstrate any clinical impact of these findings.

// Lutske Lodewijk 1 , Paul van Diest 2 , Petra van der Groep 2 , Natalie ter Hoeve 2 , Abbey Schepers 4 , Johannes Morreau 5 , Johannes Bonenkamp 6 , Adriana van Engen - van Grunsven 7 , Schelto Kruijff 8 , Bettien van Hemel 9 , Thera Links 10 , Els Nieveen van Dijkum 11 , Susanne van Eeden 12 , Gerlof Valk 3 , Inne Borel Rinkes 1 , Menno Vriens 1 1 University Medical Center Utrecht, Department of Surgery, 3584CX Utrecht, The Netherlands 2 University Medical Center Utrecht, Department of Pathology, 3584CX Utrecht, The Netherlands 3 University Medical Center Utrecht, Department of Endocrine Oncology, 3584CX Utrecht, The Netherlands 4 Leiden University Medical Center, Department of Surgery, 2333ZA Leiden, The Netherlands 5 Leiden University Medical Center, Department of Pathology, 2333ZA Leiden, The Netherlands 6 Radboud University Medical Center, Department of Surgery, Nijmegen 6525GA, The Netherlands 7 Radboud University Medical Center, Department of Pathology, Nijmegen 6525GA, The Netherlands 8 University Medical Center Groningen, Department of Surgery, 9700 RB, Groningen, The Netherlands 9 University Medical Center Groningen, Department of Pathology, 9700 RB, Groningen, The Netherlands 10 University Medical Center Groningen, Department of Internal Medicine, 9700 RB, Groningen, The Netherlands 11 Academic Medical Center Amsterdam, Department of Surgery, 1105 AZ, Amsterdam, The Netherlands 12 Academic Medical Center Amsterdam, Department of Pathology, 1105 AZ, Amsterdam, The Netherlands Correspondence to: Menno Vriens, email: mvriens@umcutrecht.nl Keywords: medullary thyroid cancer, hypoxia inducible factor 1 alpha, immunohistochemistry, tissue microarray, oncology Received: October 12, 2016 Accepted: January 24, 2017 Published: February 22, 2017 ABSTRACT Background: Medullary thyroid cancer (MTC) comprises only 4% of all thyroid cancers and originates from the parafollicular C-cells. HIF-1α expression has been implied as an indicator of worse prognosis in various solid tumors. However, whether expression of HIF-1α is a prognosticator in MTC remained unclear. Our aim was to evaluate the prognostic value of HIF-1α in patients with MTC. Methods: All patients with MTC who were operated on between 1988 and 2014 in five tertiary referral centers in The Netherlands were included. A tissue microarray was constructed in which 111 primary tumors could be analyzed for expression of HIF-1α, CAIX, Glut-1, VEGF and CD31 and correlated with clinicopathologic variables and survival. Results: The mean age of patients was 46.3 years (SD 15.6), 59 (53.2%) were male. Of the 111 primary tumors, 49 (44.1%) were HIF-1α negative and 62 (55.9%) were HIF-1α positive. Positive HIF-1α expression was an independent negative indicator for progression free survival (PFS) in multivariate cox regression analysis (HR 3.1; 95% CI 1.3 – 7.3). Five-years survival decreased from 94.0% to 65.9% for the HIF-1α positive group (p=0.007). Even within the group of patients with TNM-stage IV disease, HIF-1α positivity was associated with a worse prognosis, shown by a decrease in 5-years survival of 88.0% to 49.3% (p=0.020). Conclusion: Expression of HIF-1α is strongly correlated with adverse prognosis of MTC. This could open up new ways for targeted systemic therapy of MTC.

Purpose of review The purpose is to review recent advances concerning the role of nuclear medicine in endocrine oncology. Recent findings For I therapy of thyroid cancer a thyrotropin (TSH) more than 30 mU/l has for many years been deemed a condition sine qua non. However, new data show that patients with lower TSH levels at the time of ablation have the same rate of successful ablation as those with TSH more than 30 mU/l.I-124 combined integrated positron emission tomography and computed X-ray tomography was shown to be highly accurate in predicting findings on posttherapy radioiodine scanning and was shown to have a high prognostic power.In neuroendocrine tumors, long-term complication rates of peptide receptor radionuclide therapy were reported. Furthermore first preclinical and clinical results of peptide receptor radionuclide therapy with somatostatin receptor antagonists were published.In nuclear medicine, prostate-specific membrane antigen (PSMA)-targeted radionuclide imaging and therapy is of interest. PSMA was shown to also be expressed in neoplasms of the thyroid, the adrenal glands and neuroendocrine tumors. Summary Further individualization of thyroid cancer patient care by means of I-124-positron emission tomography and computed X-ray tomography-based selection of the therapeutic strategy is possible. I therapy might not require as intensive TSH stimulation as thought previously. For endocrine-related malignancies PSMA targeting deserves further investigation.

Primary leiomyosarcoma (LMS) of thyroid is rare malignant neoplasm usually seen in elderly patients. These tumours are characterised by a rapidly growing mass in the neck, difficult to diagnose preoperatively and are highly aggressive with high recurrence rates in spite of radical surgery, chemotherapy and radiotherapy. We herein report a case of 50-year-old female with a rapidly growing painless mass in the neck. Total thyroidectomy with bilateral neck node clearance was done. Histology and Immunohistochemistry revealed primary LMS of thyroid gland. Within 1 month of radical surgery she developed local recurrence. Diagnosis of primary LMS is difficult and immunohistochemistry is necessary to differentiate it from other malignancies of the thyroid. Primary LMS remains a life-threatening tumour and more effective treatment are needed to improve outcome.

Endocrine tumours occur rarely in pregnant women but present clinicians with unique challenges. A high index of suspicion is often required to make a diagnosis since the symptoms and signs associated with many of these tumours, including insulinoma, adrenocortical carcinoma and phaeochromocytoma, mimic those of normal pregnancy or its complications, such as pre-eclampsia. The evidence base which informs management is very limited hence decisions on investigation and therapy must be individualised and undertaken jointly by the multidisciplinary medical team and the patient. The optimal strategy will depend on the nature and stage of the endocrine tumour, gestational stage, treatments available and patient wishes. Thus, surgical intervention, appropriately timed, may be considered in pregnancy for resectable adrenocortical carcinoma or phaeochromocytoma, but delayed until the postpartum period for well-differentiated thyroid cancer. Medical therapy may be required to reduce the drive to tumour growth, control symptoms of hormone excess and to minimise the risks of surgery, anaesthesia or labour.

Adrenocortical carcinoma (ACC) is a rare and aggressive endocrine tumour deriving from the adrenal cortex. A correct therapeutic strategy requires a multidisciplinary approach between endocrinologist, surgeon and oncologist. Surgery is the mainstay treatment in ACC while mitotane, deriving from the insecticide dichloro-diphenyl-trichloro-ethane, is the main base of the medical treatment of ACC in consideration of its adrenocytolitic activity. However, the use of mitotane as adjuvant therapy is still controversial, also in consideration of the retrospective nature of several studies. A prospective randomised trial (ADIUVO), recruiting patients with low-intermediate risk of recurrence, is evaluating the utility of adjuvant treatment with mitotane in this setting. The therapeutic response is observed with plasma levels of mitotane >14 mg/L. However, the major difficulty in the management of mitotane treatment is related to side effects and to the risk of toxicity, which is related to plasmatic levels >20 mg/L, that is considered the upper limit of the therapeutic window. Mitotane therapy results in adrenal insufficiency, and glucocorticoid replacement therapy has to be administered at higher doses than those used in other aetiologies of primary adrenal insufficiency. Furthermore, other endocrine side effects related to mitotane should be considered, in particular on thyroid hormone and testosterone metabolism. Waiting for new medical strategies on molecular targets, it will be mandatory to optimise the current knowledge by prospective trials and, in consideration of the rarity of the disease, collaborative studies between endocrinologists and oncologists are necessary

Endocrine oncology is a complex area that must determine the site of a neoplastic process and the hormonal dysregulation that ensues. Patients with endocrine tumors often have delayed diagnosis because of the nonspecific and often subtle signs and symptoms. In patients with multiple endocrine neoplasia syndromes, diagnosis and clinicopathologic correlations can be even more challenging. We report a patient with multiple endocrine neoplasia type 1 (MEN-1) and a highly complex clinical story associated with multiple atypical lesions including two pituitary adenomas, a gonadotroph macroadenoma and a corticotroph microadenoma with Crooke's hyaline change and ectopic production of corticotropin-releasing hormone (CRH) from a thymic endocrine carcinoma. These lesions resulted in a highly complex clinical story, difficult diagnoses and questions about management. This case illustrates a number of clinically relevant challenges, including the diagnosis of pituitary adenomas in MEN-1, the difficulty in diagnosing Cushing's disease, and the large differential of pituitary pathologies in this disorder, double pituitary adenomas and other decoy lesions in Cushing's disease, the pathophysiology of Crooke's hyaline change in the pituitary, and the various causes of Cushing's syndrome associated with MEN-1.

The truth is that we are still almost completely ignorant about androgens and prostate cancer (PCa). If we had more robust knowledge of this delicate interrelationship, we could avoid groping in the darkness of assumptions and attempts. Researchers still have much to learn in terms of preclinical, clinical, and, especially, translational science. And endocrine oncology is certainly a fascinating field. One may wonder why such strong statements are used. In my humble opinion, PCa is an example of the fact that several aspects of endocrine, paracrine, and intracrine functions and behaviors of sex steroids may deserve an entire course of study, maybe even a lifetime of study— study of the type and depth that Giacomo Leopardi, a famous Italian poet, described as ‘‘crazy and desperate.’’ At the end of the day, what do we know? Androgens are vital for growth and maintenance of the prostate. Likewise, sex hormones have been implicated in prostate carcinogenesis through their roles in modulating cell proliferation, differentiation, and apoptosis [1]. In this context, a biological dependence between PCa and testosterone was assumed for a long time [1]. However, an association between circulatingandrogensandPCahasnotbeenclearly confirmed in epidemiologic studies [1,2]. Data from numerous population-based analyses fail to show a significant association between circulating levels of androgens (mainly, total testosterone) and increased risk of PCa [2,3]. In this respect,wehave come to think that because certain knowledge of the in vivo biology of PCa in humans is lacking, it may not be possible to draw a tenable conclusion from study of any relationship between serum steroid hormones and either the risk of developing a tumor or the pathologic features of PCa itself without considering the temporal aspect of reciprocal influence. It is certainly tough to follow the circulating hormonal milieu of a sufficient number of

The term Endocrine Related Cancers classically includes a group of sex steroid responsive cancers, such as cancers of the breast, endometrium, prostate, and testis, but also other cancers such as thyroid and ovary cancers that are responsive to pitui-tary hormones (1). Based on this widely accepted concept, at least 35–40% of newly diagnosed cancers fall into this definition (2). This concept has been useful for its clinical implications, and has lead to the use of anti-estrogenic/anti-androgenic treatments for sex hormone responsive cancers, as well as to thyroid-stimulating hormone (TSH) suppressive therapy with l-thyroxine (-T4) for differentiated thyl -roid cancer. Moreover, several studies have tried to identify physiological conditions, such as early menarche, late menopause, age of first pregnancy, and number of preg-nancies, prolonged lactation, and obesity, that may all affect sex steroids availabil-ity/exposure and modulate cancer risk. Another series of studies have identified germline polymorphisms, which are linked to the modulation of cancer risk through the genetic control of serum hormone lev-els or target tissue responses (3). Finally, other studies have addressed the possi-ble effects of the exposure to exogenous sex hormones, such as estroprogestins (4) or postmenopausal estrogen replac-ing therapy (5) or endocrine disruptors (6). While all these studies have provided useful information for cancer prevention and treatment, our understanding of how genetic traits relevant to hormone action, control and interaction with physiological conditions, hormonal supplementations, and environmental factors is still limited. Another grand challenge is represented by the possibility to achieve effective and risk-free chemoprevention for subjects predisposed to individual endocrine related cancers, as exemplified by the use of tamoxifen and other agents in breast cancer predisposed subjects (6).In recent years, several studies have challenged this classical view of endocrine related cancer. We now summarize recent data, which should be taken into account to reformulate the term “endocrine related cancer” in a more expanded way.

Thymic neuroendocrine tumours (TNETs) are uncommon but malignant neoplasms, usually associated with a poor prognosis. The number of cases reported is limited to a few hundreds and there are few prognostic factors available. All 28 patients (22 male, 6 female; median age 46.5 years) with thymic neuroendocrine tumour, treated at the Department of Endocrine Oncology, Uppsala University Hospital, Uppsala, Sweden between 1985 and 2011 were studied. The overall 3, 5 and 10-year survival was 89%, 79% and 41% respectively. Ki67

This edition of Seminars in Oncology is dedicated to the topic of endocrine tumors, a dynamic and challenging area in oncology. The field of endocrine oncology is broad and complex and the principles related to diagnosis, staging, treatment, and follow-up are, in many ways, broadly relevant to the entire field of oncology but also have specific distinct dimensions to them. The successful management of a patient with an endocrine cancer requires an understanding of the molecular basis of neoplasia and highlights the importance of coordinated multi-disciplinary treatment planning to provide the optimal clinical outcome for patients afflicted with these conditions. The chapters on endocrine cancers for this edition are based on specific disease sites, as well as some broader topics that span the entire discipline. We thank the contributing authors, all internationally recognized experts in their field, who have provided such concise, well-organized, up-to-date, and yet comprehensive reviews of their topics. There are three excellent chapters covering the spectrum of thyroid and parathyroid malignancies; one by Drs Zeiger and Burns from the Johns Hopkins School of Medicine, one by Drs Moley and Pitt from the Washington University School of Medicine, and a parathyroid cancer chapter by Dr Simonds and colleagues from the National Institutes of Health (NIH) in Bethesda, MD. Adrenal medullary and cortical cancers are very nicely reviewed by Drs Pacak and colleagues, by Drs Fojo and Balasubramaniam also from the NIH. Professor Grossman and her colleagues from the Barts and London School of Medicine have contributed a chapter on estrogen- and androgen-producing cancers and Professor Manelli and his colleagues from the University of Florence have provided a chapter on evaluation and management of patients with incidentally discovered adrenal masses; both are exceptional reviews of those subjects. Professor Oberg from Uppsala University Hospital has provided a very comprehensive chapter on the subject of pancreatic neuroendocrine tumors. Drs Stratakis and Lodish from the NIH and Drs Spiegel and Libutti from the Albert Einstein School of Medicine have contributed chapters on rare and unusual cancer syndromes and on future directions in endocrine oncology, both of which highlight the fundamental importance and emerging role of understanding the molecular basis of endocrine cancers in the diagnosis and treatment of patients afflicted with these conditions. Drs Oldfield and Sansur from the University of Virginia and the University of Maryland Schools of Medicine, respectively, have provided a very nice review of pituitary cancers and Drs Carrasquillo and Chen from the Memorial Sloan-Kettering Cancer Center and the NIH have assembled a very comprehensive review of functional imaging of endocrine cancers. Finally, we would like to express our gratitude to Dr Ernest Borden, Deputy Director at The Cleveland Clinic, Taussig Cancer Institute for the opportunity to serve as guest editors for this edition of Seminars in Oncology and we thank Michelle Weidner from his office who has kept us on schedule with respect to completion of this project. We know that the readers will find this to be a very comprehensive and authoritative review of this topic.

Após o tratamento inicial do câncer tireoidiano, a detecção de prováveis recorrências e/ou metástases se faz através da dosagem de marcadores séricos e estudos de imagem. Essas técnicas podem ser negativas apesar de evidências bioquímicas de doença metastática. A tomografia de emissão de pósitrons com fluorodeoxiglicose (FDG-PET) tem sido proposta como um teste acurado para detectá-la. O objetivo deste estudo é apresentar uma síntese das evidências obtidas através de revisão sistemática sobre a acurácia do FDG-PET na localização de metástases de câncer tireoidiano previamente tratado, nos quais as modalidades convencionais falharam na sua detecção. Foi realizada uma pesquisa bibliográfica no MEDLINE de todos os trabalhos relativos a FDG-PET e carcinoma tireoidiano diferenciado, indexados até setembro de 2005. Foram obtidas 216 citações e 17 trabalhos foram incluídos, 71% publicados a partir de 2000. A sensibilidade da FDG-PET foi elevada, com apenas um trabalho apresentando sensibilidade inferior a 75%. A especificidade, examinada em 12 estudos, foi menor que 75% em 3 estudos. Em 41% dos trabalhos existia pelo menos um teste comparativo com o FDG-PET. Os resultados apontam o FDG-PET como um teste diagnóstico útil para a detecção e localização de metástases do câncer tireoidiano, com implicações diretas no tratamento dos pacientes. After the initial thyroid cancer treatment, the detection of likely recurrences and/or metastases is made through the measurement of serum markers determinations and diagnostic image procedures. These techniques may be negative in spite of biochemical evidence of metastatic disease. The positron emission tomography with fluorodeoxyglucose (FDG-PET) has been proposed as an accurate method to detect it. The aim of this study is to present a synthesis of the evidences obtained from a systematic review regarding FDG-PET accuracy in locating suspected metastases of previously treated thyroid cancer, when the conventional methods failed to do it. A bibliographic review of all studies related to FDG-PET and differentiated thyroid cancer was made on MEDLINE, indexed until September 2005. Two hundred and sixteen citations were collected and 17 studies included, 71% were published after 2000. FDG-PET sensibility was high, with only one study presenting a sensibility lower than 75%. The specificity, examined in 12 studies was lower than 75% in 3 studies. There was at least one test compared to FDG-PET in 41% of the studies. The results point to FDG-PET as a useful diagnostic test to detect and localize thyroid cancer metastases, with direct implications in the treatment of these patients.

The molecular pathway leading to pituitary tumorigenesis is still largely unknown and is one of the challenges of the endocrine oncology. The development of pituitary adenomas in HMGA2 transgenic mice and the finding of HMGA2 amplification and overexpression in human pituitary adenomas led us to investigate the mechanism by which the HMGA2 gene plays a crucial role in pituitary oncogenesis. This mechanism has been recently described by our group: it entails the acetylation of E2F1, and its consequent enhanced activity, following the displacement of HDAC1 from the pRB/E2F1 inhibitory complex. Based on the mating between HMGA2 transgenic and E2F1 knockout mice, the activation of E2F1 appears to be the main mechanism of the onset of HMGA2-induced pituitary adenoma development. Nevertheless, other events may be also involved in this process, and are discussed here.

In this chapter I will try to report to you what I have been doing for the past 25 years and what advancements in oncology have emanated so far from the work on the hypothalamus. The discovery of hypothalamic hormones, especially luteinizing hormone-releasing hormone (LHRH) and somatostatin, has led to practical clinical use of their analogs in the field of cancer treatment. LHRH, somatostatin, growth hormone-releasing hormone (GHRH), their mRNAs and their receptors are found in diverse tumors (Schally et al., 2001a, Schally et al., 2001b). Mammalian bombesin-like peptides, such as gastrin-releasing peptide (GRP) and neuromedin B, are likewise present in various tumors, and appear to produce mitogenic effects (Cuttitta, 1985; Sunday et al., 1988; Schally et al., 2001a). Antagonists of bombesin/GRP can be also used for the development of new methods for treatment of various tumors. In addition we have synthesized and evaluated cytotoxic analogs of LHRH, somatostatin and bombesin that can be targeted to various tumors. Moreover, we have made antagonists of GHRH, not discussed here. This chapter reviews some selected experimental and clinical findings on the use of analogs of LHRH, somatostatin and bombesin for treatment of various cancers.

ISSN 2045-0869 Int. J. Endo. Oncol. (2014) 1(1), 1 On behalf of our distinguished Editorial Board, we are delighted to welcome you to the inaugural edition of the International Journal of Endocrine Oncology, a multidisciplinary journal focused on endocrine malignancies. To our knowledge, this is the first journal to have the sole focus on endocrine cancers encompassing basic and translational science, and the clinical management of endocrine cancers. Our goal in the development of this journal is to provide a high-impact venue for the many investigators and clinicians who have a focus on endocrine cancers. We are seeking to encourage submissions from all stakeholders in endocrine cancers, including laboratory scientists, endocrinologists, medical oncologists, surgeons, radiologists and pathologists, among others. The time is right to have a journal focused on endocrine malignancies (pituitary, parathyroid, adrenal, thyroid and pancreas) as the epidemiology of endocrine cancers, clinical management strategies and our understanding of the genetics/genomics have changed dramatically. Because of this, many leading academic institutions now have dedicated multidisciplinary clinical and or research programs in endocrine oncology. Given these changes in epidemiology, advances in therapy, and emerging questions and controversies, we believe ‘the time is right’ to have a journal focused on endocrine oncology. We believe this journal will have a broad readership given the many specialties involved in the management of endocrine malignancies. We welcome articles and special issue focus proposals to the editorial team, and we encourage you to submit your best work to the International Journal of Endocrine Oncology.

IN 2009, THE AMERICAN THYROID ASSOCIATION published revised management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Current recommendations suggest that ‘‘thyroid lobectomy alone may be sufficient for the treatment of small (

Adrenocortical carcinoma (ACC) represents one of the most resistant human cancers to systemic chemotherapy and a major clinical challenge in the field of endocrine oncology. Recent molecular characterizations of ACC suggest new opportunities for targeted therapy. The current study aimed to evaluate expression and function of TOP2A in human adrenocortical neoplasm, and anticancer activity of agents that target TOP2A. TOP2A mRNA and protein expression levels were evaluated in 112 adrenocortical tissue samples. In vitro siRNA knockdown of TOP2A in ACC cell lines (NCI-H295R and SW13) was used to determine its effect on cellular proliferation, cell cycle, anchorage-independent growth and cellular invasion. We screened 14 TOP2A inhibitors for their anticancer activity in ACC cell lines. TOP2A mRNA expression was significantly higher in ACC than in benign and normal adrenocortical tissue samples (p < 0.001); likewise, TOP2A protein expression was significantly higher in ACC (p < 0.05). Knockdown of TOP2A gene expression decreased cell proliferation, anchorage-independent growth and invasion (p < 0.05). Aclarubicin had the most potent antiproliferative activity out of 11 active TOP2A inhibitors, which significantly decreased proliferation and tumor spheroid size in ACC cell lines (p< 0.05). Our data indicate that most TOP2A inhibitors are effective compounds for ACC, with aclarubicin having the best anticancer activity. Thus, TOP2A inhibitors should be tested in future clinical trials for patients with locally advanced and metastatic ACC. Citation Format: Meenu Jain, Lisa Zhang, Mei He, Ya-Qin Zhang, Naris Nilubol, Min Shen, Electron Kebebew. TOP2A is a therapeutic target for adrenocortical carcinoma . [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3543. doi:10.1158/1538-7445.AM2013-3543