The Unique Importance of Differentiation and Function in Endocrine Neoplasia.

The assessment of cell differentiation in endocrine neoplasms involves not only the identification of a cell's structure and expression of specific transcription factors which regulate that cell, but also the identification of hormones and/or enzymes involved in hormone synthesis. The importance of this functional characterization is emphasized by the fact that the hormones serve as biomarkers for clinical surveillance to identify persistence, recurrence, or progression of disease. Sometimes, unusual patterns of hormone expression lead to unexpected clinical signs and symptoms. Loss of differentiated hormone production can be a sign of dedifferentiation as a tumor becomes more aggressive. In addition to prognostic information, cell differentiation can be predictive, since differentiated endocrine cells express targets for therapy, such as the sodium iodide symporter in thyroid cancers and somatostatin receptors in neuroendocrine tumors. The salient features of differentiation in the three main types of endocrine cells can be used to determine prognosis and to tailor management of patients with endocrine neoplasms.

Applications of Deep Learning in Endocrine Neoplasms.

Machine learning methods have been growing in prominence across all areas of medicine. In pathology, recent advances in deep learning (DL) have enabled computational analysis of histological samples, aiding in diagnosis and characterization in multiple disease areas. In cancer, and particularly endocrine cancer, DL approaches have been shown to be useful in tasks ranging from tumor grading to gene expression prediction. This review summarizes the current state of DL research in endocrine cancer histopathology with an emphasis on experimental design, significant findings, and key limitations.

Characteristics of 1270 Chinese sibling pairs with cancer.

BACKGROUND: Previous research found that the cancer history of an individual's sibling may be a better indicator than that of the parents. We aim to provide recommendations for opportunistic screening for individuals whose sibling had been diagnosed with cancer. METHODS: During the physical examination in Cancer Hospital, Chinese Academy of Medical Sciences, 43,300 people were asked if they have at least two siblings who developed cancer. RESULTS: A total of 1270 sibling-pairs from 766 families developed cancer, including 367 pairs of brothers (Bro-pairs), 368 pairs of sisters (Sis-pairs), and 535 pairs of brother-and-sister (BroSis-pairs). The mean ages at diagnosis of cancer for the three groups were from 58 to 62 years. More than half of Bro-pairs (55.3%) or Sis-pairs (51.1%) had cancer from the same systemic origin, and more than a quarter of Bro-pairs (28.1%) and Sis-pairs (37.2%) developed the same type of cancer. However, only 36.0% of BroSis-pairs developed cancers from the same systemic origin, and 18.9% developed the same type of cancer. In Bro-pairs and BroSis-pairs, lung cancer and digestive system cancer were the most common cancers, while in Sis-pairs, breast cancer, lung cancer, cervical cancer, liver cancer and thyroid cancer were the most common ones. CONCLUSIONS: If an individual's sibling is diagnosed with cancer, the individual should consider participating in opportunistic screening annually, especially for lung cancer and digestive system cancers for both sexes. For sisters, breast cancer, cervical cancer and thyroid cancer should be screened early. Additionally, genetic services are essential for individuals who have siblings with cancer.

Hereditary Endocrine Tumors and Associated Syndromes: A Narrative Review for Endocrinologists and Endocrine Surgeons.

OBJECTIVE: Hereditary endocrine tumors (HET) were among the first group of tumors where predisposition syndromes were recognized. The utility of genetic awareness is having the capacity to treat at an earlier stage, screen for other manifestations and initiate family cascade testing. The aim of this narrative review is to describe the most common hereditary syndromes associated with frequently encountered endocrine tumors, with an emphasis on screening and surveillance. METHODS: A MEDLINE search of articles for relevance to endocrine tumors and hereditary syndromes was performed. RESULTS: The most common hereditary syndromes associated with frequently encountered endocrine tumors are described in terms of prevalence, genotype, phenotype, penetrance of malignancy, surgical management, screening, and surveillance. CONCLUSION: Medical practitioners involved in the care of patients with endocrine tumors should have an index of suspicion for an underlying hereditary syndrome. Interdisciplinary care is integral to successful, long-term management of such patients and affected family members.

Serum Inflammation-based Scores in Endocrine Tumors.

CONTEXT: Serum inflammation-based scores reflect systemic inflammatory response and/or patients' nutritional status, and may predict clinical outcomes in cancer. While these are well-described and increasingly used in different cancers, their clinical usefulness in the management of patients with endocrine tumors is less known. EVIDENCE ACQUISITION: A comprehensive PubMed search was performed using the terms "endocrine tumor," "inflammation," "serum inflammation-based score," "inflammatory-based score," "inflammatory response-related scoring," "systemic inflammatory response markers," "neutrophil-to-lymphocyte ratio," "neutrophil-to-platelet ratio," "lymphocyte-to-monocyte ratio," "Glasgow prognostic score," "neutrophil-platelet score," "Systemic Immune-Inflammation Index," and "Prognostic Nutrition Index" in clinical studies. EVIDENCE SYNTHESIS: The neutrophil-to-lymphocyte ratio and the platelet-to-lymphocyte ratio are the ones most extensively investigated in patients with endocrine tumors. Other scores have also been considered in some studies. Several studies focused in finding whether serum inflammatory biomarkers may stratify the endocrine tumor patients' risk and detect those at risk for developing more aggressive and/or refractory disease, particularly after endocrine surgery. CONCLUSIONS: In this review, we summarize the current knowledge on the different serum inflammation-based scores and their usefulness in predicting the phenotype, clinical aggressiveness, and disease outcomes and prognosis in patients with endocrine tumors. The value of such serum inflammation-based scores in the management of patients with endocrine tumors has been emerging over the last decade. However, further research is necessary to establish useful markers and their cut-offs for routine clinical practice for individual diseases.

ENDOCRINE TUMOURS: Calcitonin in thyroid and extra-thyroid neuroendocrine neoplasms: the two-faced Janus.

An increased calcitonin serum level is suggestive of a medullary thyroid cancer (MTC), but is not pathognomonic. The possibility of false positives or other calcitonin-secreting neuroendocrine neoplasms (NENs) should be considered. Serum calcitonin levels are generally assessed by immunoradiometric and chemiluminescent assays with high sensitivity and specificity; however, slightly moderately elevated levels could be attributable to various confounding factors. Calcitonin values >100 pg/mL are strongly suspicious of malignancy, whereas in patients with moderately elevated values (10-100 pg/mL) a stimulation test may be applied to improve diagnostic accuracy. Although the standard protocol and the best gender-specific cut-offs for calcium-stimulated calcitonin are still controversial, the fold of the calcitonin increase after stimulation seems to be more reliable. Patients with MTC show stimulated calcitonin values at least three to four times higher than the basal values, whereas calcitonin-secreting NENs can be distinguished from a C-cell disease by the absence of or

Ki67 in endocrine neoplasms: to count or not to count, this is the question! A systematic review from the English language literature.

BACKGROUND: Endocrine neoplasms are generally slow-growing tumors that can show hormonal activity and give metastases. In most cases they are benign and clearly malignant forms are easy to diagnose. However, borderline forms may occur and be, for the pathologists, very difficult to classify. In these cases, there is a strong need to identify factors that may aid. Official classification systems for endocrine neoplasms are based on the evaluation of proliferation and, in most cases, they rely on mitotic count. In support, the study of Ki67 is carried out which, however, has not yet been included in any official classification system, except for neuroendocrine neoplasms of the gastro-entero-pancreatic tract. PURPOSE: The aim of the present study was to investigate the proven or unproven role of Ki67 in endocrine neoplasms, in different districts, in order to bring to light the substantial differences, in terms of proliferation, existing between neoplasms so similar, but at the same time, so different. METHODS: A thorough search of English language literature was performed, looking for articles concerning Ki67 in five endocrine neoplasms (pituitary adenomas, thyroid neoplasms, adrenocortical neoplasms, pheochromocytomas and paragangliomas). RESULTS: From 2170, 236 articles were selected and it was seen that the endocrine neoplasm in which Ki67 was most studied was the pituitary, where it still shows a controversial role. In other neoplasms different roles were identified. CONCLUSION: The pathologist should be aware of the contribution that this proliferative marker can give to the diagnosis and, sometimes, to the therapy selection, for the clinician.

Screening guidelines and recommendations for patients at high risk of developing endocrine cancers.

Screening guidelines in patients with inherited endocrine syndromes and others at high risk for developing endocrine cancers have significant implications as early tumor detection is associated with improved outcomes. Given the unique challenges in diagnosis and treatment, patients at high risk for developing endocrine cancers require multidisciplinary care. The complexity of decision making and rarity of these syndromes support referral to high-volume centers with the experience and knowledge to treat these at-risk patients.

Comparison of the clinicopathological features of pancreatic solid pseudopapillary neoplasms between males and females: gender does matter.

BACKGROUND: Solid pseudopapillary neoplasms (SPN) of the pancreas are a rare and low-grade malignant entity with a female predominance. However, it also occurs in males, but the rarity and lack of concern makes its clinicopathological features unclarified. METHODS: The morphological, immunohistochemical, prognostic features and CTNNB1 exon 3 mutation status of SPN were compared semi-quantitively between 9 male and 21 female patients. RESULTS: SPN in males grew in a distinctive solid pattern, with abundant fibrotic stroma and clear cells. Collagen tended to be the main component of tumor stroma in males, while hyaluronan composed a considerable proportion in females. A much stronger expression of androgen receptor (AR) was found in males, and CD56 and/or synaptophysin (Syn) was expressed frequently in both genders. All patients survived. One male patient had post-operational liver nodules and accepted interventional therapy without biopsy. Mutations of CTNNB1 exon 3 were observed in all cases, distributed at codon 32, 33 and 37 in both genders, as well as 34, 41 and 62 in females. CONCLUSION: SPN in males presented with significantly different morphological features from that in females, which might be helpful in differential diagnosis, especially when with extensive positivity for CD56 and/or Syn. The stronger expression of AR in males might be a clue to explore the underlying mechanism of the gender difference.

Secondary Hypertension and Complications: Diagnosis and Role of Imaging.

Hypertension is a common problem; if left untreated, it can result in significant complications, including those involving the cardiovascular system and end organs. Approximately 10% of patients with hypertension are classified as having secondary hypertension, defined as hypertension attributable to a specific and potentially remediable cause. The evaluation for secondary hypertension typically begins with acquiring the patient history and performing a physical examination and screening laboratory tests. Directed imaging may be performed, on the basis of laboratory test results, to assess for potential causes of secondary hypertension. The causes can be broadly classified as endocrine (eg, hyperaldosteronism, pheochromocytoma, hyperparathyroidism) and nonendocrine (eg, aortic coarctation, renal vascular hypertension). In addition, patients with hypertension can develop significant complications that also are diagnosed with imaging, including conditions involving the cardiovascular system (eg, aortic aneurysm, acute aortic syndrome) and central nervous system (eg, stroke, subarachnoid hemorrhage, and posterior reversible encephalopathy syndrome). The imaging workup and imaging appearances of some of the causes of secondary hypertension are reviewed, treatment options are discussed, and the imaging appearances of hypertension-related complications are described. It is important for radiologists to accurately diagnose the secondary causes of hypertension, as many of them are treatable, and treatment may result in improved symptoms or resolution of hypertension. ©RSNA, 2019.

Adipose Tissue, Obesity and Adiponectin: Role in Endocrine Cancer Risk.

Adipose tissue has been recognized as a complex organ with endocrine and metabolic roles. The excess of fat mass, as occurs during overweight and obesity states, alters the regulation of adipose tissue, contributing to the development of obesity-related disorders. In this regard, many epidemiological studies shown an association between obesity and numerous types of malignancies, comprising those linked to the endocrine system (e.g., breast, endometrial, ovarian, thyroid and prostate cancers). Multiple factors may contribute to this phenomenon, such as hyperinsulinemia, dyslipidemia, oxidative stress, inflammation, abnormal adipokines secretion and metabolism. Among adipokines, growing interest has been placed in recent years on adiponectin (APN) and on its role in carcinogenesis. APN is secreted by adipose tissue and exerts both anti-inflammatory and anti-proliferative actions. It has been demonstrated that APN is drastically decreased in obese individuals and that it can play a crucial role in tumor growth. Although literature data on the impact of APN on carcinogenesis are sometimes conflicting, the most accredited hypothesis is that it has a protective action, preventing cancer development and progression. The aim of the present review is to summarize the currently available evidence on the involvement of APN and its signaling in the etiology of cancer, focusing on endocrine malignancies.

Interpretation of Unexpectedly High Levels of Endocrine Tumor Markers.

OBJECTIVE: Endocrine tumor markers (ETMs) are important and indispensable tools in the diagnosis and follow-up of endocrine tumors. Unexpectedly high level of ETM (UHLETM) is often encountered in clinical practice. The objectives of this article are to discuss the approach to UHLETMs and describe the most common UHLETMs. METHODS: Literature review and personal experience with UHLETMs. RESULTS: A UHLETM is defined as an ETM level much higher than what an endocrinologist would expect based on the patient's clinical information, other biochemical test results, and imaging findings. Most UHLETMs are false positive, in that they do not indicate the existence or growth of an endocrine tumor. The key issue, however, is how to convincingly prove that a UHLETM is false positive. The most important question to help resolve UHLETMs is whether the UHLETMs are due to false or true results. Some UHLETMs are due to interpretation errors, laboratory errors, or spurious test results, while the true levels of the ETMs are normal or unchanged from previous results. Other UHLETMs are due to nontumor conditions or medications, and the true levels of the ETMs are indeed very high. When it is not straightforward to assess whether certain UHLETMs are due to false or true results, they may be due to novel conditions. CONCLUSION: UHLETMs provide endocrinologists great opportunities to learn the basic biology and measurement of ETMs. Unresolved UHLETMs are exciting clinical research opportunities which may lead to discovery of new diseases and new mechanisms of measurement interference. ABBREVIATIONS: 5-HIAAA = 5-hydroxyindoleacetic acid; 5-HTP = 5-hydroxytryptophan; CGA = chromogranin A; ETM = endocrine tumor marker; MTC = medullary thyroid carcinoma; UHLETM = unexpectedly high level of endocrine tumor marker.

65 YEARS OF THE DOUBLE HELIX: Genetics informs precision practice in the diagnosis and management of pheochromocytoma.

Although the authors of the present review have contributed to genetic discoveries in the field of pheochromocytoma research, we can legitimately ask whether these advances have led to improvements in the diagnosis and management of patients with pheochromocytoma. The answer to this question is an emphatic Yes! In the field of molecular genetics, the well-established axiom that familial (genetic) pheochromocytoma represents 10% of all cases has been overturned, with >35% of cases now attributable to germline disease-causing mutations. Furthermore, genetic pheochromocytoma can now be grouped into five different clinical presentation types in the context of the ten known susceptibility genes for pheochromocytoma-associated syndromes. We now have the tools to diagnose patients with genetic pheochromocytoma, identify germline mutation carriers and to offer gene-informed medical management including enhanced surveillance and prevention. Clinically, we now treat an entire family of tumors of the paraganglia, with the exact phenotype varying by specific gene. In terms of detection and classification, simultaneous advances in biochemical detection and imaging localization have taken place, and the histopathology of the paraganglioma tumor family has been revised by immunohistochemical-genetic classification by gene-specific antibody immunohistochemistry. Treatment options have also been substantially enriched by the application of minimally invasive and adrenal-sparing surgery. Finally and most importantly, it is now widely recognized that patients with genetic pheochromocytoma/paraganglioma syndromes should be treated in specialized centers dedicated to the diagnosis, treatment and surveillance of this rare neoplasm.