Genetic Determinants of Inherited Endocrine Tumors: Do They Have a Direct Role in Bone Metabolism Regulation and Osteoporosis?

Endocrine tumors are neoplasms originating from specialized hormone-secreting cells. They can develop as sporadic tumors, caused by somatic mutations, or in the context of familial Mendelian inherited diseases. Congenital forms, manifesting as syndromic or non-syndromic diseases, are caused by germinal heterozygote autosomal dominant mutations in oncogenes or tumor suppressor genes. The genetic defect leads to a loss of cell growth control in target endocrine tissues and to tumor development. In addition to the classical cancer manifestations, some affected patients can manifest alterations of bone and mineral metabolism, presenting both as pathognomonic and/or non-specific skeletal clinical features, which can be either secondary complications of endocrine functioning primary tumors and/or a direct consequence of the gene mutation. Here, we specifically review the current knowledge on possible direct roles of the genes that cause inherited endocrine tumors in the regulation of bone modeling and remodeling by exploring functional in vitro and in vivo studies highlighting how some of these genes participate in the regulation of molecular pathways involved in bone and mineral metabolism homeostasis, and by describing the potential direct effects of gene mutations on the development of skeletal and mineral metabolism clinical features in patients.

Oncocrinology.

Oncocrinology is the science which studies the complex bi-directional relationship between cancer and the endocrine system, including pathophysiological links, clinical presentation and the impact of cancer treatment and endocrine therapy. This review describes the vast spectrum of the complex, multifacted relationship between the endocrine system and malignancy. It also includes the endocrine aspects of anti-cancer treatment, and the need for oncovigilance with endocrine therapy.

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.

Malignant paraganglioma and somatotropinoma in a patient with germline SDHB mutation-genetic and clinical features.

BACKGROUND: Pituitary adenomas and paragangliomas/pheocromocytomas are rare endocrine tumours, which can be sporadic or familial. During many years their coexistence in the same individual was considered a coincidental finding. However, an association between these two entities was recently demonstrated, with the possible involvement of SDHx genes. CASE REPORT: We describe a 57-year-old female patient, who was under surveillance since 1997 for a malignant paraganglioma with vertebral bone metastasis, and harboured a germline frameshift mutation in exon 6 of SDHB gene [c.587-591DelC]. Seventeen years later, she was diagnosed with acromegaly and underwent transesphenoidal endoscopic resection of a somatotropinoma. Three months after surgery she started treatment with lanreotide for residual disease. Despite initial good response, she developed resistance to first generation of somatostatin analogues and treatment had to be switched to pegvisomant. In the immunohistochemical staining, the pituitary adenoma was positive for SDHA expression, while SDHB showed an heterogeneous staining pattern, with areas markedly positive and others with positive and negative cells. CONCLUSIONS: Our findings provide useful data for understanding the link between paragangliomas/pheocromocytomas and somatotropinomas. While we confirm the well-established link between SDHB mutations and paragangliomas/pheocromocytomas, particularly with malignant paragangliomas, the preservation-at least partially-of SDHB expression in the somatotropinoma tissue does not allow drawing definite conclusions about the involvement of the SDHB mutation in pituitary adenoma.

Endocrine Tumors Causing Arterial Hypertension: Pathophysiological Mechanisms and Clinical Implications.

Some tumors are a relatively rare and amendable cause of hypertension, often associated with a higher cardiovascular morbidity and mortality, as compared with that of both general population and patients with essential hypertension. This worse prognosis is not entirely related to blood pressure increase, because the release of substances from the tumor can directly influence blood pressure behavior. Diagnostic approach is challenging and needs a deep knowledge of the different neuro-hormonal and genetic mechanisms determining blood pressure increase. Surgical tumor removal can, but not always, cause blood pressure normalization, depending on how early was tumor detection, since a long-standing history of hypertension is often associated with a much weaker effect on blood pressure. Moreover, target organ damage can be affected by the substances themselves released by the tumors as well as by tumor removal. In this review we consider the phenotype and genetic features of patients with tumor-induced hypertension and focus on their diagnostic work-up.

Venous thromboembolism and risk of cancer in patients with diabetes mellitus.

AIM: Venous thromboembolism (VTE) has long been regarded as a marker of underlying malignancy in the general population. Patients with diabetes mellitus are at increased risk of developing VTE, but it is unclear whether VTE in diabetes patients is also a harbinger of occult cancer. METHODS: From Danish medical health databases, we identified all diabetes patients (N=8783) with a first-time diagnosis of VTE during 1978-2011. We followed the patients until a first-time diagnosis of cancer, emigration, death, or study end, whichever came first. We calculated one-year absolute cancer risk and overall and site-specific standardized incidence ratios (SIRs) for cancer based on national cancer incidence. RESULTS: During the total study period 878 cancers were observed. The one-year absolute cancer risk was 4.1% and the corresponding SIR was 3.28 (95% confidence interval [CI]: 2.94-3.64). The highest SIRs were observed for cancers of the gallbladder and biliary tract (SIR 13.59; 6.77-24.31), the pancreas (SIR 10.16; 6.85-14.50), the ovary (SIR 9.85; 5.63-16.00), and the liver (SIR 9.39; 4.30-17.84). After the first year of follow-up, the overall cancer SIR associated with VTE and diabetes decreased to 1.05 (95% CI: 0.97-1.15). CONCLUSIONS: VTE may be a marker of underlying cancer in patients with diabetes mellitus.

Predicting the risk of multiple endocrine neoplasia type 1 for patients with commonly occurring endocrine tumors.

OBJECTIVE: Endocrine diseases that can be part of the rare inheritable syndrome multiple endocrine neoplasia type 1 (MEN1) commonly occur in the general population. Patients at risk for MEN1, and consequently their families, must be identified to prevent morbidity through periodic screening for the detection and treatment of manifestations in an early stage. The aim of the study was to develop a model for predicting MEN1 in individual patients with sporadically occurring endocrine tumors. DESIGN: Cross-sectional study. METHODS: In a nationwide study in The Netherlands, patients with sporadically occurring endocrine tumors in whom the referring physician suspected the MEN1 syndrome were identified between 1998 and 2011 (n=365). Logistic regression analysis with internal validation using bootstrapping and external validation with a cohort from Sweden was used. RESULTS: A MEN1 mutation was found in 15.9% of 365 patients. Recurrent primary hyperparathyroidism (pHPT; odds ratio (OR) 162.40); nonrecurrent pHPT (OR 25.78); pancreatic neuroendocrine tumors (pNETs) and duodenal NETs (OR 17.94); pituitary tumor (OR 4.71); NET of stomach, thymus, or bronchus (OR 25.84); positive family history of NET (OR 4.53); and age (OR 0.96) predicted MEN1. The c-statistic of the prediction model was 0.86 (95% confidence interval (95% CI) 0.81-0.90) in the derivation cohort and 0.77 (95% CI 0.66-0.88) in the validation cohort. CONCLUSION: With the prediction model, the risk of MEN1 can be calculated in patients suspected for MEN1 with sporadically occurring endocrine tumors.

Hirsutism in women.

Hirsutism is excess terminal hair that commonly appears in a male pattern in women. Although hirsutism is generally associated with hyperandrogenemia, one-half of women with mild symptoms have normal androgen levels. The most common cause of hirsutism is polycystic ovary syndrome, accounting for three out of every four cases. Many medications can also cause hirsutism. In patients whose hirsutism is not related to medication use, evaluation is focused on testing for endocrinopathies and neoplasms, such as polycystic ovary syndrome, adrenal hyperplasia, thyroid dysfunction, Cushing syndrome, and androgen-secreting tumors. Symptoms and findings suggestive of neoplasm include rapid onset of symptoms, signs of virilization, and a palpable abdominal or pelvic mass. Patients without these findings who have mild symptoms and normal menses can be treated empirically. For patients with moderate or severe symptoms, an early morning total testosterone level should be obtained, and if moderately elevated, it should be followed by a plasma free testosterone level. A total testosterone level greater than 200 ng per dL (6.94 nmol per L) should prompt evaluation for an androgen-secreting tumor. Further workup is guided by history and physical examination, and may include thyroid function tests, prolactin level, 17-hydroxyprogesterone level, and corticotropin stimulation test. Treatment includes hair removal and pharmacologic measures. Shaving is effective but needs to be repeated often. Evidence for the effectiveness of electrolysis and laser therapy is limited. In patients who are not planning a pregnancy, first-line pharmacologic treatment should include oral contraceptives. Topical agents, such as eflornithine, may also be used. Treatment response should be monitored for at least six months before making adjustments.

Endocrine causes of calcium disorders.

Endocrine diseases that may cause hypercalcemia and hypocalcemia include hyperparathyroidism, hypoparathyroidism, thyroid disorders, hyperadrenocorticism, hypoadrenocorticism, and less commonly pheochromocytoma and multiple endocrine neoplasias. The differential diagnosis of hypercalcemia may include malignancy (lymphoma, anal sac carcinoma, and squamous cell carcinoma), hyperparathyroidism, vitamin D intoxication, chronic renal disease, hypoadrenocorticism, granulomatous disorders, osteolysis, or spurious causes. Hypocalcemia may be caused by puerperal tetany, pancreatitis, intestinal malabsorption, ethlyene glycol intoxication, acute renal failure, hypopararthyroidism, hypovitaminosis D, hypomagnesemia, and low albumin. This article focuses on the endocrine causes of calcium imbalance and provides diagnostic and therapeutic guidelines for identifying the cause of hypercalcemia and hypocalcemia in veterinary patients.

Pancreatic nonfunctioning neuroendocrine tumor with the main pancreatic duct obstruction presenting as excessive hyperglycemia: a case report and review of the literature.

We present the case of a 65-year-old man with a pancreatic nonfunctioning neuroendocrine tumor causing main pancreatic duct obstruction that presented as excessive hyperglycemia. We considered the tumor elicited worsening of diabetes in this case, and we performed review of the relevant literature.

Paraneoplastic syndrome of inappropriate antidiuretic hormone mimicking limbic encephalitis.

OBJECTIVE: To compare the features of paraneoplastic syndrome of inappropriate antidiuretic hormone with those of limbic encephalitis. DESIGN: Case study. SETTING: Academic medical center. PATIENT: A 46-year-old woman with progressive memory impairment, hyponatremia, and seizures. INTERVENTIONS: Magnetic resonance imaging of the brain, fluoro-2-deoxyglucose positron emission tomography of the body, and immunohistochemical analysis of a resected tumor. RESULTS: Though the patient presented with clinical features of classic limbic encephalitis, magnetic resonance imaging, electroencephalogram, and cerebrospinal fluid analysis findings were unremarkable. Her chronic hyponatremia was ultimately found to be due to ectopic secretion of antidiuretic hormone by a neuroendocrine tumor with Merkel cell carcinoma phenotype. CONCLUSIONS: Patients presenting with memory impairment, seizures, and hyponatremia should undergo a thorough workup for occult malignancy. In addition to considering classic immune-mediated paraneoplastic limbic encephalitis, the ectopic secretion of antidiuretic hormone should be included in the differential diagnosis.

Endocrine oncology in pregnancy.

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.

Skin lesions in hereditary endocrine tumor syndromes.

OBJECTIVE: To review the main cutaneous manifestations of hereditary endocrine tumor syndromes and discuss currently known molecular mechanisms involved in their pathogenesis. METHODS: On the basis of our collective experience and a comprehensive MEDLINE literature search of the English-language literature published between January 1957 and September 2010 using the search terms "skin," "cutaneous," "multiple endocrine neoplasia," "Carney complex," and "McCune-Albright syndrome," we reviewed the dermatologic findings in multiple endocrine neoplasia type 1 and type 2, Carney complex, and McCune-Albright syndrome. RESULTS: Although the category of hereditary endocrine tumor syndromes consists of a broad spectrum of conditions, only the aforementioned few are prominently associated with cutaneous features. Because the cutaneous findings associated with these diseases are generally benign, they are often ignored or dismissed as ancillary findings in the context of severe systemic involvement. Accordingly, the pertinent literature is relatively scarce and often fails to provide a comprehensive insight about this issue. Nevertheless, timely recognition of such dermatologic manifestations may have a critical role in the early diagnosis and appropriate management of the related syndromes. Moreover, specific genotype-phenotype correlations may convey important prognostic implications. CONCLUSION: Many physicians are unfamiliar with the cutaneous findings in the hereditary endocrine tumor syndromes described in this review. Nonetheless, knowledge of their existence can have a major role in establishing an early diagnosis of these syndromes and determining the patient's prognosis.

Solitary concomitant endocrine tumor and ductal adenocarcinoma of pancreas.

Pancreatic tumors with combined exocrine and endocrine features are rare. Most reported cases are classified as mixed exocrine and endocrine carcinoma of the pancreas. We report the first case of solitary concomitant endocrine tumor and ductal adenocarcinoma of the pancreas. A 58-year-old patient was admitted for uncontrolled diabetes mellitus and body weight loss. The tumor was fortuitously discovered in the pancreatic tail after a tumor survey panel. Grossly, the solitary tumor had a central fibrous band that clearly divided it into two parts. On microscopic examination, the tumor contained both endocrine and exocrine components distinctly separated by the central fibrous band. The exocrine part showed a poorly-differentiated adenocarcinoma. The endocrine part was strongly immunoreactive to chromogranin, synaptophysin and glucagon. We reviewed the literature on pancreatic tumors with combined exocrine and endocrine features. A simple classification for this group of neoplasms is suggested, including five types: amphicrine, mixed, collision, solitary concomitant and multiple concomitant.

Cutaneous manifestations of endocrine neoplasia.

Skin serves as a window to the wellbeing and disease in a person. The recognition of cutaneous markers of endocrine neoplasia can allow for the early diagnosis of tumors, for early treatment and ultimately prevention of morbidity and mortality secondary to malignancy. The following review outlines the various endocrine neoplasias which can present with cutaneous manifestations. The pathogenesis and general manifestations are reviewed as well as the cutaneous manifestations of the endocrine neoplasia. Diagnosis and management are discussed. A summary of the familial endocrine neoplastic syndromes, including the six Multiple Endocrine Neoplasia Syndromes are reviewed. A current understanding of this subject will allow for better diagnosis and recognition of endocrine tumors as they present with skin signs and symptoms.

Main pancreatic duct obstruction due to a small nonfunctioning endocrine tumor of the pancreas.

A 65-year-old Japanese male was referred to our hospital for evaluation of a main pancreatic duct obstruction. Two months previously, he had suffered an attack of acute pancreatitis that was resolved with conservative treatment. Dynamic contrast-enhanced study by multidetector row computed tomography revealed a well-enhanced 5 x 5 mm mass in the head of the pancreas with dilatation of the main pancreatic duct in the body and tail. On endoscopic retrograde pancreatography, obstruction of the main pancreatic duct in the head of the pancreas was noted. Pancreatic juice cytology was nondiagnostic. Endoscopic ultrasonography demonstrated a well-defined hypoechoic mass, about 5 mm in size, with distal main pancreatic duct dilatation. The patient underwent elective pylorus-preserving pancreaticoduodenectomy. Pathological examination revealed a well-differentiated endocrine tumor of the pancreas of uncertain behavior, 5 mm in size. Immunohistochemically, the tumor was diffusely positive for chromogranin A and synaptophysin, and focally it was positive for insulin, glucagon, and CA19-9; it was negative for gastrin. The final diagnosis was main pancreatic duct obstruction secondary to a nonfunctioning endocrine tumor of the pancreas of uncertain behavior. Of note, a small nonfunctioning endocrine tumor of the pancreas is important in the differential diagnosis of main pancreatic duct obstruction demonstrated by radiographic examinations.

Endoscopic ultrasound-guided fine-needle aspiration diagnosis of clear-cell pancreatic endocrine neoplasm in a patient with von Hippel-Lindau disease: a case report.

The cytologic findings of a clear-cell pancreatic endocrine neoplasm (PEN) diagnosed by endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) occurring in a 29-year-old man with von Hippel-Lindau (VHL) syndrome are described. Imaging studies showed multiple pancreatic masses and cysts, a single liver lesion, and pulmonary and renal cysts. Cytologic features of this clear-cell PEN included the presence of large sheets and rounded clusters of polygonal neoplastic cells with relatively abundant cytoplasm containing numerous, small, sharply-demarcated vacuoles that occasionally indented nuclei and gave the cells a "frothy" appearance. Mild anisonucleosis was present and nucleoli were visible. Rare single cells and stripped nuclei were seen. Small vessels transgressed tumor cell sheets. These cytologic findings are distinct from those of typical endocrine neoplasms, and bear resemblance to the cytologic features of renal cell carcinoma metastatic to the pancreas. To the best of our knowledge, this is the first detailed report of the EUS-FNA cytologic findings of a clear-cell PEN associated with VHL syndrome. We believe that the distinctive and characteristic cytologic features, together with immunohistochemical studies, can allow a preoperative cytologic diagnosis of this highly unusual pancreatic lesion and avoid possible confusion with other clear-cell neoplasms in the pancreas, particularly metastatic renal cell carcinoma.

Endocrine incidentalomas.

OBJECTIVES: Endocrine incidentalomas are very common in the practice of every physician, mostly primary care and family physicians. Incidentalomas are discovered in the thyroid, pituitary and adrenal glands during imaging studies performed for non-endocrine reasons. The aim of this review article is to familiarise health professionals with all three endocrine incidentalomas, and give some guidance on how to initiate the right endocrine workup. METHODS: We reviewed the most pertinent literature published on this topic through PubMed and Medline. We also discussed our own approach to incidentalomas in the endocrine clinic at Thomas Jefferson Hospital in Philadelphia. RESULTS/CONCLUSIONS: Thyroid incidentalomas are very common, with a prevalence close to 50% on imaging studies. Thyroid-stimulating hormone (TSH) is the first test to obtain; if not suppressed, next step is fine-needle aspiration biopsy of any nodule above 1 cm and/or with suspicious ultrasound characteristics. Adrenal incidentalomas have a prevalence of almost 5%. All adrenal nodules above 4 cm should be resected. Regardless of the size, a workup for pheochromocytoma should always be done. Only hypertensive patients should be screened for primary hyperaldosteronism. Pituitary incidentalomas are also common, with a prevalence of 10-20%. All patients with pituitary masses should have a workup for hormonal hypersecretion. Only patients with macroadenomas will have additional screening for hypopituitarism and visual field defects. All hyperfunctioning adenomas are resected except prolactinomas which are treated medically. Similarly, if a macroadenoma is causing hypopituitarism or visual deficit, surgery should also be considered.