[Paraneoplastic endocrine syndromes: clinical picture and laboratory diagnostics]. / Paraneoplasztikus endokrin szindrómák: klinikai kép és laboratóriumi diagnosztika.

The term paraneoplastic syndrome refers to the conditions when tumor-related symptoms are not caused by the size, invasion or metastasis of a tumor, but due to soluble mediators produced or an immune reaction induced by a tumor. Paraneoplastic syndromes occur in about 8% of all malignant tumors. Hormone-related paraneoplastic syndromes are termed paraneoplastic endocrine syndromes. In this short synopsis, the main clinical and laboratory characteristics of the most important paraneoplastic endocrine syndromes are presented including humoral hypercalcemia, the syndrome of inappropriate ADH secretion, ectopic ACTH syndrome. Two very rare diseases, paraneoplastic hypoglycemia and tumor-induced osteomalatia are also briefly presented.

Paraneoplastic autoimmune hypophysitis: a novel form of paraneoplastic endocrine syndrome.

Paraneoplastic syndromes are defined by symptoms or signs resulting from damage to organs or tissues that are remote from the site of malignant neoplasms or its metastasis. They are due to tumor secretion of functional hormones or peptides or are related to immune cross-reactivity with the host tissue. In particular, paraneoplastic endocrine syndromes are mainly caused by ectopic hormone production by the tumor such as PTHrP in humoral hypercalcemia in malignancy and ACTH in ectopic ACTH syndrome. Recently, it has been reported that a specific form of hypophysitis is caused as an immune-mediated paraneoplastic syndrome; paraneoplastic autoimmune hypophysitis, in which an ectopic pituitary antigen expression in the tumor evoked autoimmunity against pituitary-specific antigens, resulting in hypophysitis and exhibiting the injury of specific anterior pituitary cells by cytotoxic T cells. This novel clinical entity, paraneoplastic autoimmune hypophysitis consists of several conditions such as anti-PIT-1 hypophysitis and a part of isolated ACTH deficiency and immune checkpoint inhibitor-related hypophysitis with common mechanisms. These conditions can explain at least in part, the underlying mechanisms of acquired specific pituitary hormone deficiencies. In addition, it is important to apply a comprehensive discipline of onco-immuno-endocrinology to understand the pathophysiology and this approach; the expansion and application of immune-mediated paraneoplastic syndrome to endocrine diseases may give a new clue to understand pathophysiology of the autoimmunity against endocrine organs.

Malignancy-related Hypercalcemia Caused by Metameric Cutaneous Metastasis of Parathyroid Hormone-related Protein-producing Bladder Carcinoma with Squamous Cell Differentiation: An Autopsy Case of Cobb Syndrome.

A 74-year-old woman was admitted with hypercalcemia and prolonged disturbance of consciousness. The left buttock to the anterior aspect of the left thigh was swollen and erythematous, with a collection of 1.0-cm large, firm, elastic nodules distributed in a zosteriform pattern in the L1-L4 region. Based on autopsy findings, a very rare case of Cobb syndrome was diagnosed due to a spinal vascular malformation at the Th12-L4 level and L5 vertebral hemangioma. Cobb syndrome-associated cutaneous metastasis extending along the same metamere was complicated by immunohistochemically proven parathyroid hormone-related protein-producing advanced bladder carcinoma in this case.

Endocrine abnormality in paraneoplastic syndrome.

Paraneoplastic syndromes denote rare but notable phenomena caused by the tumour mediated release of bioactive substances. Peptide and non-peptide hormone causes are explored with a particular focus on pathogenesis, symptoms, diagnosis and treatment. Early detection and management of paraneoplastic syndromes can improve morbidly and mortality; definitive treatment remains effective surgical or anti-tumour therapies. Pituitary autoimmunity may provide a novel presentation of paraneoplastic syndromes for which further research is warranted.

Endocrine paraneoplastic syndromes in lung cancer: a respiratory physician's perspective.

Lung malignancy is known to be one of the leading causes of cancer-related mortality. Endocrine paraneoplastic syndromes in lung cancer are common. These are due to secretion of various substances and not because of direct tumour invasion or me-tastasis. These syndromes have also been associated with lung cancer prognosis. This review describes the many endocrine paraneoplastic syndromes seen in lung cancer and narrates their incidence, biology, clinical features, diagnosis, and management.

An Open-label Phase I/IIa Clinical Trial of 11ß-HSD1 Inhibitor for Cushing's Syndrome and Autonomous Cortisol Secretion.

CONTEXT: 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) inhibitors demonstrate antimetabolic and antisarcopenic effects in Cushing's syndrome (CS) and autonomous cortisol secretion (ACS) patients. OBJECTIVE: To confirm the efficacy and safety of S-707106 (11ß-HSD1 inhibitor) administered to CS and ACS patients. DESIGN: A 24-week single-center, open-label, single-arm, dose-escalation, investigator-initiated clinical trial on a database. SETTING: Kyushu University Hospital, Kurume University Hospital, and related facilities. PATIENTS: Sixteen patients with inoperable or recurrent CS and ACS, with mildly impaired glucose tolerance. INTERVENTION: Oral administration of 200 mg S-707106 after dinner, daily, for 24 weeks. In patients with insufficient improvement in oral glucose tolerance test results at 12 weeks, an escalated dose of S-707106 (200 mg twice daily) was administered for the residual 12 weeks. MAIN OUTCOME MEASURES: The rate of participants responding to glucose tolerance impairment, defined as those showing a 25% reduction in the area under the curve (AUC) of plasma glucose during the 75-g oral glucose tolerance test at 24 weeks. RESULTS: S-707106 administration could not achieve the primary endpoint of this clinical trial (>20% of responsive participants). AUC glucose decreased by -7.1% [SD, 14.8 (90% CI -14.8 to -1.0), P = 0.033] and -2.7% [14.5 (-10.2 to 3.4), P = 0.18] at 12 and 24 weeks, respectively. S-707106 administration decreased AUC glucose significantly in participants with a high body mass index. Body fat percentage decreased by -2.5% [1.7 (-3.3 to -1.8), P < 0.001] and body muscle percentage increased by 2.4% [1.6 (1.7 to 3.1), P < 0.001]. CONCLUSIONS: S-707106 is an effective insulin sensitizer and antisarcopenic and antiobesity medication for these patients.

Eritema necrolítico migratorio asociado a glucagonoma / Glucagonoma-related necrolytic migratory erythema

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[Paraneoplastic Cushing's syndrome as cause of refractory hypokalemia]. / Paraneoplastisches Cushing-Syndrom als Ursache von therapierefraktärer Hypokaliämie.

HISTORY: A 58-year-old man presented with refractory hypokalemia and rapid weight gain. On examination, he had high blood pressure, central obesity and bilateral pitting edema. FINDINGS AND DIAGNOSIS: Biochemical tests showed hypokalemic metabolic alkalosis due to ACTH-dependent hypercortisolism. CT of thorax and abdomen revealed a pulmonary and a right adrenal mass. Biopsy of the pulmonary mass led to the diagnosis of an ACTH-producing small cell lung cancer. TREATMENT AND COURSE: Under treatment with ketoconazole and chemotherapy a tumor response was reached and the hypercortisolism was controlled. Since the right adrenal mass remained stationary under chemotherapy, an incidental adrenal adenoma seemed the most likely diagnosis. CONCLUSION: The diagnosis of paraneoplastic Cushing's syndrome can be challenging, since classical clinical features of hypercortisolism may still be absent, even if the underlying cancer is already advanced. Therefore high clinical suspicion is warranted, especially in patients presenting with new-onset refractory hypokalemia, metabolic alkalosis and arterial hypertension.

The Impact of Mild Autonomous Cortisol Secretion on Bone Turnover Markers.

CONTEXT: Several studies have reported increased risk of fragility fractures in patients with mild autonomous cortisol secretion (MACS), discordant to the degree of bone density deterioration. OBJECTIVE: To evaluate the effect of MACS on bone metabolism in patients with adrenal adenomas. DESIGN: Cross-sectional study with prospective enrollment, 2014-2019. SETTING: Referral center. PATIENTS: 213 patients with adrenal adenomas: 22 Cushing syndrome (CS), 92 MACS and 99 nonfunctioning adrenal tumors (NFAT). MAIN OUTCOME MEASURES: Osteocalcin, procollagen I intact N-terminal (PINP), C-terminal telopeptide (CTX), sclerostin. RESULTS: Patients with CS demonstrated lower markers of bone formation compared with patients with MACS and NFAT (CS vs MACS vs NFAT: mean osteocalcin 14.8 vs 20.1 vs 21.3 ng/mL [P < 0.0001]; mean PINP 34.8 vs 48.7 vs 48.5 µg/L [P = 0.003]). Severity of cortisol excess was inversely associated with sclerostin (CS vs MACS vs NFAT: mean sclerostin 419 vs 538 vs 624 ng/L, [P < 0.0001]). In a multivariable model of age, sex, body mass index, cortisol, and bone turnover markers, sclerostin was a significant predictor of low bone mass in patients with MACS (OR 0.63 [CI 95%, 0.40-0.98] for each 100 ng/L of sclerostin increase).After adrenalectomy, osteocalcin, CTX, and sclerostin increased by a mean difference of 6.3 ng/mL, 0.12 ng/mL, and 171 pg/mL (P = 0.02 for all), respectively. CONCLUSIONS: Lower sclerostin level in patients with MACS reflects a reduction in osteocyte function or number associated with exposure to chronic cortisol excess. Increase in bone turnover markers after adrenalectomy suggests restoration of favorable bone metabolism.

Metastatic pheochromocytoma and paraganglioma: Management of endocrine manifestations, surgery and ablative procedures, and systemic therapies.

Metastatic pheochromocytomas and paragangliomas (MPPGs) are rare neuroendocrine tumors. Most patients present with advanced disease that is associated with manifestations of catecholamine release. Surgical resection of the primary tumor and ablative therapies of metastases-whenever possible-may improve clinical outcomes and, perhaps, lengthen the patient's overall survival. Significant steps in understanding the genetic alterations linked to MPPGs and scientific progress made on cancers that share a similar pathogenesis are leading to the recognition of potential systemic therapeutic options. Data derived from clinical trials evaluating targeted therapies such as tyrosine kinase inhibitors, radiopharmaceuticals, immunotherapy, and combinations of these will likely improve the outcomes of patients with advanced and progressive MPPGs. Exemplary of this success is the recent approval in the United States of the high-specific-activity iodine131 meta-iodine-benzylguanidine (MIBG) for patients with unresectable and progressive MPPGs that express the noradrenaline transporter. This review will discuss the therapeutic approaches for patients with MPPGs.

Unusual Imaging Findings Associated with Germ Cell Tumors.

Germ cell tumors, because they contain immature and mature elements, can differentiate into different tissue types. They can exhibit unusual imaging features or manifest in a syndromic fashion. The authors describe these features and assign them to one of the following categories: (a) unusual manifestations of metastatic disease (growing teratoma syndrome, choriocarcinoma syndrome, ossified metastases, and gliomatosis peritonei); (b) autoimmune manifestations (sarcoidlike reaction and paraneoplastic syndromes); (c) endocrine syndromes (sex hormone production, struma ovarii, and struma carcinoid); or (d) miscellaneous conditions (ruptured dermoid cyst, squamous cell carcinoma arising from a mature teratoma, Currarino triad, fetus in fetu, pseudo-Meigs syndrome, and pancreatitis). Rare conditions associated with germ cell tumors demonstrate characteristic imaging findings that can help lead to the appropriate diagnosis and management recommendations. When evaluating for potential metastatic disease, alternative benign diagnoses should be considered (eg, growing teratoma syndrome, ossified metastases, ruptured dermoid cyst, gliomatosis peritonei, and sarcoidlike reaction), which may impact management. Germ cell tumors may also lead to life-threatening complications such as extensive hemorrhage from choriocarcinoma metastases or the rupture of mature teratomas, cases in which timely diagnosis is crucial. Autoimmune and endocrine manifestations such as paraneoplastic encephalitis, autoimmune hemolytic anemia, and hyperthyroidism may occur owing to the presence of germ cell tumors and can create a diagnostic dilemma for clinicians. Knowledge of the syndromic and unusual imaging findings associated with germ cell tumors helps guide appropriate management. ©RSNA, 2019.

Paraneoplastic syndromes in cancers of unknown primary: An unknown field for oncologists.

Paraneoplastic syndromes are signs or symptoms that result from tissue damage at locations remote from tumour sites. Paraneoplastic syndromes associated with cancer of unknown primary (CUP) are not well recognized as they are rarely reported. These syndromes can impair various organ functions and include endocrine, neurologic, dermatologic, rheumatologic, hematologic and several other system alterations. To our knowledge, the association between the histological CUP type and the paraneoplastic syndrome has never been assessed. In some instances, paraneoplastic syndromes can become the major clinical problems determining survival. However, they can also herald earlier the occurrence of CUP in patients with asymptomatic tumors. In this article, we review the available literature of CUP patients presenting paraneoplastic syndromes by trying to collect all available published cases during the last three decades. One additional goal of this article is to make practicing oncologists aware of the coexistence of paraneoplastic syndromes in patients with CUP.

IL-6-producing Renal Cell Carcinoma Causing Renal and Endocrine Paraneoplastic Syndromes.

An 83-year-old man with stable chronic kidney disease (CKD) exhibited a sudden increase in urinary N-acetyl-ß-D-glucosaminidase and protein excretion, suggesting aggravated kidney damage. Simultaneously, he lost diabetic control, requiring up to 54 units of insulin daily. A detailed examination revealed the presence of renal cell carcinoma, which was surgically resected and confirmed to be interleukin-6-positive by immunohistochemistry. Postoperatively, his uni-nephrectomy necessitated hemodialysis, but the patient's insulin resistance was ameliorated; no medication was required to control diabetes, suggesting that the tumor had caused the insulin resistance. This report describes a case of a tumor secreting interleukin-6, which affects both the control of diabetes and CKD progression.

[CME: Paraneoplastic Endocrine Syndromes]. / CME: Paraneoplastische endokrine Syndrome.

CME: Paraneoplastic Endocrine Syndromes Abstract. Paraneoplastic endocrine syndromes are caused by ectopic hormone production by malignant tumor cells. Knowledge of paraneoplastic endocrine syndromes may allow a timely diagnosis of the underlying cancer at a treatable stage and, on the other hand, appropriate treatment of the endocrine manifestations reduces morbidity and mortality of the affected patients. The most common endocrine syndromes are paraneoplastic hypercalcaemia, caused by the secretion of PTHrP, and hyponatremia, caused by the inadequate secretion of ADH. Although there may be clinical symptoms like fatigue, nausea/vomiting and renal insufficiency for hypercalcaemia and gait disturbances and mental alterations for hyponatremia, the diagnosis must be confirmed by laboratory testing and prompt the search for associated tumors.

Endocrine paraneoplastic syndromes in lung cancer.

Paraneoplastic syndromes are defined as a combination of clinical disorders associated with malignant diseases that are caused by the secretion of various substances by the tumor without, however, being caused by the direct growth and infiltration of the primary tumor, or due to the development of distant metastases. Despite the fact that lung cancer represents the number one cause of death from cancer worldwide, the new methods of treatment increase patient survival and the incidence of paraneoplastic syndromes. The most important ones of these are humoral hypercalcemia of malignancy, syndrome of inappropriate antidiuretic hormone, hyponatremia of malignancy, ectopic Cushing's syndrome, carcinoid syndrome, and hypoglycemia and are usually a poor prognostic marker. Early diagnosis of those syndromes is achieved using specific criteria and may lead to early diagnosis of the underlying malignancy. It is essential to treat them with the overriding objective of improving the patients' quality of life.

An unusual case of ectopic corticotrophin-releasing hormone syndrome caused by an adrenal noncatecholamine-secreting pheochromocytoma: a case report.

BACKGROUND: Pheochromocytoma, especially for noncatecholamine-secreting pheochromocytoma, is an extremely rare cause of ectopic corticotrophin-releasing hormone (CRH) syndrome. CASE PRESENTATION: A 27-year-old Chinese woman was administered dexamethasone for a skin allergy, but her general condition rapidly deteriorated over a month. She was subsequently hospitalized for typical clinical features of Cushing's syndrome. Endocrinological investigation confirmed severe hypercortisolism along with elevated plasma adrenocorticotropin hormone (ACTH). However, magnetic resonance imaging (MRI) revealed no pituitary adenoma. Abdominal contrast-enhanced computed tomography (CT) revealed a 6.5 cm heterogeneous right adrenal mass with mildly contrast enhancement. The tumor was found during a routine physical check-up at a local hospital 16 months ago; however, the patient did not have any symptoms and did not seek further medical attention at that time. Laparoscopic resection of the right adrenal tumor led to a rapid remission of Cushing's syndrome. Based on pathological findings and the presence of normal catecholamine metabolites in her serum and urine, the patient was diagnosed with noncatecholamine-secreting pheochromocytoma. Immunohistochemical staining of the adrenal tumor revealed positive staining for CRH and negative staining for ACTH. CONCLUSIONS: This is an extremely rare case of ectopic CRH syndrome caused by an adrenal noncatecholamine-secreting pheochromocytoma. Both ectopic ACTH syndrome and ectopic CRH syndrome should be considered in patients presenting with ACTH-dependent Cushing's syndrome caused by extrapituitary diseases.

Preoperative medical treatment in Cushing's syndrome: frequency of use and its impact on postoperative assessment: data from ERCUSYN.

BACKGROUND: Surgery is the definitive treatment of Cushing's syndrome (CS) but medications may also be used as a first-line therapy. Whether preoperative medical treatment (PMT) affects postoperative outcome remains controversial. OBJECTIVE: (1) Evaluate how frequently PMT is given to CS patients across Europe; (2) examine differences in preoperative characteristics of patients who receive PMT and those who undergo primary surgery and (3) determine if PMT influences postoperative outcome in pituitary-dependent CS (PIT-CS). PATIENTS AND METHODS: 1143 CS patients entered into the ERCUSYN database from 57 centers in 26 countries. Sixty-nine percent had PIT-CS, 25% adrenal-dependent CS (ADR-CS), 5% CS from an ectopic source (ECT-CS) and 1% were classified as having CS from other causes (OTH-CS). RESULTS: Twenty per cent of patients took PMT. ECT-CS and PIT-CS were more likely to receive PMT compared to ADR-CS (P < 0.001). Most commonly used drugs were ketoconazole (62%), metyrapone (16%) and a combination of both (12%). Median (interquartile range) duration of PMT was 109 (98) days. PIT-CS patients treated with PMT had more severe clinical features at diagnosis and poorer quality of life compared to those undergoing primary surgery (SX) (P < 0.05). Within 7 days of surgery, PIT-CS patients treated with PMT were more likely to have normal cortisol (P < 0.01) and a lower remission rate (P < 0.01). Within 6 months of surgery, no differences in morbidity or remission rates were observed between SX and PMT groups. CONCLUSIONS: PMT may confound the interpretation of immediate postoperative outcome. Follow-up is recommended to definitely evaluate surgical results.

[Endocrine paraneoplastic syndromes]. / Endokrine paraneoplastische Syndrome.

Endocrine paraneoplastic syndromes result from the production of bioactive substances from neoplastic cells, of endocrine or neuroendocrine origin. Typically these are located in the lungs, the gastrointestinal tract, pancreas, thyroid gland, adrenal medulla, skin, prostate or breast. In endocrine paraneoplastic syndromes the secretion of peptides, amines or other bioactive substances is always ectopic and not related to the anatomical source. The clinical presentation, however, is indistinguishable from a suspected eutopic endocrine tumor posing a diagnostic challenge. The most common endocrine paraneoplastic syndromes are based on the secretion of antidiuretic hormone (ADH) resulting in hyponatremia, secretion of adrenocorticotropic hormone (ACTH) or rarely corticotropin-releasing hormone (CRH) resulting in Cushing syndrome as well as secretion of growth hormone-releasing hormone resulting in acromegaly. Paraneoplastic endocrine syndromes mainly occur in highly malignant tumors; however, the development of these tumors does not necessarily correlate with tumor stage, malignant potential or prognosis. As endocrine paraneoplastic syndromes are a rare complication, there are hardly any evidence-based therapeutic recommendations. Treatment of the underlying tumor is the first choice and in a palliative setting symptomatic therapy is possible.