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.

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.

[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.

Humoral Hypercalcemia in Uterine Cancers: A Case Report and Literature Review.

BACKGROUND Paraneoplastic hypercalcemia is a well-described complication associated with a variety of malignancies. However, its incidence in gynecological malignancies is low. CASE REPORT A 53-year-old woman presented with progressive abdominal distention and irregular vaginal bleeding of several weeks' duration. A contrast CT abdomen and pelvis was significant for a mass in the lower uterine/cervical region, multiple peritoneal and omental masses, enlarged pelvic and paraaortic lymph nodes, and large-volume ascites. A pelvic exam revealed a fungating vaginal mass, with biopsy showing a high-grade tumor with immunohistochemical staining positive for vimentin, CD10, and cyclin D1, consistent with endometrial stromal sarcoma. During her hospitalization, the patient became increasingly lethargic. Workup showed severe hypercalcemia and evidence of acute kidney injury. The patient did not have evidence of bony metastatic disease on imaging studies. Further laboratory evaluation revealed an elevated PTHrP of 301 pg/mL (nl 14-27), a depressed PTH level of 3 pg/mL (nl 15-65), and a depressed 25-OH vitamin D level of 16 ng/mL (nl 30-100), consistent with humoral hypercalcemia of malignancy. The patient was treated with pamidronate, calcitonin, and intravenous fluids. She eventually required temporary hemodialysis and denosumab for refractory hypercalcemia, which improved her electrolyte abnormalities and clinical status. CONCLUSIONS Uterine malignancies of various histologies are increasingly recognized as a cause of humoral hypercalcemia. They are an important differential diagnosis in a woman with hypercalcemia and abnormal vaginal bleeding or abdominal symptoms.

Treatment of primary intracranial germ cell tumors: Single center experience with 42 clinically diagnosed cases.

BACKGROUND AND OBJECTIVE: Primary intracranial germ cell tumors (GCTs) are a class of heterogeneous tumors. Surgery can quickly relieve tumor compression and provide histological diagnosis. It is very difficult to treat some patients who are unable to be pathologically diagnosed. We aimed to analyze clinically diagnosed GCTs patients. METHODS: Patients clinically diagnosed as primary intracranial GCTs were included in this study. RESULTS: From 2002 to 2015, 42 patients clinically diagnosed with primary intracranial GCTs received chemotherapy and/or radiotherapy. Patients were assigned to diagnostic chemotherapy group (25 cases), diagnostic radiotherapy group (5 cases) and gamma knife radiosurgery group (12 cases) based on their initial anti-tumor therapy. The 5-year survival rates were 85.8%, 75.0% and 63.6%, respectively. There were no statistically significant difference (p value = 0.44). Patients were assigned to the group (30 cases) with secretory tumors and the group (12 cases) with non-secretory tumors based on their levels of tumor makers. The 5- year survival rates were 80.7% and 68.6%, respectively. There were no statistically significant difference (p value = 0.49).The major adverse reactions were grade III - IV bone marrow suppression with an incidence of 35.2% and grade II- III nausea/vomiting with an incidence of 45.8%. CONCLUSION: Surgical removal of tumor or biopsy is recognized as the most accurate method to determine the pathological property of tumor. But for some patients who can not be pathologically diagnosed, they can receive comprehensive treatments such as chemotherapy combined with radiotherapy, and some of them can still have good responses.

Actualización diagnóstica y terapéutica de los tumores neuroendocrinos bien diferenciados / Updates on well-differentiated neuroendocrine tumors

Los tumores neuroendocrinos bien diferenciados (TNE) son neoplasias malignas poco frecuentes que incluyen tanto los carcinoides como los tumores neuroendocrinos pancreáticos (TNEP). Estos tumores se asocian en general con metástasis en el momento del diagnóstico. Si bien la supervivencia prolongada es frecuente, la supervivencia global se reduce de manera acentuada cuando los pacientes presentan síntomas, así como cuando el tumor progresa pese a la terapia con análogos de la somatostatina. Aunque estos fármacos pueden contribuir a tratar la sintomatología y ralentizar el crecimiento tumoral, en especial en neoplasias de bajo grado, no se ha demostrado que el tratamiento a largo plazo sea eficaz en estos pacientes. Recientemente, los ensayos preclínicos y dos estudios de fase III han brindado avances promisorios, sobre todo en el tratamiento de los TNEP. La aparición de terapias dirigidas contra el factor de crecimiento vascular endotelial (VEGF), los inhibidores de la diana de la rapamicina (mTOR) y el tratamiento con receptores de péptidos radiomarcados se ha asociado con eficacia moderada, pero pueden vincularse con toxicidad relevante. En esta revisión, discutiremos los ensayos recientes y las terapias actuales de los TNE bien diferenciados.

Actualización diagnóstica y terapéutica de los tumores neuroendocrinos bien diferenciados / Updates on well-differentiated neuroendocrine tumors

Los tumores neuroendocrinos bien diferenciados (TNE) son neoplasias malignas poco frecuentes que incluyen tanto los carcinoides como los tumores neuroendocrinos pancreáticos (TNEP). Estos tumores se asocian en general con metástasis en el momento del diagnóstico. Si bien la supervivencia prolongada es frecuente, la supervivencia global se reduce de manera acentuada cuando los pacientes presentan síntomas, así como cuando el tumor progresa pese a la terapia con análogos de la somatostatina. Aunque estos fármacos pueden contribuir a tratar la sintomatología y ralentizar el crecimiento tumoral, en especial en neoplasias de bajo grado, no se ha demostrado que el tratamiento a largo plazo sea eficaz en estos pacientes. Recientemente, los ensayos preclínicos y dos estudios de fase III han brindado avances promisorios, sobre todo en el tratamiento de los TNEP. La aparición de terapias dirigidas contra el factor de crecimiento vascular endotelial (VEGF), los inhibidores de la diana de la rapamicina (mTOR) y el tratamiento con receptores de péptidos radiomarcados se ha asociado con eficacia moderada, pero pueden vincularse con toxicidad relevante. En esta revisión, discutiremos los ensayos recientes y las terapias actuales de los TNE bien diferenciados.(AU)

[Ectopic hormone secretion by neuroendocrine tumors]. / Ektope Hormonsekretion bei neuroendokrinen Tumoren.

Ectopic hormone production is a rare complication in neuroendocrine tumors. Tumors producing corticotropin-releasing hormone (CRH) and adrenocorticotropic hormone (ACTH) are most commonly observed, leading to the classical symptoms of Cushing's syndrome. Additionally, a very low percentage of neuroendocrine tumors can produce growth hormone-releasing hormone (GHRH) leading to classical features of acromegaly. Moreover, ectopic antidiuretic hormone (ADH) secretion has been described in neuroendocrine tumors presenting as hyponatremia due to the syndrome of inappropriate ADH secretion. Other ectopic hormone secretions, such as paraneoplastic gonadotropin release are rarely observed. Ectopic hormone secretion is not usually associated with a detectable pituitary mass and diagnosis is based on the measurement of circulating peptides. This is frequently assisted by imaging techniques, such as somatostatin receptor scintigraphy. Therapeutically a curative approach is the primary goal but in advanced tumors palliative treatment aims to control symptoms with the help of specific antihormonal compounds, such as somatostatin analogues.

Pancreatic endocrine tumors.

Pancreatic endocrine tumors have been steadily growing in incidence and prevalence during the last two decades, showing an incidence of 4-5/1,000,000 population. They represent a heterogeneous group with very varying tumor biology and prognosis. About half of the patients present clinical symptoms and syndromes related to substances released from the tumors (Zollinger-Ellison syndrome, insulinoma, glucagonoma, etc) and the other half are so-called nonfunctioning tumors mainly presenting with symptoms such as obstruction, jaundice, bleeding, and abdominal mass. Ten percent to 15% of the pancreatic endocrine tumors are part of an inherited syndrome such as multiple endocrine neoplasia type 1 (MEN-1), von Hippel-Lindau (VHL), neurofibromatosis, or tuberousclerosis. The diagnosis is based on histopathology demonstrating neuroendocrine features such as positive staining for chromogranin A and specific hormones such as gastrin, proinsulin, and glucagon. Moreover, the biochemical diagnosis includes measurement of chromogranins A and B or specific hormones such as gastrin, insulin, glucagon, and vasoactive intestinal polypeptide (VIP) in the circulation. In addition to standard localization procedures, radiology (computed tomography [CT] scan, magnetic resonance imaging [MRI], ultrasound [US]), somatostatin receptor scintigraphy, and most recently positron emission tomography with specific isotopes such as (11)C-5 hydroxytryptamin ((11)C-5-HTP), fluorodopa and (68)Ga-1,4,7,10-tetra-azacyclododecane-N,N',N″,N‴-tetra-acetic acid (DOTA)-octreotate are performed. Surgery is still one of the cornerstones in the management of pancreatic endocrine tumors, but curative surgery is rarely obtained in most cases because of metastatic disease. Debulking and other cytoreductive procedures might facilitate systemic treatment. Cytotoxic drugs, biological agents, such as somatostatin analogs, alpha interferons, mammalian target of rapamycin (mTOR) inhibitors and tyrosine kinase inhibitors are routinely used. Tumor-targeted radioactive treatment is available in many centres in Europe and is effective in patients with tumors that express high content of somatostatin receptors type 2 and 5. In the future, treatment will be based on tumor biology and molecular genetics with the aim of so-called personalized medicine.

[Ectopic hormonal syndrome].

Ectopic hormonal syndrome, the most common cause of paraneoplastic syndrome, is due to an inappropriate secretion of peptide hormones by neoplasms derived from non-endocrine tissue, often discovered even by an occult neoplasm. The diagnosis of ectopic hormonal syndrome is established based on the following criteria;1. abnormal clinical signs and symptoms and/or inappropriate hormonal secretion associated with tumors;2. the abnormal endocrine syndrome and hormone secretion are reversed by tumor resection, and relapsed after tumor recurrence; 3. an arteriovenous gradient for the hormone across the tumor; and 4. the hormone can be detected in the tumor tissue. The treatment of choice for ectopic hormonal syndrome is directed at the primary tumor by surgical resection, radiotherapy, or chemotherapy, and the palliative treatment to control excess hormone secretion is effective in alleviation of symptoms.

[Paraneoplastic endocrine syndromes: diagnosis and management]. / Syndromes paranéoplasiques endocriniens: diagnostic et prise en charge.

Paraneoplastic endocrine syndromes define a group of secondary signs and symptoms associated to a neoplasia, independently from the location of the primary tumor or its metastases. Paraneoplastic or ectopic endocrine syndromes usually result from aberrant hormone precursors or hormone-like substances by tumours. Knowledge of paraneoplastic endocrine complications is important both for the early diagnosis of neoplasia and the prognosis of the patient. In this review we discuss almost all reported paraneoplastic endocrine syndromes. We analyze their prevalence, etiology, laboratory diagnosis and treatment.

Paraneoplastic syndromes in patients with urological malignancies.

INTRODUCTION: Paraneoplastic syndromes (PNS) may represent the main clinical problem in cancer patients; however, the knowledge of their clinical aspect remains quite poor among urologists. OBJECTIVE: To provide urologists with an overview on main clinical aspects of PNS that have been reported to be associated to urological cancers. METHODS: Literature search of peer-reviewed papers published by July 2008. RESULTS: All genitourinary tumors can cause a PNS, and renal cell carcinoma is the most frequent urological malignancy involved. Prostate cancer is the second urological tumor associated with PNS which, conversely, are uncommon in bladder cancer and rare in testicular cancer. Tumor neuroendocrine differentiation is involved in most endocrine PNS. Neurologic PNS are very uncommon but may dominate the clinical picture and need a high suspicion index to be recognized. Important advances have been made on radionuclide scan methods in order to detect the primary tumor. The most effective treatment strategy is always represented by the radical therapy of the underlying cancer, but specific therapeutic options are sometimes available. CONCLUSIONS: Endocrine PNS are frequently associated with urological cancers, especially renal and prostate carcinoma. PNS have been rarely reported in association with cancers of bladder, urethra and testicle.

Paraneoplastic Cushing's syndrome as the first sign of progression of prostate cancer.

Cushing's syndrome accompanying the small cell de-differentiation of the prostatic adenocarcinoma is a relatively rare clinical entity, associated with poor overall prognosis. Despite several treatment options available, there is still no effective standard therapy for this clinical condition. Herein, we report two patients with prostate cancer presenting with clinical and laboratory features of Cushing's syndrome as the first sign of disease progression (Ref. 4). Full Text (Free, PDF) www.bmj.sk.

[Beta-hCG producing urothelial carcinoma of the urinary bladder: a case report].

A 74-year-old man visited our hospital presenting with pollakisuria. Cystoscopy revealed a bladder cancer with necrotic tissue. The patient was initially treated by transurethral resection of bladder tumor (TUR-Bt). Pathologically, the tumor was shown to be a carcinoma of bladder with human chorionic gonadotropin (hCG) positivity. After TUR-Bt, chemotherapy with M-VAC (methotrexate, vinblastine, adriamycine and cisplatin) was performed. This patient is still alive eight months after resection. To our knowledge, there are 37 cases of beta-hCG-producing urothelial carcinoma of the urinary bladder reported in the Japanese literature.

Multimodality management of a polyfunctional pancreatic endocrine carcinoma with markedly elevated serum vasoactive intestinal polypeptide and calcitonin levels.

We present an unusual case of a 52-year-old woman with severe, uncontrollable, refractory diarrhea attributable to pancreatic endocrine carcinoma (ECA) with markedly elevated serum vasoactive intestinal polypeptide (VIP) and calcitonin levels. After initial correction of fluid and electrolyte abnormalities, the patient was treated with high-dose octreotide. Shortly thereafter, due to the intractable nature of her diarrhea, she underwent cytoreductive hepatic surgery. The pancreatosplenectomy specimen showed a poorly differentiated ECA of the distal pancreas, immunoreactive for synaptophysin, CD56, and S100 protein, with morphologically similar hepatic and lymph node metastases. Postoperatively, her diarrhea improved, along with decline in serum VIP and calcitonin levels. Systemic chemotherapy with etoposide and cisplatin did not result in any radiographic and biochemical improvement. Having radiologically stable disease with depot-octreotide and short-acting octreotide (Sandostatin), she was subjected to peptide receptor radiotherapy with [177Lu-DOTA0,Tyr]octreotate (LuTate) that resulted in marked clinical and biochemical improvement, along with dramatic reduction in the number and size of hepatic metastases. In summary, this is a unique case of metastatic VIP- and calcitonin-secreting pancreatic ECA with dramatic sustained clinical, biochemical, and objective tumor response to peptide receptor radionuclide therapy.