Autocrine parathyroid hormone-like hormone promotes intrahepatic cholangiocarcinoma cell proliferation via increased ERK/JNK-ATF2-cyclinD1 signaling.

BACKGROUND AND AIMS: Intrahepatic cholangiocarcinoma (ICC) is an aggressive tumor with a high fatality rate. It was recently found that parathyroid hormone-like hormone (PTHLH) was frequently overexpressed in ICC compared with non-tumor tissue. This study aimed to elucidate the underlying mechanisms of PTHLH in ICC development. METHODS: The CCK-8 assay, colony formation assays, flow cytometry and a xenograft model were used to examine the role of PTHLH in ICC cells proliferation. Immunohistochemistry (IHC) and western blot assays were used to detect target proteins. Luciferase reporter, chromatin immunoprecipitation (ChIP) and DNA pull-down assays were used to verify the transcription regulation of activating transcription factor-2 (ATF2). RESULTS: PTHLH was significantly upregulated in ICC compared with adjacent and normal tissues. Upregulation of PTHLH indicated a poor pathological differentiation and intrahepatic metastasis. Functional study demonstrated that PTHLH silencing markedly suppressed ICC cells growth, while specific overexpression of PTHLH has the opposite effect. Mechanistically, secreted PTHLH could promote ICC cell growth by activating extracellular signal-related kinase (ERK) and c-Jun N-terminal kinase (JNK) signaling pathways, and subsequently upregulated ATF2 and cyclinD1 expression. Further study found that the promoter activity of PTHLH were negatively regulated by ATF2, indicating that a negative feedback loop exists. CONCLUSIONS: Our findings demonstrated that the ICC-secreted PTHLH plays a characteristic growth-promoting role through activating the canonical ERK/JNK-ATF2-cyclinD1 signaling pathways in ICC development. We identified a negative feedback loop formed by ATF2 and PTHLH. In this study, we explored the therapeutic implication for ICC patients.

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.

[Hypercalcemia related to PTH-rP revealing malignant hepatic epithelioid hemangioendothelioma]. / Une hypercalcémie humorale maligne révélant un hémangioendothéliome épithélioïde du foie.

Hypercalcemia caused by tumor production of PTH-rp occurs most often in cases of squamous cell carcinoma of the lung, aerodigestive tract cancer, gynecological cancer and lymphoma. We report an exceptional case of PTH-rp related to a hepatic hemangioendothelioma. A 70 years-old male admitted for deterioration of the general state. The laboratory investigations revealed hypercalcemia, related to tumor production of PTH-rp. Imaging revealed tumoral hepatic lesions. Histopathological study and immunohistochemistry showed diffuse response for CD31 marker, CK20 (+) with CK7 (-) and hepatocyt antigen (-). The diagnosis of PTH-rp related to hepatic hemangioendothelioma was make. The patient died with recurrence of fatal hypercalcemia. Management of patients presenting with humoral hypercalcemia includes a vigorous search for tumor lesions. Elevated PTH-rp can be a bad prognostic factor. In front of tumoral liver lesions, a hepatic epithelioid hemangioendothelioma must be considered. Immunohistochemistry is necessary to make diagnosis.

Syndromes that Link the Endocrine System and Genitourinary Tract.

The endocrine system and genitourinary tract unite in various syndromes. Genitourinary malignancies may cause paraneoplastic endocrine syndromes by secreting hormonal substances. These entities include Cushing`s syndrome, hypercalcemia, hyperglycemia, polycythemia, hypertension, and inappropriate ADH or HCG production. The most important syndromic scenarios that links these two systems are hereditary renal cancer syndromes with specific genotype/phenotype correlation. There are also some very rare entities in which endocrine and genitourinary systems are involved such as Carney complex, congenital adrenal hyperplasia and Beckwith-Wiedemann syndrome. We will review all the syndromes regarding manifestations present in endocrine and genitourinary organs.

Recurrent solitary fibrous tumor of the pleura with malignant transformation and non-islet cell tumor-induced hypoglycemia due to paraneoplastic overexpression and secretion of high-molecular-weight insulin-like growth factor II.

A 41-year-old man was diagnosed with a solitary fibrous tumor (SFT) of the pleura in the posterior mediastinum. Despite two surgeries for excision, the SFT recurred and progressed with direct invasion of the chest wall and bone metastases. He was hospitalized because of cerebral infarction and presented with recurrent severe hypoglycemia fourteen years later. High-molecular-weight (HMW) insulin-like growth factor II (IGF-II) was identified in the serum and tumor using Western blotting and immunohistochemistry. These findings suggested that the cause of the recurrent severe hypoglycemia was SFT production of HMW IGF-II, a mediator of non-islet cell tumor-induced hypoglycemia (NICTH).

Acromegaly caused by growth hormone-releasing hormone-producing tumors: long-term observational studies in three patients.

We report on three newly diagnosed patients with extracranial ectopic GHRH-associated acromegaly with long-term follow-up after surgery of the primary tumor. One patient with a pancreatic tumor and two parathyroid adenomas was the index case of a large kindred of MEN-I syndrome. The other two patients had a large bronchial carcinoid. The first patient is still in remission now almost 22 years after surgery. In the two other patients GHRH did not normalize completely after surgery and they are now treated with slow-release octreotide. IGF-I normalized in all patients. During medical treatment basal GH secretion remained (slightly) elevated and secretory regularity was decreased in 24 h blood sampling studies. We did not observe development of tachyphylaxis towards the drug or radiological evidence of (growing) metastases. We propose life-long suppressive therapy with somatostatin analogs in cases with persisting elevated serum GHRH concentrations after removal of the primary tumor. Independent parameters of residual disease are elevated basal (nonpulsatile) GH secretion and decreased GH secretory regularity.

Neuroendocrine tumors secreting growth hormone-releasing hormone: Pathophysiological and clinical aspects.

Hypothalamic GHRH is secreted into the portal system, binds to specific surface receptors of the somatotroph cell and elicits intracellular signals that modulate pituitary GH synthesis and/or secretion. Moreover, GHRH is synthesized and expressed in multiple extrapituitary tissues. Excessive peripheral production of GHRH by a tumor source would therefore be expected to cause somatotroph cell hyperstimulation, increased GH secretion and eventually pituitary acromegaly. Immunoreactive GHRH is present in several tumors, including carcinoid tumors, pancreatic cell tumors, small cell lung cancers, endometrial tumors, adrenal adenomas, and pheochromocytomas which have been reported to secrete GHRH. Acromegaly in these patients, however, is uncommon. The distinction of pituitary vs. extrapituitary acromegaly is extremely important in planning effective management. Regardless of the cause, GH and IGF-1 are invariably elevated and GH levels fail to suppress (<1 microg/l) after an oral glucose load in all forms of acromegaly. Dynamic pituitary tests are not helpful in distinguishing acromegalic patients with pituitary tumors from those harbouring extrapituitary tumors. Plasma GHRH levels are usually elevated in patients with peripheral GHRH-secreting tumors, and are normal or low in patients with pituitary acromegaly. Unique and unexpected clinical features in an acromegalic patient, including respiratory wheezing or dyspnea, facial flushing, peptic ulcers, or renal stones sometimes are helpful in alerting the physician to diagnosing non pituitary endocrine tumors. If no facility to measure plasma GHRH is available, and in the absence of MRI evidence of pituitary adenoma, a CT scan of the thorax and abdominal ultrasound could be performed to exclude with good approximation the possibility of an ectopic GHRH syndrome. Surgical resection of the tumor secreting ectopic GHRH should be the logical approach to a patient with ectopic GHRH syndrome. Standard chemotherapy directed at GHRH-producing carcinoid tumors is generally unsuccessful in controlling the activated GH axis. Somatostatin analogs provide an effective option for medical management of carcinoid patients, especially those with recurrent disease. In fact, long-acting somatostatin analogs may be able to control not only the ectopic hormonal secretion syndrome, but also, in some instances, tumor growth. Therefore, although cytotoxic chemotherapy, pituitary surgery, or irradiation still remain available therapeutic options, long-acting somatostatin analogs are now preferred as a second-line therapy in patients with carcinoid tumors and ectopic GHRH-syndrome.

Ectopic adrenocorticotropic hormone-syndrome in medullary carcinoma of the thyroid: a retrospective analysis and review of the literature.

Cushing's syndrome (CS) in medullary thyroid carcinoma (MTC) is rare. Only 50 cases have been reported. We report 10 cases of MTC with ectopic adrenocorticotropic hormone (ACTH)-dependent syndrome (EAS), analyzed retrospectively. Among 1640 patients with MTC, 13 developed EAS (0.7%). In 10 patients CS could unequivoqually be related to MTC (0.6%). CS was always clinically obvious. It revealed MTC in 3 cases and followed diagnosis by an average of 34.5 months in the others. Metastases were often present at diagnosis. Immunohistochemistry with ACTH antibodies was positive in one case. Diagnosis of ectopic CS was established according to clinical and biologic features, and absence of corticotropic adenoma as well as parallel evolution between tumor and CS. Therapy was medical and surgical: anticortisolic drugs alone or in association with somatostatin analogue, somatostatin analogue alone, and bilateral adrenalectomy. Eight patients died within 2 to 30 months, 4 of hypercortisolism complications (3 peritonitis and 1 hypokalaemia), 4 of MTC progression. EAS is a rare complication of MTC. The prognosis is poor because of frequency of metastasis at diagnosis. Persistent hypercortisolism can, by itself, lead to death, and has to be treated specifically.

[Neuro-endocrine tumors of the gastrointestinal tract: epidemiology, classification, prognosis, diagnosis and therapeutic modalities]. / Neuroendokrine Tumoren des Gastrointestinaltraktes.

The neuro-endocrine tumors of the gastrointestinal tract comprise a heterogeneous group of slow-growing malignancies with great differences regarding their localization, tissue of origin and their entopic and ectopic production of hormones. They can be subdivided in carcinoid tumors and endocrine tumors of the pancreas. According to their secreted products they manifest as endocrinological syndromes or as local space-occupying tumors. This review focuses, besides summarizing the available epidemiological data and describing tumor localization and classification, on the differing symptom complexes and the prognosis of the various tumor entities. Furthermore, the value of available diagnostic techniques and the role of different therapeutic modalities like surgery, radiation, biotherapy and cytostatic chemotherapy are discussed.

Symptomatic epidural lipomatosis in ectopic Cushing's syndrome.

We report a case of spinal epidural lipomatosis (SEL) caused by ectopic Cushing's syndrome and give a review of the literature. The most common cause of SEL is prolonged therapy with glucocorticoids, only a very few cases are related to endogenous Cushing's syndrome. The pathophysiological mechanism is not clear but there is a possible role for the autonomic nervous system in the stimulation of growth of epidural fat. Severe neurological symptoms which indicate myelopathy and radiculopathy can occur, but there is often a delay in diagnosis because the non-specific initial symptoms are not recognized. The epidural fat is mostly located in the thoracic and lumbar region. Magnetic resonance imaging can establish the diagnosis rapidly. In patients with severe neurological symptoms, surgical decompression of the myelum and removal of the epidural fat is the treatment of choice. Most patients have partial or complete recovery of neurological deficits after surgical treatment or after discontinuing glucocorticoid therapy; mild cases can also be treated conservatively. Routine imaging for the detection of epidural-located lipomatosis in patients at risk is probably useful.

Ovarian non-small cell neuroendocrine carcinoma with paraneoplastic parathyroid hormone-related hypercalcemia.

Ovarian tumors associated with hypercalcemia due to ectopic secretion of parathyroid hormone (PTH) are extremely rare. A 33-year-old woman presented with a pelvic mass and profound hypercalcemia accompanied by an elevated serum level of PTH. Laparotomy demonstrated a left ovarian tumor that on histological examination was a neuroendocrine carcinoma of non-small cell type admixed with a component of endometrioid adenocarcinoma. After left salpingo-oophorectomy, the serum calcium and PTH levels normalized. The cells of the neuroendocrine carcinoma were positive for neuron-specific enolase, synaptophysin, chromogranin A, and PTH. Hypercalcemia and elevated serum PTH levels recurred during tumor relapse, and the patient died of disease 6 months postoperatively. This is the eleventh case of neuroendocrine carcinoma of non-small cell type associated with surface epithelial neoplasm of the ovary, and the first such tumor to be associated with hypercalcemia.

Ectopic TSH-secreting pituitary adenoma of the vomerosphenoidal junction.

OBJECTIVE: We describe an unusual case of ectopic TSH-secreting pituitary adenoma arising from the vomerosphenoidal junction. CLINICAL PRESENTATION: A 52-Year-old man with a long-standing history of hyperthyroidism was referred to the University Hospital in September 2001 because of increasingly disabling symptoms of nasal obstruction. For the past 18 Years the patient had complained of palpitations, hypertension, weight loss, and nervousness. A presumptive diagnosis of Graves' disease was made. Treatment with methimazole was begun, but the patient was lost to follow-up. On admission, physical examination revealed signs of hyperthyroidism and a large diffuse goiter. Tests of thyroid function showed inappropriate secretion of TSH with hyperthyroidism. Both a TSH-secreting pituitary adenoma and resistance to thyroid hormone could be taken into account. There was no evidence of pituitary tumour by magnetic resonance imaging (MRI), but a large space-occupying lesion involving the nasal cavity and the nasopharynx was incidentally discovered. INTERVENTATION AND TECHNIQUE: Using an endoscopic endonasal approach, the tumour was removed en bloc together with the sphenoid floor, sphenoid rostrum, bony septum, and part of the soft palate mucosa. Histological features and immunophenotype were those of a TSH-secreting tumour. CONCLUSION: Although exceedingly rare, ectopic TSH-secreting pituitary tumour should be borne in mind in cases of inappropriate secretion of TSH with hyperthyroidism and no evidence of pituitary tumour by computed tomography and/or MRI when a mass located along the migration path of the Rathke's pouch is demonstrated by radiological examination. To our knowledge, this is only the second reported case in the literature.

[Pituitary adenomas: neurosurgical treatment]. / Hypophysenadenome: Neurochirurgische Therapie.

Due to their diversity, pituitary adenomas represent an interdisciplinary therapeutic challenge in regard to endocrinology, radiology and neurosurgery. Advanced radiological methods such as magnetic resonance imaging (MRI) and the possibility of three-dimensional reconstruction have profoundly improved surgical planning and intraoperative neuronavigation. With the application of modern surgical techniques like endoscope-assisted microsurgery or pure endoscopic surgery further improvements in the treatment of pituitary adenomas at difficult locations can be expected. Major prognostic factors predicting surgical outcome are extension of the adenoma and invasivity into adjacent structures. Both may be perfectly visualized by high-resolution MRI. The proliferation marker MIB-1 as a parameter of growth-rate and invasivity of pituitary adenomas provides information for postoperative management in terms of additional treatment and follow-up imaging. The current management of pituitary adenomas is discussed according to the different therapeutic options available and new developments are presented.

[Imaging of endocrine tumours of the pancreas]. / Bildgebende Diagnostik von Endokrinen Pankreastumoren.

Islet cell tumors are rare pancreatic or peripancreatic neoplasms that produce and secrete hormones to a variable degree. Neuroendocrine tumors of the pancreas can occur sporadically or in association with multiple endocrine neoplasia type 1 (MEN I). Biologically active neuroendocrine tumors produce early symptoms and are often difficult to diagnose owing to their small dimensions, whereas biologically inactive forms are often large and sometimes found by chance. Imaging has a major role in the preoperative localization of the primary tumor and detection of metastases, providing an anatomic substrate whereas it plays a primary role in the regional staging of these neoplasm, for which surgery is the first and essential therapeutic approach. Several techniques are available including computed tomography (CT), magnetic resonance imaging (MRI), endoscopic ultrasound, intraoperative ultrasound, somatostatin receptor scintigraphy, and arterial stimulation with venous sampling; each with unique advantages and certain limitations. Recent technical advances in Multidetector CT, and dynamic MRI using breath hold sequences have improved the sensitivity of these modalities markedly.

Primary neuroendocrine tumors of the thymus.

Primary neuroendocrine tumors of the thymus are highly aggressive tumors that rarely occur. A little more than 200 cases have been reported, many of which were single case reports. Only a few articles contained modest series from single centers for analysis. A review of 157 cases collected from the major series reported to-date show a clinical pattern with male preponderance (male:female ratio, 3:1) and a mean age of 54 years. Most patients presented with symptoms and signs of local compression. Almost 50% of these tumors were functionally active and were associated with endocrinopathies. Several histologic variants have been described, all with similar ultrastructural features. The biologic behavior of these tumors shows a direct relation to the degree of differentiation. Whenever possible, surgical resection is the treatment of choice as adjuvant therapy is controversial and has been used with variable success. Potential therapies exploit the presence of somatostatin receptors on a variety of these tumors. Use of radiolabeled Octreotide for radionuclide therapy has yielded tumor inhibition in animal models and may have clinical application. Fifty-one percent of the patients survived 3 years, 27% survived 5 years, and less than 10% survived beyond 10 years. Histologic grade, tumor extension, and early detection are the most important factors affecting survival. Other prognostic factors that impact outcome include presence of endocrinopathy, incomplete resectability, nodal status, and presence of distant metastasis.

Analysis of numerical chromosomal aberrations in adrenal cortical neoplasms by fluorescence in situ hybridization.

PURPOSE: We identified numerical chromosomal aberrations in adrenal cortical neoplasms using interphase fluorescence in situ hybridization (FISH) and correlated these aberrations with DNA ploidy and endocrine dysfunction. MATERIALS AND METHODS: Our study included 25 adenomas and 2 carcinomas associated with primary aldosteronism or Cushing's syndrome. Eight normal adrenal tissue samples served as controls. Isolated nuclei from frozen samples were used for FISH and formalin fixed, paraffin embedded tissues from the same materials were analyzed by flow cytometry for DNA ploidy. For FISH we used centromere specific probes for chromosomes 3, 7, 8, 11 and 12. RESULTS: None of the normal adrenal tissues had any numerical chromosomal aberrations in any chromosome analyzed or any abnormal findings on DNA ploidy analysis. Tetrasomy of chromosomes 3, 7, 8, 11 and 12 was detected in 8, 13, 14, 11 and 12 of the 17 adenomas associated with primary aldosteronism, and in 2, 0, 0, 0 and 0 of the 8 associated with Cushing's syndrome, respectively. DNA flow cytometry revealed tetraploidy in 11 of the 17 cases of primary aldosteronism and in 1 of the 8 of Cushing's syndrome. Five diploid adenomas associated with primary aldosteronism also showed tetrasomy in 2 or more chromosomes. One of the 2 carcinomas showed aneuploidy and aneusomy of chromosomes 8, 11 and 12 but the other showed no abnormal peaks on DNA histography and no numerical chromosomal aberrations. CONCLUSIONS: All chromosomes analyzed in adenomas associated with primary aldosteronism frequently showed tetrasomy, whereas few chromosomal abnormalities were detected in adenomas associated with Cushing's syndrome. Our results indicate that DNA tetraploidy is common in adrenal cortical adenomas associated with primary aldosteronism. Interphase FISH strongly supported flow cytometry findings and could provide further information on individual chromosomes.