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.

Parathyroid carcinoma occurred in two glands in multiple endocrine neoplasia 1: a report on a rare case.

Primary hyperparathyroidism is the most common hormonal manifestation associated with multiple endocrine neoplasia 1 (MEN1). It is generally caused by parathyroid hyperplasia, and parathyroid carcinoma is rare. Here, we report a case of MEN1 with parathyroid carcinoma in two parathyroid glands causing primary hyperparathyroidism. A 40-year-old man with primary hyperparathyroidism due to MEN1 underwent a total parathyroidectomy. His corrected calcium and intact PTH (i-PTH) serum levels were 10.8 mg/dL and 203 pg/mL, respectively. Although three glands were successfully removed, the left upper parathyroid gland could not be detected. Since the right lower parathyroid lesion had invaded into the thyroid, right lobectomy was performed. A portion of the left lower parathyroid tissue was transplanted into his forearm. The histological findings of the left lower and the right upper parathyroid glands were consistent with hyperplasia while that of the right lower parathyroid gland was parathyroid carcinoma. Since the post-surgical i-PTH levels remained high, the intrathyroidal lesion of the left lobe, which was initally diagnosed as an adenomatous nodule, was suspected to contain parathyroid tumor. A fine needle aspiration of the tumor revealed a high concentration of i-PTH. One week after the first surgery, a left thyroid lobectomy was performed. The pathological diagnosis of the tumor was parathyroid carcinoma. After the surgery, calcium and i-PTH levels were normal. Although it is rare, parathyroid carcinoma should be considered as a cause of hyperparathyroidism in MEN1 patients. Since it is difficult to diagnose parathyroid carcinoma before surgery, intraoperative findings are important for the appropriate treatment.

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.

A Patient With a Thyrotropin-Secreting Microadenoma and Resistance to Thyroid Hormone (P453T).

CONTEXT: Resistance to thyroid hormone (RTH) ß is due to mutations in the ß-isoform of the thyroid hormone receptor (TR). TSH-secreting adenomas (TSHomas) are presumed to represent clonal expansion and have been reported to contain TRß gene mutations. Mice with a knock-in mutation in the TRß gene spontaneously develop TSHomas, although as yet no patient has been reported to have both a TSHoma and RTHß. OBJECTIVE: We investigated a 12-year-old girl with elevated serum T4 concentration, inappropriately high TSH levels, and a pituitary adenoma. DESIGN AND INTERVENTION: Clinical, biochemical, and radiological assessments were performed at baseline and after a transsphenoidal pituitary adenomectomy. RESULTS: The patient's laboratory results included: TSH, 21.12 mIU/L (0.35-4.94 mIU/L); free T3, 14.25 pmol/L (2.63-5.7 pmol/L); free T4, 28.79 pmol/L (9.01-19.05 pmol/L); serum glycoprotein hormone alpha-subunit (α-GSU), 0.32 ng/ml (0.22-0.39 ng/ml); and α-GSU/TSH, 0.15. Thyroid radioiodine uptake was increased by 94.4% at 24 hours. A T3 suppression test showed incomplete suppression of the serum TSH concentration and blunted response of the peripheral thyroid hormone markers. The sequence of TRß exons confirmed a P453T mutation in the TRß gene. Pituitary magnetic resonance imaging revealed a microadenoma in the left side of the pituitary. The patient underwent transsphenoidal pituitary adenomectomy. Histologically, the tumor stained positively for TSH-ß, human Chorionic Gonadotropin alpha (HCG-α), GH, prolactin, and ACTH. After removal of the tumor, the patient's thyroid function improved significantly, and she experienced the onset of menarche and an increase in linear growth as well. CONCLUSIONS: This patient with RTHß had a TSHoma consistent with previous findings linking somatic TRß mutations to TSHomas.

Hypoglycemia Observed on Continuous Glucose Monitoring Associated With IGF-2-Producing Solitary Fibrous Tumor.

CONTEXT: Tumors producing IGF-2 (IGF-2oma) are a major cause of spontaneous hypoglycemia. The treatment mainstay is surgical resection. Many case reports note resolution of hypoglycemia after IGF-2oma resection; however, outcomes are variable according to tumor type. We report a case of resolving hypoglycemia, observed on continuous glucose monitoring, after resection of an IGF-2-producing solitary fibrous tumor of pleura and review the current literature. CASE REPORT: A 69-year-old woman presented with impaired consciousness because of hypoglycemia. An IGF-2oma was diagnosed as the cause for hypoglycemia because of decreased serum insulin and IGF-1, the presence of a pleural tumor, and a high-molecular-weight form of serum IGF-2 detected by Western immunoblot. Surgical resection was performed; pathological examination demonstrated a solitary fibrous tumor with low-grade malignancy. Continuous glucose monitoring showed reversal of hypoglycemia after tumor resection. Approximately 2 years after resection, the patient has no signs of tumor recurrence or hypoglycemia. CONCLUSIONS: An IGF-2-producing solitary fibrous tumor of pleura in this case caused hypoglycemia. From a search of the literature of 2004-2014, 32 cases of IGF-2oma with hypoglycemia that underwent radical surgery were identified; in 19 (59%) patients, hypoglycemia was reversed, and there was no subsequent recurrence. The remaining 13 (41%) patients experienced tumor recurrence or metastasis an average of 43 months after initial tumor resection. The tumor of the present case was a low-grade malignancy. Regular follow-up with biomarker monitoring of glucose metabolism and assessment of hypoglycemic symptomatology, in conjunction with imaging tests, is important for detecting possible tumor recurrence and metastasis.

Leukemoid reaction and autocrine growth of bladder cancer induced by paraneoplastic production of granulocyte colony-stimulating factor--a potential neoplastic marker: a case report and review of the literature.

INTRODUCTION: Granulocyte colony-stimulating factor produced by nonhematopoietic malignant cells is able to induce a leukemoid reaction by excessive stimulation of leukocyte production. Expression of granulocyte colony-stimulating factor and its functional receptors have been confirmed in bladder cancer cells. In vitro studies have demonstrated that granulocyte colony-stimulating factor/receptor exhibits a high affinity binding and this biological axis increases proliferation of the carcinoma. Urothelial carcinoma of the bladder is rarely associated with a leukemoid reaction and autocrine growth induced by paraneoplastic production of granulocyte colony-stimulating factor. In the world literature, there have been less than 35 cases reported in the last 35 years. The clinicopathological aspects, biology, prognosis and management of granulocyte colony-stimulating factor-secreting bladder cancers are poorly understood. CASE PRESENTATION: A 39-year-old Caucasian woman with an invasive high-grade urothelial carcinoma presented with hematuria and low-grade fevers. Laboratory tests revealed an elevated white blood cell count and absolute neutrophil count and an elevated 24-hour urine protein. Upon further evaluation she was found to have locally advanced high-grade urothelial carcinoma without nodal or distant metastasis. Her serum granulocyte colony-stimulating factor level was 10 times the normal limit. This led to the diagnosis of a paraneoplastic leukemoid reaction. Her white blood cell count immediately normalized after cystectomy but increased in concordance with recurrence of her disease. Unfortunately, she rapidly progressed and expired within 10 months from the time of first diagnosis. CONCLUSIONS: This is one of the few cases reported that illustrates the existence of a distinct and highly aggressive subtype of bladder cancer which secretes granulocyte colony-stimulating factor. Patients presenting with a leukemoid reaction should be tested for granulocyte colony-stimulating factor/receptor biological axis. Moreover, granulocyte colony-stimulating factor could be a potential neoplastic marker as it can follow the clinical course of the underlying tumor and thus be useful for monitoring its evolution. Neoadjuvant chemotherapy should be considered in these patients due to the aggressive nature of these tumors. With a better understanding of the biology, this autocrine growth signal could be a potential target for therapy in future.

[A case of nasopharyngeal carcinoma accompanying erythroderma].

We describe a 58-years-old man with a primary nasopharyngeal carcinoma accompanying erythroderma. His first symptoms were systemic scattered erythema and itching for six months. Lower right cervical lymphadenectasis was found by physical examination. A neoplasm in nasopharynx could be seen with nasal endoscope. The pathology of the neoplasm was non-keratinizing carcinoma. This case illustrates that "erythroderma" could be a paraneoplastic effect of nasopharyngeal carcinoma.

Acromegaly induced by ectopic secretion of GHRH: a review 30 years after GHRH discovery.

Ectopic acromegaly is very rare and since the discovery of growth hormone-releasing hormone (GHRH), 30 years ago, only 74 cases have been reported in the literature. Except for a recent French series of 21 cases, most of them were case reports. The present review summarizes the current knowledge on clinical presentation, diagnosis and prognosis. Tumors secreting GHRH are neuroendocrine tumors, usually well differentiated and mainly from pancreatic or bronchial origin. They are usually large and easy to localize using TDM and somatostatin receptor scintigraphy. Clinical presentation is an acromegaly of variable intensity, whose features are similar to that of a somatotropic adenoma. Pituitary may be normal or enlarged at MRI which may be difficult to interpret especially in MEN1 patients where the association of a microprolactinoma to a pancreatic tumor secreting GHRH may be misleading. GHRH plasmatic measurement has an excellent specificity for the diagnosis, using a threshold of 250 to 300ng/L and is a good tool for follow-up of patients after treatment. These tumors have a good overall prognosis, even in metastatic forms which represent 50% of cases. Surgical approach is recommended and, when a complete tumoral resection is feasible, results, in most patients, in long-lasting remission. In such cases, GHRH concentration is normalized and its increase is an accurate indicator of recurrence. In uncured patients, somatostatin analogs control GH secretion but inhibit, only partially, GHRH secretion. MEN1 mutation should be systematically investigated in patients with a pancreatic tumor.

Ectopic secretion of GHRH by a pancreatic neuroendocrine tumor associated with an empty sella.

Acromegaly is usually the result of a pituitary growth hormone cell-adenoma or is more rarely due to ectopic secretion of growth hormone releasing hormone (GHRH).We report the case of a 60-year-old woman with acromegaly due to a GH-RH-secreting pancreatic tumor. Laboratory evaluation confirmed the diagnosis of acromegaly. Magnetic resonance imaging revealed a partial empty sella with no signs of adenoma. Ultrasound sonography performed for abdominal pains showed a calcified large heterogeneous infrahepatic mass. Computed tomography scan discovered a heterogeneous pancreatic head mass with a diameter of 10cm. Measurement of fasting plasma GHRH was performed showing a high concentration of 604ng/L (normal 10-60). We therefore concluded that the acromegaly was caused by ectopic overproduction of GHRH likely due to the pancreatic tumor. The patient underwent a cephalic duodenopancreatectomy. Histology revealed a well-circumscribed tumor with organoid architecture. Immunohistochemistry demonstrated diffuse positivity for chromogranin A, neuronal specific enolase and synaptophysin and negative immunoreactivity for prolactin, GH and serotonin. These features were concordant with a well-differentiated neuroendocrine tumor of the pancreas. Surgical resection of this pancreatic tumor was followed by significant amelioration of acromegalic signs and normalization of GHRH and GH levels.

Hipercalcemia humoral secundaria a carcinoma mixto de endometrio / Humoral hypercalcemia in mixed endometrial carcinoma

La hipercalcemia secundaria a enfermedad neoplásicaes una entidad frecuente causada en la mayor partede los casos por secreción ectópica de PTHrp. A pesarde esto hay ciertos tumores, como los carcinomas uterinos,en donde este tipo de manifestación paraneoplásicaestá muy poco descrita. Presentamos un caso dehipercalcemia humoral en un carcinoma mixto de endometrio (AU)

Hypercalcemia secondary to neoplastic diseaseis a frequent entity caused in the majority of cases byectopic secretions of PTHrP. Despite this there are certaintumours, such as uterine carcinomas, in which thistype of paraneoplastic manifestation has been describedvery little. We present a case of humoral hypercalcemiain a mixed endometrial carcinoma (AU)

Isolated luteinizing hormone (LH) elevation in a woman with secondary amenorrhea: a clue to the diagnosis of an inhibin B-producing thecoma and insights into the influence of inhibin B on LH.

OBJECTIVE: To review the diagnostic possibilities that exists when the workup of amenorrhea reveals an isolated LH elevation; and to examine the effect of inhibin B on LH levels in vivo. DESIGN: Case report. SETTING: University hospital. PATIENT(S): A 20-year-old woman presented with secondary amenorrhea. Her FSH measurement was low, and the LH level was elevated. The recognition that this was an unusual pattern led to the diagnosis of a rare but very treatable inhibin B-producing thecoma, despite the fact that results on the initial pelvic ultrasound examination performed 10 months after presentation of amenorrhea were relatively unremarkable. INTERVENTION(S): Surgical removal of an ovarian thecoma. MAIN OUTCOME MEASURE(S): Gonadotropins, E2, inhibin B, menstrual bleeding, and fertility. RESULT(S): Removal of the ovarian thecoma resulted in a normalization of FSH, LH, and inhibin B levels and a return of spontaneous menses 28 days later. Pregnancy occurred with the third postoperative menstrual cycle, followed by the delivery of a healthy full-term girl. CONCLUSION(S): Inhibin B-producing sex cord granolosa-stromal cell tumors should be considered in women who present with amenorrhea with isolated LH elevations, even in the setting of a previously normal pelvic ultrasound report. Diagnostic considerations that arise in the workup of amenorrhea when there is an isolated elevation in LH that is accompanied by normal or low FSH levels are reviewed. This rare clinical presentation provides the opportunity to observe the impact of inhibin B on gonadotropins in vivo.

Paraneoplastic syndromes in patients with nasopharyngeal cancer.

Paraneoplastic syndromes (PNS) represent the clinical manifestation of the remote and indirect effects produced by tumor metabolites or other products. Paraneoplastic effects are not directly mediated by tumor invasion of normal tissue, or by the disruption of normal function of the involved organ, or by distant metastases. More than 260 cases of nasopharyngeal carcinoma (NPC) associated with PNS have been reported in the literature. These syndromes can be divided into six main groups: cutaneous or dermatologic, endocrine, hematologic, osteoarticular or rheumatologic, neurologic, and ocular. The most common dermatologic manifestation is dermatomyositis, while the syndrome of inappropriate secretion of antidiuretic hormone and occasionally Cushing's syndrome due to ectopic ACTH production are the endocrinologic manifestations. Tumor fever and leukemoid reaction, osteoarticular or rheumatic syndromes, including clubbing of the fingers and toes, sensory neuropathy and demyelinating motor polyneuropathy, and rarely optic neuritis represent the most prominent examples of the other groups of syndromes. PNS may occur before the NPC is manifest, or while it is in an occult stage, and thus the possibility of NPC should be considered in patients with these various disorders. While some PNS will respond to direct treatment, most often the PNS subsides in parallel to response of the NPC, and thus may be useful for monitoring tumor response or recurrence.

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.