Positive Staining For Chromogranin Research Articles

ODP309 Ectopic Cushing's Syndrome: Importance of Methodical Approach to Hide and Seek

Abstract Cushing's syndrome (CS) is associated with high morbidity and fivefold excess mortality. Ectopic ACTH syndrome accounts for 20% of CS cases. It is crucial to identify and localize the source of extrapituitary ACTH secretion because surgical resection of the primary, often malignant, tumor has a high probability of cure with complete remission in 80% of cases. A 72-year-old female was admitted to a community hospital for lateral chest pain after a fall. She endorsed progressive weight gain, new HTN, emotional lability and worsening cognition over the prior 6 months. ACTH and cortisol levels were elevated. MRI brain failed to identify a pituitary lesion. CT chest showed multiple rib fractures and anterior mediastinal mass which was biopsied. While awaiting pathology results, IPS sampling attempted but aborted due to pulmonary edema necessitating ICU care. She was transferred to our institution for planned TSR of suspected pituitary adenoma. Examination showed Cushingoid features. Labs showed hypokalemia, high cortisol and high ACTH. MRI pituitary showed normal sella. MRI spine showed multilevel vertebral compression fractures. CT chest showed interval growth of mediastinal mass. A 1 mg dexamethasone suppression test failed to suppress ACTH and cortisol, confirming ACTH dependent hypercortisolism. A high dose 8 mg dexamethasone test failed to suppress ACTH and cortisol, a 10 mcg DDAVP stimulation test showed a flat response, with ACTH and cortisol levels remaining comparable before and after DDAVP injection. Dynamic testing therefore consistent with ectopic ACTH dependent hypercortisolism. Gallium-68 DOTA-TATE PET Scan demonstrated uptake in mediastinal mass suggestive of somatostatin receptor positive neuroendocrine tumor. Biopsy specimens processed at our institution showed cells positive for epithelial markers Cytokeratin and PAX8. Sample showed neuroendocrine differentiation with positive staining for Chromogranin A, synaptophysin and CD 117. Findings consistent with neuroendocrine thymic neoplasm. The patient was started on oral ketoconazole to control hypercortisolism. Surgical resection of tumor was planned with intent to cure CS. Ultimately, due to proximal myopathy and multiple vertebral fractures her performance status was too poor for safe tumor resection. Unfortunately, she died of complications related to CS while attempting preoperative rehabilitation. This case illustrates the importance of a timely, systematic evaluation for ACTH source in ACTH dependent hypercortisolism. Delay in CS diagnosis and localizing correct ACTH source led to missing the window of fitness for curative surgery. If ACTH is elevated, the most common source is pituitary neoplasia, however ectopic ACTH production must be ruled out. Dynamic testing including high dose dexamethasone suppression test, CRH and DDAVP stimulation tests should be used for preliminary localization of ACTH production. IPS sampling is invasive with greater potential for complications, as in the case of our patient. Therefore, it is only indicated if there are conflicting results from different dynamic tests and imaging studies. Presentation: No date and time listed

Well-Differentiated Malignant Neuroendocrine Cell Tumor Originating From the Jejunum With Excessive Insulin Secretion

Background: Insulinomas are rare, well-differentiated insulin-secreting neuroendocrine tumors of the pancreas. Insulin-secreting, extra-pancreatic tumors have rarely been reported in the literature. We present a case of a well-differentiated neuroendocrine tumor with clinical, laboratory, and immunohistochemical tumor findings supportive of ectopic insulin production in a non-pancreatic neuroendocrine tumor of the small bowel. Clinical Case: A 70 year-old female with past medical history of end stage renal disease, Type II diabetes mellitus, and hypertension presented to our facility with multiple episodes of dizziness and syncope due to hypoglycemia. She had initially managed her diabetes with metformin but stopped taking the medication due to increasingly frequent episodes of hypoglycemia. Significant labs during the hospitalization include blood glucose <20 mg/dL, insulin 75.9 IU/mL (2.6-21.9 IU/mL) and C-peptide 57.7 ng/mL (1.1-4.4 ng/mL). Her symptoms persisted despite dextrose supplementation. Abdominal and Pelvic CT showed proximal small bowel obstruction and sclerosing mesenteritis with a calcified lymph node but no pancreatic mass. A diagnostic laparoscopy was performed, showing 18 inches of small bowel with malignant appearing masses that were adherent to the mesentery. A 21.0 cm segment of jejunum was resected. There were at least 30, variably sized masses throughout the bowel, involving the mucosa, submucosa, muscularis propria and subserosal fat; along with lymphatic, venous, and perineural space tumor permeation, and metastases involving multiple regional lymph nodes. The tumors ranged in size from 0.5 up to 1.5 cm. They showed well-differentiated nuclear morphology, a mitotic count of 0 per 80 high power fields, and a Ki-67 proliferation index of 1%, indicative of a G1 NET. Immunohistochemical stains confirmed neuroendocrine differentiation with positive staining for chromogranin, synaptophysin, and INSM1 (insulinoma-associated protein 1) transcription factor, while insulin staining was negative. The patient was diagnosed with a pT3N1, G1, ectopic insulin-secreting neuroendocrine tumor of small bowel origin. She was started on diazoxide with significant improvement in her hypoglycemia. Conclusion: Insulin production by non-pancreatic tumors is extremely rare. Clinical, laboratory, and immunohistochemical tumor findings in this case support ectopic insulin production by a well-differentiated neuroendocrine tumor of small bowel origin.

Neuroendocrine tumor of the rectum: A case report

Neuroendocrine tumors are a frequent and clinically enigmatic group of tumors originating from the cells of diffuse neuroendocrine system. The incidence of neuroendocrine tumors of the rectum is 0.86 per 100,000 people. In our paper, the patient was 58 years old, sent to a gastroenterologist because of intermittent abdominal bloating and positive findings on a fecal occult test. Upper endoscopy diagnosed an ulcer in the duodenal bulb, which explained the positivity of the fecal occult test. Using colonoscopy at 10th centimeter in the rectum a sessile polypoid resizing of 15 millimeters was found, and the histopathologic findings showed that it was an interstitial colitis, without the elements of malignant cells. Computed tomography of the pelvis showed a lesion in the rectal region that had infiltrated the wall of the rectum without propagation to the surrounding structures and with no enlarged lymph nodes. Histopathological material was sent to immunohistochemistry, which showed that it were welldifferentiated neuroendocrine tumors, with the invasion of the lamina muscularis propria and positive staining for chromogranin A and neuron-specific enolase, and the nuclear antigen Ki-67 was 17%. The values of chromogranin A levels in serum were three times higher than normal. 15 months after the tumor was removed surgically, computerized tomography scan showed multiple lesions in the liver. Octreoscan (somatostatin receptor scintigraphy) confirmed multiple lesions in the liver with the expression of somatostatin receptors. A rare case of tumor was shown, diagnosed in a nonspecific way, that at the time of diagnosis, despite its size and infiltration into the muscle tissue did not have distant metastases.

Abdominal Pain and Liver Lesions in Zollinger‐Ellison Syndrome

van Os, Erim Schrama, Martijn Kamphuis, Karin de Herder, Wouter W Damen, Gerard M Case Reports United States J Pediatr Gastroenterol Nutr. 2012 Mar;54(3):435-7.

Adrenal cortical tumors, pheochromocytomas and paragangliomas

Distinguishing adrenal cortical adenomas from carcinomas may be a difficult diagnostic problem. The criteria of Weiss are very useful because of their reliance on histologic features. From a practical perspective, the most useful criteria to separate adenomas from carcinomas include tumor size, presence of necrosis and mitotic activity including atypical mitoses. Adrenal cortical neoplasms in pediatric patients are more difficult to diagnose and to separate adenomas from carcinomas. The diagnosis of pediatric adrenal cortical carcinoma requires a higher tumor weight, larger tumor size and more mitoses compared with carcinomas in adults. Pheochromocytomas are chromaffin-derived tumors that develop in the adrenal gland. Paragangliomas are tumors arising from paraganglia that are distributed along the parasympathetic nerves and sympathetic chain. Positive staining for chromogranin and synaptophysin is present in the chief cells, whereas the sustentacular cells are positive for S100 protein. Hereditary conditions associated with pheochromocytomas include multiple endocrine neoplasia 2A and 2B, Von Hippel–Lindau disease and neurofibromatosis I. Hereditary paraganglioma syndromes with mutations of SDHB, SDHC and SDHD are associated with paragangliomas and some pheochromocytomas.

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.

Association of malignant insulinoma and type 2 diabetes mellitus: A case report

We report a case of recurrent hypoglycemia due to malignant insulinoma in a type 2 diabetic patient correctly controlled for years with the same doses of oral antidiabetic agents.A 79-year-old woman was admitted for recurrent severe hypoglycemia. She had a history of type 2 diabetes since 2000. HbA1c was 7.8% when she reported mild hypoglycemia and 5.8% when recurrent hypoglycemia appeared despite progressive diminution of glicazide. Severe hypoglycemia continued despite interrupting diabetes medications. At admission, results showed inappropriately elevated insulin, C-peptide and proinsulin levels despite significant hypoglycemia. CT scan showed “cystic” nodes in the pancreas and in the liver. Liver biopsy found a well-differentiated neuroendocrine carcinoma with positive staining for chromogranin A and negative staining for insulin. Hypoglycemia improved with diazoxide, lanreotide and dextrose infusion. Liver chemoembolization was planned. Severe edema, dyspnea, hyponatremia, and hypo-osmolarity occurred. The patient's clinical status deteriorated rapidly with severe cardiac, renal and hepatic failure. She died in a few days. Association of diabetes mellitus and insulinoma is extremely rare. Malignant insulinoma survival is less than two years, shorter when hepatic localizations are present at diagnosis. Association of diabetes with insulinoma delays the diagnosis, but does not alter prognosis or favor carcinoma frequency. Lanreotide was inefficient in our patient despite good responses described in the literature. Heart, respiratory and renal failures have been described with diazoxide independently of the doses; this may in part explain the rapid death. Insulinoma should be considered as a cause of unusual and recurrent hypoglycemia in a diabetic patient especially if it persists after interrupting antidiabetic agents.

Malignant Insulinoma

Malignant Insulinoma

Small cell neuroendocrine carcinoma of the cervix: outcome and patterns of recurrence

Objective. To analyze the sites of relapse and overall survival in women with neuroendocrine marker-positive small cell carcinoma of the cervix. Methods. The records of all women who had their initial treatment for cervical cancer at The University of Texas M.D. Anderson Cancer Center between 1980 and 2000 were reviewed. Fifty-one patients had stages I–III cancers that were originally described as “small cell” or “neuroendocrine.” Histological material was available for reexamination in 45 cases; of these, 21 were found to have small cell neuroendocrine carcinoma (SCNEC) as indicated by positive staining for chromogranin, synaptophysin, or CD56. Local treatment consisted of a radical hysterectomy in six patients and radiation therapy in 15. Thirteen patients received chemotherapy as part of their initial treatment. The median follow-up for surviving patients was 83 months (range, 25–209 months). Results. Fourteen (66%) of the 21 patients had a relapse. The median time to first relapse from the initiation of treatment was 8.4 months (range, 3.6–28 months). Most patients developed hematogenous distant metastases before their death. Only 2 of 15 patients who were treated with radiation therapy had a recurrence within the radiation fields. However, five patients had a recurrence above the radiation fields in the paraaortic lymph nodes, and two patients had a recurrence distal to the pelvic fields in the vagina. No patient had brain metastases as the sole site of first recurrence. However, two patients developed brain metastases concurrently with lung metastases. The overall survival rate was 29% at 5 years; none of the patients who had disease more extensive than stage IB1 or clinical evidence of lymph node metastases survived their disease. Conclusions. Patients with small cell neuroendocrine cervical cancer have a poor prognosis. Their course is frequently characterized by the development of widespread hematogenous metastases; locoregional recurrence outside irradiated fields is also frequent. Brain metastases were seen only in patients who also had lung metastases, suggesting that prophylactic cranial irradiation would be of little benefit.

Neuroendocrine (carcinoid) tumor of the mandible: A case report and review of the literature

The aim of this article is to present a case of primary neuroendocrine tumor (typical carcinoid) of the mandible that occurred in a 46-year-old black woman who was seropositive for the human immunodeficiency virus. Radiologically the lesion presented as a poorly circumscribed honeycomb radiolucency that extended from tooth 21 to the ascending ramus. Histologically the tumor cells were variously arranged in small islands, trabeculae, follicles, and slitlike spaces lined by a single layer of palisaded low-columnar cells. The follicles contained an eosinophilic colloid-like substance. Immunocytochemical staining showed diffuse, intense positivity for MAK 6, pancytokeratin, S-100, and neuron-specific enolase and focal, intense, positive staining for chromogranin A. Electron microscopy showed the presence of interdigitating cell membranes, rudimentary cell attachments, and varying numbers of membrane-bound dense core granules. Special investigations failed to reveal a primary tumor, and no metastases were found. Urine and hematologic assessment did not show any evidence of functional activity. The tumor was resected, and no recurrence or spread has been seen for 2 years. Origin from foregut-derived, immature, and functionally uncommitted endocrine cells is presumed.