The tumors originate from a group of cells widely dispersed in different organs.

1. An Overview of Neuroendocrine TumorsAli A Ghazi M.D.Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences.Tehran, Iran

6. NEUROENDOCRINE tumors are a group of non-homogeneous neoplasms arising from different organs that share in common the ability to elaborate and secret a wide range of substances.

7. In first decade of20th century, a different group of small intestinal tumors were diagnosed that seemed not to be truly malignant, hence were named carcinoid tumors. • In 1938 it was discovered that some of these tumors are really malignant. • Ability of the cells to secret serotonin was discovered in 1953.

8. The tumors originate from a group of cells widely dispersed in different organs. • These cells were formerly named Amine Precursor Uptake and Décorboxilation (APUD) cells and tumors originating from those were called carcinoids or apudomas.

9. At present this cellular system is called Diffuse Neuroendocrine System (DNES) Cells and the tumors originating from those, are collectively named neuroendocrine tumors (NET).

12. Increasing knowledge about these tumors and implementation of more sensitive diagnostic technics have led to detection of greater numbers of patients. • The study from John Hopkins Hospital revealed that among 125 patients with pancreatic and peripancreatic NET, 1/3 has been diagnosed between 1949 and 1988 and 2/3between 1988 and 1996.

14. Formerly the tumors were classified as typical or atypical carcinoid. In 2000 WHO proposed a new classification based on biologic properties of the tumors without considering the tissue of the origin.

15. According to this classification, NETs are divided into 3 categories: • Well differentiated NET • Well differentiated NE carcinoma • Poorly differentiated NE carcinoma • IHC and determination of KI 67 were advised to be done for diagnostic, staging and prognostic purposes.

16. 30 – 50% of NETs are functional. • Endocrinologists are involved in this aspect of disease, (Ectopic Hormone Syndromes). • Most prevalent clinical pictures are as follows: Ectopic Hormone Clinical presentation ACTH Cushing’s Syndrome CRH Cushing’s Syndrome ADH SIADH PTHrP Hypercalcemia GHRH Acromegaly IGF2 Hypoglycemia Gastrin Z-E syndrome VIP Verner-Morrison Syndrome

17. While every organ may be involved, different clinical presentations can be anticipated. • Nonfunctional tumors may be discovered incidentally or because of the mass effect. • Functioning tumors present with symptoms related to the secretion of hormones.

18. A 32 YO man presented because of fullness in his abdomen. The patient was an active young man without any complaint. Laboratory evaluation was negative.

20. Gene study done at Oxford University, UK showed that the patient does not have any mutation in NF1, VHL, RET, SDH (A, B, C, D), SDHAF2, TMEM 127, HIF2A and MAX genes.

21. A 63 Y.O man was hospitalized because of watery diarrhea, muscle weakness and 10 Kg weight loss during last year. • Upper and lower endoscopy were negative, Hb=10.2, K=2.6 me/L and ABG was in favor of metabolic acidosis.

22. Abdominal CT scan revealed multiple hepatic lesions in favor of metastasis. • The largest diameter was 2 Cm. Light microscopic evaluation of liver biopsy revealed, metastatic carcinoma with neuroendocrine differentiation.

23. IHC of the liver biopsy was positive for Vasoactive Intestinal Peptide (VIP).

24. A 35 Y.O pregnant woman became somnolent after cesarian section, she gradually became severely dehydrated and developed subcomatose state. • Hypercalcemia of the neonate prompted us to evaluate mother’s calcium which was around 16-17 mg/dl. Serum phosphorus and PTH were low.

25. Due to low iPTH in 3 occasions, tumor induced hypercalcemia was proposed. • Abdominal CT scan revealed a big nonhomogenous tumor in pancreas.

27. Tissue specimen showed positivity with PTHrP in IHC.

29. A 53 Y.O lady was referred to us because of acromegalic features. • Her work up in another hospital revealed high IGF1, and unsuppressed GH after glucose challenge. • Her pituitary MRI was interpreted as normal in 2 occasions. Ectopic acromegaly was highly suspected.

32. Histopathologic evaluation revealed the mass is indeed a Paraganglioma. • IHC was positive for chromogranin

33. IHC showed positivity for GHRH.

34. GHRH staining Lung CA-positive control Tumor tissue

35. A 44 YO man was referred because of facial puffiness, abdominal striae, polyuria, polydipsia, weight gain and history of recurrent renal stones. Laboratory evaluation revealed hypercalcemia, high iPTH and hypercortisolism.

39. He was finally proved to have ECS secondary to a thymic NET in the setting of MEN1. • IHC was positive for ACTH.

40. A 49- year- old woman was referred to us for evaluation of palpitation, profuse sweating and attacks of severe headache. Her past medical history was significant for a total thyroidectomy at age 21 years that was histopathologically proved to be a 5 x 2 cm medullary thyroid carcinoma. She also had attacks of severe hypertension up to 210/140 mm Hg during the last 1.5 years.

41. Laboratory evaluations revealed high urine catecholamine metabolite, normal calcitonin and high serum calcium and PTH. • CT scan of the abdomen showed bilateral adrenal tumors. • Diagnosis of MEN-2 A was proposed . The patient was operated and both tumors were taken out.

43. Sequencing of the RET proto-oncogene was done at our research institute . • The study showed Cys634Arg mutation and 3 polymorphisms; Gly691Ser, Ser 836 Ser and Ser904 Ser

45. In some cases the secretory ability of the tumor is obvious.

49. The 66 year old man was hospitalized because of asthenia, muscle weakness and 10 kg weight loss. Laboratory evaluation revealed, anemia, sever hypokalemia, hypercortisolism and metabolic alkalosis. Imaging showed multiple small lesions in lung and liver