Csaba Halászlaki

Marked Increase in CYP24A1 Gene Expression in Human Papillary Thyroid Cancer

The active metabolite of vitamin D3, 1,25-dihydroxyvitamin D3 (1,25-D3) inhibits cell growth and induces cell differentiation and apoptosis in numerous tumors, such as colon, breast, and prostate cancers (1–3). However, the anticancer effect of 1,25-D3 cannot always be seen in a clinical setting. In case of colon cancers, a marked increase in the expression of the 1,25D3 inactivating enzyme, the 24-hydroxylase (CYP24A1), has been observed (4). The role of 1,25-D3 in the development of thyroid carcinomas has not yet been established. However, Sharma et al. (5) observed the correlation of high baseline CYP24A1 and relatively low stimulation after calcitriol treatment (compared with sensitive cells) with lack of growth inhibition in numerous thyroid cancer cell lines. We have also examined the gene expression of the inactivating CYP24A1 and the activating 1-alpha-hydroxylase (CYP27B1) enzyme in human thyroid cancers. To date, gene expression analysis of thyroid samples (both normal and papillary tumor tissue of the same patient) was carried out in six unrelated, consecutive, Hungarian, Caucasian patients at our Thyroid Clinic. All surgically removed thyroid tissue samples underwent histological examination, and papillary tumor was identified in all cases. The study was approved by the Regional Committee of Science and Research Ethics, Semmelweis University (SOTE-TUKEB 1160-0/20101018EKU), and all patients gave written informed consent. Total RNA was isolated from each sample with Roche High Pure Total RNA Isolation kit. Five hundred nanograms of total RNA was reverse-transcribed to cDNA. The expression differences of selected genes were analyzed by Taqman probe-based quantitative real-time reverse transcriptase– polymerase chain reaction. Relative quantification was carried out from collected data (threshold cycle numbers) by Applied Biosystems 7500 System SDS software 1.3. CYP24A1 mRNA expression was markedly increased in all but one papillary cancer compared with that of normal thyroid tissue, sometimes reaching 300-fold elevation (Supplementary Fig. S1; Supplementary Data are available online at www.liebertonline.com/thy). No significant alteration was seen in CYP27B1 gene activity between neoplastic and normal tissues. There was no significant difference in serum 25-OHvitamin D3 concentrations among patients (mean: 28.03 ng/ mL, range: 22.7–31.9 ng/mL). In this letter, we report marked increases in the 1,25-D3neutralizing CYP24A1 gene expression in human papillary thyroid cancer. The tumor cell growth-inhibiting role of vitamin D3 has been extensively studied in different malignancies (1–3). The interest in the association of vitamin-D3 serum levels with various cancer incidences has dramatically increased. However, only very limited data are available on the relationship between serum vitamin D3 concentrations and malignant thyroid conditions (6,7). The pilot study of Laney et al. showed levels of vitamin D and rates of vitamin D deficiency to be similar between patients with thyroid nodules, thyroid cancer in remission, and active thyroid cancer (8). However, the results of Stepien et al. revealed significantly lower calcitriol concentrations in patients with papillary, follicular, and anaplastic thyroid cancers (7). This finding could be attributable to higher CYP24A1 levels cleaving calcitriol, as there were no differences in serum 25-OH-vitamin D3. Earlier, calcitriol had also been shown to attenuate thyrotropinstimulated growth and iodide uptake by rat thyroid cells (FRTL-5) (9,10). Papillary cancer is the most common thyroid malignancy. The role of vitamin D3 in the prevention or development of this disorder has to be yet determined. The increase in CYP24A1 expression in this cancer type could be a ‘‘protective’’ mechanism against the well-known anticancer effect of calcitriol. The observation of Sharma et al. (5) regarding increased expression of CYP24A1 in thyroid cancer cell lines corroborates this notion. One of the cell lines they used was human papillary thyroid carcinoma cell line, whereas the other ones showed the features of human anaplastic thyroid carcinoma. Also, the most resistant cell lines to calcitriol had the highest baseline levels of CYP24A1. In our study at this stage, the number of examined tumor tissues does not allow drawing of statistically significant conclusion about the correlation of tumor histopathological stage or aggressiveness with CYP24A1 levels. Khadzkou et al. demonstrated enhanced 1-alphahydroxylase expression but concluded that this elevation did not show large differences in CYP27B1 expression in papillary thyroid cancer and its metastasis compared with normal

Novel Genetic Mutation in the Background of Carney Complex

Carney complex is a rare disease inherited in an autosomal dominant manner. It is mostly caused by inactivating mutations of the subunit of protein kinase A. Carney complex is associated with atrial myxoma, nevi or myxomas of the skin, breast tumor and endocrine overactivity. Primary pigmented nodular adrenocortical disease is the specific endocrine manifestation. The authors present the history of a 53-year-old female patient who had undergone surgery for atrial myxomas, thyroid tumor and breast cancer. She was also operated for an adrenal adenoma causing Cushing’s syndrome. Genetic study revealed a novel mutation in the regulatory subunit of protein kinase A (ivs2-1G>A splice mutation in intron 2). Her heterozygous twins were also genetically screened and one of them carried the same mutation. The authors emphasize that despite the absence of specific treatment for patients with Carney complex, confirmation of the diagnosis by genetic studies is important for the close follow-up of the patient and early identification of novel manifestations.

Novel mutation in a patient with Carney complex

Carney complex is a rare disease inherited in an autosomal dominant manner. It is mostly caused by inactivating mutations of the subunit of protein kinase A. Carney complex is associated with atrial myxoma, nevi or myxomas of the skin, breast tumors and endocrine overactivity. Primary pigmented nodular adrenocortical disease is the specific endocrine manifestation. The authors present the history of a 53-year-old female patient who had undergone surgery for atrial myxomas, thyroid tumor and breast cancer. She was also operated for an adrenal adenoma causing Cushings syndrome. Genetic study revealed a mutation in the regulatory subunit of protein kinase A (ivs2-1G>A splice mutation in intron 2). Her heterozygous twins were also genetically screened and one of them carried the same mutation. The authors emphasize that despite the absence of specific treatment for patients with Carney complex, confirmation of the diagnosis by genetic studies is important for the close follow-up of the patient and early identification of novel manifestations.

Comparative study of somatic oncogene mutations in normal thyroid tissues and thyroid neoplasms

Az elmult evekben tobb munkacsoportnak sikerult olyan szomatikus mutaciokat (BRAF, NRAS, HRAS, KRAS genekben) es genatrendeződeseket (RET/PTC, PAX8/PPAR-gamma) azonositani, amelyek osszefuggest mutatnak a pajzsmirigydaganatok kialakulasaval. Jelen vizsgalatban 11 szemely 22 (11 koros es 11 betegsegmentes) intraoperativ pajzsmirigy-szovetmintait elemeztek. A RAS gencsalad es a BRAF genek szomatikus egypontos nukleotid polimorfizmusait LigthCycler olvadaspontanalizis-modszerrel, mig a genatrendeződeseket valos idejű polimeraz lancreakcio modszerevel vizsgaltak. A daganatos mintakban 3 BRAF-, 2 NRAS-, 1 HRAS-mutaciot, valamint 1 RET/PTC1 atrendeződest talaltak. Az eredmenyek megerősitik a nemzetkozi adatokat, miszerint ezek az egypontos nukleotidpolimorfizmusok es genatrendeződesek megtalalhatok a daganatos pajzsmirigyszovetekben. Valoszinűsithető, hogy ezen genetikai vizsgalatokkal kiegeszult citologiai vizsgalat segitheti a malignus gobok azonositasat, illetve elkepzelhető, hogy prognosztikai faktorkent el...It is established that numerous somatic oncogene mutation (BRAF, NRAS, HRAS, KRAS) and gene translocations (RET/PTC, PAX8/PPAR-gamma) are associated with the development of thyroid cancer. In this study 22 intraoperative thyroid tissue samples (11 pathologic and 11 normal) were examined. Somatic single nucleotide polymorphisms were analyzed by LigthCycler melting method, while translocations were identified by real-time polymerase chain reaction technique. In tumorous sample 3 BRAF, 2 NRAS and one HRAS mutations were found, as well as one RET/PTC1 translocation. Results confirm international data showing that these oncogene mutations and translocations are linked to thyroid cancer. Cytological examination completed with genetic data may support the diagnosis of thyroid malignancies. In addition, genetic alterations may indicate malignant transformation and may become prognostic factors in future.

Comprehensive examination of somatic oncogene mutation in normal and pathologic thyroid tissues

Az elmult evekben tobb munkacsoportnak sikerult olyan szomatikus mutaciokat (BRAF, NRAS, HRAS, KRAS genekben) es genatrendeződeseket (RET/PTC, PAX8/PPAR-gamma) azonositani, amelyek osszefuggest mutatnak a pajzsmirigydaganatok kialakulasaval. Jelen vizsgalatban 11 szemely 22 (11 koros es 11 betegsegmentes) intraoperativ pajzsmirigy-szovetmintait elemeztek. A RAS gencsalad es a BRAF genek szomatikus egypontos nukleotid polimorfizmusait LigthCycler olvadaspontanalizis-modszerrel, mig a genatrendeződeseket valos idejű polimeraz lancreakcio modszerevel vizsgaltak. A daganatos mintakban 3 BRAF-, 2 NRAS-, 1 HRAS-mutaciot, valamint 1 RET/PTC1 atrendeződest talaltak. Az eredmenyek megerősitik a nemzetkozi adatokat, miszerint ezek az egypontos nukleotidpolimorfizmusok es genatrendeződesek megtalalhatok a daganatos pajzsmirigyszovetekben. Valoszinűsithető, hogy ezen genetikai vizsgalatokkal kiegeszult citologiai vizsgalat segitheti a malignus gobok azonositasat, illetve elkepzelhető, hogy prognosztikai faktorkent el...It is established that numerous somatic oncogene mutation (BRAF, NRAS, HRAS, KRAS) and gene translocations (RET/PTC, PAX8/PPAR-gamma) are associated with the development of thyroid cancer. In this study 22 intraoperative thyroid tissue samples (11 pathologic and 11 normal) were examined. Somatic single nucleotide polymorphisms were analyzed by LigthCycler melting method, while translocations were identified by real-time polymerase chain reaction technique. In tumorous sample 3 BRAF, 2 NRAS and one HRAS mutations were found, as well as one RET/PTC1 translocation. Results confirm international data showing that these oncogene mutations and translocations are linked to thyroid cancer. Cytological examination completed with genetic data may support the diagnosis of thyroid malignancies. In addition, genetic alterations may indicate malignant transformation and may become prognostic factors in future.

Verner-Morrison syndrome: a case study

Verner and Morrison described a syndrome of watery diarrhea, hypokalemia, and achlorhydria (WDHA) in 1958. VIPomas producing high amounts of vasoactive intestinal peptide (VIP) commonly originate from the pancreas. Typical symptoms play a momentous role in the diagnosis of VIPoma. Diarrhea may persist for years before the diagnosis. Morbidity from untreated WDHA syndrome is associated with long-standing dehydration and with electrolyte and acid-base metabolism disorders, which may cause chronic renal failure. Assessment of specific marker (VIP) offers high sensitivity in establishing the diagnosis. Imaging modalities include endoscopic ultrasonography, computed tomography and magnetic resonance imaging, and particularly, scintigraphy with somatostatin analogues. Treatment options include resection of the tumor, chemotherapy or the reduction of symptoms with somatostatin analogues. Early diagnosis and management may affect survival of patients favorably. VIPoma cases may be associated with multiple endocrine neoplasia type 1.1958-ban Verner es Morrison irta le az elnevezeseben a vizes hasmenesre, hypokalaemiara es achlorhydriara utalo szindromat (watery diarrhea, hypokalaemia, achlorhydria – WDHA). A nagy mennyisegű vazoaktiv intestinalis peptidet (VIP) termelő VIPomak rendszerint a hasnyalmirigyből szarmaznak. A tipikus tunetek fontos szerepet jatszanak a VIPoma diagnozisaban. A hasmenes a diagnozis felismerese előtt evekig perzisztalhat. A kezeletlen WDHA-szindroma a hosszabb ideig fennallo exsiccosis, illetve az elektrolit- es sav-bazis haztartas zavara miatt kronikus veseelegtelenseghez vezethet, ami a betegseg lefolyasat sulyosbithatja. Specifikus marker (VIP) meghatarozasa erzekeny modszer a korisme felallitasahoz. A felismeresben segitseget nyujt az endoszkopos ultrahang, komputertomografia, magneses rezonancia es főleg a szomatosztatinanalogokkal vegzett szcintigrafias vizsgalat. A kezelesi lehetősegek koze tartozik a daganat reszekcioja, a kemoterapia es a tunetek csokkentese erdekeben a szomatosztatinanalogok alkalmazasa. A korai diagnozis es kezeles kedvezően hathat a betegek eletben maradasara. A VIPomak tarsulhatnak az 1-es tipusu multiplex endokrin neoplasia (MEN-1) szindromahoz. | Verner and Morrison described a syndrome of watery diarrhea, hypokalemia, and achlorhydria (WDHA) in 1958. VIPomas producing high amounts of vasoactive intestinal peptide (VIP) commonly originate from the pancreas. Typical symptoms play a momentous role in the diagnosis of VIPoma. Diarrhea may persist for years before the diagnosis. Morbidity from untreated WDHA syndrome is associated with long-standing dehydration and with electrolyte and acid-base metabolism disorders, which may cause chronic renal failure. Assessment of specific marker (VIP) offers high sensitivity in establishing the diagnosis. Imaging modalities include endoscopic ultrasonography, computed tomography and magnetic resonance imaging, and particularly, scintigraphy with somatostatin analogues. Treatment options include resection of the tumor, chemotherapy or the reduction of symptoms with somatostatin analogues. Early diagnosis and management may affect survival of patients favorably. VIPoma cases may be associated with multiple endocrine neoplasia type 1.

PREDICTIVE VALUE OF SOMATIC MUTATIONS FOR THE DEVELOPMENT OF MALIGNANCY IN THYROID NODULES BY CYTOPATHOLOGY

OBJECTIVE The purpose of our prospective longitudinal study was to evaluate the predictive efficacy of genetic testing for malignancies in fine-needle aspiration biopsy samples that are cytologically benign at the time of biopsy. METHODS A total of 779 aspirated cytological samples collected from thyroid nodules of 626 patients were included in a 3-year follow-up study. Consecutive patients with cytologically benign thyroid nodules by the Bethesda System for Reporting Thyroid Cytopathology were enrolled in the study. At enrollment, somatic 1-point nucleotide polymorphisms of BRAF and RAS family genes were tested by melting-point analysis, while RET/PTC and PAX8/PPAR-gamma rearrangements were examined by real-time polymerase chain reaction. The genetic test was considered to be positive if a somatic mutation was found. Malignant cytopathologic diagnoses were confirmed by histopathology. RESULTS In samples collected from 779 thyroid nodules, there were 39 BRAF, 33 RAS mutations, and 1 RET/PTC rearrangements found at the beginning of the study. No PAX8/PPAR-gamma rearrangement was identified. There were 52 malignant thyroid tumors removed during follow-up, out of which 24 contained a somatic mutation. The specificity of the presence of somatic mutations for malignancies was as high as 93.3%, and sensitivity was 46.2%. The negative predictive value of genetic testing reached 96.0%. CONCLUSION Our results show that our set of genetic tests can predict the appearance of malignancy in benign thyroid nodules (at the beginning of follow-up) with high specificity and strong negative predictive value. ABBREVIATIONS BRAF = v-raf murine sarcoma viral oncogene homolog B1 FLUS = follicular lesion of undetermined significance FNAB = fine-needle aspiration biopsy FTC = follicular thyroid carcinoma HRAS = homologous to the oncogene from the Harvey rat sarcoma virus KRAS = homologous to the oncogene from the Kirsten rat sarcoma virus NRAS = first isolated from a human neuroblastoma/neuroblastoma RAS = viral oncogene homolog PAX8 = paired box 8 PCR = polymerase chain reaction PPAR-gamma = peroxisome proliferator-activated receptor gamma PTC = papillary thyroid carcinoma RAS = rat sarcoma RET = rearranged during transfection tyrosine-kinase proto-oncogene SM = somatic mutation SNP = single-nucleotide polymorphism.

Szomatikus onkogén mutációk összehasonlí tó vizsgálata egészséges és tumoros pajzsmirigy-szövetmintákban

Az elmult evekben tobb munkacsoportnak sikerult olyan szomatikus mutaciokat (BRAF, NRAS, HRAS, KRAS genekben) es genatrendeződeseket (RET/PTC, PAX8/PPAR-gamma) azonositani, amelyek osszefuggest mutatnak a pajzsmirigydaganatok kialakulasaval. Jelen vizsgalatban 11 szemely 22 (11 koros es 11 betegsegmentes) intraoperativ pajzsmirigy-szovetmintait elemeztek. A RAS gencsalad es a BRAF genek szomatikus egypontos nukleotid polimorfizmusait LigthCycler olvadaspontanalizis-modszerrel, mig a genatrendeződeseket valos idejű polimeraz lancreakcio modszerevel vizsgaltak. A daganatos mintakban 3 BRAF-, 2 NRAS-, 1 HRAS-mutaciot, valamint 1 RET/PTC1 atrendeződest talaltak. Az eredmenyek megerősitik a nemzetkozi adatokat, miszerint ezek az egypontos nukleotidpolimorfizmusok es genatrendeződesek megtalalhatok a daganatos pajzsmirigyszovetekben. Valoszinűsithető, hogy ezen genetikai vizsgalatokkal kiegeszult citologiai vizsgalat segitheti a malignus gobok azonositasat, illetve elkepzelhető, hogy prognosztikai faktorkent el...It is established that numerous somatic oncogene mutation (BRAF, NRAS, HRAS, KRAS) and gene translocations (RET/PTC, PAX8/PPAR-gamma) are associated with the development of thyroid cancer. In this study 22 intraoperative thyroid tissue samples (11 pathologic and 11 normal) were examined. Somatic single nucleotide polymorphisms were analyzed by LigthCycler melting method, while translocations were identified by real-time polymerase chain reaction technique. In tumorous sample 3 BRAF, 2 NRAS and one HRAS mutations were found, as well as one RET/PTC1 translocation. Results confirm international data showing that these oncogene mutations and translocations are linked to thyroid cancer. Cytological examination completed with genetic data may support the diagnosis of thyroid malignancies. In addition, genetic alterations may indicate malignant transformation and may become prognostic factors in future.

Verner-morrison-szindróma egy esete

Verner and Morrison described a syndrome of watery diarrhea, hypokalemia, and achlorhydria (WDHA) in 1958. VIPomas producing high amounts of vasoactive intestinal peptide (VIP) commonly originate from the pancreas. Typical symptoms play a momentous role in the diagnosis of VIPoma. Diarrhea may persist for years before the diagnosis. Morbidity from untreated WDHA syndrome is associated with long-standing dehydration and with electrolyte and acid-base metabolism disorders, which may cause chronic renal failure. Assessment of specific marker (VIP) offers high sensitivity in establishing the diagnosis. Imaging modalities include endoscopic ultrasonography, computed tomography and magnetic resonance imaging, and particularly, scintigraphy with somatostatin analogues. Treatment options include resection of the tumor, chemotherapy or the reduction of symptoms with somatostatin analogues. Early diagnosis and management may affect survival of patients favorably. VIPoma cases may be associated with multiple endocrine neoplasia type 1.1958-ban Verner es Morrison irta le az elnevezeseben a vizes hasmenesre, hypokalaemiara es achlorhydriara utalo szindromat (watery diarrhea, hypokalaemia, achlorhydria – WDHA). A nagy mennyisegű vazoaktiv intestinalis peptidet (VIP) termelő VIPomak rendszerint a hasnyalmirigyből szarmaznak. A tipikus tunetek fontos szerepet jatszanak a VIPoma diagnozisaban. A hasmenes a diagnozis felismerese előtt evekig perzisztalhat. A kezeletlen WDHA-szindroma a hosszabb ideig fennallo exsiccosis, illetve az elektrolit- es sav-bazis haztartas zavara miatt kronikus veseelegtelenseghez vezethet, ami a betegseg lefolyasat sulyosbithatja. Specifikus marker (VIP) meghatarozasa erzekeny modszer a korisme felallitasahoz. A felismeresben segitseget nyujt az endoszkopos ultrahang, komputertomografia, magneses rezonancia es főleg a szomatosztatinanalogokkal vegzett szcintigrafias vizsgalat. A kezelesi lehetősegek koze tartozik a daganat reszekcioja, a kemoterapia es a tunetek csokkentese erdekeben a szomatosztatinanalogok alkalmazasa. A korai diagnozis es kezeles kedvezően hathat a betegek eletben maradasara. A VIPomak tarsulhatnak az 1-es tipusu multiplex endokrin neoplasia (MEN-1) szindromahoz. | Verner and Morrison described a syndrome of watery diarrhea, hypokalemia, and achlorhydria (WDHA) in 1958. VIPomas producing high amounts of vasoactive intestinal peptide (VIP) commonly originate from the pancreas. Typical symptoms play a momentous role in the diagnosis of VIPoma. Diarrhea may persist for years before the diagnosis. Morbidity from untreated WDHA syndrome is associated with long-standing dehydration and with electrolyte and acid-base metabolism disorders, which may cause chronic renal failure. Assessment of specific marker (VIP) offers high sensitivity in establishing the diagnosis. Imaging modalities include endoscopic ultrasonography, computed tomography and magnetic resonance imaging, and particularly, scintigraphy with somatostatin analogues. Treatment options include resection of the tumor, chemotherapy or the reduction of symptoms with somatostatin analogues. Early diagnosis and management may affect survival of patients favorably. VIPoma cases may be associated with multiple endocrine neoplasia type 1.

Verner–Morrison-szindróma egy esete = Verner-Morrison syndrome: a case study

Verner and Morrison described a syndrome of watery diarrhea, hypokalemia, and achlorhydria (WDHA) in 1958. VIPomas producing high amounts of vasoactive intestinal peptide (VIP) commonly originate from the pancreas. Typical symptoms play a momentous role in the diagnosis of VIPoma. Diarrhea may persist for years before the diagnosis. Morbidity from untreated WDHA syndrome is associated with long-standing dehydration and with electrolyte and acid-base metabolism disorders, which may cause chronic renal failure. Assessment of specific marker (VIP) offers high sensitivity in establishing the diagnosis. Imaging modalities include endoscopic ultrasonography, computed tomography and magnetic resonance imaging, and particularly, scintigraphy with somatostatin analogues. Treatment options include resection of the tumor, chemotherapy or the reduction of symptoms with somatostatin analogues. Early diagnosis and management may affect survival of patients favorably. VIPoma cases may be associated with multiple endocrine neoplasia type 1.1958-ban Verner es Morrison irta le az elnevezeseben a vizes hasmenesre, hypokalaemiara es achlorhydriara utalo szindromat (watery diarrhea, hypokalaemia, achlorhydria – WDHA). A nagy mennyisegű vazoaktiv intestinalis peptidet (VIP) termelő VIPomak rendszerint a hasnyalmirigyből szarmaznak. A tipikus tunetek fontos szerepet jatszanak a VIPoma diagnozisaban. A hasmenes a diagnozis felismerese előtt evekig perzisztalhat. A kezeletlen WDHA-szindroma a hosszabb ideig fennallo exsiccosis, illetve az elektrolit- es sav-bazis haztartas zavara miatt kronikus veseelegtelenseghez vezethet, ami a betegseg lefolyasat sulyosbithatja. Specifikus marker (VIP) meghatarozasa erzekeny modszer a korisme felallitasahoz. A felismeresben segitseget nyujt az endoszkopos ultrahang, komputertomografia, magneses rezonancia es főleg a szomatosztatinanalogokkal vegzett szcintigrafias vizsgalat. A kezelesi lehetősegek koze tartozik a daganat reszekcioja, a kemoterapia es a tunetek csokkentese erdekeben a szomatosztatinanalogok alkalmazasa. A korai diagnozis es kezeles kedvezően hathat a betegek eletben maradasara. A VIPomak tarsulhatnak az 1-es tipusu multiplex endokrin neoplasia (MEN-1) szindromahoz. | Verner and Morrison described a syndrome of watery diarrhea, hypokalemia, and achlorhydria (WDHA) in 1958. VIPomas producing high amounts of vasoactive intestinal peptide (VIP) commonly originate from the pancreas. Typical symptoms play a momentous role in the diagnosis of VIPoma. Diarrhea may persist for years before the diagnosis. Morbidity from untreated WDHA syndrome is associated with long-standing dehydration and with electrolyte and acid-base metabolism disorders, which may cause chronic renal failure. Assessment of specific marker (VIP) offers high sensitivity in establishing the diagnosis. Imaging modalities include endoscopic ultrasonography, computed tomography and magnetic resonance imaging, and particularly, scintigraphy with somatostatin analogues. Treatment options include resection of the tumor, chemotherapy or the reduction of symptoms with somatostatin analogues. Early diagnosis and management may affect survival of patients favorably. VIPoma cases may be associated with multiple endocrine neoplasia type 1.