[Neuroendocrine expression markers in triple-negative, luminal-A, luminal-B and HER2neu breast cancer]. / Expresión de marcadores neuroendócrinos en cáncer de mama triple-negativo, luminal-A, luminal-B y HER2neu.

Background: Primary breast tumors with neuroendocrine (NE) differentiation are a heterogeneous tumor group with diversity of biological behavior, with poorly defined prevalence and prognosis. Objective: To evaluate the chromogranin, synaptophysin, CD56, INSM1 markers expression prevalence and the association between NE differentiation and tumor molecular type. Material and methods: Observational, cross-sectional study which included 110 breast tissue samples with primary invasive carcinoma. Immunohistochemistry was performed for chromogranin, synaptophysin, CD56 and INMS1 markers. NE differentiation was considered with 10-90% positive cells, and NE tumor with > 90% positive cells. Results: 26.3% showed neuroendocrine differentiation. Out of these, 48.2% were luminal-A type, 24.1% luminal-B, 11.5% HER2neu, 17.2% triple-negative; 1.8% were NE tumors. Tumors were marker positive, and out of these to chromogranin in 24.5%, synaptophysin in 28.2%, CD56 in 2.7%, INSM1 in 16.4%. Synaptophysin was expressed in 17.3% luminal-A type, 6.4% luminal-B, 0.9% HER2neu, 3.6% triple-negative. NE differentiation showed association with synaptophysin expression (r = 0.586, p = 0.0001). Conclusion: The NE differentiation prevalence was 26.3% in primary invasive breast cancers, with luminal-A molecular type predominance.

Introducción: los tumores primarios de mama con diferenciación neuroendócrina (NEBC por sus siglas en inglés) son un grupo heterogéneo de tumores con diversidad de comportamiento biológico, con prevalencia y pronóstico poco definido. Objetivo: evaluar la prevalencia de la expresión los marcadores cromogranina, sinaptofisina, CD56, INSM1 y la asociación entre la diferenciación neuroendócrina y el tipo molecular del tumor. Material y métodos: estudio observacional, transversal que incluyó 110 muestras de tejido mamario con carcinoma invasor primario. Se realizó inmunohistoquímica para los marcadores cromogranina, sinaptofisina, CD56 y INMS1. La presencia 10-90% de células positivas se consideró diferenciación neuroendócrina y tumor neuroendócrino con > 90% de células positivas. Resultados: el 26.3% mostró diferenciación neuroendócrina. De estos, 48.2% fueron tipo luminal-A, 24.1% luminal-B, 11.5% HER2neu y 17.2% triple-negativo; 1.8% resultaron tumores neuroendócrinos. Los tumores presentaron marcadores positivos y de estos, 24.5% fueron a cromogranina, 28.2% a sinaptofisina, 2.7% a CD56 y 16.4% a INSM1. La sinaptofisina se expresó en 17.3% del tipo luminal-A, 6.4% luminal-B, 0.9% HER2neu, 3.6% triple-negativo. La diferenciación neuroendócrina mostró asociación con la expresión de sinaptofisina (r = 0.586, p = 0.0001). Conclusión: la prevalencia de la diferenciación neuroendócrina fue del 26.3% en los cánceres invasores primarios de mama, con predominio en el tipo molecular luminal-A.

Atrophic violaceous plaques as the first manifestation of a disorder of GNAS inactivation.

We report the case of a 10-month-old girl who presented with failure to thrive and multiple small atrophic violaceous plaques, with no other findings on her physical examination. The laboratory examinations, abdominal ultrasound and bilateral hand radiography performed were unremarkable. The skin biopsy revealed fusiform cells and focal ossification in the deep dermis. The genetic study showed a pathogenic variant of GNAS.

Mucinous Adenocarcinoma With Intrapulmonary Metastasis Harboring KRAS and GNAS Mutations Arising in Congenital Pulmonary Airway Malformation.

OBJECTIVES: Mucinous adenocarcinoma arising in unresected congenital pulmonary airway malformation (CPAM) is rare. Underlying driver mutations in addition to KRAS gain-of-function mutations in this setting and the long-term outcomes of these patients are unknown. METHODS: We report a case of metastatic mucinous adenocarcinoma harboring both KRAS and GNAS mutations arising in a type 1 CPAM of a 14-year-old male. A literature review was performed. RESULTS: Next-generation sequencing revealed identical KRAS (G12V) mutations in both the CPAM and metastatic adenocarcinoma and a missense mutation in the GNAS (R201C) gene in the metastatic adenocarcinoma only. Median survival was 23 and 4 years for patients with localized (no or limited spread within the same lobe of CPAM) and distant involvement (spread to any different lobe of CPAM) of mucinous cells, respectively (95% confidence interval, 23-23 and 1.5-22 years, respectively; P = .017). CONCLUSIONS: Mucinous cell proliferation associated with type 1 CPAM has exceptionally good long-term outcomes if confined within the same lobe of CPAM. A second oncogenic mutation in the GNAS gene may be necessary for progression to malignancy and distant spread.

Expression of GNAS, TP53, and PTEN Improves the Patient Prognostication in Sonic Hedgehog (SHH) Medulloblastoma Subgroup.

Medulloblastoma (MB) is the most common malignant brain tumor in children. It is currently classified in four main molecular subgroups with different clinical outcomes: sonic hedgehog, wingless, group 3, and group 4 (MBSHH, MBWNT, MBGRP3, or MBGRP4). Presently, a 22-gene expression panel has been efficiently applied for molecular subgrouping using nCounter technology. In this study, formalin-fixed, paraffin-embedded samples from 164 Brazilian medulloblastomas were evaluated, applying the 22-gene panel, and subclassified into the low and high expression of nine key medulloblastoma-related genes. In addition, TP53 mutation status was assessed using TruSight Tumor 15 Panel, and its correlation with expression and prognostic impact was evaluated. Samples from 149 of 164 patients (90%) were classified into MBSHH (47.7%), MBWNT (16.1%), MBGRP3 (15.4%), and MBGRP4 (20.8%). GNAS presented the highest expression levels, with higher expression in MBSHH. TP53, MYCN, SOX2, and MET were also up-regulated in MBSHH, whereas PTEN was up-regulated in MBGRP4. GNAS, TP53, and PTEN low expression was associated with the unfavorable patient outcome only for MBSHH (P = 0.04, P = 0.01, and P = 0.02, respectively). TP53 mutations were detected in 28.57% of MBSHH cases and exhibited association with lower expression and worse clinical outcome, although not statistically significant. The 22-gene panel for molecular classification of medulloblastoma associated with the expression of GNAS, TP53, and PTEN improves the patient prognostication in MBSHH subgroup and can be easily incorporated in the 22-gene panel without any additional costs.

Intragenic Deletions of GNAS in Pseudohypoparathyroidism Type 1A Identify a New Region Affecting Methylation of Exon A/B.

CONTEXT: Pseudohypoparathyroidism type 1A (PHP1A) and pseudopseudohypoparathyroidism (PPHP) are caused by inactivating mutations in the exons of GNAS that encode the alpha-subunit of the stimulatory G protein (Gsα). In some cases abnormal methylation of exon A/B of GNAS, a hallmark of PHP1B, has been reported. OBJECTIVE: To identify the underlying genetic basis for PHP1A/PPHP in patients in whom molecular defects were not detected by GNAS sequencing and microarray-based analysis of copy number variations. METHODS: Whole genome sequencing (WGS) and pyrosequencing of differentially methylated regions (DMRs) of GNAS using genomic deoxyribonucleic acid from affected patients. RESULTS: We identified 2 novel heterozygous GNAS deletions: a 6.4 kb deletion that includes exon 2 of GNAS in the first proband that was associated with normal methylation (57%) of exon A/B DMR, and a 1438 bp deletion in a second PHP1A patient that encompasses the promoter region and 5' untranslated region of Gsα transcripts, which was inherited from his mother with PPHP. This deletion was associated with reduced methylation (32%) of exon A/B DMR. CONCLUSIONS: WGS can detect exonic and intronic mutations, including deletions that are too small to be identified by microarray analysis, and therefore is more sensitive than other techniques for molecular analysis of PHP1A/PPHP. One of the deletions we identified led to reduced methylation of exon A/B DMR, further refining a region needed for normal imprinting of this DMR. We propose that deletion of this region can explain why some PHP1A patients have reduced of methylation of the exon A/B DMR.

Elevated expression of GNAS promotes breast cancer cell proliferation and migration via the PI3K/AKT/Snail1/E-cadherin axis.

PURPOSE: Although it has been well established that G protein plays pivotal roles in physiologic or pathologic conditions, including cancer formation, its role in breast cancer, especially specific subunits, remains largely unknown. Our work aimed to evaluate the correlation of the G protein alpha subunit (GNAS) with breast cancer and to investigate the underlying molecular mechanism. METHODS: The expression of GNAS was determined by breast tumor tissue microarray of 150 patients with complete follow-up information. The correlation between GNAS expression and clinical features was assessed. CCK8, EdU incorporation, flow cytometry, wound healing, transwell, western blot and tumor formation assays were carried out in nude mice to study the biological function of GNAS and the underlying molecular mechanism in breast cancer by silencing GNAS using a specific siRNA. RESULTS: High GNAS expression showed a close correlation with a reduced overall survival (p = 0.021), frequent distal metastasis (p = 0.026), advanced clinical stage (p = 0.001), stronger cell proliferation (ki67+ positive cell rate, p = 0.0351) and enhanced cancer cell migration, which was further confirmed by in vitro and in vivo assays and might be dependent on the PI3K/AKT/Snail1/E-cadherin axis. CONCLUSION: The data suggested that GNAS promoted breast cancer cell proliferation and migration (EMT) through the PI3K/AKT/Snail1/E-cadherin signaling pathway. These findings also indicate that GNAS can serve as a potential prognostic indicator and novel therapeutic target in breast cancer.

Using Digital Droplet Polymerase Chain Reaction to Detect the Mosaic GNAS Mutations in Whole Blood DNA or Circulating Cell-Free DNA in Fibrous Dysplasia and McCune-Albright Syndrome.

The GNAS postzygotic mosaic activating mutations involved in fibrous dysplasia and McCune-Albright syndrome (MAS) are not detectable in leukocytes by Sanger sequencing. Digital droplet polymerase chain reaction detects GNAS mutations in 7 of 12 patients (58.3%) suspected to have fibrous dysplasia/MAS from whole blood DNA, and in 4 of 5 patients (80%) from circulating cell-free DNA.

Fibrous dysplasia of the jaws: Integrating molecular pathogenesis with clinical, radiological, and histopathological features.

Fibrous dysplasia is a non-neoplastic developmental process that affects the craniofacial bones, characterized by painless enlargement as a result of bone substitution by abnormal fibrous tissue. Postzygotic somatic activating mutations in the GNAS1 gene cause fibrous dysplasia and have been extensively investigated, as well as being helpful in the differential diagnosis of the disease. Fibrous dysplasia may involve one (monostotic) or multiple bones (polyostotic), sporadically or in association with McCune-Albright syndrome, Jeffe-Lichenstein syndrome, or Mazabreud syndrome. This review summarizes the current knowledge on fibrous dysplasia, emphasizing the value of integrating the understanding of its molecular pathogenesis with the clinical, radiological, and histopathological features. In addition, we address important aspects related to the differential diagnosis and patient management.

Carcinoma neuroendocrino primario de vagina. Revisión de literatura a propósito de un caso / Primary neuroendocrine carcinoma of the vagina. Literature review on the subject of a case

RESUMEN El carcinoma primario de vagina representa 1 a 2% de los cánceres ginecológicos, siendo la diferenciación histológica neuroendocrina de células pequeñas extremadamente infrecuente, sólo se han reportado 28 casos en la literatura, describiéndose en orden de frecuencia en cérvix, endometrio, ovario, vagina y vulva. Se observa con más frecuencia en mujeres postmenopáusicas. Se presenta el caso de paciente femenino, de 39 años de edad, quien acude a la consulta por presentar secreción genital serohemática, fétida, de 1 mes de evolución, evidenciándose al examen físico lesión exofítica, friable, renitente, de aproximadamente 4 cm de diámetro, en tercio superior y cara posterolateral izquierda de vagina, por lo que se realiza biopsia excisional de dicha lesión, siendo el diagnóstico anatomopatológico carcinoma neuroendocrino de células pequeñas, grado histológico: 3. A propósito de este caso, se realiza una revisión del tema, haciendo hincapié en la importancia de la exploración ginecológica exhaustiva que incluya tomas de citologías y colposcopias periódicas, tomando en cuenta la vagina y así, realizar diagnóstico precoz en vista que el riesgo de carcinoma en dicha zona es infrecuente, mejorando el pronóstico y sobrevida de las pacientes.

ABSTRACT The primary carcinoma of the vagina represents 1 to 2 % of gynecologic cancers, being the histological differentiation neuroendocrine of small cells extremely infrequent, only 28 cases have been reported in the literature, describing in order of frequency: in the cervix, endometrium, ovary, vagina and vulva. It is most commonly seen in postmenopausal women. We present the case of a female patient, 39 years old, who comes to medical consult due to serohematic, fetid, genital discharge of 1 month of evolution, evidencing at physical examination an exophytic lesion, friable, renitent, with a diameter of approximately 4 cm, in the upper third and posterolateral left side of the vagina, for which an excisional biopsy of said lesion is performed, being the anatomopathological diagnosis neuroendocrine carcinoma of small cells, histological grade: 3. A bibliography reviewed was made, emphasizing the importance of exhaustive gynecological exploration with periodic cytology and colposcopy examinations, including the vagina for early diagnosis in view of carcinoma risk in this area is uncommon, improving the prognosis and survival of patients.

[Neuroendocrine carcinoma of the urinary bladder. A case report]. / Carcinoma neuroendocrino de vejiga. Reporte de un caso.

BACKGROUND: Small cell carcinoma of the urinary bladder is an infrequent lesion. CLINICAL CASE: We present the case of a 68-year-old male who arrived at the emergency room with a history of 24-h gross hematuria. Imaging studies show a urinary bladder tumor with a 218 cc volume that during a 20-day period increased to 426 cc. Histopathological images with hematoxylin-eosin show an infiltrating solid mass with uneven borders. It is composed of neoplastic cells with evident nuclei predominance and scant cytoplasm (small cells). Chromogranin immunohistochemical staining shows a diffusely positive cytoplasmic granular pattern on neoplastic cells. High molecular weight cytokeratin staining shows a negative pattern on neoplastic cells along with a positive pattern on reporsurrounding normal urothelium. Tumoral mass is positive for synaptophysin and CD-56 and negative for CK-7 and CK-20. Patient therapy was based on radiation plus chemotherapy. CONCLUSION: Small cell carcinoma of the urinary bladder represents 0.35-0.70% of urinary bladder tumors. Histological and immunohistochemical identification are key elements in the diagnosis. Treatment approach is based on cisplatin-based chemotherapy plus radical cystectomy, except when metastatic disease is present.

Antecedentes: el carcinoma neuroendocrino de células pequeñas primario de vejiga es una lesión maligna muy poco frecuente. Caso clínico: paciente masculino de 68 años de edad, que tuvo hematuria macroscópica de 24 horas de evolución. Estudios de imagen mostraron tumoración vesical de 218 cc, que en 20 días alcanzó un volumen de 426 cc. A la tinción con hematoxilina-eosina, histológicamente se apreció: placa sólida infiltrante de bordes irregulares, compuesta por células neoplásicas con claro predominio de núcleo y escaso citoplasma (células pequeñas). A la tinción inmunohistoquímica con cromogranina parecía difusamente positivo en células neoplásicas, en un patrón granular citoplasmático. A la tinción con citoqueratina de alto peso molecular se observó patrón negativo en células neoplásicas con control interno positivo en el urotelio acompañante en espécimen. De igual manera, la tumoración fue positiva para sinaptofisina y CD-56 y negativa para CK-7 y CK-20. El paciente recibió tratamiento a base de radioterapia y quimioterapia. Conclusión: el carcinoma neuroendocrino de células pequeñas primario de vejiga representa de 0.35 a 0.70% de los tumores vesicales primarios. Su diagnóstico se basa en el reconocimiento histológico e inmunohistoquímico. El tratamiento se fundamenta en quimioterapia con cisplatino más cistectomía radical, excepto cuando existe enfermedad metastásica.

GNAS is frequently mutated in both low-grade and high-grade disseminated appendiceal mucinous neoplasms but does not affect survival.

We analyzed a series of 55 disseminated appendiceal mucinous neoplasms treated at our institution for GNAS and KRAS mutations in an attempt to correlate mutation status with clinicopathological findings and patient survival. GNAS mutations (p.R201H, c.602G>A and p.R201C, and c.602C>T) were identified in 17 (31%) of 55 of disseminated mucinous neoplasms and were found in 8 (35%) of 23 low-grade mucinous neoplasms, 7 (37%) of 19 high-grade mucinous adenocarcinomas lacking a signet ring cell component, and 2 (15%) of 13 high-grade mucinous adenocarcinomas with a signet ring cell component. All 7 mucinous adenocarcinomas composed of pure (>95%) signet ring cells harbored wild-type GNAS. There was no significant association between GNAS mutations and sex and age (both with P > .05) or between GNAS mutations and individual adverse histologic features including cytologic grade, destructive invasion, tumor cellularity, angiolymphatic invasion, perineural invasion, and signet ring cells (all with P > .05). KRAS mutations were identified in 22 (40%) of 55 disseminated mucinous neoplasms. GNAS-mutated disseminated appendiceal mucinous neoplasms more frequently harbored concurrent KRAS mutations compared with GNAS wild-type tumors (65% versus 29%, P = .018). GNAS mutations were not significantly associated with overall survival (both with P > .05). Only overall tumor grade was an independent predictor of overall survival in the multivariate analysis (P = .01). Our results indicate that GNAS mutations are frequently identified in both low-grade and high-grade disseminated appendiceal mucinous neoplasms indicating that GNAS mutation status cannot be used to distinguish between low-grade from high-grade appendiceal mucinous neoplasms.

Giant insulinoma: a report of 3 cases and review of the literature.

Insulinoma is a rare pancreatic neuroendocrine tumor that is usually described as benign, sporadic, and very small (<2 cm). However, there have been rare case reports of insulinoma presenting as a giant tumor. We describe 3 cases of giant insulinomas, all of which developed liver metastases. The patients were aged 38, 63, and 67 years. Clinically, all patients presented with Whipple's triad associated with a large mass located in the pancreatic tail. The tumors ranged in size from 10 to 15 cm. On microscopic examination, the tumors were well differentiated with amyloid deposition ranging between 20% and 30%. Immunohistochemically, all 3 tumors showed strong diffuse expression of chromogranin and synaptophysin, whereas they were only focally positive for insulin. One patient developed liver recurrence 3 years after resection of the primary tumor yet remained asymptomatic without treatment. Another patient with liver recurrence underwent right hepatectomy and has been free of disease for 2 years. The third patient died of metastatic disease 13 years after initial surgery. Giant insulinomas are characterized by focal expression of insulin and high rates of liver metastases. Long-term follow-up is mandatory in these patients, as recurrence is expected after primary surgery.

Genetics of pituitary adenomas.

Pituitary adenomas are common tumors of the adenohypophysis which can cause considerable morbidity, due to excessive hormonal secretion or compression and local invasion of surrounding structures. The vast majority of pituitary adenomas occur sporadically. Altered gene expression is commonly detected but somatic mutations, epigenetic changes and abnormal microRNAs have also been described. Occurrence of GNAS mutations at a postzygotic stage lead to McCune-Albright syndrome (MAS), a disease causing endocrine hyperfunction and tumors in several organs, including the pituitary. Familial pituitary adenomas occur as part of a syndrome affecting other organs, such as in MEN1 or Carney complex, or occur with pituitary adenomas only as in familial isolated pituitary adenoma (FIPA). FIPA, an autosomal-dominant disease with variable penetrance, is explained in 20% of patients by germline mutations in the tumor suppressor aryl hydrocarbon receptor interacting protein(AIP), while no gene abnormality has been identified to date in the majority of the FIPA families. AIP mutation-positive patients have a characteristic clinical phenotype with usually young- or childhood-onset growth hormone (GH) and/or prolactin (PRL)-secreting adenomas and can be seen in cases with no apparent family history as well. Understanding the tumorigenic process in AIP-positive and AIP-negative FIPA patients could result in better diagnostic and treatment options for both familial and sporadic cases.

Pseudohypoparathyroidism type Ia: a novel GNAS mutation in a Brazilian boy presenting with an early primary hypothyroidism.

Pseudohypoparathyroidism type Ia (PHP Ia) is a rare disease characterized by an elevated parathyroid hormone due to the resistance to its action in target tissues. We report a new GNAS mutation causing PHP Ia and an atypical early-onset primary hypothyroidism. A 3-year-old boy was diagnosed with obesity, delayed pyschomotor development, and round face. The laboratory evaluation at the age of 1 year showed primary hypothyroidism, hypocalcemia, hyperphosphatemia, elevated alkaline phosphatase, and parathyroid hormone. These data led to the diagnosis of PHP Ia. Molecular analysis revealed a novel missense mutation in GNAS exon 1 (TCG→CGC, Cys3→Arg) in both the child and his mother. Although previously reported cases described delayed subclinical hypothyroidism as the more common thyroid abnormality, we report a not previously described GNAS mutation associated with an atypical early-onset primary hypothyroidism. These observations broaden the clinical spectrum of PHP Ia and its associated mutations.

SAGE analysis highlights the putative role of underexpression of ribosomal proteins in GH-secreting pituitary adenomas.

BACKGROUND: Although the molecular pathogenesis of pituitary adenomas has been assessed by several different techniques, it still remains partially unclear. Ribosomal proteins (RPs) have been recently related to human tumorigenesis, but they have not yet been evaluated in pituitary tumorigenesis. OBJECTIVE: The aim of this study was to introduce serial analysis of gene expression (SAGE), a high-throughput method, in pituitary research in order to compare differential gene expression. METHODS: Two SAGE cDNA libraries were constructed, one using a pool of mRNA obtained from five GH-secreting pituitary tumors and another from three normal pituitaries. Genes differentially expressed between the libraries were further validated by real-time PCR in 22 GH-secreting pituitary tumors and in 15 normal pituitaries. RESULTS: Computer-generated genomic analysis tools identified 13,722 and 14,993 exclusive genes in normal and adenoma libraries respectively. Both shared 6497 genes, 2188 were underexpressed and 4309 overexpressed in tumoral library. In adenoma library, 33 genes encoding RPs were underexpressed. Among these, RPSA, RPS3, RPS14, and RPS29 were validated by real-time PCR. CONCLUSION: We report the first SAGE library from normal pituitary tissue and GH-secreting pituitary tumor, which provide quantitative assessment of cellular transcriptome. We also validated some downregulated genes encoding RPs. Altogether, the present data suggest that the underexpression of the studied RP genes possibly collaborates directly or indirectly with other genes to modify cell cycle arrest, DNA repair, and apoptosis, leading to an environment that might have a putative role in the tumorigenesis, introducing new perspectives for further studies on molecular genesis of somatotrophinomas.

Tumor carcinoide de la apéndice cecal: Reporte de cuatro casos en la Clínica Carlos Ardila Lülle, Floridablanca, Colombia / Carcinoid tumor of the cecal appendix: A report of four cases in the Clinica Carlos Ardila Lulle, Floridablanca, Colombia

Introducción: Los tumores carcinoides son las neoplasias más frecuentes del apéndice cecal, se caracterizan por un crecimiento lento y curso clínico asintomático, su incidencia se calcula en 1-2 casos por cada 100,000 habitantes, se encuentran en menos del 1% de las apendicetomías y se presentan con mayor frecuencia en mujeres entre la cuarta a quinta época de la vida. Por lo general se trata de lesiones pequeñas que se diagnostican luego de la apendicetomía. Metodología El presente trabajo corresponde a una descripción de casos de tumor carcinoide del apéndice cecal, realizado en el laboratorio de patología MEGA, de la Clínica Ardila Lulle (CAL) que incluye revisión de protocolos de especímenes quirúrgicos analizados entre enero 1 de 2000 y diciembre 31 de 2010. Resultados: Durante el periodo propuesto se encuentran cuatro casos de tumor carcinoide confinado al apéndice cecal en cuatro mujeres jóvenes. Tres de las lesiones presentan patrón histológico tipo A o insular y el restante un patrón tipo B o trabecular, en todos los casos se documentó reactividad con las sales de plata con la coloración de Fontana Masson y en los cuatro se encontró positividad con el marcador neuroendocrino cromogranina. Conclusión: Los tumores carcinoides de apéndice son lesiones de origen neuroendocrino, la mayoría circunscritas a la punta del órgano y de curso clínico indolente, sin embargo algunos de estos tumores tienen un comportamiento agresivo, que depende de su tamaño y de la actividad mitótica de sus células, por lo que se recomienda incluir en la evaluación diagnostica la cromogranina y el Ki67, marcadores neuroendocrino y de proliferación celular. Salud UIS 2011; 43 (2): 203-210.

Introduction: The carcinoids tumours are the most common neoplasm of the cecal appendix, are characterized by a slow growth and asymptomatic clinical course, its incidence is estimated at 1-2 cases per 100.000 inhabitants, are less than 1% of appendicectomies and occur most often in women between the fourth o fifth decade of life. Usually these are small lesions diagnosed after appendicectomy. Methodology: This work belongs to a description of cases of carcinoid tumor of cecal appendix, conduced in the MEGA anatomic pathology laboratory of Carlos Ardila Lulle Clinic (CAL), wich includes protocols review of surgical specimens analized between January 1, 2000 and December 31, 2010. Results: During the proposed period are four cases of carcinoid tumor confined to the cecal appendix in four young women. Three of the lesions have the A histological type or insular pattern, and the remainder have the B histological type or trabecular pattern, in all cases documented reactivity with silver salts with Masson-Fontana stain and all four were found positive with the neuroendocrine marker chromogragin. Conclusion: The carcinoid tumors of the apenddix are lesions of neuroendocrine origen, most of them located at the tip of the organ, and having a indolent clinical course; however some of these tumors have an aggressive behavior, which depends on its size and the mitotic activity of its cells, that's the reason why the diagnostic evaluation of neuroendocrine markers like chromogranin, and Ki67 (proliferation cell index) are recommended. Salud UIS 2011; 43 (2): 203-210.

Impact of gsp oncogene on the mRNA content for somatostatin and dopamine receptors in human somatotropinomas.

INTRODUCTION: It has been reported in some series that gsp+ somatotropinomas are more sensitive to somatostatin analogues (SA) and dopamine's actions which may be related to their somatostatin receptor (SSTR) and dopamine receptor (DR) profile. No previous studies have been undertaken to evaluate the SSTR and DR profile related with the gsp status in somatotropinomas. OBJECTIVES: To determine if (1) gsp status is correlated with response to octreotide LAR (LAR) and tumor expression patterns of SSTR1-5 and DR1-5 and (2) cAMP level can directly modulate SSTR and DR mRNA levels. METHODS: Response to SA was evaluated by GH and IGF-I percent reduction after 3 and 6 months of treatment with LAR. Conventional PCR and sequencing were used to identify gsp+ tumors. Quantitative real-time PCR was used to determine SSTR and DR tumor expression. Primary pituitary cell cultures of primates were used to study whether SSTR and DR expression is regulated by forskolin. RESULTS: The response to LAR did not significantly differ between patients with gsp+ and gsp- tumors; however, gsp+ tumors expressed higher levels of SSTR1, SSTR2, DR2 and a lower level of SSTR3. Forskolin increased SSTR1, SSTR2, DR1 and DR2 expression in cell cultures. CONCLUSION: Elevated SSTR1, SSTR2, and DR2 tumor expression may help improve responsiveness to SA and DA therapy; however, this study may not have been appropriately powered to observe significant effects in the clinical response. Elevated cAMP levels could be directly responsible for the upregulation in SSTR1, SSTR2 and DR2 mRNA levels observed in gsp+ patients.