Expression and Clinicopathological Significance of CD9 in Gastrointestinal Stromal Tumor

This study investigated the expression and clinicopathological significance of CD9 in gastrointestinal stromal tumor (GIST). Immunohistochemistry staining for CD9 was performed on tumor tissues from 74 GIST patients. The correlation with clinicopathological features, risk classification and prognosis was analyzed. CD9-positive staining comprised 59.5% (44/74) of the GIST patients. The CD9-positive expression rate of the sample was significantly associated with diameter (P = 0.028), mitotic counts (P = 0.035), risk classification (P = 0.018) and three-year recurrence-free survival (RFS) (P < 0.001). Cox proportional hazards regression (HR = 0.352; P = 0.015) showed that CD9 is an independent factor for post-operative RFS. The subgroup analysis showed that CD9 expression in gastric stromal tumor (GST) is significantly associated with diameter (P = 0.031), risk classification (P = 0.023) and three-year RFS (P = 0.001). The Cox proportional hazards regression (HR = 0.104; P = 0.006) also showed that CD9 is an independent factor for RFS of GST. However, CD9 expression does not have a statistically significant correlation with clinicopathological features, risk classification, and prognosis in non-GST. In conclusion, CD9 expression in GIST appears to be associated with the recurrence and/or metastasis of GIST patients, especially in GST, which may indicate the important role of CD9 in the malignant biological behavior and prognosis of GST.

Características genético-moleculares de los tumores estromales gastrointestinales (GIST) / Molecular and genetic features of gastrointestinal stromal tumors (GIST)

Los tumores estromales gastrointestinales (GIST) son neoplasias mesenquimales que típicamente surgen a nivel del estómago, intestino delgado, colon, y otros sitios en la cavidad abdominal y su identificación se ha incrementado por mejoras en los criterios de detección. La mayor parte de los tumores GIST son causados por mutaciones activadoras en los genes de receptores transmembranares tirosina quinasa c-KIT y receptor alpha del factor de crecimiento derivado de plaquetas (PDGFRA). Las mutaciones causales de GIST se restringen solo a ciertas regiones del gen que corresponden a importantes zonas funcionales de c-KIT o PDGFRA. Se reporta que hasta 70% de casos de GIST se debe a mutaciones en el exón 11 del gen c-Kit que corresponde a la región yuxtamembrana del receptor. La región y el tipo de mutación determinan diferencialmente cómo se desarrolla la neoplasia, el pronóstico y su respuesta a inhibidores de las tirosina quinasas como el Imanatib. Por tal motivo, el genotipado de KIT y PDGFRA es importante para el diagnóstico y establecimiento de la sensibilidad a los inhibidores tirosina quinasa.

Gastrointestinal stromal tumors (GISTs) are mesenchymal neoplasms typically arising in the stomach, small intestine, colon, and other sites in the abdominal cavity and its identification has improved dramatically mainly due to better criteria in its detection. Most GISTs tumors harbor activating mutations in the tyrosine kinase receptor c-KIT or platelet derived growth factor receptor-alpha (PDGFRA). Those mutations are restricted to a few regions corresponding to important functional domains of c-KIT or PDGFRA. Upto 70% of cases are due to mutations in exon 11 of c-KIT corresponding to its juxtamembrane region of the receptor. The location and type of mutation will differentially determine the development of the disease, its prognosis and the response to inhibitors of tyrosine kinases as Imanatib. For this reason, genotyping c-KIT and PDGFRA is important for GIST diagnosis and assessment of sensitivity to tyrosine kinase inhibitors.

Ki-67 expression score correlates to survival rate in gastrointestinal stromal tumors (GIST) / Escore de expressão de Ki-67 correlaciona-se com taxa de sobrevida em tumores estromais gastrointestinais (GIST)

PURPOSE: To evaluate the immunohistochemical expression of p16, Ki-67, p53 and Bcl-2 proteins in gastrointestinal stromal tumors (GIST); to assess the possible association between these variables and clinical and histopathological factors of cancer; and to check for prognostic value of these variables (survival and recurrence). METHODS: A sample of 55 patients treated surgically for GIST in three hospitals was studied. The surgically excised tumors were confirmed as GIST by KIT, vimentin, desmin S100 protein, CD117, 1A4 and CD34 assessment in paraffin blocks. RESULTS: Only 9 (16%) cases of GIST were positive for p53, p16 was positive among 43.6%; 80% of GISTs showed staining for Bcl-2. The proliferative index (expressed as the proportion of positive cells) assessed by immunohistochemical expression of Ki-67 was high in 49% of cases. Elevated Ki-67 scores were associated to high histological grade (p=0.0026) and mitosis index, MI (p=0.0001). High Ki-67 index was associated to death. Expression of p53, p16 and Bcl-2 did not correlate to morphological or clinical variables. CONCLUSIONS: Ki-67 immunohistochemical evaluation should be included in preoperative evaluation of GIST biopsies or surgical specimens as a prognostic tool for clinical staging; and all other proteins studied (Bcl-2, p53 and p16) did not play a role in GIST metabolic or carcinogenic process, remaining without prognostic value.

OBJETIVO: Avaliar a expressão imunoistoquímica de p16, Ki-67, p53 e Bcl-2 proteínas em tumores gastrointestinais estromais (GIST); determinar a possível associação entre essas variáveis e fatores clínicos e histopatológicos de câncer, e para verificar o valor prognóstico destas variáveis (sobrevivência e recorrência). MÉTODOS: Uma amostra de 55 pacientes tratados cirurgicamente para GIST em três hospitais foi estudada. Os tumores extirpados cirurgicamente foram confirmados como GIST por KIT, vimentina, proteína desmina S100, CD117, 1A4 e avaliação de CD34 em blocos de parafina. RESULTADOS: Apenas nove (16%) casos de GIST foram positivos para p53, p16 foi positiva em 43,6%, 80% dos GIST apresentaram coloração para Bcl-2. O índice proliferativo (expresso como a proporção de células positivas), avaliado pela expressão imunoistoquímica de Ki-67, foi elevado em 49% dos casos. Escores de Ki-67 elevados foram associados com alto grau histológico (p=0,0026) e índice de mitose, MI (p=0,0001). Alto índice de Ki-67 foi associado à morte. Expressão da p53, p16 e Bcl-2 não se correlacionou com as variáveis morfológicas ou clínicas. CONCLUSÕES: A avaliação imunoistoquímica de Ki-67 deve ser incluída na avaliação pré-operatória de biópsias ou peças cirúrgicas de GIST como uma ferramenta prognóstica para o estadiamento clínico, e todas as outras proteínas estudadas (Bcl-2, p53 e p16) não desempenharam um papel no processo metabólico ou carcinogênico em GIST, mantendo-se sem valor prognóstico.

Tumores del estroma gastrointestinal (GIST): características clinico-morfológicas y perfil inmunohistoquímico / Gastrointestinal stromal tumors (GIST): clinical-morphological features and immunohistochemical profile

Los tumores del estroma gastrointestinal (GIST) son neoplasias de origen mesenquimático que representan aproximadamente el 0,3 por ciento de todas las neoplasias del tubo digestivo, caracterizadas inmunohistoquímicamente por expresar CD117 en el 95 por ciento de los casos y afectando más frecuentemente estómago e intestino delgado. El objetivo de este estudio fue describir aspectos clínicos, morfológicos y de inmunohistoquímica en pacientes con diagnóstico de GIST en la Unidad de Anatomía Patológica del Hospital Hernán Henríquez Aravena de Temuco, Chile. Estudio de cohorte retrospectiva. Se estudiaron 30 pacientes con diagnóstico de GIST intervenidos entre 1999 y 2010 en el Hospital Hernán Henríquez Aravena de Temuco. Las variables clínicas y morfológicas estudiadas fueron edad, género, localización y tamaño tumoral, tipo histológico, índice mitótico, compromiso de mucosa, grado de pleomorfismo nuclear y presencia de necrosis. El estudio inmunohistoquímico consideró c-KIT, CD34 y S-100. Se utilizaron estadísticas descriptivas y analíticas; aplicando chi-cuadrado de Pearson y exacto de Fisher para las variables categóricas; y, T-test para variables continuas. El promedio de edad fue 60 años (17-81 años), verificándose un 60 por ciento de mujeres en el grupo estudiado. El 90 por ciento correspondió a tumores de localización gastro-intestinal, representando estómago e intestino delgado el 80 por ciento de los casos. El tamaño tumoral promedio fue 75,9 mm. Correspondió a patrón fusocelular el 77 por ciento, observándose necrosis en el 37 por ciento de los casos. El 50 por ciento presentó > 5 mitosis/50 CAM, verificándose compromiso de la mucosa en un 67 por ciento. Según el grupo pronóstico se verificó 7 por ciento grupo 1, 23 por ciento grupo 2, 20 por ciento grupo 3, 0 por ciento grupo 4, 10 por ciento grupo 5 y 40 por ciento grupo 6. El 100 por ciento expresó positividad para c-KIT, 63 por ciento para CD34 y 3 por ciento para S-100. Los GIST afectan mayormente...

Gastrointestinal stromal tumors (GIST) are mesenchymal neoplasms that represent approximately 0.3 percent of all malignancies of the gastrointestinal tract, characterized immunohistochemically for CD117 expression in 95 percent of cases and most commonly affects the stomach and small intestine. The aim of this study is to describe the clinical, morphological and immunohistochemical diagnosis of gist patients in the unit of pathology Hernán Henríquez Aravena Hospital in Temuco. Retrospective cohort study. We studied 30 patients with gist who underwent surgery between 1999 and 2010 in the Hernan Henríquez Aravena Hospital in Temuco. The clinical and morphological variables studied were age, gender, location and tumor size, histological type, mitotic index, commitment mucosa, degree of nuclear pleomorphism and necrosis. immunohistochemical study found c-KIT, CD34 and S-100. Descriptive statistics and analytical, using Pearson chi-square and Fisher exact tests for categorical variables, and T-test for continuous variables. The average age was 60 years (17-81 years), verified 60 percent of women in the study group. 90 percent corresponded to tumors located gastro-intestinal, stomach and small intestine represents 80 percent of cases. The average tumor size was 75.9 mm. spindle pattern accounted for 77 percent, with necrosis in 37 percent of cases. 50 percent had> 5 mitosis/50 cam, mucosal involvement verified by 67 percent. according to the prognostic group was observed 7 percent group 1, group 2 23 percent, 20 percent in group 3, 0 percent in group 4, 10 percent and 40 percent group 5 group 6. 100 percent expressed positive for c-KIT, CD34 63 percent and 3 percent for S-100. GIST mostly affect patients from the 4 th -6 decade of life with a slight female predominance, stomach and small intestine being the organs most commonly affected. Immunohistochemical study showed positivity for c-KIT and CD34 in 100 percent and 63 percent of cases.

Tumor del estroma gastrointestinal (TEGI): un estudio de su frecuencia y perfil de inmunohistoquímica / Gastrointestinal stromal tumors: analysis of 51 cases, immunohistochemical expression

Background: Gastrointestinal Stromal Tumors (GIST) have a mesenchymal origin and correspond to 1 percent of all gastrointestinal tumors. They have a benign behavior in approximately 75 percent of cases. They express CD117, CD34, smooth muscle actin, S-100 and desmin, markers that are useful in the differential diagnosis of smooth muscle tumors and those of neurogenic origin. Aim: To report our experience with GIST. Material and Methods: A retrospective, observational study. The pathology reports of GIST in the period 2004-2008 were reviewed. Immunohistochemical expression, pathological grade, mitotic index and histological patterns were reviewed. The medical records of patients were reviewed to obtain age and gender, location, size and presence of metastases. Results: A total of 51 GIST were identified, coming from 21 males and 30 females. Nineteen tumors were located in the small bowel, 18 in the stomach, four in the rectum, two in the colon and in five, the location was not specified. In 28 cases, the pathological pattern was spindle cell, in 12 mixed, in six epithelioid, in three pleomorphic, in one signet ring cell and giant cell in one. Forty nine percent of tumors were of high grade. Metastases were found in the liver in two cases, in the omentum in two and in the spleen, kidney, retroperitoneum and pancreas, in one case each. Two had lymph node involvement. Conclusions: GIST tumor corresponded to a 0.12 percent of all pathology reports during the study period. Most tumors in this series were of high grade.

Introducción: Los Tumores del Estroma Gastrointestinal (TEGI) son de origen mesenquimal comprendiendo el 1 por ciento de todos los tumores GI. Son benignos del 70 a 80 por ciento. Expresan CD117, CD34, actina de músculo liso, S-100 y desmina, marcadores útiles en el diagnóstico diferencial de tumores de músculo liso y tumores de origen neurogénico. Material y Método: Es un estudio retrospectivo y descriptivo. Se revisaron los reportes en el período 2004-2008 registrados como TEGI, valorando la expresión Inmunohistoquímica, grado histológico, índice mitótico, y patrones histológicos. Del reporte histológico se obtuvo la edad y sexo del paciente, localización, tamaño y metástasis. Resultados: Se recolectaron 51 casos corroborados como TEGI. Encontrando una prevalencia del sexo femenino (30) y una edad media de 52 años. Las localizaciones fueron: Intestino delgado (19), estómago (18), no especificado (5), recto (4), colon (2), retroperitoneo (2), no encontramos en esófago. Los patrones encontrados fueron el fusocelular (28), mixto (12), epitelioide (6), pleomórfico (3), células en anillo de sello (1), células gigantes (1). La mayoría (49 por ciento) fue de alto grado, presentando metástasis a hígado (2), ganglios (2), epiplón (2), bazo (1), riñón (1), retroperitoneo (1) y páncreas (1). Discusión: Se realizaron un total de 41.035 estudios histopatológicos, de los cuales 51 casos corresponden a LEGI, esto equivale al 0,12 por ciento. Encontramos tumores en los que su morfología, tamaño e índice mitótico fueron de bajo grado y presentaron metástasis y recidivas al momento del diagnóstico. Veinticinco casos fueron de alto grado (49 por ciento), lo cual es mayor a lo reportado por la literatura 20-30 por ciento, probablemente porque este es un hospital de concentración y generalmente los pacientes acuden a atención médica en una etapa avanzada de la enfermedad.

Expresión inmunohistoquímica de vimentina, CD 34 y c-Kit (CD 117) en tumores estromales gastrointestinales (GISTs) / Inmunohistochemistry expression of vimentin, CD 34 and c-Kit (CD117) in gastrointestinal stromal tumors

Los tumores estromales gastrointestinales (GISTs) comprenden a tumores de origen mesenquimal que antes eran clasificados como "tumores del músculo liso", no obstante los avances en el campo de la microscopía electrónica e inmunohistoquímica han permitido su diferenciación. Derivan de las células intersticiales de Cajal, representan el 1-2 por ciento de todas las neoplasias del tubo digestivo y son más frecuentes en personas mayores de 40 años, con igual incidencia en ambos sexos. Se estudiaron 30 casos de GISTs en un análisis prospectivo y retrospectivo, en el período comprendido entre los años 1987 y 2007. Para el material retrospectivo se estudiaron bloques de tejidos en parafina. El material se fijó en formaldehído al 10 por ciento y se incluyó en parafina, realizando tinciones habituales con H&E y técnicas histoquímicas (P.A.S y tricrómico de Masson). Se realizó, además, panel inmunohistoquímico: Vimentina, Actina de músculo liso, CD-34 y c-Kit (CD-117). Con el fin de estudiar las características anatomopatológicas, en relación a la sintomatología clínica que presentan los GISTs, se observó el comportamiento de los mismos teniendo en cuenta diferentes variables. Con respecto a la inmunohistoquímica, la vimentina fue positiva en el 100 por ciento de los casos, mientras que CD-34 y CD-117 fueron positivos en aproximadamente el 90 por ciento. La tendencia de estos tumores a seguir un curso clínico impredecible, con riesgo de recidiva tardía y de metástasis, hace recomendable el seguimiento del paciente regularmente y por un período indefinido. El haber tenido la oportunidad de estudiar 30 pacientes portadores de GISTs mediante la implementación de técnicas inmunohistoquímicas, a los fines de confirmar la histogénesis tumoral, motivan la presente comunicación.

GIST’s are tumors of mesenchymal origin that were previously classified as smooth muscle tumors despite the advances in the field of electron microscopy and immunohistochemistry have allowed their differentiation. They derive from interstitial cells of Cajal. They account for 1-2 percent of all cancers of the digestive tract. They are more common in people over 40 years of age, with equal incidence in both sexes. We studied 30 cases of gastrointestinal stromal tumors in a prospective and retrospective analysis in the period between 1987 and 2007. For retrospective material were studied in paraffin tissue blocks. They were fixed in formaldehyde to 10 percent and included in paraffin by routine staining with H&E and histochemical techniques (PAS and Masson trichrome). We performed further, immunohistochemical de panel: Vimentin, smooth muscle actin, CD-34 and c-Kit (CD-117). To study the pathological features in relation to the clinical symptoms presented by GIST’s, we observed the behavior of the same taking into account different variables. With regard to immunohistochemistry, vimentin was positive in 100 percent of the cases, whereas CD-34 and CD-117 were positive in approximately 90 percent. The tendency of these tumors follow an indolent clinical course with late recurrence risk, does recommend monitoring patients regularly and for an indefinite period. The rarity of this disease, having had the opportunity to study 30 cases of GISTs and analysis of the value of immunohistochemistry for the confirmation of the histogenesis object of the present communication.