Differential expression, diagnostic and prognostic significance of stathmin-1 and CD147 in various uterine smooth muscle tumors / Expresión diferencial, diagnóstico y significado de pronóstico de stathmin-1 y CD147 en diferentes tumores del músculo liso uterino

SUMMARY: Uterine smooth muscle tumors (USMT) are common, behavior-distinct gynecological tumors; including: leiomyoma (ULM), leiomyosarcoma (ULMS), and smooth muscle tumors of undetermined malignant potential (STUMP). Pre-operative distinction is difficult, thus diagnosis relies on histopathology. Immunohistochemistry (IHC) had been used to help in distinction. We studied two markers (stathmin-1 and CD147) to demonstrate whether they have diagnostic/ prognostic assist. Sixty seven USMT are studied. Age, follow up, and recurrence/metastasis data were collected. Representative slides were stained and Histologic score (HS) calculated as stain intensity (SI) X percentage of positive tumor cells (PP). Results were grouped as low expression (LE) and high expression (HE); then correlated to tumor types, and risk of recurrence/ metastasis. Statistical analysis (P < 0.05); Sensitivity, specificity, positive and negative predictive values and confidence intervals in diagnosing ULMS were calculated. Stathmin-1 HS (p= 0.000) and HE (p=0.002) were different among groups. Same as for CD147 HS and HE (both p=0.000), with a gradient increase from LM to STUMP to ULMS. Sensitivity, specificity, positive and negative predictive values and confidence intervals in diagnosing ULMS were as following: For stathmin-1 HS: 92 %; 20 %; 42 %; and 80 % (CI= 44-96 %). For Stathmin-1 HE: 80 %; 66 %; 60 %; and 84 % (CI=66-94 %). For CD147 HS: 85 %; 22 %; 41 %; and 69 %. For CD147 HE: 58 %; 49 %; 42 %; and 65 % (CI= 45-80 %), respectively. Recurrence / metastasis were documented in 6 cases (4 ULMS; 2 STUMP) with follow up ranging from 6 months to 102 months. 5 tumors had stathmin-1 HE (p=0.099); 2 had CD147 HE (p=0.393) in the primary tumors. STMN1 and CD147 are helpful diagnostic tests for USMT sub-typing, especially for ULMS. Gradient increase of expression from LM, to STUMP, to ULMS may indicate a role in malignant transformation in USMT, and in increased risk of recurrences/metastasis.

RESUMEN: Los tumores del músculo liso uterino (USMT, por sus siglas en inglés) son tumores ginecológicos comunes y de comportamiento distinto; incluyendo: leiomioma (ULM), leiomiosarcoma (ULMS) y tumores de músculo liso de potencial maligno indeterminado (STUMP). La distinción preoperatoria es difícil, por lo que el diagnóstico se basa en la histopatología. La inmunohistoquímica (IHQ) se había utilizado para ayudar en la distinción. Estudiamos dos marcadores (stathmin-1 y CD147) para demostrar si había efecto diagnóstico / pronóstico. Se estudiaron 67 USMT. Se recopilaron los datos de edad, seguimiento y recurrencia / metástasis. Las muestras representativas se tiñeron y la puntuación histológica (HS) se calculó como la intensidad de la tinción (IS) x porcentaje de células tumorales positivas (PP). Los resultados se agruparon como expresión baja (EB) y expresión alta (EA); luego se correlacionaeon con los tipos de tumores y el riesgo de recurrencia / metástasis. Análisis estadístico (P <0,05); se calcularon la sensibilidad, la especificidad, los valores predictivos positivos y negativos y los intervalos de confianza en el diagnóstico de ULMS. Stathmin-1 HS (p = 0,000) y HE (p = 0,002) fueron diferentes entre los grupos. Igual que para CD147 HS y HE (ambos p = 0,000), con un aumento de gradiente de LM a STUMP a ULMS. La sensibilidad, la especificidad, los valores predictivos positivos y negativos y los intervalos de confianza en el diagnóstico de ULMS fueron los siguientes: Para stathmin-1 HS: 92 %; 20 %; 42 %; y 80 % (IC = 44-96 %). Para Stathmin-1 HE: 80 %; 66 %; 60 %; y 84 % (IC = 66-94 %). Para CD147 HS: 85 %; 22 %; 41 %; y el 69 %. Para CD147 HE: 58 %; 49 %; 42 %; y 65 % (IC = 45-80 %), respectivamente. La recurrencia / metástasis se documentaron en 6 casos (4 ULMS; 2 STUMP) con un seguimiento que osciló entre 6 meses y 102 meses. Cinco tumores tenían stathmin-1 HE (p = 0,099); dos tenían CD147 HE (p = 0,393) en los tumores primarios. STMN1 y CD147 son pruebas de diagnóstico útiles para la subclasificación de USMT, especialmente para ULMS. El aumento en el gradiente de la expresión de LM, a STUMP, a ULMS puede indicar un papel en la transformación maligna en USMT y en un mayor riesgo de recurrencias / metástasis.

Increased Expression of EMMPRIN and VEGF in the Rat Brain after Gamma Irradiation

The extracellular matrix metalloproteinase inducer (EMMPRIN) has been known to play a key regulatory role in pathological angiogenesis. A elevated activation of vascular endothelial growth factor (VEGF) following radiation injury has been shown to mediate blood-brain barrier (BBB) breakdown. However, the roles of EMMPRIN and VEGF in radiation-induced brain injury after gamma knife surgery (GKS) are not clearly understood. In this study, we investigated EMMPRIN changes in a rat model of radiation injury following GKS and examined potential associations between EMMPRIN and VEGF expression. Adult male rats were subjected to cerebral radiation injury by GKS under anesthesia. We found that EMMPRIN and VEGF expression were markedly upregulated in the target area at 8-12 weeks after GKS compared with the control group by western blot, immunohistochemistry, and RT-PCR analysis. Immunofluorescent double staining demonstrated that EMMPRIN signals colocalized with caspase-3 and VEGF-positive cells. Our data also demonstrated that increased EMMPRIN expression was correlated with increased VEGF levels in a temporal manner. This is the first study to show that EMMPRIN and VEGF may play a role in radiation injuries of the central nervous system after GKS.