RESUMEN
Endometrial stromal sarcomas (ESS) are rare uterine malignant mesenchymal neoplasms, which are currently treated by surgery, as effective adjuvant therapies have not yet been established. Tyrosine kinase inhibitors have rarely been applied in ESS therapy, with few reports describing imatinib responsivity. The aim of this study was to analyze the status of different tyrosine kinase receptors in an ESS series, in order to evaluate their potential role as molecular targets. Immunohistochemistry was performed for EGFR, c-KIT, PDGFR-α, PDGFR-ß, and ABL on 28 ESS. EGFR, PDGFR-α, and PDGFR-ß gene expression was investigated by real-time polymerase chain reaction (qRT-PCR) on selected cases. "Hot-spot" mutations were screened for on EGFR, c-KIT, PDGFR-α, and PDGFR-ß genes, by sequencing. All analysis was executed from formalin-fixed, paraffin-embedded specimens. Immunohistochemical overexpression of 2 or more tyrosine kinase receptors was observed in 18 of 28 tumors (64%), whereas only 5 tumors were consistently negative. Gene expression profiles were concordant with immunohistochemical overexpression in only 1 tumor, which displayed both high mRNA levels and specific immunoreactivity for PDGFR-α, and PDGFR-ß. No activating mutations were found on the tumors included in the study. This study confirms that TKRs expression is frequently observed in ESS. Considering that the responsiveness to tyrosine kinase inhibitors is known to be related to the presence of specific activating mutations or gene over-expression, which are not detectable in ESS, TKRs immunohistochemical over-expression alone should not be considered as a reliable marker for targeted therapies in ESS. Specific post-translational abnormalities, responsible for activation of TKRs, should be further investigated.
Asunto(s)
Neoplasias Endometriales/química , Proteínas Tirosina Quinasas Receptoras/análisis , Sarcoma Estromático Endometrial/química , Adulto , Anciano , Neoplasias Endometriales/genética , Receptores ErbB/análisis , Receptores ErbB/genética , Femenino , Humanos , Inmunohistoquímica , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Proteínas Proto-Oncogénicas c-kit/análisis , Proteínas Proto-Oncogénicas c-kit/genética , Receptor alfa de Factor de Crecimiento Derivado de Plaquetas/análisis , Receptor alfa de Factor de Crecimiento Derivado de Plaquetas/genética , Receptor beta de Factor de Crecimiento Derivado de Plaquetas/análisis , Receptor beta de Factor de Crecimiento Derivado de Plaquetas/genética , Sarcoma Estromático Endometrial/genéticaRESUMEN
We investigated lymphoma risk following hepatitis infection in a case-control study of 274 incident lymphoma cases, defined according to the WHO classification, and 336 population controls in Sardinia, Italy. Part of our study population (198 cases and 219 controls) was included in the EPILYMPH study of Hepatitis C virus (HCV) infection in relation to non-Hodgklin's lymphoma risk. Based on questionnaire information on whether and at what age a diagnosis of hepatitis was posed by a physician, systematic anti-HCV antibodies testing in cases and controls by enzyme-linked immunoassay, and HCV-RNA assessment by PCR analyses in positive samples, we investigated more in detail whether hepatitis non-C is also associated with lymphoma risk, and whether risk varies by clinical form of hepatitis (acute or chronic infection). After adjusting by age, gender, education, and area of birth whether from the study area or elsewhere in Italy, a previous generic diagnosis of hepatitis was associated with a significantly elevated lymphoma risk [odds ratio (OR) = 1.8; 95% CI 1.1, 2.8], which was equally increased for hepatitis B (OR = 1.8; 95% CI 0.9, 3.5), for HCV positive subjects overall (OR = 2.0; 95% CI 0.8, 4.8), and for hepatitis non-B non-C (OR = 1.6; 95% CI 0.7, 3.9). Once concurrent infection from other hepatitis viruses was excluded, acute or chronic hepatitis C was the only one showing a consistent risk increase in all lymphoma subtypes, but follicular lymphoma. Some indications of an excess risk of lymphoma were observed also for acute, but not chronic forms of hepatitis B and hepatitis non-B, non C. Self-limited hepatitis C did not show an association. No significant heterogeneity in the risk of major lymphoma subtype was observed. Our results confirm a role of either acute or chronic active HCV infection in lymphomagenesis. Further studies are warranted to test the hypothesis that acute infection from other hepatitis viruses might also increase lymphoma risk.
Asunto(s)
Hepatitis B/complicaciones , Hepatitis B/epidemiología , Hepatitis C Crónica/complicaciones , Hepatitis C Crónica/epidemiología , Linfoma no Hodgkin/epidemiología , Linfoma no Hodgkin/etiología , Adulto , Anciano , Femenino , Hepatitis B/virología , Hepatitis C Crónica/virología , Humanos , Italia/epidemiología , Linfoma no Hodgkin/sangre , Linfoma no Hodgkin/virología , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Factores de Riesgo , Encuestas y CuestionariosRESUMEN
AIMS AND BACKGROUND: Evidence linking the glucose-6-phosphate dehydrogenase (G6PD) polymorphism and risk of non-Hodgkin's lymphoma is conflicting. Risk of non-Hodgkin's lymphoma was increased in subjects expressing the G6PD deficient phenotype, whereas subjects under medication with statins, a lipid-lowering class of drugs partially mimicking G6PD deficiency, seemed to enjoy a protective effect. METHODS: We conducted a case-control study on lymphoma risk associated with the self-reported G6PD deficient phenotype in 122 lymphoma male cases and 116 male controls in Sardinia, Italy. The association with the GdMed+ genotype, the most frequent variant expressing a deficient enzyme activity, was also tested in 49 male lymphoma cases and 31 controls. The WHO classification was used to identify lymphoma subentities. RESULTS: Neither self-reported G6PD deficient phenotype nor the GdMed+ genotype showed an association with lymphoma risk or its subentities. CONCLUSIONS: Our results do not confirm an association either positive or negative between the G6PD polymorphism and lymphoma risk.
Asunto(s)
Glucosafosfato Deshidrogenasa/genética , Linfoma no Hodgkin/genética , Polimorfismo Genético , Anciano , Estudios de Casos y Controles , Femenino , Predisposición Genética a la Enfermedad , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Linfoma no Hodgkin/etiología , Masculino , Persona de Mediana EdadRESUMEN
Germinotropic lymphoproliferative disorders were previously described as localized disorders associated with coinfection by human herpes virus 8 and Epstein-Barr virus and characterized by good clinical outcome. We report the clinical, morphological, phenotypical, and molecular features of three cases of a hitherto unreported variant of Epstein-Barr virus (EBV)-positive, human herpes virus 8 (HHV8)-negative large B cell lymphoma with exclusive intrafollicular localization. All cases occurred in elderly individuals (63, 77, and 65 years old; one male, two females) without obvious immunedeficiency, who presented with high stage disease. Lymph nodes showed an effaced nodular architecture with abnormal B follicles colonized by EBV+ large, pleomorphic atypical cells, including Reed-Sternberg-like cells, showing an activated B cell phenotype (CD10-FOXP1-Bcl6-IRF4+ or CD10-FOXP1+Bcl6+IRF4+) and intense expression of CD30. No monoclonal light-chain restriction was detected by immunohistochemistry or in situ hybridization, and IGH rearrangement was polyclonal; notably, EBV clonality was detectable in one case. Lymphoma cells in all cases showed diffuse expression of the c-Myc protein, while Bcl2 was dim or negative; moreover, the strong expression of phosphorylated-STAT3 in tumor cell nuclei suggested activation of the JAK-STAT pathway. FISH analysis was performed in two cases and showed no translocations of BCL2, BCL6, MYC, and PAX5 genes. Response to treatment was poor in 2/3 patients: one died after 18 months, one is alive with disease after 12 months. The intrafollicular EBV-positive large B cell lymphoma expands the spectrum of EBV-associated lymphoproliferative disorders in immunocompetent individuals.
Asunto(s)
Infecciones por Virus de Epstein-Barr/complicaciones , Centro Germinal/patología , Linfoma de Células B Grandes Difuso/patología , Anciano , Femenino , Humanos , Inmunohistoquímica , Inmunofenotipificación , Hibridación Fluorescente in Situ , Linfoma de Células B Grandes Difuso/virología , Masculino , Persona de Mediana Edad , Fenotipo , Reacción en Cadena de la PolimerasaRESUMEN
Nodal tumor-forming accumulations of plasmacytoid monocytes/interferon-producing cells (PMs/IPCs) have been described in patients with myeloproliferative disorders. Here we report a series of 9 additional cases of such association. The patients were predominantly adult (median, 62 years), males (male/female ratio, 7:2), who presented with chronic myelomonocytic leukemia (4 cases), acute myeloid leukemia (1), acute monocytic leukemia (2), unclassifiable chronic myeloproliferative (1), or myeloproliferative/myelodysplastic disease (1). The prognosis was poor (median survival, 24 months) and related to progression of the underlying myeloid neoplasm. We found that in addition to lymph nodes, PMs/IPCs accumulated to bone marrow (8 cases) and skin (4 cases). Immunohistochemical markers typically expressed by PMs/IPCs (CD68, CLA/HECA452, CD123) were found in all cases and shown useful to identify cells with variations from classic morphology. In addition, PMs/IPCs expressed the interferon-alpha (IFN-alpha) inducible protein MxA, the B-cell oncogene TCL1, and granzyme B. The biologic and clinical significance of the association between PMs/IPCs and myeloid disorders remains not clarified. Using fluorescence in situ hybridization analysis in a case known to harbor monosomy 7 in the myeloid leukemia, we demonstrated that PMs/IPCs share the same chromosomal abnormality, thus indicating that they are clonal, neoplastic in nature, and closely related to the associated myeloid tumor. Recently, a novel CD56+ hematologic neoplasm has been reported and retained to stem from PMs/IPCs. The majority of PMs/IPCs in the present series failed to express CD56, thus indicating that variants of PMs/IPCs neoplasms exist, which might represent parts of a spectrum.
Asunto(s)
Interferones/metabolismo , Leucemia/patología , Ganglios Linfáticos/patología , Monocitos/patología , Trastornos Mieloproliferativos/patología , Células Plasmáticas/patología , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/metabolismo , Médula Ósea/metabolismo , Médula Ósea/patología , Células Clonales , ADN de Neoplasias/análisis , Femenino , Humanos , Técnicas para Inmunoenzimas , Hibridación Fluorescente in Situ , Interfase , Leucemia/metabolismo , Ganglios Linfáticos/metabolismo , Masculino , Persona de Mediana Edad , Monocitos/metabolismo , Trastornos Mieloproliferativos/metabolismo , Células Plasmáticas/metabolismo , Piel/metabolismo , Piel/patologíaRESUMEN
UNLABELLED: The aim of our study was to evaluate the efficacy and tolerability of a ciprofloxacin-based regimen for H. pylori eradication failures as an alternative to bismuth based quadruple therapy. Methods. DESIGN: prospective single-center study. Patients in whom a first eradication trial with omeprazole/esomeprazole, clarithromycin plus amoxicillin or tinidazole/metronidazole had failed were included. H. pylori status: established by histology, rapide urease test and polymerase chain reaction. INTERVENTION: esomeprazole 20 mg, ciprofloxacin 500 mg, and metronidazole 500 mg, administered together before breakfast and dinner for 10 days. Susceptibility testing was performed by the Epsilometer test. Ciprofloxacin resistance was defined as a MIC of ≥1 µg/mL. Eradication was established by a negative 13C-UBT and 4-6 weeks post-therapy. Efficacy and side effects were determined. Results. 34 patients were enrolled, 32 completed the study. Compliance was excellent (100%). Side effects were mild. Ciprofloxacin-based therapy cured 65% (22/34) of patients by intention to treat and 69% (22/32) per protocol analysis. The prevalence of ciprofloxacin resistance was 8%. Conclusions. The effectiveness of ciprofloxacin-based therapy was greatly reduced despite the high prevalence of ciprofloxacin sensitive H. pylori strains. Bismuth based quadruple therapy still remain the best choice as a "rescue" regimen in our region.
RESUMEN
Colorectal cancer is ranked the third most common cancer worldwide in terms of incidence and the second in terms of mortality. Recent advances in therapeutic approaches to colorectal cancer have identified a potential role of anti-epidermal growth factor receptor (EGFR) targeted therapies as adjuvant treatment in advanced disease. New evidences showed that patients harboring KRAS mutations on codons 12 and 13 are not responsive to anti-EGFR monoclonal antibodies. Therefore, new mutational screening tools have been proposed to select patients who will benefit from anti-EGFR targeted therapy, reducing inappropriate, expensive treatments and unwarranted side effects. We evaluated the performance of a reverse-hybridization-based assay in the identification of the most frequent KRAS mutations on a series of 50 formalin-fixed, paraffin-embedded, advanced colorectal cancer specimens, in comparison with the direct gene sequencing technique. Thirty-two of the 50 cases (64%) showed KRAS single point mutations by reverse-hybridization technique. In particular, 93.8% of the mutations were reported on codon 12, whereas 6.2% of the mutations were reported on codon 13. Direct gene sequencing showed KRAS mutations on 28 of the 50 cases (56%) with 96.4% of the mutations on codon 12 and 3.6% on codon 13. Concordance between the assays was observed in 92% of the cases. Both reverse hybridization and gene sequencing methods have been shown to be suitable tests in detecting KRAS mutations from formalin-fixed, paraffin-embedded tumor specimens. In our experience, reverse-hybridization technique has been shown to be an effective and more sensitive assay for the identification of the most common KRAS mutations.
Asunto(s)
Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Mutación Missense , Hibridación de Ácido Nucleico/métodos , Patología Molecular/métodos , Proteínas Proto-Oncogénicas/genética , Proteínas ras/genética , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias Colorrectales/tratamiento farmacológico , Femenino , Formaldehído , Humanos , Masculino , Persona de Mediana Edad , Adhesión en Parafina , Proteínas Proto-Oncogénicas p21(ras) , Sensibilidad y Especificidad , Fijación del TejidoRESUMEN
Nephrogenic adenoma is a benign lesion that may occur at any site of the genitourinary tract, usually in association with previous urothelial injuries. Although its pathogenesis is still debated, recent studies seem to confirm its derivation from renal tubular epithelium, rather than from a metaplastic process of urothelium. In addition to its uncertain origin, there can be diagnostic difficulty in distinguishing nephrogenic adenoma from prostatic adenocarcinoma, particularly with lesions arising in the prostatic urethra. So far, immunohistochemical stains are often needed to make such a distinction, and several markers have been proposed, often with controversial results. S100A1 is a calcium binding protein that has been recently reported to be expressed in renal tubular cells and in a subset of renal cell neoplasms. Alpha-methylacyl-CoA racemase (AMACR), a recently identified prostate cancer marker, has also been found to be expressed in renal tubules and in some renal epithelial neoplasms. In this study, we investigated the expression of S100A1 and AMACR in 18 nephrogenic adenomas and in 100 prostatic adenocarcinomas. A strong and distinct cytoplasmic or nucleocytoplasmic staining of S100A1 was found in 17 out of 18 cases of nephrogenic adenoma (94%), but never in prostatic adenocarcinoma. In contrast, AMACR expression was detected in 14 of 18 nephrogenic adenomas (78%) and in 96 of 100 prostatic adenocarcinomas (96%). We conclude that (1) S100A1 is a specific and sensitive immunohistochemical marker to differentiate nephrogenic adenoma from prostatic adenocarcinoma; (2) AMACR immunostaining does not seem to be a useful marker in distinguishing between these 2 lesions; (3) given that both S100A1 and AMACR have been reported to be expressed in renal tubular cells and in a subset of renal cell neoplasms, our findings confirm the histogenetic relationship between nephrogenic adenoma and renal tubular epithelium.
Asunto(s)
Adenocarcinoma/diagnóstico , Adenoma/diagnóstico , Neoplasias de la Próstata/diagnóstico , Proteínas S100/biosíntesis , Neoplasias Urogenitales/diagnóstico , Adenocarcinoma/metabolismo , Adenoma/metabolismo , Biomarcadores de Tumor/análisis , Diagnóstico Diferencial , Humanos , Inmunohistoquímica , Masculino , Neoplasias de la Próstata/metabolismo , Racemasas y Epimerasas/biosíntesis , Sensibilidad y Especificidad , Neoplasias Urogenitales/metabolismoRESUMEN
We report the clinicopathologic, immunohistochemical and ultrastructural features of two unusual tumors of the uterus composed of spindle and epithelioid cells strongly positive for HMB45. The two patients of 56 and 48 years of age had, respectively, hemoperitoneum and abnormal uterine bleeding. Morphologically, both tumors showed atypia and extensive necrosis. The neoplastic cells express immunohistochemically both melanogenesis (HMB45) and smooth muscle markers (actin). Ultrastructural analysis showed the presence of intracytoplasmic membrane-bound granules. We viewed these neoplasms as perivascular epithelioid cell (PEC) tumors with aggressive features. Follow-up has shown the death of one patient whereas the other is alive without disease 36 months after the surgery. The two patients were evaluated for signs of tuberous sclerosis complex, and findings were negative.
Asunto(s)
Células Epitelioides/patología , Neoplasias Uterinas/patología , Células Epitelioides/ultraestructura , Resultado Fatal , Femenino , Hemoperitoneo/etiología , Humanos , Persona de Mediana Edad , Necrosis , Hemorragia Uterina/etiología , Neoplasias Uterinas/complicaciones , Neoplasias Uterinas/ultraestructuraRESUMEN
La enfermedad de Erdheim-Chester es una proliferación anormal de histiocitos no-Langerhans, de etiología desconocida, que casi invariablemente aparece en edades adultas. Presenta una ligera predilección por el sexo masculino, y el compromiso óseo es característico. El 50% de los casos cursan con enfermedad sistémica que afecta frecuentemente el corazón, los pulmones, los riñones, el retroperitoneo, el sistema nervioso central y la piel. Se presentan dos pacientes de sexo masculino, con edades de 61 y 22 años, respectivamente, ambos con afección del sistema óseo. Histológicamente, en ambos casos se observó una proliferación de células fusiformes y de histiocitos espumosos. En la investigación inmunohistoquímica, las biopsias mostraron proliferación histiocítica negativa para CD1a y S100, y positiva para CD68 (AU)
Erdheim-Chester Disease is a rare systemic xanthogranulomatous disease of unknown aetiology in which there is an abnormal proliferation of mononuclear non-Langer hans cell histiocytes. It affects both sexes, with a slight male predominance, and usually occurs in middle age, between the fifth and sixth decade of life. Although long bone involvement is almost universal, 50% of patients also have extra skeletal manifestations, heart, lungs, kidneys, retroperitoneal space, central nervous system and skin being the most frequent involved sites. We present two cases of Erdheim-Chester disease in male patients aged 61 and 22 years, both of whom had bone lesions. A proliferation of spindle cells and foamy histiocytes was present in both cases. In all the biopsies, immunohistochemistry showed histiocytes positive for CD68 and negative for CD1a and S100 (AU)
Asunto(s)
Humanos , Masculino , Adulto Joven , Persona de Mediana Edad , Enfermedad de Erdheim-Chester/patología , Histiocitosis de Células no Langerhans/patología , Aorta Abdominal/patología , Diagnóstico DiferencialRESUMEN
Las mastocitosis son un grupo de trastornos neoplásicos clonales caracterizados por proliferación tisular de mastocitos morfológica y/o molecularmente anormales; son sistémicas cuando tienen localización extracutánea. El cuadro clínico es variable e inespecífico. Se han descrito casos asociados a otras neoplasias hematológicas, especialmente las de tipo mieloide y, en menor medida, linfoide. En la presente revisión informamos los casos de 2 mujeres en la sexta y séptima décadas de la vida con mastocitosis sistémica que involucraba la médula ósea, el ganglio linfático y la piel, con diagnóstico clínico inicial de linfoma en el que tras la reevaluación histológica con la coloración de Giemsa se identificaron mastocitos, agregados en acúmulos, morfológicamente anormales que fueron confirmados mediante la positividad para CD117, CD25 y CD45. Uno de los casos presentó una evolución clínica rápidamente desfavorable(AU)
Mastocytosis is a group of clonal neoplastic disorders characterized by tissue proliferation of mastocytes morphologically and/or molecularly abnormal, being systemic when it has extracutaneous location. The clinical picture is variable and nonspecific. Cases have been described associated to other hematological neoplasms, especially those of myeloid and, to a lesser extent, lymphoid type. We present two cases of systemic mastocytosis involving bone marrow, lymph nodes and skin in elderly female patients which were initially diagnosed clinically as lymphoma. However, an abnormal proliferation in cumulus of mastocytes was identificated histologically using Giemsa and confirmed by CD117, CD25 and CD45. One of the patients had a rapid, unfavorable clinical evolution(AU)