Annick Haller

The role of RAS oncogene in survival of patients with lung cancer: a systematic review of the literature with meta-analysis

The proto-oncogene RAS, coding for a 21 kDa protein (p21), is mutated in 20% of lung cancer. However, the literature remains controversial on its prognostic significance for survival in lung cancer. We performed a systematic review of the literature with meta-analysis to assess its possible prognostic value on survival. Published studies on lung cancer assessing prognostic value of RAS mutation or p21 overexpression on survival were identified by an electronic search. After a methodological assessment, we estimated individual hazard ratios (HR) estimating RAS protein alteration or RAS mutation effect on survival and combined them using meta-analytic methods. In total, 53 studies were found eligible, with 10 concerning the same cohorts of patients. Among the 43 remaining studies, the revelation method was immunohistochemistry (IHC) in nine and polymerase chain reaction (PCR) in 34. Results in terms of survival were significantly pejorative, significantly favourable, not significant and not conclusive in 9, 1, 31, 2, respectively. In total, 29 studies were evaluable for meta-analysis but we aggregated only the 28 dealing with non-small-cell lung cancer (NSCLC) and not the only one dealing with small-cell-lung cancer (SCLC). The quality scores were not statistically significantly different between studies with or without significant results in terms of survival, allowing us to perform a quantitative aggregation. The combined HR was 1.35 (95% CI: 1.16–1.56), showing a worse survival for NSCLC with KRAS2 mutations or p21 overexpression and, particularly, in adenocarcinomas (ADC) (HR 1.59; 95% CI 1.26–2.02) and in studies using PCR (HR 1.40; 95% CI 1.18–1.65) but not in studies using IHC (HR 1.08; 95% CI 0.86–1.34). RAS appears to be a pejorative prognostic factor in terms of survival in NSCLC globally, in ADC and when it is studied by PCR.

Evolution of microRNA expression during human bronchial squamous carcinogenesis

MicroRNAs, negative post-transcriptional regulators of gene expression, are involved in cancer. Their role in early bronchial carcinogenesis was analysed in 60 biopsies obtained by fluorescence bronchoscopy (six per stage: normal tissue of nonsmokers, normal normofluorescent and hypofluorescent bronchial tissue of smokers, hyperplasia, metaplasia, mild, moderate and severe dysplasia, in situ carcinoma and invasive squamous cell carcinoma (SQCC)). In total, 69 microRNAs were found to be differentially expressed in the course of bronchial carcinogenesis. Among them, some microRNAs showed a linear evolution of their expression level, such as miR-32 and miR-34c, whose expression progressively decreased from normal bronchial tissues of nonsmokers to SQCC. Others behaved differently at successive stages, such as miR-142-3p or miR-9, or are only altered from a specific stage, such as miR-199a or miR-139. MicroRNAs globally followed a two-step evolution, first decreasing (a reverse of their increase during embryogenesis) during the earliest morphological modifications of bronchial epithelium, and thereafter increasing at later stages of lung carcinogenesis. Moreover, microRNA expression was very efficient for the prediction of the histological classification between low- and high-grade lesions and between in situ and invasive carcinoma. The present data show, for the first time, that microRNAs are involved in bronchial carcinogenesis from the very early steps of this process and, thus, could provide tools for early detection of lung cancer.

Endobronchial ultrasound and positron emission tomography positive mediastinal lymph nodes

Positron emission tomography with 18F-fluoro-2-deoxy-d-glucose (FDG-PET) is more accurate than computed tomography for staging of mediastinal (hilar) lymph nodes. In the case of positive findings, tissue sampling of lymph nodes is required. The diagnostic/staging yield of transbronchial needle aspiration (TBNA) following endobronchial ultrasound (EBUS) localisation was assessed in this particular clinical setting. The number of avoided surgical procedures was evaluated. All consecutive patients referred for staging and/or diagnosis of mediastinal FDG-PET positive lesions were included. Data were prospectively collected. TBNA sampling of lymph nodes was performed after EBUS localisation. If no diagnosis was reached, further surgical sampling or adequate follow-up was performed. From January 2003 to June 2004, 33 patients were included. The average number of TBNA samples per patient was 4.2±1.5. Cytological or histological diagnoses were obtained in 27 (82%) of the patients, of which 78% were obtained after previous EBUS localisation. In 25 (76%) of the 33 patients, surgical staging procedures were suppressed. In conclusion, transbronchial needle aspiration after endobronchial ultrasound localisation should be considered as a primary method of evaluation of lymph nodes positive by positron emission tomography with 18F-fluoro-2-deoxy-d-glucose, and may replace the majority of surgical mediastinal staging/diagnostic procedures.

Has Cox-2 a prognostic role in non-small-cell lung cancer? A systematic review of the literature with meta-analysis of the survival results

Cyclooxygenase-2 (COX-2) is overexpressed in lung cancer, especially in adenocarcinoma (ADC). Our aim was to determine the prognostic value of COX-2 on survival in patients with lung cancer. Studies evaluating the survival impact of COX-2 in lung cancer, published until December 2005, were selected. Data for estimation of individual hazard ratios (HR) for survival were extracted from the publications and combined in a pooled HR. Among 14 eligible papers, all dealing with non-small-cell lung cancer, 10 provided results for meta-analysis of survival data (evaluable studies). Cyclooxygenase-2 positivity was associated with reduced survival, improved survival or no statistically significant impact in six, one and seven studies, respectively. Combined HR for the 10 evaluable studies (1236 patients) was 1.39 (95% confidence intervals (CI): 0.97–1.99). In stage I lung cancer (six evaluable studies, 554 patients), it was 1.64 (95% CI: 1.21–2.24). No significant impact was shown in ADC. A slight detrimental effect on survival in patients with lung cancer is associated with COX-2 expression, but the statistical significance is not reached. This effect is statistically significant in stage I, suggesting that COX-2 expression could be useful at early stages to distinguish those with a worse prognosis.

An unusual presentation of a cystic duplication of the sigmoid colon entirely lined with squamous epithelium.

Alimentary tract duplications are rare congenital malformations that occur most commonly in the jejunoileal part of the gastrointestinal tract. Management of this pathologic condition is usually drawn up. We report a case of descending colonic communicating duplication in which clinical presentation and anatomopathologic results were unexpected. A slightly echogenic abdominal mass reaching 72 x 36 mm in the left flank was diagnosed in a female fetus during the third trimester ultrasound examination. At birth, volume of the mass rapidly evolved, and despite no intestinal obstruction was observed by compression of the adjacent gastrointestinal tract, abdomen was distended. Abdominal plain film showed a large air collection, and the barium enema demonstrated a slight leak of contrast in the aerated mass, suggesting a communication with the sigmoid colon. No other abnormalities were seen. The patient underwent surgery in emergency. The mass was then totally excised through an antimesenteric resection of the tubular tract joining cystic mass and sigmoid colon. A lateral suture of the colon was subsequently performed. The wall of the duplication is usually composed of a smooth muscle layer covered by an epithelium, mostly of intestinal type. Herein, we describe a descending colonic duplication completely lined with nonkeratinizing squamous epithelium. Therefore, the association of a colonic mucosa (of endodermic origin) and a squamous epithelium (derived from the ectoderm) in our case is an interesting finding and is not explained by the various theories. Furthermore, the clinical characteristics, diagnosis, and treatment of intestinal duplications are discussed with regard to literature.

The role of NPM, p14arf and MDM2 in precursors of bronchial squamous cell carcinoma

Murine double minute clone 2 (MDM2), p14 alternate reading frame (p14arf), and nucleophosmin (NPM) regulate p53 activity. A total of 200 biopsies, including normal bronchial, pre-invasive and invasive tissues, were examined for changes in NPM, p14arf, MDM2 and p53 expression patterns by immunohistochemistry and immunofluorescence with confocal microscopy. NPM and p14arf displayed a diffuse nuclear staining in most normal bronchial tissue. The fraction of biopsies displaying an increased MDM2 staining or a nucleolar relocalisation of NPM increased at mild and moderate dysplasia, respectively. Two different modifications occurred in p14arf expression, i.e. its loss or its nucleolar relocalisation, both increasing at severe dysplasia and both being associated with high MDM2 expression. In addition, the nucleolar relocalisation of p14arf was associated with that of NPM. Immunofluorescence staining indicated that NPM and p14arf either co-localised in the nucleoplasm or in the nucleoli, before and as a result of severe dysplasia, respectively. MDM2 was not detected in the nucleoli. Thus, changes occur in murine double minute clone 2, p14 alternate reading frame and nucleophosmin level of expression and/or cellular distribution during early steps of lung carcinogenesis. Their relative localisation as determined by immunofluorescence, supports the hypothesis that p14 alternate reading frame nucleolar relocalisation impairs p14 alternate reading frame–murine double minute clone 2 complex formation and that nucleophosmin might sequester p14 alternate reading frame. The demonstration of this hypothesis requires further functional studies.

Atypical Hyperplasia of the Marginal Zone of B Follicles in a Polymorphic Epstein-Barr Virus–Associated Lymphoproliferative Disorder Occurring in an Adolescent with Human Immunodeficiency Virus Infection

Epstein-Barr virus (EBV)-associated lymphoid proliferations that are similar to post-transplantation lymphoproliferative disorders may occasionally occur in the setting of human immunodeficiency virus (HIV) infection. Herein, we describe such a lesion involving the adenoids in a HIV-seropositive adolescent who acquired immunity against EBV during childhood. On microscopic examination, the marginal zone of B follicles and the interfollicular area were enlarged due to the accumulation of small or intermediate-sized lymphocytes, immunoblasts, epithelioid histiocytes, and plasma cells. A few atypical immunoblasts resembling Reed-Sternberg cells were also present. Most of the cells seen in these expanded regions belonged to the B-cell lineage and displayed a phenotype consistent with that of postgerminal center B cells. No clonal rearrangement of the genes coding for the heavy chain of the immunoglobulin could be demonstrated by polymerase chain reaction analysis. In-situ hybridization studies revealed the presence of EBV early RNA in a significant number of these cells, which suggests the participation of this virus in the pathogenesis of such a B-cell proliferation. The clinical course was benign; no progression or recurrence could be seen more than 24 months after the diagnosis. This atypical lymphoproliferative disorder is probably related to polyclonal reactivation of a latent EBV infection due to a local or systemic immune imbalance induced by HIV replication. Recognition of this reactive condition is important to prevent overtreatment.