Metastatic grade 1 meningioma lacking genetic abnormalities commonly associated with bad prognosis.

AIMS: Meningioma metastasis is a rare event, observed primarily in World Health Organization (WHO) grade 3 tumors, although it has also been reported in WHO grade 1 meningiomas. This study aims at clarifying whether the metastasis of a WHO grade 1 meningioma was associated with genetic abnormalities commonly found in cases that are more aggressive. METHODS: Using next generation sequencing of a panel of 174 genes, we analyzed the genetic alterations of a WHO grade 1 skull-base meningioma and its paired lung metastases detected 22 years after craniotomy. RESULTS: Similar to the primary tumor, lung metastases did not show mitoses or histological signs of malignancy. Consistent with their origin from intracranial tumor, they harbored the same genetic alterations as this one. These consisted of the pathogenic mutation p. E17K of AKT1 and variants of unknown significance in NOTCH1 (p. P2133T), SERPINB8 (p. H359Y) and SMARCA4 (p. P277S). CONCLUSIONS: The E17K AKT1 mutation is frequently found in skull base meningiomas and without prognostic significance. Our findings suggest that metastasis of grade 1 meningiomas is independent of genetic alterations (CDKN2A homozygous deletion, pTERT mutation, or 1p, 9p, 14q and 18q loss of heterozygosity) commonly found in more aggressive tumors.

Recurrent primary endobronchial fetal rhabdomyoma: a case report and literature review.

Fetal rhabdomyoma is an extremely rare benign rhabdomyoblastic tumor with myotube-like differentiation, mainly arising on mucosal surfaces of the head and neck region of both children and young patients, almost invariably definitively treated with surgical excision. Herein the case of a male adult suffering from a recurrent fetal rhabdomyoma primary involving the bronchial structures is reported, along with a detailed literature review. This is the first fetal rhabdomyoma described to originate in such a localization; furthermore, an 11-year interval period between the first lesion and the recurrent one has never been reported.

Expression of programmed cell death ligand 1 in non-small cell lung cancer: Comparison between cytologic smears, core biopsies, and whole sections using the SP263 assay.

BACKGROUND: Evaluation of programmed cell death ligand 1 (PD-L1) expression can be made on both resection specimens and diagnostic biopsies; however, more than 30% of patients with advanced non-small cell lung cancer (NSCLC) do not have adequate histologic material to perform PD-L1 assays and require additional biopsies. In addition, in our practice, more than 16% of cases have cytological smears as the only available material. Our aim was to validate the PD-L1 immunocytochemistry assay on cytological smears and compare its accuracy with the results obtained from tissue cores and whole tumor sections using the clinically relevant cutoff of 50%. METHOD: We compared the PD-L1 staining results of cytological smears to those from tissue cores or whole sections in 50 and 53 NSCLC cases, respectively, using the SP263 assay after scanning hematoxylin and eosin slides. RESULTS: We found an overall agreement of 90.6% between cytological smears and whole sections; specifically, we found absolute concordance between smears with PD-L1 expressed in <10% and ≥50% of cells and whole sections with PD-L1 expressed in <50% and ≥50% of cells, respectively. In addition, slightly lower diagnostic accuracy was found for the cytological smears in comparison with the tissue cores, but the difference was not statistically significant. We found excellent intraobserver and good interobserver agreement in the evaluation of PD-L1 on smears. CONCLUSION: Immunocytochemistry on cytological smears is a reliable method for determination of PD-L1 at the 50% cutoff when positive cells are <10% or ≥50%; for cases showing PD-L1 expression in 10% to 49% of cells, additional tissue sampling may be necessary.

Mesothelial/monocytic incidental cardiac excrescences (MICE): report of a case and review of literature with focus on pathogenesis.

Mesothelial/monocytic incidental cardiac excrescence (MICE) is a benign lesion composed of histiocytes and mesothelial cells, usually found during cardiac surgery. To date, no more than 50 cases are reported in literature, and pathogenesis is still unclear even if different theories have been proposed. Here we report a case of MICE encountered during aortic valve replacement with typical histological features and extensive immunohistochemical investigation. To date, little information is available about the pathogenesis of MICE. We review the current literature focusing on the role of adhesion molecules such as CD31.

Pulmonary Adenocarcinoma With Enteric Differentiation: Immunohistochemistry and Molecular Morphology.

Pulmonary adenocarcinoma with enteric differentiation (PAED) is a rare subtype of lung adenocarcinoma recently recognized in the WHO classification. It is defined as an adenocarcinoma in which the enteric component exceeds 50% and have to show the expression of at least 1 immunohistochemical marker of enteric differentiation. Although the definition of this tumor type is very important, above all in the differential diagnosis between a primary lung tumor and a metastasis of colorectal adenocarcinoma, this cancer still lacks a distinctive immunohistochemical and molecular signature. We recruited the largest series in the literature of PAEDs according to the morphology and the positivity for intestinal markers. Then, we evaluated the immunohistochemical and molecular profile of these adenocarcinomas. In our series, CDX-2 and CK7 were the immunohistochemical markers mostly expressed by PAEDs. There was an inverse relationship between the expression of pnuemocytes markers, such as TTF-1, and intestinal markers. Molecular analysis revealed KRAS as the most frequently mutated gene (>60% of cases), with very few cases harboring abnormalities affecting EGFR, BRAF, and ALK genes. PAEDs are morphologically very heterogenous. The immunohistochemical profile based on CDX-2 and CK7 positivity of PAEDs appears very robust to support this diagnosis, and it is applicable also on small biopsies. KRAS appears as the most important mutated gene in such tumors.

Increased frequency of bronchiolar histotypes in lung carcinomas associated with idiopathic pulmonary fibrosis.

AIMS: The association between lung cancer and idiopathic pulmonary fibrosis (IPF) is well known, but the significance of this association is poorly understood. Bronchiolar honeycomb cysts have been proposed as possible precursors for the development of carcinoma, but limited evidence in support of this hypothesis is available. The aim of this study was to investigate this hypothesis analysing a series of carcinomas arising in IPF by immunohistochemistry. METHODS AND RESULTS: Thirty-three lung carcinomas arising in patients with IPF were analysed with a panel of immunohistochemical markers. The antibodies included those against pneumocyte markers [thyroid transcription factor 1 (TTF1), napsin-A, and surfactant protein A], the goblet cell marker mucin 5AC, markers of basal/squamous cell differentiation [cytokeratin (CK) 5/6 and ΔN-p63], and markers related to enteric differentiation (CDX2, mucin 2, CK20, and villin). A series of 100 consecutive lung adenocarcinomas arising in smokers without IPF were investigated as controls. All carcinomas arising in IPF patients were peripherally located on imaging analysis. The diagnoses were: eight squamous cell carcinomas, 20 adenocarcinomas, three small-cell carcinomas (including one composite small-cell carcinoma and adenocarcinoma), and two large-cell carcinomas. Among adenocarcinomas, a 'pneumocyte' profile (TTF1/napsin-A/SPA1-triple-positive) was observed in seven of 20 (35% versus 84% in non-IPF controls, P = 0.0001). The remaining 13 adenocarcinomas (65%) showed rare histotypes: four invasive mucinous adenocarcinomas (20% in IPF patients versus 1% in non-IPF controls, P = 0.002), seven tumours (35%) that were characterized by variable expression of markers of enteric differentiation, and two tumours (10%) that showed a peculiar basaloid component. CONCLUSIONS: The immunohistochemical characterization of carcinomas arising in IPF patients shows striking divergence from that in non-IPF smokers. The prevalence of rare entities showing bronchiole-related markers is in line with the hypothesis that these tumours arise from transformed small airways in honeycomb lung areas where abnormal bronchiolar proliferation takes place.

Epithelial to mesenchymal transition-related proteins ZEB1, ß-catenin, and ß-tubulin-III in idiopathic pulmonary fibrosis.

Epithelial to mesenchymal transition has been suggested as a relevant contributor to pulmonary fibrosis, but how and where this complex process is triggered in idiopathic pulmonary fibrosis is not fully understood. Beta-tubulin-III (Tubß3), ZEB1, and ß-catenin are partially under the negative control of miR-200, a family of micro-RNAs playing a major role in epithelial to mesenchymal transition, that are reduced in experimental lung fibrosis and idiopathic pulmonary fibrosis. We wonder whether in situ expression of these proteins is increased in idiopathic pulmonary fibrosis, to better understand the significance of miR-200 feedback loop and epithelial to mesenchymal transition. We investigated the immunohistochemical and immunofluorescent expression and precise location of ZEB1, Tubß3, and ß-catenin in tissue samples from 34 idiopathic pulmonary fibrosis cases and 21 controls (5 normal lungs and 16 other interstitial lung diseases). In 100% idiopathic pulmonary fibrosis samples, the three proteins were concurrently expressed in fibroblastic foci, as well in damaged epithelial cells overlying these lesions and in pericytes within neo-angiogenesis areas. These results were also confirmed by immunofluorescence assay. In controls the abnormal expression of the three proteins was absent or limited. This is the first study that relates concurrent expression of Tubß3, ZEB1, and ß-catenin to abnormal epithelial and myofibroblast differentiation in idiopathic pulmonary fibrosis, providing indirect but robust evidence of miR-200 deregulation and epithelial to mesenchymal transition activation in idiopathic pulmonary fibrosis. The abnormal expression and localization of these proteins in bronchiolar fibro-proliferative lesions are unique for idiopathic pulmonary fibrosis, and might represent a disease-specific marker in challenging lung biopsies.

ALK gene copy number in lung cancer: Unspecific polyploidy versus specific amplification visible as double minutes.

BACKGROUND: Gains of a gene due to DNA polyploidy versus amplification of the specific locus are distinct molecular alterations in tumors. OBJECTIVE: We quantified copy number gains of ALK gene due to unspecific polyploidy versus amplifications of the specific locus in a series of non-small cell lung cancers. METHODS: The locus specific ALK copy (LSI) number status was evaluated in 205 cases by FISH. Ratio LSI ALK copy number corrected for control probes CEP2, CEP3 and CEP17 (CEPs) was scored. Amplification of the specific ALK locus was defined when ratio set to ≥ 2 while polyploidy was interpreted when the increase in gene copy resulted < 2 in ratio (LSI/control CEPs). RESULTS: Twenty one cases (10.2%) showed ≥ 8 ALK signals, 68 cases (33.2%) 3-7 signals and 116 cases (56.6%) a mean of 2 signals. Only 2/21 cases of the cohort harboring ≥ 8 signals showed a ratio ≥ 2 after CEPs correction interpretable as amplified, showing numerous doubled fluorescent spots. All the remaining cases showed a mirrored number of fluorescent spots per each CEPs, interpretable as polyploidy. CONCLUSION: We detected a high prevalence of ALK gene copy number usually due to polyploidy rather than ALK locus amplification, the latter visible prevalently as double minutes.

Transient Receptor Potential Ankyrin 1 Channels Modulate Inflammatory Response in Respiratory Cells from Patients with Cystic Fibrosis.

Pseudomonas aeruginosa colonization, prominent inflammation with massive expression of the neutrophil chemokine IL-8, and luminal infiltrates of neutrophils are hallmarks of chronic lung disease in patients with cystic fibrosis (CF). The nociceptive transient receptor potential ankyrin (TRPA) 1 calcium channels have been recently found to be involved in nonneurogenic inflammation. Here, we investigate the role of TRPA1 in CF respiratory inflammatory models in vitro. Expression of TRPA1 was evaluated in CF lung tissue sections and cells by immunohistochemistry and immunofluorescence. Epithelial cell lines (A549, IB3-1, CuFi-1, CFBE41o-) and primary cells from patients with CF were used to: (1) check TRPA1 function modulation, by Fura-2 calcium imaging; (2) down-modulate TRPA1 function and expression, by pharmacological inhibitors (HC-030031 and A-967079) and small interfering RNA silencing; and (3) assess the effect of TRPA1 down-modulation on expression and release of cytokines upon exposure to proinflammatory challenges, by quantitative RT-PCR and 27-protein Bioplex assay. TRPA1 channels are expressed in the CF pseudostratified columnar epithelium facing the bronchial lumina exposed to bacteria, where IL-8 is coexpressed. Inhibition of TRPA1 expression results in a relevant reduction of release of several cytokines, including IL-8 and the proinflammatory cytokines IL-1ß and TNF-α, in CF primary bronchial epithelial cells exposed to P. aeruginosa and to the supernatant of mucopurulent material derived from the chronically infected airways of patients with CF. In conclusion, TRPA1 channels are involved in regulating the extent of airway inflammation driven by CF bronchial epithelial cells.

ALK/EML4 fusion gene may be found in pure squamous carcinoma of the lung.

INTRODUCTION: The report of cases of lung squamous cell cancers harboring anaplastic lymphoma kinase (ALK) gene rearrangements raises the question whether this histologic subtype should be also evaluated for such molecular predictive test. METHODS: A consecutive series of 40 lung pure squamous cell carcinomas were analyzed for ALK gene status by fluorescence in situ hybridization. Squamous differentiation was validated using an immunohistochemical panel including n-p63 (p40), cytokeratin (CK) 5/6, sex-determining region Y (SRY)-Box2 (SOX2), thyroid transcription factor 1, CK7, and Napsin-A. RESULTS: Squamous differentiation was confirmed in all tumors as they stained positive for n-p63 and CK5/6 and negative for thyroid transcription factor 1 and Napsin-A. One of 40 cases (2.5%) showed an ALK rearrangement on fluorescence in situ hybridization analysis. CONCLUSIONS: ALK translocation may be found in lung pure squamous cell carcinomas. Our data suggest the opportunity to test ALK rearrangements on biopsy samples harboring squamous cell cancer differentiation.

True 3q chromosomal amplification in squamous cell lung carcinoma by FISH and aCGH molecular analysis: impact on targeted drugs.

Squamous lung carcinoma lacks specific "ad hoc" therapies. Amplification of chromosome 3q is the most common genomic aberration and this region harbours genes having role as novel targets for therapeutics. There is no standard definition on how to score and report 3q amplification. False versus true 3q chromosomal amplification in squamous cell lung carcinoma may have tremendous impact on trials involving drugs which target DNA zones mapping on 3q. Forty squamous lung carcinomas were analyzed by FISH to assess chromosome 3q amplification. aCGH was performed as gold-standard to avoid false positive amplifications. Three clustered patterns of fluorescent signals were observed. Eight cases out of 40 (20%) showed ≥8 3q signals. Twenty out of 40 (50%) showed from 3 to 7 signals. The remaining showed two fluorescent signals (30%). When corrected by whole chromosome 3 signals, only cases with ≥8 signals maintained a LSI 3q/CEP3 ratio >2. Only the cases showing 3q amplification by aCGH (+3q25.3-3q27.3) showed ≥8 fluorescent signals at FISH evidencing a 3q/3 ratio >2. The remaining cases showed flat genomic portrait at aCGH on chromosome 3. We concluded that: 1) absolute copy number of 3q chromosomal region may harbour false positive interpretation of 3q amplification in squamous cell carcinoma; 2) a case results truly "amplified for chromosome 3q" when showing ≥8 fluorescent 3q signals; 3) trials involving drugs targeting loci on chromosome 3q in squamous lung carcinoma therapy have to consider false versus true 3q chromosomal amplification.

Acute respiratory distress caused by a giant mediastinal lipoblastoma in a 16-month-old boy.

Lipoblastoma is a rare benign tumor arising from embryonic fat; it occurs mainly in the extremities and almost exclusively in infants and children younger than 3 years. We present a case of giant mediastinal lipoblastoma in a 16-month-old boy who presented with acute respiratory distress. The mass was completely excised through a left posterolateral thoracotomy. The postoperative course was uneventful, and the pathologic final diagnosis was lipoblastoma. Although extremely rare, mediastinal lipoblastoma can be life threatening; therefore, it should be included in the differential diagnosis of mediastinal mass in younger subjects.

The reproducibility of CIN diagnoses among different pathologists: data from histology reviews from a multicenter randomized study.

The reproducibility of cervical histology diagnoses is critical for efficient screening and to evaluate the effectiveness of new technologies. The vast majority of cervical intraepithelial neoplasia (CIN) diagnoses reported in the New Technologies for Cervical Cancer study were blindly reviewed by 2 independent pathologists. Only H&E-stained slides were used for the review. The reviewers were asked to reclassify cases using the following categories: normal CIN 1, CIN 2, CIN 3, and squamous and glandular invasive cancer. We reviewed 1,003 cases. The interobserver agreement was 0.36 (95% confidence interval [CI], 0.32-0.40) with an unweighted kappa and 0.54 with a weighted kappa (95% CI, 0.50-0.58). The kappa values from dichotomous classifications with the threshold at CIN 2 were 0.69 (95% CI, 0.64-0.73) and 0.57 (95% CI, 0.51-0.63) with the threshold at CIN 3. The CIN 2 diagnosis had the lowest class-specific agreement, with fewer than 50% of cases confirmed by the panel members, which supports the fact that CIN 2 is not a well-defined stage in the pathogenesis of cervical neoplasia.

[Spontaneous rupture of the femoral artery after radiotherapy: a case report]. / Rottura spontanea dell'arteria femorale dopo radioterapia: presentazione di un caso clinico.

Radiation-induced arteriopathy is a well-known disease whose incidence is not known and which usually arises chronically many years after radiation therapy. When it arises acutely, spontaneous rupture or, more rarely, thrombosis of the involved vessel may occur. Spontaneous rupture can occur within 4 to 32 weeks of radiotherapy, and usually affects the carotid artery involved in radiotherapy of the neck and head. Spontaneous rupture of the femoral artery is a very rare event and only a few cases have been reported in the literature. In this paper we report a case of spontaneous rupture of the left femoral superficial artery after adjuvant radiotherapy following surgery for a liposarcoma of the spermatic cord with multiple local recurrences, successfully treated with an extra-anatomic bypass through the obturator canal and rectal muscle flap.

Primary bi-atrial Burkitt lymphoma with severe inflow impairment in an immunocompetent patient.

We report herein a case of sporadic primary cardiac bi-atrial Burkitt lymphoma (BL) occurred in a 67-year-old white immunocompetent patient and presenting with signs and symptoms of severe bilateral atrioventricular inflow impairment. Extranodal BL involving the heart is rare and seldom recognized clinically. Delayed discovery contributes to significant mortality. In the case presented extended surgical excision and intensive combination chemotherapy regiments resulted in complete remission at 1 year.

Primary lymphoepithelioma-like carcinoma of the urinary bladder: report of one case with review and update of the literature after a pooled analysis of 43 patients.

BACKGROUND AND OBJECTIVES: Lymphoepithelioma-like carcinoma (LELC) is an undifferentiated epithelial tumor with a dense inflammatory infiltrate that resembles the lymphoepithelioma of the nasopharinx occurring in other sites. Primary LELC of the bladder (LELCB) was first reported by Zukerberg et al in 1991. The incidence of LELCB is 0.4%-1.3% of all bladder carcinomas. The mean age at diagnosis is 69 years. Of the patient population 69% are men. Herein we report on one more case of primary predominant LELCB and review all the English literature concerning this subject after performing a pooled analysis of the cases recorded in the English literature including the present one. MATERIALS AND METHODS: The reports of 43 patients including the present case of primary LELCB from the English literature were collected from 1991 to 2002. Patients were evaluated for age, sex, primary and adjuvant treatments, clinical staging, follow-up and outcome, and disease related survival. The overall patient population was separated into 3 groups according to the LELCB classification of Amin. RESULTS: The overall patient population included 31 males and 12 females. Average age was 68.4 years (range 52-84). LELCB histological subtypes resulted pure in 17 cases (40%), predominant in 16 (37%) and focal in 10 (23%). Mean follow-up was 37.7 months (range 0-216). Outcome resulted as follows: 26 patients (62%) did not show evidence of diasease, 11 (26%) died of disease, 1 (2%) was alive with metastases, and 4 (10%) died for causes unrelated to the primary disease. Survival rate related to specific disease resulted 71%. Mean follow-up was 48.1 in the first group (pure LELCB), 32 in the second (predominant LELCB), and 30.3 in the third one (focal LELCB). Patients with not evidence of disease were 13 (81%) in group 1, 13 (82%) in group 2, and 0 in group 3. Patients who died of their disease resulted 1 (6%) in the first group, 1 (6%) in the second, and 9 (90%) in the third one. Patients who died for disease not related to the primary tumor were 2 (13%) in the first group, 1 (6%) in the second, and 1 (10%) in the third one. One patient (6%) was alive with metastases in group 2. Survival rate related to specific disease resulted 93% in the first group, 93% in the second one, and 0% in the third one. CONCLUSIONS: To date, there are no clear guide lines for the treatment of LELCB. Treatments performed include both deep transurethral resection of the tumor (TUR-B) as well as partial or radical cystectomy, with or without adjuvant treatments including systemic chemotherapy and radiotherapy. The prognosis is favorable for patients presenting with the pure and predominant forms with a diploid DNA pattern and very poor for patients presenting with focal LELCB. Bladder salvage therapy by performing both TUR-B alone or combined with adjuvant systemic chemotherapy may be a reasonable option for patients with pure or predominant LELCB, while radical surgery with adjuvant systemic therapy may be indicated for focal muscle invasive LELCB.