Axonemal Symmetry Break, a New Ultrastructural Diagnostic Tool for Primary Ciliary Dyskinesia?

Diagnosis testing for primary ciliary dyskinesia (PCD) requires a combination of investigations that includes study of ciliary beat pattern by high-speed video-microscopy, genetic testing and assessment of the ciliary ultrastructure by transmission electron microscopy (TEM). Historically, TEM was considered to be the "gold standard" for the diagnosis of PCD. However, with the advances in molecular genetic techniques, an increasing number of PCD variants show normal ultrastructure and cannot be diagnosed by TEM. During ultrastructural assessment of ciliary biopsies of patients with suspicion of PCD, we observed an axonemal defect not previously described that affects peripheral doublets tilting. To further characterize this defect of unknown significance, we studied the ciliary axonemes by TEM from both PCD-confirmed patients and patients with other sino-pulmonary diseases. We detected peripheral doublets tilting in all the PCD patients, without any significant difference in the distribution of ciliary beat pattern or mutated gene. This defect was also present in those patients with normal ultrastructure PCD subtypes. We believe that the performance of axonemal asymmetry analysis would be helpful to enhance diagnosis of PCD.

Value of KI-67/MIB-1 labeling index and simpson grading system to predict the recurrence of who grade I intracranial meningiomas compared to who grade II.

Simpson grading of resection has been used as a predictor of intracranial meningioma (IM) recurrence. Histopathological findings, like the Ki-67/MIB-1 labeling index, may be useful in the assessment risk of recurrence. Our objective was to analyze the predictive value of meningioma recurrence using both parameters. We retrospectively studied 322 consecutive patients with histopathological diagnosis of IM WHO grade I and 43 patients with IM WHO grade II in a 13-year period. Multivariate survival analysis was performed. In the WHO grade I IM group, recurrence was observed in 28 patients (8.69%). The Cox regression model for WHO grade I IM, provided a significative hazard ratio (HR) for Ki-67/MIB-1 index ≥3 (HR = 36.35, p < 0.001) and Simpson's grading resection, grade II (HR = 2.03, p = 0.045), grade III (HR = 3.41, p = 0.034) and grade IV (HR = 19.75, p ≥ 0.001). In the WHO grade II IM group, recurrence was observed in 10 patients (23.25%). The Cox regression model for WHO grade II IM, provided a significative hazard ratio (HR) for Ki-67/MIB-1 index ≥3% (HR = 1.66, p < 0.001) and Simpson's grading resection grade III (HR = 3.96, p = 0.027). The Kaplan-Meier survival curve showed a similar distribution of survival between WHO grade I IM with Ki-67/MIB-1 ≥3% and WHO grade II IM. In WHO grade I meningiomas, the Ki-67/MIB-1 index and Simpson grading were both independent predictors of recurrence. A similar management protocol should be advisable for WHO grade I with Ki-67/MIB-1 ≥3% and WHO grade II meningiomas.

Intratumoral immunosuppression profiles in 11q-deleted neuroblastomas provide new potential therapeutic targets.

High-risk neuroblastoma (NB) patients with 11q deletion frequently undergo late but consecutive relapse cycles with fatal outcome. To date, no actionable targets to improve current multimodal treatment have been identified. We analyzed immune microenvironment and genetic profiles of high-risk NB correlating with 11q immune status. We show in two independent cohorts that 11q-deleted NB exhibits various immune inhibitory mechanisms, including increased CD4+ resting T cells and M2 macrophages, higher expression of programmed death-ligand 1, interleukin-10, transforming growth factor-beta-1, and indoleamine 2,3-dioxygenase 1 (P < 0.05), and also higher chromosomal breakages (P ≤ 0.02) and hemizygosity of immunosuppressive miRNAs than MYCN-amplified and other 11q-nondeleted high-risk NB. We also analyzed benefits of maintenance treatment in 83 high-risk stage M NB patients focusing on 11q status, either with standard anti-GD2 immunotherapy (n = 50) or previous retinoic acid-based therapy alone (n = 33). Immunotherapy associated with higher EFS (50 vs. 30, P = 0.028) and OS (72 vs. 52, P = 0.047) at 3 years in the overall population. Despite benefits from standard anti-GD2 immunotherapy in high-risk NB patients, those with 11q deletion still face poor outcome. This NB subgroup displays intratumoral immune suppression profiles, revealing a potential therapeutic strategy with combination immunotherapy to circumvent this immune checkpoint blockade.

[Gastric gastrointestinal stromal tumour and schwannoma: An unusual presentation in a patient without neurofibromatosis]. / Tumor del estroma gastrointestinal y schwannoma gástricos: una presentación inusual en un paciente sin neurofibromatosis.

The majority of gastric neoplasms are of epithelial type. Stromal tumours are the next most frequent and are most commonly gastrointestinal stromal tumours, followed by leiomyoma and schwannoma. We present an exceptional case of a patient with a gastrointestinal stromal tumour with suspicion of residual gastric disease, which was diagnosed post-operatively as a schwannoma.

The Frequency and Prognostic Significance of the Histologic Type in Early-stage Ovarian Carcinoma: A Reclassification Study by the Spanish Group for Ovarian Cancer Research (GEICO).

The frequency and prognostic significance of the histologic type in early-stage ovarian cancer (OC) is not as well established as in advanced stages. In addition, histologic typing based only on morphologic features may be difficult, especially in high-grade tumors. In this study, we have analyzed a prospective cohort of 502 early-stage OCs to investigate their frequency, immunohistochemical characteristics, and survival of the 5 main histologic types. Histotype was assigned according to not only the morphologic features but also according to the expression pattern of WT1, p53, Napsin A, and progesterone receptors. In addition, an extended panel including p16, ß-catenin, HER2, Arid1A, HINF1B, CK7, CDX2, and CK20 was used to refine the diagnosis in difficult cases. In this series, the frequency of the 5 major histologic types was as follows: endometrioid carcinoma, 32.7%; clear cell carcinoma, 25.1%; high-grade serous carcinoma (HGSC), 24.7%; mucinous carcinoma, 10.2%; low-grade serous carcinoma, 4.6%; and others, 2.8%. The combination of morphology and immunohistochemistry allowed the reclassification of 23% of OCs. The lowest concordance was found between samples initially diagnosed as endometrioid, but finally classified as high-grade serous tumors (22% error rate). Endometrioid carcinoma was the most favorable histologic type, whereas HGSC and low-grade serous carcinoma had the worst prognosis. Clear cell carcinoma with abnormal p53 immunostaining pattern also had poor prognosis. Although histologic grade was not a prognostic factor among early-stage endometrioid OCs, distinction between grade 3 endometrioid OC and HGSC is recommended, taking into account differences in prognosis and molecular alterations that can guide different treatments.

[Tubulocystic renal cell carcinoma. A rare entity in neoplastic renal pathology]. / Carcinoma tubuloquístico. Una entidad infrecuente en la patología tumoral renal.

Tubulocystic renal carcinoma is an uncommon neoplasm. We present a case of a patient presenting with multiple renal colic. A nodular cystic lesion was an incidental sonographic finding which increased in size during subsequent follow-ups. The patient underwent radical nephrectomy and tubular renal carcinoma was diagnosed histopathologically and immunohistochemically.

Orthokeratinized odontogenic cysts: a Spanish tertiary care centre study based on HPV DNA detection.

BACKGROUND: The role of human papillomavirus (HPV) in orthokeratinized odontogenic cysts (OOCs) has rarely been studied. The objective is to describe the clinicopathological findings in a series of OOCs from a Spanish population that were investigated in relation to the possible presence of HPV. METHODS: A clinicopathological retrospective analysis followed by a molecular analysis of 28 high- and low-risk HPV genotypes was performed in OOC samples of patients seen during the last 15-years in a Spanish tertiary care center. RESULTS: Of 115 odontogenic cysts with keratinization, 16 cases of OOCs were confirmed and evaluated. OOCs occurred predominantly in the mandible of males (mean age 36.06 ± 13.16 years). Swelling of the jaw followed by pain were the most common clinical symptoms, and 56.5% of the OOC cases were associated with an unerupted tooth. After a mean post-cystectomy follow-up of 3.8 years, only one recurrent case was observed, resulting in a verrucous cystic lesion that was considered premalignant after immunohistological examination. DNA extraction was successful from 14 of the 16 OOC cases. None of the primary OCCs or the single recurrent OOC were positive for HPV in the molecular analysis. CONCLUSIONS: OOCs show a very limited potential for recurrence. Our results suggest that neither high- or low-risk HPV subtypes are likely to play a role in the etiology or neoplastic transformation of OOC, at least in the Spanish population.

Palatal ancient schwannoma: optical, immunohistochemical and ultrastructural study with literature review.

Schwannoma or neurilemmoma is a benign encapsulated slow-growing tumor that originates from a Schwann cell of a nerve, and is rare at intraoral locations. Different histological variants of schwannomas have been described, of these degenerative or ancient schwannoma is probably one of the least common in the oral cavity with only 16 previously reported cases, of which only one has been described in palatal location. Although ancient schwannoma shows particular characteristics, it is difficult to diagnose based on clinical and imaging appearance alone; as a result, morphological examination assisted by ancillary techniques is necessary to establish a definite diagnosis. We present a clinicopathological description of this rare variant of schwannoma, located in an unusual intraoral site, of a 26-year-old female. We illustrate the optical, immunohistochemical and ultrastructural characterization that aid diagnosis, as well as providing a review of the relevant published data of this unusual tumor.

[Perioperative mortality of lung transplantation in chronic obstructive pulmonary disease]. / Mortalidad perioperatoria del trasplante pulmonar en la enfermedad pulmonar obstructiva crónica.

INTRODUCTION: Lung transplantation (LT) has been considered an alternative therapeutic approach in terminal patients. However, this process in COPD is not controversy-free. This paper aimed to analyze 30-day mortality (PM) patterns and their risk factors in COPD patients undergoing LT. PATIENTS AND METHOD: A retrospective cohort with 107 COPD patients, transplanted at the University La Fe Valencia, Spain, treated from January 1991 to December 2008. Demographics values, degree of dyspnoea, diagnosis, BODE index, single versus bilateral LT, cardio-pulmonary bypass, donor age, steroid dependence, presence of bronchiectasis, retrograde perfusion, transfusion of blood products, and PaO2/FiO2 were analyzed. Continuous variables were expressed as mean±SD and categorical variables as absolute frequency and percentage. A Cox regression model was used for multivariate analysis. RESULTS: Ninety-four men and 13 women of a mean age of 52.58±8.05 years were transplanted. Of all patients, 75% obtained a BODE score above 7. There were 76 bilateral LT. PM was established at 14%. Main causes of death were infection (53.3%) and surgical complications (33.3%). Presence of bronchiectasis and chronic use of corticosteroids, donor/recipient difference in size and presence of fat in retrograde perfusion fluid were important risk factors for PM. Moreover, PaO2/FiO2 ratio at 6h was a protective factor for the event, thus a higher ratio value, lowered the risk of PM. CONCLUSIONS: LT is a procedure with a high PM rate. Use of corticosteroids, the presence of bronchiectasis and fat emboli in the retrograde reperfusion, and PaO2/FiO2 significantly determine PM.

Immunohistochemical expression of glucose transporter 1 in keratin-producing odontogenic cysts.

BACKGROUND: Keratin-producing odontogenic cysts (KPOCs) are a group of cystic lesions that are often aggressive, with high rates of recurrence and multifocality. KPOCs included orthokeratinised odontogenic cyst (OOC) and parakeratotic odontogenic cysts, which are now considered true tumours denominated keratocystic odontogenic tumours (KCOTs). GLUT1 is a protein transporter that is involved in the active uptake of glucose across cell membranes and that is overexpressed in tumours in close correlation with the proliferation rate and positron emission tomography (PET) imaging results. METHODS: A series of 58 keratin-producing odontogenic cysts was evaluated histologically and immunohistochemically in terms of GLUT1 expression. Different data were correlated using the beta regression model in relation to histological type and immunohistochemical expression of GLUT1, which was quantified using two different morphological methods. RESULTS: KPOC cases comprised 12 OOCs and 46 KCOTs, the latter corresponding to 6 syndromic and 40 sporadic KCOTs. GLUT1 expression was very low in OOC cases compared with KCOT cases, with statistical significant differences when quantification was considered. Different GLUT1 localisation patterns were revealed by immunostaining, with the parabasal cells showing higher reactivity in KCOTs. However, among KCOTs cases, GLUT1 expression was unable to establish differences between syndromic and sporadic cases. CONCLUSIONS: GLUT1 expression differentiated between OOC and KCOT cases, with significantly higher expression in KCOTs, but did not differentiate between syndromic and sporadic KCOT cases. However, given the structural characteristics of KCOTs, we hypothesised that PET imaging methodology is probably not a useful diagnostic tool for KCOTs. Further studies of GLUT1 expression and PET examination in KCOT series are needed to confirm this last hypothesis.

NCAM (CD56) expression in keratin-producing odontogenic cysts: aberrant expression in KCOT.

OBJECTIVE: To investigate immunohistochemically the expression of neural cell adhesion molecule (NCAM), which has been identified as a signaling receptor with frequent reactivity in ameloblastomas (AB), in a series of keratin-producing odontogenic cysts (KPOCs). MATERIAL AND METHODS: Immunohistochemical expression of NCAM, using a monoclonal antibody, was determined in a series of 58 KPOCs comprising 12 orthokeratinized odontogenic cysts (OOCs) and 46 keratocystic odontogenic tumors (KCOTs), corresponding to 40 non-syndromic KCOT (NS-KCOTs) and 6 syndromic KCOT (S-KCOTs), associated with nevic basocellular syndrome (NBCS). RESULTS: NCAM expression was negative in all OOCs, but 36.45% of KCOTs exhibited focal and heterogeneous expression at the basal cell level, as well as in basal budding areas and the basal cells of daughter cysts. The latter two locations were especially applicable to S-KCOTs, with focal NCAM reactivity occurring in 66.66% of cases. CONCLUSIONS: Aberrant NCAM expression, in KCOTs but especially in S-KCOTs, together with its immunomorphological location, suggests that this adhesion molecule and signaling receptor plays a role in the pathogenesis of KCOTs, with a probable impact on lesional recurrence.

Prognostic Factors in Non-Small Cell Lung Cancer Less Than 3 Centimeters: Actuarial Analysis, Accumulative Incidence and Risk Groups.

INTRODUCTION: In TNM classification, factors determining the tumor (T) component in non-small cell lung cancer have scarcely changed over time and are still based solely on anatomical features. Our objective was to study the influence of these and other morphopathological factors on survival. METHODS: A total of 263 patients undergoing lung resection due to stage I non-small cell lung cancer ≤3cm in diameter were studied. A survival analysis and competing-risk estimate study was made on the basis of clinical, surgical and pathological variables using actuarial analysis and accumulative incidence methods, respectively. A risk model was then generated from the results. RESULTS: Survival at 5 and 10 years was 79.8 and 74.3%, respectively. The best prognostic factors were presence of symptoms, smoking habit and FEV1>60%, number of resected nodes>7, squamous histology, absence of vascular invasion, absence of visceral pleural invasion and presence of invasion more proximal than the lobar bronchus. All these were statistically significant according to the actuarial method. The factor "age<50 years" was close to the margin of statistical significance. Pleural invasion and vascular invasion were entered in the multivariate analysis. The competing-risk analysis showed a probability of death due to cancer of 14.3 and 35.1% at 5 and 10 years, respectively. Significant variables in the univariate and multivariate analyses were similar, with the exception of FEV1>60%. CONCLUSIONS: Pleural invasion and vascular invasion determine survival or risk of death due to non-small cell lung cancer ≤3cm and can be used for generating a predictive risk model.

[Mortality in early-stage, surgically resected non-small cell lung cancer less than 3 cm of size: Competing risk analysis]. / Mortalidad en carcinoma pulmonar no microcítico resecado, con tamaño máximo de 3 cm y sin afectación ganglionar: análisis de riesgos competitivos.

BACKGROUND AND OBJECTIVE: Survival studies of non-small cell lung cancer (NSCLC) are usually based on the Kaplan-Meier method. However, other factors not covered by this method may modify the observation of the event of interest. There are models of cumulative incidence (CI), that take into account these competing risks, enabling more accurate survival estimates and evaluation of the risk of death from other causes. We aimed to evaluate these models in resected early-stage NSCLC patients. PATIENTS AND METHOD: This study included 263 patients with resected NSCLC whose diameter was ≤ 3 cm without node involvement (N0). Demographic, clinical, morphopathological and surgical variables, TNM classification and long-term evolution were analysed. To analyse CI, death by another cause was considered to be competitive event. For the univariate analysis, Gray's method was used, while Fine and Gray's method was employed for the multivariate analysis. RESULTS: Mortality by NSCLC was 19.4% at 5 years and 14.3% by another cause. Both curves crossed at 6.3 years, and probability of death by another cause became greater from this point. In multivariate analysis, cancer mortality was conditioned by visceral pleural invasion (VPI) (P=.001) and vascular invasion (P=.020), with age>50 years (P=.034), smoking (P=.009) and the Charlson index ≥ 2 (P=.000) being by no cancer. CONCLUSIONS: By the method of CI, VPI and vascular invasion conditioned cancer death in NSCLC >3 cm, while non-tumor causes of long-term death were determined.

Functional outcomes after lung transplant in chronic obstructive pulmonary disease.

INTRODUCTION: Lung transplantation (LT) is a therapeutic option with controversial results in chronic obstructive pulmonary disease (COPD). We aimed to analyze the outcomes of transplantation in terms of lung function and to identify prognostic factors. METHOD: A retrospective analysis of 107 patients with COPD receiving lung transplants in the La Fe Hospital between 1991 and 2008 was performed. Preoperative variables, pulmonary function tests before and after LT, surgical procedure variables and long-term monitoring, expressed as mean or percentage, as applicable, were analyzed. Spirometric results before and after LT were analyzed. Linear or logistic regression were used for multivariate analysis depending on the variable. RESULTS: Ninety-four men (87.9%) and 13 women (12.1%) were transplanted, with a mean age±standard deviation of 52.58±8.05 years; 71% of LTs were double-lung transplantations. Spirometric values improved after LT: FVC: +1.22L (+34.9%), FEV1: +1.66L (+56.7%) and FEF25-75: +1.85L (+50.8%); P=.001. This functional improvement was maintained after 5 years only in the group with BODE score >7 (P=.001). Recipient height, type of LT, use of extracorporeal circulation during the surgical procedure, presence of bronchiolitis obliterans syndrome and the age and cause of death of the donor significantly influenced lung function over time. CONCLUSIONS: LT improves lung function in COPD patients. This improvement was maintained at 5years only in patients with BODE>7. Double lung transplantation provides better functional results than single-lung transplantation.

Differential expression of cyclin D1 in keratin-producing odontogenic cysts.

OBJECTIVES: The aim of the present study was to analyze the expression levels of Cyclin D1 (CCD1), a nuclear protein that plays a crucial role in cell cycle progression, in a series of keratin-producing odontogenic cysts. STUDY DESIGN: A total of 58 keratin-producing odontogenic cysts, diagnosed over ten years and classified according to the WHO 2005 criteria, were immunohistochemically analyzed in terms of CCD1 expression, which was quantified in the basal, suprabasal and intermediate/superficial epithelial compartments. The extent of immunostaining was measured as a proportion of total epithelial thickness. Quantified immunohistochemical data were correlated with clinicopathological features and clinical recurrence. RESULTS: Keratin-producing odontogenic cysts were classified as 6 syndromic keratocystic odontogenic tumors (S-KCOT), 40 sporadic or non-syndromic KCOT (NS-KCOT) and 12 orthokeratinized odontogenic cysts (OOC). Immunohistochemically, CCD1 staining was evident predominantly in the parabasal region of all cystic lesions, but among-lesion differences were apparent, showing a clear expansion of parabasal compartment especially in the S-KCOT, followed to a lesser extent in the NS-KCOT, and being much more reduced in the OOC, which had the greatest average epithelial thickness. CONCLUSIONS: The differential expression of CCD1 noted in the present study suggests that dysregulation of cell cycle progression from G1 to the S phase contributes to the different aggressiveness of these lesions. However, CCD1 expression levels did not predict NS-KCOT recurrence, which is likely influenced by factors unrelated to lesion biology.

Multiple granular cell tumors with metachronous occurrence in tongue and vulva. Clinicopathological and immunohistochemical study.

Granular cell tumor (GCT) usually occurs as a single tumor, although sometimes multiple lesions can occur. In present report we analyze the clinicopathological and immunohistochemical features of a multiple GCT involving the tongue of a 14-year-old girl, with no other abnormalities, with a metachronous occurrence of a second GCT in vulva, after a period of 10 years. Both tumors revealed S-100, vimentin and CD57 positivity. In addition, over expression of calretinin was observed in tumor cells located in the vicinity of pseudoepitheliomatous hyperplasia (PEH) of the tongue. Tumor vasculature situated close to the PEH showed marked CD105 reactivity, data not described so far, suggesting an interaction between PEH cells and underlying stroma, since GCT completely lacks CD105 vessels. Our study emphasizes that patients with GCT, especially young patients, should be followed long-term, looking for multiple tumors or other abnormalities suggestive of a systemic syndrome, given the associations described in multiple GCT.

[Lung transplantation in sporadic lymphangioleiomyomatosis: study of 7 cases]. / Trasplante pulmonar en la linfangioleiomiomatosis esporádica. Estudio de 7 casos.

BACKGROUND AND OBJECTIVE: Sporadic lymphangioleiomyomatosis (S-LAM) is a rare disease that affects only women. It is characterized by an abnormal proliferation of immature smooth muscle cells (LAM cells) that grow in an aberrant manner in the airway, parenchymal lung lymph and blood vessels, determining the onset of pulmonary cystic lesions. The disease has no treatment, progressing to respiratory failure, and lung transplantation (LT) may be a treatment option at this stage. Our goal was to study 7 patients undergoing LT for S-LAM. MATERIAL AND METHOD: We studied a series of clinical and demographic characteristics, diagnostic modality and post-transplant outcomes. We performed a descriptive analysis of the series. The Kaplan-Meier method was used to estimate survival. RESULTS: The mean age of onset of symptoms was 35 years, the diagnosis of 37 years and that of LT 38 years. The most common symptom was dyspnea. Four patients had a history of pneumothorax and pleural effusion. The mean forced expiratory volume in one second was 32.7% and the diffusing capacity for carbon monoxide was 29%. All patients were subjected to LT and survival was 100, 85.7 and 57.1% at one, 3 and 5 years, respectively. Three died of bronchiolitis obliterans and 2 necropsies did not show evidence of disease recurrence. CONCLUSIONS: LT is a therapeutic option in patients with S-LAM with an advanced respiratory functional impairment.

Solitary polypoid laryngeal xanthoma.

We report the case of a 51-year-old male smoker with diabetes mellitus and hyperlipidaemia and a long history of human immunodeficiency virus (HIV)/hepatitis C virus (HCV) infection treated with various antiretroviral regimes, who was referred to the otolaryngology department with progressive dysphonia. Fibre-optic laryngoscopy showed a solitary, yellowish-white pedunculated polyp on the anterior third of the left cord, with no other abnormality. Pathological analysis revealed a polypoid laryngeal xanthoma that was immunoreactive against CD68, perilipin, and adipophilin. This unusual laryngeal lesion in the clinical context of our patient suggests a possible role of antiretroviral treatment in the pathogenesis of these xanthomas.

[Immunophenotypic classification of 3 cases of hepatocellular adenoma. Differential diagnosis with focal nodular hyperplasia]. / Clasificación inmunofenotípica de 3 casos de adenomas hepatocelulares. Diagnóstico diferencial con hiperplasia nodular focal.

Interest in adenomas has been renewed by the discovery of the molecular changes in these tumors. The latest World Health Organization publication on gastrointestinal tract tumors (2010) includes four types of hepatic adenomas, which are well characterized immunohistochemically, genotypically and phenotypically. In these tumors, medical history and morphological behavior play an important role in determining the risk of malignancy, mainly in adenomas with a b-catenin mutation. The presence of steatosis, inflammation, vascular changes linked to response to L-FABP, serum amyloid A, and glutamyl synthetase help to classify these tumors into four groups: hepatocellular adenomas with the HNF1A mutation (H-HCA), those with the b-catenin mutation (b-HCA), inflammatory HCA (IHCA), and HCA without markers. The absence of glypican 3 expression, HSP 70 and perivenular mapping of glutamyl synthetase helps to distinguish these tumors from well differentiated hepatocellular carcinoma. We describe the clinical, morphological and immunophenotypic features of three patients diagnosed with hepatic adenomas in a 2-year period.