The 2015 World Health Organization Classification of lung tumors: new entities since the 2004 Classification.

In the last few years different new pulmonary neoplastic lesions have been recognised and some of them, namely NUT carcinoma, PEComatous tumors, pneumocytic adenomyoepithelioma, pulmonary myxoid sarcoma, myoepithelial tumors/carcinomas entered in the last 2015-WHO classification of lung tumors. In addition angiomatoid fibrous histiocytoma and ciliated muconodular papillary tumor have been morphologically and genetically characterized albeit not yet included in the 2015-WHO classification.In the present paper we summarised the clinical, morphological, immunohistochemical and molecular features of these new entities. The knowledge of key histologic and molecular characteristics may help pathologists in achieving a correct diagnosis thus leading to an adequate therapeutic approach.

Carcinosarcoma of the Female Urethra.

Carcinosarcoma is a rare malignant tumor with a biphasic morphology characterized by the presence of a malignant epithelial and mesenchymal component. It has been reported in many organs, including the genitourinary tract. We describe a case of a 47-year-old woman admitted to our hospital for history of recurrent urinary tract infection, dysuria and discharge of bloody fluid from the urethra at the end of urination. A tender palpable mass under the anterior vaginal wall was found and pathological examination showed a urethral carcinosarcoma. The histopathogenetic hypothesis and clinical management were considered in this report.

Poly (ADP-ribose) polymerase 1 protein expression in normal and neoplastic prostatic tissue.

A genetic background has been implicated in the development of prostate cancer. Protein microarrays have enabled the identification of proteins, some of which associated with apoptosis, that may play a role in the development of such a tumor. Inhibition of apoptosis is a co-factor that contributes to the onset and progression of prostate cancer, though the molecular mechanisms are not entirely understood. Poly (ADP-ribose) polymerase 1 (PARP-1) gene is required for translocation of the apoptosis-inducing factor (AIF) from the mitochondria to the nucleus. Hence, it is involved in programmed cell death. Different PARP-1 gene expression has been observed in various tumors such as glioblastoma, lung, ovarian, endometrial, and skin cancers. We evaluated the expression of PARP-1 protein in prostatic cancer and normal prostate tissues by immunohistochemistry in 40 men with prostate cancer and in 37 normal men. Positive nuclear PARP-1 staining was found in all samples (normal prostate and prostate cancer tissues). No cytoplasmic staining was observed in any sample. PARP-1-positive cells resulted significantly higher in patients with prostate carcinoma compared with controls (P<0.001). PARP-1 over-expression in prostate cancer tissue compared with normal prostate suggests a greater activity of PARP-1 in these tumors. These findings suggest that PARP-1 expression in prostate cancer is an attempt to trigger apoptosis in this type of tumor similarly to what reported in other cancers.

PARP-1 protein expression in glioblastoma multiforme.

One of the most common type of primary brain tumors in adults is the glioblastoma multiforme (GBM) (World Health Organization grade IV astrocytoma). It is the most common malignant and aggressive form of glioma and it is among the most lethal ones. Poly (ADP-ribose) polymerase 1 (PARP-1) gene, located to 1q42, plays an important role for the efficient maintenance of genome integrity. PARP-1 protein is required for the apoptosis-inducing factor (AIF) translocation from the mitochondria to the nucleus. PARP-1 is proteolytically cleaved at the onset of apoptosis by caspase-3. Microarray analysis of PARP-1 gene expression in more than 8,000 samples revealed that PARP-1 is more highly expressed in several types of cancer compared with the equivalent normal tissues. Overall, the most differences in PARP-1 gene expression have been observed in breast, ovarian, endometrial, lung, and skin cancers, and non-Hodgkin's lymphoma. We evaluated the expression of PARP-1 protein in normal brain tissues and primary GBM by immunohistochemistry. Positive nuclear PARP-1 staining was found in all samples with GBM, but not in normal neurons from controls (n=4) and GBM patients (n=27). No cytoplasmic staining was observed in any sample. In conclusion, PARP-1 gene is expressed in GBM. This finding may be envisioned as an attempt to trigger apoptosis in this tumor, as well as in many other malignancies. The presence of the protein exclusively at the nucleus further support the function played by this gene in genome integrity maintenance and apoptosis. Finally, PARP-1 staining may be used as GBM cell marker.

Is a single focus of low-grade prostate cancer diagnosed on saturation biopsy predictive of clinically insignificant cancer?

OBJECTIVES: To evaluate the incidence of indolent prostate cancer (PCa; <0.5 ml cancer and Gleason score, GS,

Prostate cancer detection by TURP after repeated negative saturation biopsy in patients with persistent suspicion of cancer: a case-control study on 75 consecutive patients.

To evaluate prostate cancer (PCa) detection after repeated negative saturation biopsy, 75 patients, aged 53-78 years, underwent transurethral resection of prostate (TURP) because of persistent suspicion of cancer; median PSA was 11.8 ng ml(-1) and 58 men complained lower urinary tract symptoms (LUTS). In 12 (16%) and 3 (4%) men a T1a and T1b PCa was found with median PSA and Gleason score equal to 14.2 vs 23.6 ng ml(-1) and 5.6 vs 7 ng ml(-1). In case of persistent suspicion of PCa after repeated negative saturation biopsy, TURP may be proposed, aside from the coexistence of LUTS, to rule out a PCa, in younger patients with high PSA values (> or =20 ng ml(-1)).

Is quantitative histologic examination useful to predict nonorgan-confined prostate cancer when saturation biopsy is performed?

OBJECTIVES: To evaluate the role of quantitative histologic findings in predicting nonorgan-confined (non-OC) prostate cancer (PCa) in patients undergoing saturation prostate biopsy (SPBx). METHODS: A total of 69 patients who had undergone SPBx underwent radical retropubic prostatectomy. Their prostate-specific antigen level was <10 ng/mL, and 49 and 20 patients had T1c and T2 PCa, respectively. The following biopsy variables from the quantitative histologic examination were evaluated as predictive of OC vs non-OC PCa: Gleason score (6), total percentage of PCa (20%), greatest percentage of PCa (50%), number of PCa-positive cores (2), presence of PCa-positive cores in both lateral margins (yes vs no), and PCa localization (unilateral vs bilateral). The results obtained from patients who had undergone SPBx were compared with those of 183 patients who had undergone 12-core prostate biopsy before radical retropubic prostatectomy. RESULTS: Overall, 32 patients had non-OC PCa. Among the men with Stage T1c PCa, the quantitative histologic findings were predictive of non-OC PCa in 12 of 17 cases. The area under the receiver operating characteristic curve was 0.935 +/- 0.29, supporting the high accuracy of quantitative histologic examination in predicting for non-OC PCa. The sensitivity in patients who underwent SPBx vs the 12-core biopsy was 78.1% and 89.4%, respectively. Also, although the specificity of each histologic parameter was significantly lower in the SPBx group, it was equivalent using quantitative histologic examination (85.6% vs 86.5%). CONCLUSIONS: In the preoperative staging of patients with clinical Stage T1c-T2 PCa and a prostate-specific antigen level <10 ng/mL who had undergone SPBx, quantitative histologic examination demonstrated good accuracy in predicting for non-OC PCa only when all pathological variables were considered.

Right leg swelling as primary presentation of metastatic Merkel cell carcinoma.

Merkel cell carcinoma (MCC) is a rare malignant cutaneous neuroendocrine tumour with an aggressive behaviour and frequent regional lymph node and distant metastases. It mostly occurs in old patients and the commonest sites are the skin of the head, neck and the extremities. Typically, the primary tumour presents as a fast-growing, painless, reddish nodule with an iceberg-like effect, broadening in the depth. Although the pathogenesis of MCC remains largely unknown, ultraviolet radiation and immunosuppression are likely to play a significant pathogenetic role. The authors describe an unusual case of MCC clinically presenting as lymphedema on the right leg due to an inguinal lymphonodal metastasis. Although extensive investigations were performed the authors were unable to discover the cutaneous primary tumor. The authors examine the etiopathogenesis and hypothesis of this rare tumour and describe the clinical differential diagnosis. They suggest that clinical features together with imaging studies and morphological and immuno-histochemical findings are important for the correct diagnosis.

Primary high grade sarcoma of the specialised prostatic stroma: a case report with clinico-pathological considerations.

Malignant tumours of the prostate other than carcinomas are rare. One such malignant tumours arising from the specialised stromal tissue of the prostate is stromal prostatic sarcoma (namely low-grade and high-grade). Herein, we report the clinico-pathological features of a high grade stromal sarcoma of the prostate occurring in a 65-year-old man who presented for urinary obstructive symptoms. The clinical picture suggested a benign prostatic hyperplasia, and surgery consisting in a transcapsular adenomectomy was performed. Following a pathological diagnosis of high grade prostatic stromal sarcoma, a radical cystoprostatectomy and bilateral pelvic node dissection was performed showing residual high grade stromal sarcoma of the prostate and incidental in situ urothelial carcinoma of the bladder. No further medical treatments were planned. One year after surgery the patient is well with no evidence of local disease or distant metastases.

Prediction by quantitative histology of pathological stage in prostate cancer.

AIMS: To find a predictor of extraprostatic extension in clinically localized prostate cancer (PCa), pre-operative ultrasound-guided prostate needle biopsies and clinico-pathological data were reviewed. METHODS: One hundred and eighty-three consecutive patients who underwent radical retropubic prostatectomy for clinical T1-T2 PCa and serum PSA <10 ng/ml were reviewed. Pre-operative biopsy was performed according to an extended protocol and whole-mount prostatectomy specimens were processed. The following biopsy variables were categorized to this analysis: Gleason score (< or =6, >6), TPC (< or =20%; >20%), GPC (< or =50%; >50%), cancer-positive cores (< or =2; >2), cancer-positive cores in both lateral portions (yes; no), PCa (monolateral; bilateral). RESULTS: Only 60/183 specimens showed an organ-confined PCa; the remaining ones showed pT3a in 57 cases, pT3b in 11 and pT3 with positive surgical margins in 55. A locally advanced PCa was found in 60.2 and 76.8% of T1c and T2 clinical stage, respectively. The positive predictive value and negative predictive value of biopsy findings to predict a locally advanced PCa was 89.9 and 75%, respectively. All biopsy variables associations were statistically significant; however, among these variables (non-categorized), in multivariate logistic regression analysis, only GPC was significantly associated with pathologic stage (odds ratio estimate was 1.075, 95% CI: 1.053-1.098). CONCLUSIONS: Quantitative histology, especially GPC, seems to be helpful for pre-operative staging of PCa in patients with T1c-T2 clinical stage and PSA < 10 ng/ml.

Schwannoma of the epiglottis: case report focusing on clinico-pathological aspects.

Laryngeal schwannomas are uncommon lesions with only few cases reported. Herein we present a further case of a schwannoma of the epiglottis, occurring in a 62-year-old with a clinical history of a cutaneous malignant melanoma and laryngeal glottic keratosis. The schwannoma was incidentally discovered as a small polypoid lesion located on the laryngeal surface of the epiglottis and was removed endoscopically. The procedure was uneventful and the patient is well six months later. Authors focus on the diagnostic and therapeutic options for this unusual lesion and discuss the differential diagnosis of the spindle cell proliferation of the larynx.

Independent prognostic value of fascin immunoreactivity in stage I nonsmall cell lung cancer.

Fascin-1, the most expressed form of fascin in vertebrate tissues, is an actin-bundling protein that induces cell membrane protrusions and increases motility of normal and transformed epithelial cells. Very few data are available on the role of this protein in nonsmall cell lung cancer (NSCLC). Two hundred and twenty patients with stage I NSCLC and long-term follow-up were evaluated immunocytochemically for fascin expression. Overall, variable fascin immunoreactivity was detected in 98% of 116 squamous cell carcinomas, in 78% of 96 adenocarcinomas, in 83% of six large cell carcinomas, and in the two adenosquamous carcinomas under study. Neoplastic emboli were commonly decorated by the antifascin antibody (P<0.001), also when the surrounding invasive carcinoma was unreactive. Fascin immunoreactivity correlated with high tumour grade (P=0.017) and, in adenocarcinomas, with high Ki-67 labelling index (P=0.021). Adenocarcinomas with a prevalent bronchiolo-alveolar in situ component were less commonly immunoreactive for fascin than invasive tumours (P=0.005). Contralateral thoracic or distant metastases were associated significantly with diffuse (>60% immunoreactive tumour cells) fascin expression in adenocarcinomas (P=0.043), and marginally with strong fascin immunostaining in squamous cell carcinomas (P=0.13). No associations were noted with any other clinicopathological variables tested. Patients with tumours showing diffuse (>60% immunoreactive neoplastic cells) and/or strong immunoreactivity for fascin had a shorter survival (P=0.006 for adenocarcinomas and P=0.026 for squamous cell carcinomas), even after multivariate analysis (P=0.014 and 0.050, respectively). The current study documents for the first time that fascin is upregulated in invasive and more aggressive NSCLC, being an independent prognostic predictor of unfavourable clinical course of the disease. Targetting the fascin pathway could be a novel therapeutic strategy of NSCLC.

CD 34 expression in chronic and neoplastic liver diseases.

BACKGROUND: Capillarisation of hepatic sinusoids is a well recognized phenomen occurring in long standing liver disease, in hepatic cirrhosis as well as in hepatocellular carcinoma. To study immunohistochemically the expression and distribution of CD34 in chronic liver disease and hepatocellular carcinoma in order to evaluate the possible diagnostic implication of this marker. METHODS: Sixty-five samples of liver tissue showing normal liver, different degrees of chronic inflammation, cirrhosis and histological features of hepatocellular adenoma and carcinoma (HCC) were included in the study. The specimens were fixed in formalin and embedded in paraffin and an immunohistochemical investigation was performed by the standard avidin-biotin-peroxidase complex method with CD34. RESULTS: The sinusoids of normal liver showed no immunoreactivity. The sinusoids of liver affected by different degrees of chronic active hepatitis showed no or focal immunostaining for CD34; an increased immunoreactivity was observed in the periportal sinusoids of the cirrhotic nodules whereas diffuse and strong staining was observed in the overall HCC as well as in the hepatocellular adenoma tested. CONCLUSIONS: In HCC, immunoreactivity for CD34 represents an effective method to evaluate angiogenesis and to distinguish well-differentiated HCC from non-neoplastic liver. Its role in clinical stage and prognostic evaluation needs further investigation.

Pulmonary epithelial-myoepithelial tumor of unproven malignant potential: report of a case and review of the literature.

Epithelial-myoepithelial tumors of the lung are rare neoplasms whose biological behavior and clinical course still remain to be defined. A case of epithelial-myoepithelial tumor of the lung arising from bronchial mucosa-submucosa and occurring as a polypoid lesion of the upper left bronchus in a 47-year-old man is reported. The tumor did not infiltrate the cartilaginous wall of the bronchus and showed a biphasic histological appearance with a double layering of epithelial and myoepithelial cells. Myoepithelial spindle cells with eosinophilic cytoplasm were also observed. Mitotic figures were very rare and necrosis absent. Immunohistochemical study for epithelial and muscular markers confirmed the presence of a double-cell component in the tumor, namely epithelial and myoepithelial. The patient is alive and well, with no evidence of recurrent or metastatic disease 6 months after surgery. On the basis of the present case and the six previously reported cases, we suggest using the noncommittal term pulmonary epithelial-myoepithelial tumor of unproven malignant potential (PEMTUMP) for this type of neoplasm. In addition, we first introduce p63 as a novel marker for highlighting the myoepithelial cells of the respiratory tract and speculate on the role of these cells in the development of this unusual tumor.

Immunoreactivity for thyroid transcription factor-1 in stage I non-small cell carcinomas of the lung.

Thyroid transcription factor-1 (TTF-1) is a nuclear protein regulating the transcriptional activity of lung-specific genes in the normal and neoplastic bronchioloalveolar cells. It has been implicated in the normal growth and development of the lung, and the disruption of the TTF-1 locus leads to neonatal death with pulmonary hypoplasia. We evaluated retrospectively the prevalence and clinical significance of TTF-1 immunoreactivity in 222 patients with stage I non-small cell lung carcinoma (NSCLC) with a follow-up time of at least 5 years, and we investigated its relationship with other markers of tumor growth, namely cell proliferation and angiogenesis. TTF-1 immunoreactivity was documented by using the commercially available monoclonal antibody 8G7G3/1 in 72% of 97 adenocarcinomas, 5% of 119 squamous cell carcinomas, and in the glandular component of two adenosquamous carcinomas. Four large cell carcinomas were completely unreactive. In adenocarcinomas, but not squamous cell carcinomas, TTF-1 immunoreactivity correlated significantly with microvessel density (p = 0.04) and inversely with the tumor proliferation fraction assessed by Ki-67 immunostaining (p = 0.03). Also, TTF-1-immunoreactive adenocarcinomas showed a trend for a size less than 3 cm (p = 0.08). TTF-1 expression was not related to specific growth patterns, tumor grade, or tumor cell typing. TTF-1 immunoreactivity did not significantly affect patient survival, although patients with more than 75% immunoreactive neoplastic cells showed a trend for longer overall and disease-free survival. Our findings suggest that TTF-1 could be involved in the development of small pulmonary adenocarcinomas, but it has not prognostic implications in patients with stage I NSCLC.

Cathepsin D is a marker of ganglion cell differentiation in the developing and neoplastic human peripheral sympathetic nervous tissues.

Cathepsin D (CD) is an aspartic proteinase which has been immunolocalised in intestinal ganglion cells of human neonates and adults. The aim of the present study was to define whether CD is a reliable ganglion cell differentiation marker in routinely fixed, paraffin-embedded tissues. For this purpose, we investigated immunohistochemically the expression and distribution of CD in the developing human peripheral sympathetic nervous system (PSNS) and gastroenteric nervous system (GENS), and in childhood neuroblastic tumours (NTs; neuroblastomas, ganglioneuroblastomas and ganglioneuromas), where ganglion cells differentiate from immature neuroblastic cells. During ontogenesis, CD expression is restricted to ganglion cell lineage with a progressively more intense cytoplasmic staining, mirroring the morphological differentiation of ganglion cells with increasing gestational ages. In neoplastic tissues, CD immunoreactivity was restricted to neuroblastic cells showing morphological features of gangliocytic differentiation (differentiating neuroblastomas, ganglioneuroblastomas) as well as to neoplastic ganglion cells (ganglioneuroblastomas, ganglioneuromas). We conclude that CD is a reliable ganglion cell differentiation marker, which can be used routinely to stain developing and mature ganglion cells in formalin-fixed, paraffin-embedded tissues. Furthermore, our results indicate that CD immunoreactivity in childhood NTs recapitulates the changes during normal PSNS development, as previously reported for Bcl-2 oncoprotein, c-ErbB2, insulin-like growth factor 2 and beta2-microglobulin. This is consistent with the current view that childhood NTs exhibit gene expression profiles mirroring those occurring during PSNS ontogenesis.