New entity of microsecretory adenocarcinoma of salivary glands: first case with recurrence and metastases - proof of malignancy.

Microsecretory adenocarcinoma (MSA) of the salivary glands is a recently described entity. Due to lack of reported metastases, in 30 cases described until now, the designation as low-grade cancer was so far solely based on demonstration of local tumor invasion and in a single case with perineural invasion. We herein describe the first documented case with local recurrence and hematogenous metastases.

Effect of postoperative radiotherapy in pT1pN1cM0 and pT2p/cN0cM0 oropharyngeal squamous cell carcinoma.

OBJECTIVES/HYPOTHESIS: Consulting of patients with oropharyngeal carcinoma, classified as pT1pN1cM0 and pT2p/cN0cM0, about postoperative radiotherapy is a precarious task as data are lacking. The aim of this study was to evaluate the effects of postoperative radiotherapy for patients with intermediate-stage oropharyngeal carcinoma. STUDY DESIGN: Multicentric retrospective study. METHODS: This analysis was conducted at seven Austrian institutions and included data of patients treated between 2000 and 2012. A total of 81 patients with oropharyngeal squamous cell carcinoma were included, of whom 33 patients received postoperative radiotherapy. p16 status determined by immunohistochemistry was available in 68 patients. RESULTS: Median follow-up was 47.9 months. Postoperative radiotherapy showed no benefits in regard to overall survival (P = .701). In contrast, disease-free survival was significantly shortened in all patients without postoperative radiotherapy (P = .001). When dividing the cohort in dependence of p16, p16-positive patients did not benefit from postoperative radiotherapy regarding overall and disease-free survival (P = .934 and P = .102), whereas p16-negative patients showed improved disease-free survival after postoperative radiotherapy (P = .007). Multivariate analysis showed that outcome of postoperative radiotherapy is dependent on p16 status. CONCLUSIONS: In terms of disease-free survival, patients with p16-negative tumors may benefit from postoperative radiotherapy, whereas survival of p16-positive patients is good regardless of additional treatment. LEVEL OF EVIDENCE: 4. Laryngoscope, 128:1075-1082, 2018.

Fine-Needle Aspiration with Immunohistochemistry Using a Modified Scrape Cell Block Technique for the Diagnosis of Thyroid and Parathyroid Nodules.

OBJECTIVE: To evaluate the diagnostic accuracy of a modified scrape cell block (SCB) technique in a large series of patients. The technique was especially developed and tested for fine-needle aspiration of thyroid and parathyroid nodules. STUDY DESIGN: Eighty-two ultrasound-guided fine-needle aspiration specimens with the sonographic aspect of a thyroid (n = 33) or a possible parathyroid nodule (n = 49) were studied. Immunohistochemistry (IHC) was used on cell blocks containing plasma, thromboplastin, and selected 3-dimensional cell aggregates scraped off Papanicolaou-stained smears. Antibodies for chromogranin A, thyroglobulin, parathyroid hormone, calcitonin, and carcinoembryonic antibody (CEA) were used. In cases of reduced immunosensitivity or suspected metastases or rare primary tumors, additional IHC markers were employed. RESULTS: Chromogranin A was expressed in all 28 parathyroid adenomas (PA), in 7 of 8 hyperplastic parathyroid glands, and in 13 of 14 medullary thyroid carcinomas (MTC). When combining positivity for chromogranin A and calcitonin/CEA, the specificity for the detection of MTC was 100%. Parathyroid hormone was expressed in 26 of 36 parathyroid nodules (72.2%). When combining follicular microarchitecture and expression of chromogranin A, the specificity for the detection of parathyroid tissue was 97%. CONCLUSION: With the modified SCB technique, accurate cytological diagnoses were obtained in 97.6% of 82 patients.

A case report of an ependymoblastoma in the rectovaginal space and a review of the literature.

INTRODUCTION: Ependymomas are glial neoplasms that arise at or close to the inner ependymal surface of the ventricular system. They are most frequently located intraventricularly, but they may also occur in the spinal cord or, very seldom, at extraneural sites. Here we report a case of an ectopic ependymoma, arising in the pelvic cavity. CASE REPORT: A 35 year-old female patient was diagnosed with a suspect tumor mass in the rectovaginal space, infiltrating the perirectal adipose tissue and the vagina. Three years later, liver and peritoneal metastases of the same tumor were diagnosed. Two years after that, the patient experienced a recidive in the left adnexa. Histological analysis revealed an anaplastic tumor of dual nature, comprising of mesenchymal and epithelial features. There were ependymoma-like rosettes and pseudorosettes, indicating an ependymal differentiation. Immunohistochemically, the tumor was positive for epithelial membrane antigen (EMA) and glial fibrillary acidic protein (GFAP). Accordingly, the diagnosis "grade 3 ependymoma, i.e. ependymoblastoma" was made. REVIEW: Ependymomas are most frequently located in the ventricular system, but may also occur in the spinal cord or rarely at extraneural sites. Extraneural ependymomas represent a diagnostic challenge, since they can mimic other tumor types and the immunohistochemical profile may be non-specific. The most important features of ependymal differentiation are rosette- or pseudorosette formation. Extraneural ependymomas can be located in the ovary or elsewhere in the pelvic cavity. Locations in the lung, liver and the small bowel have also been described. In the present article we review several reported cases of ectopic, extraneural ependymomas. DISCUSSION: The origin of extraneural ependymomas is not completely clarified. They probably arise from glial tissue that is a residue from the embryonic development, pinched-off from the neural tube during its closure. We propose, that extraneural ependymoma should be considered in differential diagnosis for anaplastic tumors of the pelvic cavity.

Tubulin tyrosine ligase like 12 links to prostate cancer through tubulin posttranslational modification and chromosome ploidy.

Prostate cancer is a common cause of death, and an important goal is to establish the pathways and functions of causative genes. We isolated RNAs that are differentially expressed in macrodissected prostate cancer samples. This study focused on 1 identified gene, TTLL12, which was predicted to modify tubulins, an established target for tumor therapy. TTLL12 is the most poorly characterized member of a recently discovered 14-member family of proteins that catalyze posttranslational modification of tubulins. We show that human TTLL12 is expressed in the proliferating layer of benign prostate. Expression increases during cancer progression to metastasis. It is highly expressed in many metastatic prostate cancer cell lines. It partially colocalizes with vimentin intermediate filaments and cellular structures containing tubulin, including midbodies, centrosomes, intercellular bridges and the mitotic spindle. Downregulation of TTLL12 affects several posttranslational modifications of tubulin (detyrosination and subsequent deglutamylation and polyglutamylation). Overexpression alters chromosomal ploidy. These results raise the possibility that TTLL12 could contribute to tumorigenesis through effects on the cytoskeleton, tubulin modification and chromosome number stability. This study contributes a step toward developing more selective agents targeting microtubules, an already successful target for tumor therapy.

Insulin-like growth factor binding protein-3 (IGFBP-3) in the prostate and in prostate cancer: local production, distribution and secretion pattern indicate a role in stromal-epithelial interaction.

BACKGROUND: Insulin-like growth factor binding protein 3 (IGFBP-3) exerts inhibitory and proapoptotic effects on prostate cancer cells. Serum levels of IGFBP-3 were found to be associated with the risk of prostate cancer, but the data are still inconclusive. We present a detailed analysis of the expression and localization of IGFBP-3 in the prostate and a comparison with its expression pattern in tumors. METHODS: Expression and localization of IGFBP-3 were analyzed in cellular models and tissue by real-time RT-PCR, ELISA, immunohistochemistry, and immunofluorescence. RESULTS: All cell types of a panel of benign epithelial, stromal and tumor prostate cells expressed IGFBP-3. Significantly higher expression levels were registered in stromal cells. TGF-beta stimulation boosted IGFBP-3 levels 60-fold in stromal cells. The pattern of expression was confirmed in microdissected tissue samples. Protein levels measured by ELISA paralleled the mRNA levels and more than 80% of IGFBP-3 was secreted. On tissue immunostaining, IGFBP-3 was found to be mainly located in the epithelium. The pattern suggested secretion of IGFBP-3, which was confirmed in prostate tissue cultured ex vivo and the ejaculate of vasectomized men. IGFBP-3 levels were increased in primary tumors but did not differ from benign epithelium in metastases and local recurrent tumors. CONCLUSIONS: We registered a significant local production of IGFBP-3 in the prostate, which may well override the effect of protein entering from blood. The stroma--particularly reactivated stroma--is the main source of IGFBP-3 in the prostate, suggesting that this peptide acts as a mediator of stromal-epithelial interactions.

Differential radioactive quantification of protein abundance ratios between benign and malignant prostate tissues: cancer association of annexin A3.

A differential quantitative protein expression study, comparing matched prostate cancerous and benign tissues from 31 patients, revealed proteins newly associated with prostate cancer. Average effects for 17 proteins whose abundance was significantly different (p<0.01) across patients ranged from 1.5- to 6.1-fold, and included a number of known cancer markers. The most differentially abundant proteins between cancer and benign samples were isopeptidase T, serum amyloid P (SAP), annexin A3 (ANXA3) and mitochondrial enoyl coenzyme-A hydratase. SAP is restricted to stroma in healthy tissue, and the lower abundance in tumours may be explained by the reduced stromal content. ANXA3 is present in healthy epithelial cells, exhibits strong staining in precancerous prostatic intraepithelial neoplasia, and is relatively less abundant in individual tumour cells of increasing Gleason pattern (GP), despite exhibiting higher overall tissue abundance in tumours. ANXA3 staining was predominantly cytoplasmic, yet nuclear localization was also observed. Strongly staining single cells, possibly phagocytes, were interspersed in highly dedifferentiated GP5 tumour areas among tumour cells without measurable ANXA3. Local recurrent androgen ablation therapy-resistant tumours exhibit heterogenous low levels of ANXA3 staining. Results are discussed focussing on the potential implications for tumour tissues.

Gain of chromosome X in prostatic atrophy detected by CGH and FISH analyses.

BACKGROUND: Focal atrophy is presumed to be an indirect forerunner of prostate cancer. The aim of this study was to examine genetic alterations in prostate epithelia deriving from atrophic areas and compare these findings with those of cells deriving from paired prostate cancer in the same patient. METHODS: Formalin fixed paraffin wax-embedded prostatectomy specimens from 20 prostate cancer patients were utilized in this study. Comparative Genomic Hybridization (CGH) was performed on atrophic areas. To validate the CGH results, Fluorescence in Situ Hybridization (FISH) analysis was performed on atrophic areas and paired cancer tissue. RESULTS: Gain of the whole chromosome X was found as sole aberration in seven (70%) atrophic tissues by CGH. A gain of centromere X was observed in 13 (68.4%) atrophic areas and in 18 (90%) cancer tissues using FISH. CONCLUSIONS: Our investigation reconfirms the genetical instability of cells of the atrophic acini and attention of relevance of gain of chromosome X in atrophic areas.

Different types of atrophy in the prostate with and without adenocarcinoma.

OBJECTIVES: The purpose of this study was to evaluate, according to a classification proposed by a working group, the extent and type of atrophy lesions in radical prostatectomy specimens obtained from patients with prostatic carcinoma and benign prostatic hyperplasia (BPH), and to compare the prevalence and types of atrophy between two investigated groups. METHODS: Histologic analysis of 1096 slides from 50 patients with carcinoma and 277 slides from 31 patients with BPH was performed to evaluate, according to the new prostatic atrophy classification, the number of foci and type of atrophic lesions. RESULTS: Age, Gleason grade, and TNM showed no significant correlation with the number of proliferative atrophy (PA) and proliferative inflammatory atrophy (PIA) foci (p>0.05). PIA was significantly more frequent in prostates with carcinoma (1.63 vs 1.27 atrophic lesions per slide) (p<0.001), whereas PA displayed an increased frequency in BPH (2.28 vs 0.76 atrophic lesions per slide) (p<0.001). CONCLUSIONS: We confirmed that PA and PIA are common findings in prostates with and without carcinoma, but the question of whether inflammation produces tissue damage and PA or whether some other insult induces the tissue damage and atrophy directly, with inflammation occurring secondarily, is still unresolved.

Assessment of aberrations on chromosome 8 in prostatic atrophy.

OBJECTIVE: To systematically examine the genetic alterations on chromosome 8 in prostate epithelia deriving from atrophic areas, and to compare these alterations with those of cells derived from prostatic intraepithelial neoplasia (PIN) and prostate cancer in the same organ. MATERIAL AND METHODS: Tissue microarrays were constructed from 50 patients with histologically different tissues, including normal, PIN, atrophy and cancer lesions. Control samples were obtained from 10 patients who died from causes other than prostate cancer. Multicolour DNA probes for 8p22, centromere 8 and 8q24 were used to detect genetic alterations by fluorescence in situ hybridisation analysis. RESULTS: Chromosomal alterations were detected on chromosome 8 in all analysed tissues. Including all observed signal patterns, a gradual increase of nuclei with loss of 8p22 was detected in normal (16%), in atrophy (21%), in PIN (25%) and in cancer tissue (31%), and there was gain in 8q24 in normal tissue (10%), in atrophy lesions (19%), in PIN (21%) and in cancer (27%). Generally, in all three lesion types the percentage of cells with 8q24 gain was significantly lower than the percentage of cells with loss of 8p22. CONCLUSION: This investigation confirms the presence of severe chromosomal aberrations in the epithelium of the atrophic glands of the prostate. The aberrations are the same those that can be found in PIN and in prostate cancer. These findings confirm the genetic instability of the cells in the atrophic areas of the prostate, which can be a target for further injuries, leading to prostate cancer.

The expression of transcription factor activating transcription factor 3 in the human prostate and its regulation by androgen in prostate cancer.

PURPOSE: ATF3 is a member of the basic leucine zipper/cyclic adenosine monophosphate responsive element binding protein family of transcription factors. There is overwhelming evidence that it is a stress inducible factor acting in a signal-type and cell-type dependent manner, and it is involved in cell proliferation and survival. We found that ATF3 was differently expressed in an in vitro prostate cancer tumor progression model and we investigated the possible role of ATF3 in prostate cancer. MATERIALS AND METHODS: ATF3 up-regulation in vivo/in vitro and androgen regulation were assessed by immunohistochemistry and immunoblot analysis. Results after forced ATF3 transfection were evaluated by proliferation assay and cell cycle analysis. RESULTS: Immunohistochemistry and immunoblot analysis revealed ATF3 up-regulation in prostate cancer in vitro and in vivo, and stimulation of expression by androgens. Antiandrogen treatment decreased ATF3 expression in androgen sensitive cells but acted as a stimulator in long-term androgen ablated cells representing a model for therapy refractory disease. Expression in tumors increased with higher Gleason scores and highest expression was observed in samples of therapy refractory tumor tissue. Forced ATF3 over expression in a prostate cancer cell line induced cell proliferation and accelerated cell cycle progression from G1 to S-phase. CONCLUSIONS: These data provide new insight into the role of ATF3 in prostate cancer development and/or progression. They indicate that ATF3 is an androgen regulated gene that is highly expressed in prostate tumors and stimulating cell proliferation. It represents a possible target for prostate cancer therapy.

Correlation of periacinar retraction clefting in needle core biopsies and corresponding prostatectomy specimens of patients with prostatic adenocarcinoma.

One of the underemphasized supportive criteria for the diagnosis of prostatic cancer is the presence of retraction clefting around neoplastic glands. We analyzed a series of 152 prostatic cancer cases to determine the frequency, extent, and correlation of periacinar retraction clefting between needle core biopsies (NCB) and corresponding matched radical prostatectomy (RP) specimens. Clefting was significantly more frequent in neoplastic compared to nonneoplastic acini in NBC and RP (p<0.05). There was no significant difference in the frequency of retraction clefting in neoplastic acini between NCB and corresponding RP (p>0.05). We have also found a concordance in matched RP and NCB (Kappa=0.582). We conclude that periacinar retraction clefting appears more frequently in neoplastic acini and could serve as a reliable criterion in the diagnosis of prostatic adenocarcinoma.

Access of tumor-derived macromolecules and cells to the blood: an electron microscopical study of structural barriers in microvessel clusters in highly malignant primary prostate carcinomas.

BACKGROUND: The neo-angiogenetic microvessels forming a major reactive stromal element in highly malignant prostate neoplasms may exhibit fine-structural features relevant to our understanding of the passage of macromolecules from tumor to blood, on the one hand, and of events facilitating the metastatic cascade, on the other hand. METHODS: Ensuring rapid, optimal fixation in buffered glutaraldehyde was a foremost concern. Thin parings from radical prostatectomy specimens of Gleason scores (GS) 5-9 were taken from the tumor and from the contralateral side of the gland, glutaraldehyde-fixed, diced to smaller than 1 mm(3), postfixed in osmium tetroxide, embedded in Epon, ultrathin-sectioned, contrasted with lead and uranyl salts, and viewed in a transmission electron microscope. RESULTS: In dysplastic tissue areas, intraductal microvessels located in gland ducts were occasionally observed, and found to be aggressively invasive and highly active in producing neo-angiogenetic sprouts. Closely spaced microvessel clusters contained almost exclusively neo-angiogenetic microvessels, which were in cell-cell contact with numerous ameboid migratory cells, some of which were likely to be tumor cells. In these microvessel clusters, all structural barriers hindering passage of tumor-derived molecules or cells to the blood were eliminated. CONCLUSION: In microvessel clusters, the ultrastructural equivalent of microvascular hotspots, tumor invasion of microvessels is facilitated, but equally microvessels are observed invading the gland duct epithelial walls. This reciprocal invasivity of tumor cells and microvascular endothelial cells generates ideal conditions for tumor products and metastatic cells to enter the blood.

Synchronous bilateral malignant mesothelioma of tunica vaginalis testis: early diagnosis.

We report a case of bilateral synchronous malignant mesothelioma of the testis. A 21-year-old man presented with an acute scrotum after 3 months of recurrent pain on the right side. Ultrasonography demonstrated an irregular thickening of the tunica vaginalis testis, scrotolyths, and an increased blood flow to the right epididymis testis. Bilateral exploration revealed torsion of the hydatid and a bilateral malignant mesothelioma of the tunica vaginalis. One year later, elective bilateral exploration showed one minute area on the parietal tunica vaginalis of malignant mesothelioma. After 2 years of follow-up, the patient had no signs of distant disease.

Molecular cytogenetic analysis of human spermatocytic seminomas.

We performed comparative genomic hybridization (CGH) on 8 formalin-fixed, paraffin wax-embedded primary spermatocytic seminomas (SS) from 7 patients, one of whom developed metastatic disease. In general, this tumour type is not associated with development of metastases. Since there are only few reported cases of metastatic SS in the literature, this study is the first report of chromosomal constitution in a patient with metastatic disease. Chromosomal imbalances were observed in all 8 tumours analysed by CGH. Frequent copy number alterations were enh(9), dim(16 or 16p), enh(20) and enh(X), each in 6 samples, followed by dim(7) in 4, and enh(1), enh(18) and dim(15), each in 3 samples. In addition to the CGH analysis, interphase fluorescence in situ hybridisation (I-FISH) was applied to evaluate the CGH results and to define the size of the aberrant cell population. Interphase cytogenetics showed gain of material on chromosomes 9 and X in all tumours analysed. Overall, the I-FISH results were in agreement with the CGH data. In conclusion, gain of chromosome 9 seems to be restricted to SS and point to an important role for this aberration in the development of this tumour type.

Complication rate of transrectal ultrasound guided prostate biopsy: a comparison among 3 protocols with 6, 10 and 15 cores.

PURPOSE: We assessed the complication rate of ultrasound guided prostate biopsies performed at a single center in a screening population. Moreover the impact of different biopsy protocols comprising varying numbers of biopsy cores on the complication rate was evaluated. MATERIALS AND METHODS: A total of 5957 biopsies performed in 4303 clinically healthy men between January 1993 and August 2002 was evaluated retrospectively. Due to changes in the biopsy protocol, the number of biopsies obtained increased with time from 6 cores (January 1993 to October 1995) to 10 (November 1995 to March 2000) to 15 cores (March 2000 to August 2002). RESULTS: Minor complications such as hematospermia (36.3%), hematuria (14.5%) and rectal bleeding persisting for up to 2 days (2.3%) were noted frequently, while major complications requiring further treatment were far less common. Post-biopsy fever was seen in 48 patients (0.8%), rectal bleeding requiring surgical intervention or persisting for more than 2 days occurred in 36 patients (0.6%) and urinary retention was observed in 12 patients (0.2%). The increase in biopsy cores with time did not result in increased post-biopsy morbidity. Prostate cancer at biopsy was not associated with a higher complication rate. CONCLUSIONS: Prostate specific antigen screening has led to an increase in the number of patients undergoing prostate biopsy which, in turn, has increased the incidence of post-biopsy complications. However, most of the complications are minor and self-limiting. In this large study population the increased number of biopsy cores did not result in an increased incidence of major post-biopsy complications.

Clinical and pathologic features of prostate cancer detected after repeat false-negative biopsy in a screening population.

BACKGROUND: The present study was designed to investigate whether the clinical or pathologic features of prostate cancer (PCa) are related to the number of repeat biopsies required to establish the diagnosis of PCa. METHODS: Between February 1993 and August 2000, 653 patients were evaluated in this retrospective study. All patients underwent transrectal ultrasound-guided biopsy of the prostate prior to radical retropubic prostatectomy. The pathologic findings of specimens obtained at radical prostatectomy and pelvic lymph node dissection as well as PSA levels, findings on DRE, prostate volumes, transition zone volumes, and age were analyzed separately for all PCa patients diagnosed at the first set of biopsies (group A) and compared with the data of those diagnosed at the 2nd-5th set of biopsies (group B). In a second step, we compared the results obtained from patients diagnosed at the 2nd set of biopsies (group B1) with those of patients diagnosed at the 3rd to 5th set of biopsies (group B2). RESULTS: Gleason scores, pathologic tumor stages, and tumor volumes in group B were found to be significantly decreased compared to group A. But from the 2nd to 5th serial biopsy no further decrease in pathologic stage, Gleason score, or tumor volume was observed. On the contrary, there was a tendency towards higher tumor stages and Gleason scores. Of the tumors detected after the second false-negative set of biopsies almost 70% were lesions with Gleason scores of 6 or higher. CONCLUSIONS: False-negative results at the first needle biopsy are predictive of a lower pathologic stage and grade as well as smaller tumor volumes of PCa diagnosed at repeat sets of biopsies. False-negative results on repeat biopsy, however, have no prognostic significance for the tumor stage of PCas detected at subsequent sets of biopsies.

Stromal testis tumors in infants. a report of two cases.

Gonadal stroma tumors account for 8% of pediatric testicular tumors and are therefore exceedingly rare. They generally exhibit a benign behavior. We report two consecutive cases of gonadal stroma tumors in infants. A 5-month-old boy presented with a Sertoli cell tumor and a 2-month-old boy with a juvenile granulosa cell tumor without systemic disease. Both were diagnosed incidentally during routine examinations. Organ-sparing surgery and radical orchiectomy, respectively, was the therapy of choice. Although neonatal testicular tumors are rare, they should be considered in the differential diagnosis of a newborn with a scrotal mass.