Molecular analysis of NUT-positive poromas and porocarcinomas identifies novel break points of YAP1::NUTM1 fusions.

BACKGROUND: Poromas, and their malignant counterparts, porocarcinomas, harbor recurrent translocations involving YAP1-MAML2, YAP1-NUTM1, and infrequently WWTR1-NUTM1; YAP1-NUTM1 being the most common in porocarcinomas. NUT immunohistochemistry (IHC) can be used to identify NUTM1-translocated tumors. This study sought to investigate potential novel NUTM1-fusion partners among NUT IHC-positive poromas and porocarcinomas. METHODS: Thirteen NUT IHC-positive poroid tumors (four poromas and nine porocarcinomas) were identified within a multi-institutional international cohort. Next-generation sequencing (NGS) assessed for NUTM1 fusion partners. RESULTS: NGS detected a NUTM1 fusion in 12 of 13 cases: YAP1-NUTM1 (11/12 cases) and WWTR1-NUTM1 (1/12 cases). Two of the cases (2/12) with NUTM1 fusion were not called by the NGS algorithm but had at least one read-spanning YAP1-NUTM1 break point upon manual review. A NUTM1 fusion was not identified in one case; however, the sample had low RNA quality. The following fusion events were identified: YAP1 exon 4::NUTM1 exon 3 in six cases, YAP1 exon 6::NUTM1 exon 2 in one case, YAP1 exon 3::NUTM1 exon 3 in three cases, WWTR1 exon 3::NUTM1 exon 3 in one case, and YAP1 exon 8::NUTM1 exon 3 fusion in one case. CONCLUSION: While no novel NUTM1 fusion partners were identified within our cohort, 12 of 13 cases had discoverable NUTM1 fusions; YAP1-NUTM1 fusion was detected in 11 cases (92%) and WWTR1-NUTM1 in 1 case (8%). These data corroborate findings from other recent investigations and further substantiate the utility of NUT IHC in diagnosing a subset of poroid neoplasms. In addition, two of our cases harbored fusions of YAP1 exon 6 to NUTM1 exon 3 and YAP1 exon 8 to NUTM1 exon 2, which have not been reported before in poroid neoplasms and indicate novel break points of YAP1.

Rationale for the application of RANKL inhibition in the treatment of Langerhans cell histiocytosis.

CONTEXT: Langerhans Cell Histiocytosis (LCH) is a rare disease exhibiting both neoplastic and inflammatory features including abundant cytokine secretion both at the lesional and systemic level. OBJECTIVE: Evaluation of RANKL expression within LCH lesions in various tissues. DESIGN: Cross-sectional study involving paraffin blocks from the diagnostic biopsies of adults with LCH. SETTING: The study was conducted among patients followed in an adult outpatient clinic. SUBJECTS: Eleven patients with active LCH, who were 41.27 ± 3.44 years old, and five patients who were 46.8 ± 7.19 years old with non-LCH diagnosis serving as controls. INTERVENTIONS: RANKL, p65 and CD1a immunostaining of deparaffinized sections from LCH lesions and control tissues. MAIN OUTCOME MEASURE: Comparison of RANKL and p65 expression between LCH lesions, as indicated from concomitant CD1a immunostaining, and control tissue counterparts. RESULTS: A focal positive granular cytoplasmic RANKL staining was found at all lesional sites in a number of cells of the pathological infiltrate, mostly with morphologic features of pathological Langerhans cells (LCs). Compared to control tissues, RANKL positivity in LCH cases showed an excess of staining, both in intensity of staining and the number of stained cells, especially in areas of pathologic infiltration. RANKL staining also coincided with strong p65 NFκB nuclear positivity, especially in lesional infiltrates. CONCLUSIONS: RANKL is highly expressed in active LCH at the lesional level, concomitant to p65 NFκB activation. The use of RANKL inhibition as a rational therapeutic approach of the disease now needs further clinical evaluation.

Abdominal wall endometrioma: a case report and review of the literature.

Endometriosis is the presence of ectopic endometrial tissue that can respond to ovarian hormonal stimulation. Although it is uncommon, extrapelvic endometriosis can form a discrete mass known as an abdominal wall endometrioma. Endometriomas are thought to be caused by transfer of endometrial cells into a surgical wound, most often after a cesarean delivery. Endometriomas are diagnosed via ultrasound, computed tomography, magnetic resonance imaging, and ultrasound-guided fine needle aspiration. Treatment options can be medical, but surgical excision is the treatment of choice. Perioperative nursing care includes patient teaching, taking steps to prevent surgical site infection and inadvertent hypothermia, ensuring availability of supplies (eg, the graft for abdominal wall repair if needed), and postoperative pain management.

Correlation of androgen receptor status, neuroendocrine differentiation and angiogenesis with time-to-biochemical failure after radical prostatectomy in clinically localized prostate cancer.

UNLABELLED: The aim of this study was to elucidate the prognostic value of the immunohistochemical detection of the androgen receptor (AR) status, the chromogranin A assessment of neuroendocrine differentiation (NED) and the CD34 assessment of microvessel density (MVD) with time-to-biochemical failure among surgically treated patients with clinically localized prostate cancer. PATIENTS AND METHODS: Surgical specimens from 130 patients with clinically localized prostate cancer, treated with radical prostatectomy, were analyzed by immunohistochemistry on paraffin tissue sections. Full-length follow-up records were available for 94 patients. RESULTS: Biochemical failure was observed in 37% of these patients. A statistically significant inverse relationship was observed between AR status and: (i) seminal vesicle invasion and (ii) surgical margin infiltration. Positive association was also detected between NED and: (i) Gleason's score, (ii) extracapsular extension, (iii) seminal vesicle invasion, (iv) surgical margin infiltration and (v) tumour volume. In addition, MVD was related to: (i) Gleason score, (ii) extracapsular extension, (iii) seminal vesicle invasion, (iv) pelvic lymph node metastasis and (v) tumour volume. Kaplan-Meier survival curves confirmed that Gleason score, extracapsular extension, seminal vesicle invasion, pelvic lymph node metastasis, tumour volume, NED, MVD and coexistence of increased NED and MVD may be potential biochemical failure predictors. However, in the multivariate analysis, MVD was the only independent prognostic factor for biochemical failure. CONCLUSION: A high MVD index can estimate the risk for biochemical failure in clinically localized prostate cancer after radical prostatectomy.

Concurrent development of testicular seminoma and choriocarcinoma of the superior mediastinum, presented as cervical mass: a case report and implications about pathogenesis of germ-cell tumours.

BACKGROUND: Synchronous presentation of more than one germ cell tumours of different histology in the same patient is considered to be very rare. In these cases of multiple germ cell tumours, strong theoretical and clinical data suggest an underlying common pathogenetic mechanism concerning genetic instability or abnormalities during the pluripotent embryonic differentiation and maturation of the germ cell. CASE PRESENTATION: A 25 year-old young man presented with an enlarging, slightly painful left cervical mass. Despite the initial disorientation of the diagnosis to a possible thyroid disorder, the patient underwent complete surgical resection of the mass revealing mediastinal choriocarcinoma. Subsequent ultrasound of the scrotum indicated the presence of a small lobular node in the upper pole of the left testicle and the patient underwent radical left inguinal orchiectomy disclosing a typical seminoma. Based on these results, the patient received 4 cycles of Bleomycin, Etoposide and Platinum chemotherapy experiencing only mild toxicity and resulting in complete ongoing clinical and biochemical remission. CONCLUSION: The pathogenesis of concurrent germ cell tumours in the same patient remains an area of controversy. Although the genetic instability of the pluripotent germ cell offers an adequate explanation, the possibility of metastasis from the primary, less differentiated tumour to a distant location as a more mature subtype cannot be excluded. Possible development of a metastatic site of different histology and thus biological behaviour (e.g choriocarcinoma) should be anticipated. Furthermore, urologists, pathologists and medical oncologists should be meticulous in the original pathological diagnosis in these patients, since there is a significant frequency of germ cell tumours with mixed or overlapping histological elements with diverse potential of evolution and differentiation.

Isolated metachronous contralateral adrenal metastasis from renal cell carcinoma.

Isolated contralateral adrenal metastasis from renal carcinoma is extremely rare. Patients who present with this entity often undergo surgery with the presumed diagnosis of an incidentaloma. A mass in the contralateral adrenal diagnosed following radical nephrectomy for renal carcinoma should be viewed with a high index of suspicion for the presence of metastatic disease. Surgery is the only effective management option and should be offered to these patients.

Aggressive digital papillary adenoma-adenocarcinoma.

Aggressive digital papillary adenocarcinoma and aggressive digital papillary adenoma are rare tumours of the sweat glands. They are most common in the most distal part of the fingers and are locally aggressive with a 50% local recurrence rate; 14% of tumours metastasize. We present two cases.

Prostate cancer with small-cell morphology: an immunophenotypic subdivision.

OBJECTIVE: To study the immunophenotypic characteristics and clinical outcome of morphologically undifferentiated prostatic carcinoma with small-cell morphology (U-PC-SCM). MATERIAL AND METHODS: Sixteen patients with U-PC-SCM were enrolled. The streptavidin-biotin complex immunohistochemical method was used on paraffin-embedded tissue sections to test positivity for prostate-specific antigen, prostate-specific acid phosphatase, CD57, androgen receptors, CK8-18, epithelial membrane antigen, carcinoembryonic antigen, CD56, neuron-specific enolase, chromogranin, synaptophysin, serotonin, various hormones, thyroid transcriptional factor-1 and Ki-67/MIB1. RESULTS: Based on immunophenotypic criteria, we identified two groups of patients. The final diagnosis was U-PC (Gleason score 10) in Group 1 (n=9) and pure or mixed neuroendocrine small-cell carcinoma in Group 2 (n=7). Group 1 underwent total androgen blockade (TAB) with no major response and had a median survival of 9 months. In Group 2, three patients underwent TAB, two of whom died of progressive disease. The third patient showed a partial response (PR) for 18 months but eventually relapsed with liver metastatic lesions. He was then treated with cisplatin + etoposide and showed a PR for 3 months and survived for 5 months after the initiation of the second-line chemotherapy (CTH) treatment. The other four patients received six cycles of cisplatin + etoposide. There were two complete responses of >14 and >22 months, respectively and 2 PRs of 11 and 17 months, respectively, the partial responders surviving for 14 and 21 months, respectively. CONCLUSION: U-PC-SCM with a neuroendocrine immunophenotype is a histogenetically distinct entity with different clinical and laboratory manifestations which responds well to a cisplatin + etoposide CTH regimen.

p27(kip1) and Ki-67 (MIB1) immunohistochemical expression in radical prostatectomy specimens of patients with clinically localized prostate cancer.

The immunohistochemical expressions (IE) of p27(kip1) and Ki-67 (MIB-1), both involved in cell cycle regulation and cell proliferation, and their ability to predict biochemical failure, were assessed in patients with clinically localized prostate cancer who had underdone radical prostatectomy of curative intent. In addition, p27(kip1) and Ki-67 (MIB1) expressions were correlated with several pre-operative and post-operative parameters, such as Gleason score, extracapsular extension, seminal vesicle involvement, pelvic lymph nodes metastasis, positive surgical margins, coexistence of high-grade prostatic intraepithelial neoplasia, tumour size, prostate volume and PSA levels. Our analysis involved 130 consecutive radical prostatectomy specimens. A statistically significant correlation of low p27(kiP1) IE with seminal vesicles involvement, increased tumour volume and high pre-operative PSA values was documented. Low p27(kiP1) IE was significantly correlated with an increased likelihood of biochemical failure after radical prostatectomy. In addition, the increased IE of Ki-67 (MIB1) correlated significantly with metastatic disease in the pelvic lymph nodes and was a significant predictor of biochemical failure. Cox regression analysis, which included p27(kip1) expression, Ki-67 (MIB1) expression and all the pre-operative and post-operative parameters, showed that pelvic lymph node involvement and Ki-67 (MIB1) IE were independent prognostic markers of biochemical failure after radical prostatectomy.

Immunohistochemical expression of Bcl2 is an independent predictor of time-to-biochemical failure in patients with clinically localized prostate cancer following radical prostatectomy.

BACKGROUND: Whether the immunohistochemical expression (IHCE) of the bcl2, the p53 and of the prostate apoptosis response-4 (PAR4) proteins is associated with pre-operative PSA levels, post-operative parameters of prostate cancer (PC) pathology, surgical staging or biochemical failure (BF) of patients with clinically localized PC who underwent radical prostatectomy (RP) of curative intent, was investigated. PATIENTS AND METHODS: A retrospective analysis of clinical data evaluating surgical specimens of 131 patients with PC, consecutively treated with RP for clinically localized disease, was performed. The IHC method of streptavidin biotin peroxidase on paraffin tissue sections was used to detect bcl2 and p53 oncoproteins and PAR4 pro-apoptotic protein expression in surgical specimens. RESULTS: Statistically significant relationships were detected between: (i) p53 IHC expression and infiltration of periprostatic tissue (IPT; p = 0.011); (ii) tumor volume (TV; p = 0.027); and (iii) bcl2 IHCE and absence of prostatic intraepithelial neoplasia (PIN) (p = 0.004). Biochemical failure (BF) was documented in 37% of these patients. Kaplan-Meier survival curves showed that the IHCE of bcl2 and p53 was significantly related to BF. Taking the hazard ratio (HR) estimated from the Cox proportional hazard regression model to be 1.00 for patients with negative bcl2 IHCE, a value of 2.82 was found for patients with positive bcl2 IHCE (p = 0.015, 95% CI = 1.22-6.47). The HR for patients with positive p53 IHCE was 2.05 (p = 0.048, 95% CI = 1.00-4.19). Multivariate analysis showed that only seminal vesicle invasion (SVI), pelvic lymph node metastasis (PLNM) and bcl2 IHCE were independent predictors for BF (HR = 3.06, 3.31 and 3.15; p = 0.048, p = 0.031 and p = 0.031 for SVI, PLNM and bcl2 IHCE, respectively). CONCLUSION: Bcl2 immunohistochemical overexpression in specimens of RP suggests high risk for BF in clinically localized PC.

Immunohistochemical localization of human kallikreins 6 and 10 in pancreatic islets.

Tissue kallikreins are thought to be present in the pancreatic islets of Langerhans and to aid in the conversion of proinsulin to insulin. In recent immunohistochemical studies, we observed strong staining of the newly identified human kallikreins 6 and 10 (hK6 and hK10) in the islets of Langerhans. Here, we examine hK6 and hK10 immunoexpression in different types of islet cells of the endocrine pancreas, in order to obtain clues for hK6 and hK10 function in these cells. Ten cases of normal pancreatic tissue, two cases of nesidioblastosis, five insulin-producing tumours and one case of multiple endocrine neoplasia 1 syndrome, containing an insulin-, a somatostatin- and several glucagon-producing tumours, as well as tiny foci of endocrine dysplasia with different predominance of the secreted hormones (mainly glucagon and pancreatic polypeptide) were included in the study. A streptavidin--biotin--peroxidase and an alkaline phosphatase protocol, as well as a sequential immunoenzymatic double staining method were performed, using specific antibodies against hK6, hK10, insulin, glucagon, somatostatin, pancreatic polypeptide, and serotonin. hK6 and hK10 immunoexpression was observed in the islets of Langerhans, including the pancreatic polypeptide-rich islets, in the normal pancreas. Scattered hK6 and hK10 positive cells were localized in relationship with pancreatic acinar cells. In the exocrine pancreas, a cytoplasmic and/or brush border hK6 and hK10 immunoexpression was observed in the median and small sized pancreatic ducts, while the acinar cells were negative. Foci of nesidioblastosis and endocrine dysplasia expressed both kallikreins. hK6 and hK10 were also strongly and diffusely expressed throughout all insulin-, glucagon- and somatostatin-producing tumours. The double staining method revealed co-localization of each hormone and hK6/hK10 respectively, in the same cellular population, in the normal as well as in the diseased pancreas. Our results support the view that hK6 and hK10 may be involved in insulin and other pancreatic hormone processing and/or secretion, as well as in physiological functions related to the endocrine pancreas.